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. 2020 Jun 29;9:F1000 Faculty Rev-653. [Version 1] doi: 10.12688/f1000research.22092.1

An overview of mammalian p38 mitogen-activated protein kinases, central regulators of cell stress and receptor signaling

Jiahuai Han 1,a, Jianfeng Wu 1, John Silke 2,3,b
PMCID: PMC7324945  PMID: 32612808

Abstract

The p38 family is a highly evolutionarily conserved group of mitogen-activated protein kinases (MAPKs) that is involved in and helps co-ordinate cellular responses to nearly all stressful stimuli. This review provides a succinct summary of multiple aspects of the biology, role, and substrates of the mammalian family of p38 kinases. Since p38 activity is implicated in inflammatory and other diseases, we also discuss the clinical implications and pharmaceutical approaches to inhibit p38.

Keywords: p38, MAPK, inflammation, signalling

p38 mitogen-activated protein kinases

p38α (originally named p38) was identified and cloned as a 38 kDa protein that was tyrosine-phosphorylated in response to LPS stimulation in mammalian cells 1, 2. Sequence comparison, on the day p38α was cloned, revealed that it belonged to the mitogen-activated protein kinase (MAPK) family and that a Saccharomyces cerevisiae osmotic response protein kinase HOG1 was a p38α homologue 35. p38α was also named cytokine suppressive drug binding protein (CSBP) because it was identified as the target of a series of anti-inflammatory pyridinyl-imidazole compounds and as reactivating kinase (RK) because it phosphorylated and activated MK2 35. There are four members of the p38 group of MAPKs encoded by four different genes in mammals: p38α ( MAPK14, chromosome 6p21.31 in humans), p38β ( MAPK11, SAPK2b, Chr22q13.33) 6, p38γ ( MAPK12, ERK6, SAPK3, Chr22q13.33) 7, 8, and p38δ ( MAPK13, SAPK4, Serk4, Chr6p21.31) 9, 10. As can be surmised from their chromosomal locations, MAPK14/p38α and MAPK13/p38δ are physically close and separated by just over 15 kb, as are MAPK12/p38β and MAPK11/p38γ, which are separated by less than 2 kb. All the p38s contain a conserved Thr–Gly–Tyr (TGY) dual phosphorylation motif within the kinase activation loop, and both Thr and Tyr phosphorylation are necessary to fully activate the kinase 11. However, monophosphorylated p38α Thr 180 has some kinase activity in vitro, but a different substrate specificity, when compared with dual-site phosphorylated p38α 12. p38 group members are expressed ubiquitously, but p38γ and p38δ are enriched in certain cell types and tissues, such as p38γ in skeletal muscle and p38δ in the salivary, pituitary, and adrenal glands 13. p38β shares more amino acid sequence identity with p38α (~70%), while p38γ and p38δ share ~60% identity with p38α. p38γ and p38δ also share high sequence homology with cyclin-dependent kinases (CDKs) and are sensitive to some CDK inhibitors 14.

Activation and inactivation of p38

p38α is involved in the response to almost all stressful stimuli, including LPS, UV light, heat shock, osmotic shock, inflammatory cytokines, T cell receptor ligation, glucose starvation, and oncogene activation 2, 4, 5, 1520. Under certain circumstances, it is also activated upon growth factor stimulation. It should be noted that the activation of p38 in some cases is cell type specific, since an activating stimulus in one cell type may inhibit p38 in other cell types 21. The study of p38 group members other than p38α has been less intensive; however, where it has been examined, the other p38s are frequently co-activated with p38α 22.

Like other MAPK signaling pathways, the activation of all p38s is mediated by a kinase cascade: MAPKKK (MAP3K), which activates MAPKK (MAP2K), which in turn activates MAPK. The MAP2K kinases MKK3 and MKK6 are the major upstream kinases for p38 activation 2325. Although MKK3 and MKK6 phosphorylate most p38 isoforms in vitro, selective activation and substrate specificity have been observed in vivo 26. MKK4 has also been reported to phosphorylate p38α and p38δ in specific cell types 9. A number of MAP3Ks have been reported to participate in p38 activation including TAK1 27, ASK1 28, DLK 29, and MEKK4 29, 30. Low-molecular-weight GTP-binding proteins in the Rho family, such as Rac1 and Cdc42, can activate p38 through binding to MEK1 or MLK1, which function as upstream activators of MAP3K 31, 32.

p38α can also be activated by MAP2K-independent mechanisms. TAB1 (TAK1-binding protein 1) directly interacts with p38α and can promote trans autophosphorylation on Thr 180 and Tyr 182 and thus full activation of p38α 33. A subsequent study revealed that autophosphorylation of Thr 180 and Tyr 182 requires a conserved Thr 185 residue 34. TAB1-dependent p38α activation has been implicated in ischemic myocardial injury and T cell anergy 35, 36. TAB1 is also claimed to play a role in Sestrin-mediated p38α activation 12. Another MAP2K-independent activation is mediated by ZAP70 after T cell receptor ligation. ZAP70 can directly phosphorylate p38α/β on Tyr 323 18, leading to autophosphorylation on Thr 180, one of the dual phosphorylation sites. As discussed, mono-Thr 180 phosphorylated p38 still has some kinase activity 37, and loss of ZAP70-mediated p38 activation in p38αβ Y323F double knock-in mice reduces autoimmunity and inflammation in several autoimmune disease models 3840. Interestingly, p38α also phosphorylates ZAP70, resulting in a decrease in the size and persistence of the T cell receptor signaling complex, and therefore acts as a feedback regulator of ZAP70 41.

Conversely, de-phosphorylation of both threonine and tyrosine residues in the activation loop inactivates MAPKs, and this is mainly carried out by dual-specificity phosphatases of the MAPK phosphatase (MKP)/dual specificity phosphatase (DUSP) family 42. Although several MKPs have been reported to dephosphorylate p38α, MKP1/DUSP1, MKP5/DUSP10, MKP8/DUSP26, and DUSP8 are more potent inhibitors of p38α and JNK than ERK 43. A recent report showed that DUSP12 is also a p38α phosphatase 44. While there are a number of p38α DUSPs, no DUSP for p38γ or p38δ has been reported, and these two p38s are resistant to several known p38α MKPs such as MKP1, 3, 5, and 7 45. p38α-dependent upregulation of MKP1 was reported and is believed to be part of a negative feedback loop of p38α activation 46. Other types of phosphatases have also been reported to target p38 MAPKs, such as CacyBP/SIP 47, Wip1 48, and PP2C 49, 50. The substrate specificity between p38 and phosphatases and the related physiological functions in vivo still need further investigation. p38γ has also been reported to be degraded by a p38/JNK/ubiquitin-proteasome-dependent pathway, which represents an additional mechanism by which p38 kinases may cross regulate each other 51. Yet other ways of regulating p38 are suggested from studies in Caenorhabditis elegans, where a genetic screen for resistance against bacterial infection identified RIOK-1, an atypical serine kinase and human RIO kinase homolog, as a suppressor of the p38 pathway 52. As RIOK-1 is a transcriptional target of the p38 pathway in C. elegans, this suggests that RIOK-1 is part of a negative feedback loop. A brief summary of the p38 pathway is shown in Figure 1.

Figure 1. A diagram of the p38 pathway.

Figure 1.

MKP, mitogen-activated protein kinase phosphatase; TAB1, TAK1-binding protein 1; Tyr, tyrosine.

Downstream substrates of p38

Protein kinases

The p38 MAPK cascade does not end at p38. Members of the MAPK-activated protein kinase (MAPKAPK) family such as MK2, MK3, and MK5 (PRAK) are all p38 substrates 3, 4, 5355. The MKs have a broad range of substrates that extend the range of functions regulated by p38 kinases. Mitogen- and stress-activated protein kinase-1/2 (MSK1/2), which are important for CREB activation and chromosome remodeling, have also been identified as substrates of p38α 56. MNK1/2, kinases that phosphorylate the eukaryotic initiation factor-4e (eIF-4E), are phosphorylated by p38α 57, 58. p38α has also been reported to inactivate murine GSK3β by phosphorylating Ser 389, and since GSK3β is required for the continuous degradation of β-catenin in the Wnt signaling pathway, this can lead to an accumulation of β-catenin 59, 60. It was also reported that p38δ negatively regulates insulin secretion by catalyzing an inhibitory phosphorylation of PKD1 61. A number of p38 protein kinase substrates are summarized in Table 1.

Table 1. Substrates of p38 group members – kinases.

Substrate Kinase Function References
MAPKAPK2
(MK2)
p38α, p38β, p38γ,
p38δ
Activates the kinase substrate Freshney NW et al., Cell, 1994 4
Rouse J et al., Cell, 1994 3
MAPKAPK3
(MK3)
p38α, p38β, p38γ,
p38δ
Activates the kinase substrate McLaughlin MM et al., J Biol Chem,
1996 54
MNK1/2 p38α Activates the kinase substrate Fukunaga R et al., EMBO J, 1997 58
Waskiewicz AJ et al., EMBO J,
1997 57
MSK1/2 p38α Activates the kinase substrate Deak M et al., EMBO J, 1998 56
Pierrat B et al., J Biol Chem, 1998 77
PAK6 p38α Activates the kinase substrate Kaur R et al., J Biol Chem, 2005 78
PIP4Kb p38α Inactivates the kinase substrate Jones DR et al., Mol Cell, 2006 79
RPAK
(MK5)
p38α, p38β Activates the kinase substrate New L et al., EMBO J, 1998 55
PKCε p38α, p38β Completes cytokinesis Saurin AT et al., Nat Cell Biol, 2008 80
GSK3β p38α Inactivates the kinase
substrate, activates Wnt
pathway.
Bikkavilli RK et al., J Cell Sci, 2008 60
Thornton TM et al., Science, 2008 59

GSK3β, glycogen synthase kinase 3 beta; MAPKAPK, mitogen-activated protein kinase activated protein kinase; MSK1/2, mitogen- and stress-activated protein kinase; PAK6, p21-activated kinase 6; PIP4Kb, phosphatidylinositol 5 phosphate 4-kinase; PKCε, protein kinase C epsilon type.

Transcription factors

p38 targets a large number of transcription factors, including myocyte-specific enhancer factor 2 (MEF2) family members, cyclic AMP-dependent transcription factor 1, 2, and 6 (ATF-1/2/6), CHOP (growth arrest and DNA damage inducible gene 153, or GADD153), p53, C/EBPβ, MITF1, DDIT3, ELK1/4, NFAT, and STAT1/4. p38 phosphorylation of transcription factors predominantly leads to enhanced transcriptional activity. However, in some cases, it represses transcription, and this is summarized in Table 2. Transcription factor phosphorylation by p38 is often stimulus and cell type dependent and plays a role in the cellular response to inflammation, DNA damage, metabolic stress, and many other stresses 6276. The effects of p38 on transcription seem to constitute the major part of p38’s responses to stress stimuli.

Table 2. Substrates of p38 group members – transcription factors.

Substrate Kinase Function References
ATF2 p38α, p38β,
p38γ, p38δ
Enhances transcriptional activity Cuenda A et al., EMBO J, 1997 81
Jiang Y et al., J Biol Chem, 1997 9
C/EBPα p38α Enhances transcriptional activity Qiao L et al., J Biol Chem, 2006 82
C/EBPβ p38α Enhances transcriptional activity Engelman JA et al., J Biol Chem, 1998 83
C/EBPε p38α Enhances transcriptional activity Williamson EA et al., Blood, 2005 84
CHOP p38α, p38β Enhances transcriptional activity Wang XZ et al., Science, 1996 68
E2F4 p38α Enhances transcriptional activity Morillo SM et al., Mol Cell Biol, 2012 85
Elk-1 p38α Enhances transcriptional activity
in specific cell types
Janknecht R et al., EMBO J, 1997 67
Whitmarsh AJ et al., Mol Cell Biol,
1997 66
ERα p38α Enhances nuclear localization
and transcriptional activity
Lee H et al., Mol Cell Biol, 2002 86
Fos p38α, p38β,
p38γ, p38δ
Enhances transcriptional activity Tanos T et al., J Biol Chem, 2005 87
FOXO3a p38α Enhances nuclear relocalization Ho KK et al., J Biol Chem, 2012 88
GR p38α Enhances transcriptional activity Miller AL et al., Mol Endocrinol,
2005 89
IUF1 p38α, p38β Enhances transcriptional activity Macfarlane WM et al., J Biol Chem, 1997 90
JDP2 p38α N/D Katz S et al., Biochem J, 2002 91
c-JUN p38α, p38β,
p38γ
Enhances transcriptional activity Humar M et al., Int J Biochem Cell
Biol, 2007 92
MafA p38α, p38β,
p38γ, p38δ
Enhances transcriptional activity Sii-Felice K et al., FEBS Lett, 2005 93
MEF2A p38α, p38β,
p38δ
Enhances transcriptional activity Zhao M et al., Mol Cell Biol, 1999 94
MEF2C p38α, p38β
p38γ, p38δ
Enhances transcriptional activity Han J et al., Nature, 1997 62
MEF2D p38α Enhances recruitment of Ash2L
to muscle-specific promoters
Zhao M et al., Mol Cell Biol, 1999 94
Rampalli S et al., Nat Struct Mol Biol,
2007 73
MITF p38α Enhances transcriptional activity Mansky KC et al., J Biol Chem,
2002 95
MRF4 p38α Represses transcriptional activity Suelves M et al., EMBO J, 2004 96
NFATc1 p38α Enhances transcriptional activity
and interaction with PU.1
Matsumoto M et al., J Biol Chem,
2004 97
NFATc4 p38α, p38β
p38γ
Represses nuclear localization
and transcriptional activity
Yang TT et al., Mol Cell Biol, 2002 98
NR4A p38α Enhances transcriptional activity Sekine Y et al., J Cell Sci, 2011 99
Nur77 p38α Disrupts interaction with p65 and
represses transcriptional activity
Li L et al., Nat Chem Biol, 2015 100
Osterix p38α Enhances recruitment of
coactivators
Ortuño MJ et al., J Biol Chem,
2010 101
p53 p38α Increases protein stability and
apoptosis
Bulavin DV et al., EMBO J, 1999 69
Pax6 p38α Enhances transcriptional activity Mikkola I et al., J Biol Chem, 1999 102
PPARα p38α Enhances transcriptional activity Barger PM et al., J Biol Chem, 2001 103
SAP1 p38α, p38β
p38γ, p38δ
Enhances transcriptional activity Janknecht R et al., EMBO J, 1997 67
Smad3 p38α Enhances nuclear translocation Hayes SA et al., Oncogene, 2003 104
Snail p38α Increases protein stability and
transcriptional activity
Ryu KJ et al., Cancer Res, 2019 105
STAT1 p38α, p38β Enhances transcriptional activity Kovarik P et al., Proc Natl Acad Sci
U S A, 1999 106
STAT4 p38α Enhances transcriptional activity Visconti R et al., Blood, 2000 107
TEAD4 p38α Enhances cytoplasmic
translocation and suppresses
transcriptional activity
Lin KC et al., Nat Cell Biol, 2017 76
Twist1 p38α Increases protein stability and
transcriptional activity
Hong J et al., Cancer Res, 2011 108
USF1 p38α Enhances transcriptional activity Galibert MD et al., EMBO J, 2001 71
Xbp1s p38α Enhances nuclear translocation
and transcriptional activity
Lee J et al. , Nat Med, 2011 75

ATF2, activating transcription factor 2; C/EBP, CCAAT/enhancer binding protein; CHOP, CCAAT/enhancer-binding protein homologous protein; ER, estrogen receptor; GR, glucocorticoid receptor; IUF1, insulin upstream factor 1; JDP2, Jun dimerization protein 2; MEF, myocyte-specific enhancer factor; MITF, microphthalmia transcription factor; MRF, muscle regulatory factor; NFAT, nuclear factor of activated T cells; Pax6, paired box 6; PPARα, peroxisome proliferator-activated receptor alpha; TEAD4, TEA domain family transcription factor 4; USF1, upstream transcription factor 1; Xbp1s, spliced form of X-box binding protein 1.

Transcriptional regulators

A large number of transcriptional regulators, including epigenetic enzymes, are substrates of p38, and these are summarized in Table 3. The SWI–SNF complex subunit BAF60 is phosphorylated and inactivated by p38 during skeletal myogenesis 109, 110, and EZH2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2), was also found to be phosphorylated by p38, particularly in ER-negative breast cancer samples 111. Besides its transcriptional function, dATF-2 is also involved in heterochromatin formation, and stress-induced phosphorylation of dATF-2 by p38 disrupts heterochromatin in Drosophila 112.

Table 3. Substrates of p38 group members – transcriptional regulators.

Substrate Kinase Function References
Chromatin
remodeling
regulators
BAF60c p38α, p38β Activates transcription of MyoD-
target genes
Simone C et al., Nat Genet,
2004 109
Forcales SV et al., EMBO J,
2012 110
RNF2 p38α Modulates gene expression and
histone 2B acetylation
Rao PS et al., Proteomics,
2009 124
EZH2 p38α Promotes cytoplasmic localization Anwar T et al., Nat Commun,
2018 111
dAFF2 p38α, p38β Disrupts heterochromatin
formation
Seong K-H et al., Cell, 2011 112
Other
regulators
CRTC2 p38α Enhances nucleocytoplasmic
transport and represses
transcription activity
Ma H et al., Mol Cell Biol, 2019 125
E47 p38α, p38β Enhances the formation of MyoD/
E47 heterodimers
Page JL et al., J Biol Chem, .
2004 126
Lluís F et al., EMBO J, 2005 127
HBP1 p38α Increases protein stability and
represses transcription
Xiu M et al., Mol Cell Biol, 2003 128
p18(Hamlet) p38α, p38β Increases protein stability and
enhances transcription
Cuadrado A et al., EMBO J,
2007 129
PGC-1α p38α, p38β Increases protein stability and
enhances transcription
Puigserver P et al., Mol Cell,
2001 130
Rb1 p38α, p38γ Induces Rb degradation and cell
death; suppresses Rb activity and
promotes the G0-to-G1 transition
Delston RB et al., Oncogene,
2011 131
Tomás-Loba A et al., Nature,
2019 14
SRC-3 p38α Induces SRC-3 degradation and
suppresses RARα-dependent
transcription
Giannì M et al., EMBO J, 2006 132

CRTC2, CREB-regulated transcription coactivator 2; HBP1, HMG-box transcription factor 1; PGC-1α, peroxisome proliferator-activated receptor gamma co-activator 1 alpha; RAR, retinoic acid receptor; RNF2, ring finger protein 2.

Other substrates

Given the wide range of responses that p38 is involved in, it is not surprising that many p38 substrates cannot be so easily categorized into groups, and these miscellaneous substrates are summarized in Table 4. Some of them are involved in metabolism such as Raptor phosphorylation by p38β, which enhances mTORC1 activity in response to arsenite-stress 113, and DEPTOR (mTOR-inhibitory protein) phosphorylation by p38γ and p38δ, leading to its degradation and mTOR hyperactivation 114. p38α phosphorylation of Tip60 at Thr 158 promotes senescence and DNA-damage-induced apoptosis 115, 116. Some p38 substrates are cell death regulators. In the ER stress response, p38α locates to the lysosome and phosphorylates the chaperone-mediated autophagy (CMA) receptor LAMP2A, leading to activation of CMA and thus protecting cells from ER stress-induced death 117.

Table 4. Substrates of p38 group members – others.

Substrate Kinase Function References
Cell-cycle
regulators
Cdc25A p38α Increases protein stability Goloudina A et al. , Cell Cycle, 2003 133
Cdc25B p38α Increases protein stability Lemaire M et al., Cell Cycle, 2006 134
Cyclin D1 p38α Causes ubiquitination and degradation
of cyclin D1
Casanovas O et al., J Biol Chem , 2000 135
Cyclin D3 p38α, p38β
p38γ, p38δ
Causes ubiquitination and degradation
of cyclin D3
Casanovas O et al., Oncogene, 2004 136
p57kip2 p38α Enhances interaction with CDKs and
inhibits CDKs
Joaquin M et al., EMBO J, 2012 137
Cell-death
regulators
Bax p38α Prevents Bcl-2–Bax heterodimer
formation, enhances apoptosis
Min H et al., Mol Carcinog, 2012 138
BimEL p38α Enhances apoptosis Cai B et al., J Biol Chem, 2006 139
Caspase-3 p38α Inhibits caspase-3 activity and
apoptosis
Alvarado-Kristensson M et al., J Exp Med,
2004 140
Caspase-8 p38α Inhibits caspase-8 activity and
apoptosis
Alvarado-Kristensson M et al., J Exp Med,
2004 140
Caspase-9 p38α Inhibits caspase-9 activity and
apoptosis
Seifert A et al., Cell Signal, 2009 141
DNA/RNA
binding proteins
Cdt1 p38α, p38β Increases protein stability Chandrasekaran S et al. , Mol Cell Biol,
2011 142
Drosha p38α Enhances nuclear export and
degradation
Yang Q et al. , Mol Cell, 2015 143
FBP2 p38α Promotes prothrombin mRNA 3' end
processing
Danckwardt S et al. , Mol Cell, 2011 144
FBP3 p38α Promotes prothrombin mRNA 3' end
processing
Danckwardt S et al. , Mol Cell, 2011 144
H2AX p38α, p38β Promotes serum starvation-induced
apoptosis
Lu C et al. , FEBS Lett, 2008 145
H3 p38α N/D Zhong SP et al. , J Biol Chem, 2000 146
HuR p38α, p38β Enhances cytoplasmic accumulation
and increases mRNA stability
Lafarga V et al. , Mol Cell Biol, 2009 147
KSRP p38α, p38β Prevents KSRP-mediated ARE-directed
mRNA decay
Briata P et al. , Mol Cell, 2005 148
Rps27 p38α N/D Knight JD et al., Skelet Muscle, 2012 149
SPF45 p38α Inhibits Fas alternative splicing (exon 6
exclusion)
Al-Ayoubi AM et al., Mol Cell Biol, 2012 150
Endocytosis
regulators
EEA1 p38α Promotes recruitment to endocytic
membranes and enhances MOR
endocytosis
Macé G et al. , EMBO J, 2005 151
Rabenosyn-5 p38α Promotes recruitment to endocytic
membranes and enhances MOR
endocytosis
Macé G et al. , EMBO J, 2005 151
GDI-2 p38α Enhances GDI:Rab5 complex formation
and modulates endocytosis
Cavalli V et al. , Mol Cell, 2001 152
MAPK pathway
regulator
JIP4 p38α Enhances p38 activity Kelkar N et al. , Mol Cell Biol, 2005 153
Tip60 p38α Enhances the pro-senescent function
of Tip60
Zheng H et al. , Mol Cell, 2013 115
TAB1 p38α Inhibits TAK1 activity Cheung PC et al. , EMBO J, 2003 154
TAB3 p38α Inhibits TAK1 activity Mendoza H et al. , Biochem J, 2008 155
FRS2 p38α Downregulates FGF1-induced signaling Zakrzewska M et al., Int J Mol Sci, 2019 156
Membrane
proteins
EGFR p38α Induces EGFR internalization Winograd-Katz SE et al., Oncogene, 2006 157
FGFR1 p38α Regulates translocation of exogenous
FGF1 into the cytosol/nucleus
Sørensen V et al., Mol Cell Biol, 2008 158
Nav1.6 p38α Promotes interaction with NEDD-4 and
protein degradation
Gasser A et al., J Biol Chem, 2010 159
NHE1 p38α Induces intracellular alkalinization Khaled AR et al. , Mol Cell Biol, 2001 160
PLA2 p38α N/D Börsch-Haubold AG et al. , J Biol Chem, 1998 161
TACE p38α, p38β Increases TACE-mediated ectodomain
shedding and TGF-alpha family ligand
release
Xu P et al. , Mol Cell, 2010 162
ZAP70 p38α Phosphorylation of ZAP70 increases
stability of T cell receptor
Giardino Torchia ML et al. , Proc Natl Acad Sci
U S A, 2018 41
Structure
proteins
Caldesmon p38α N/D Hedges JC et al., Am J Physiol, 1998 163
Hsp27 p38α N/D Knight JD et al., Skelet Muscle, 2012 149
Keratin 8 p38α Regulates cellular keratin filament
reorganization
Ku NO et al., J Biol Chem, 2002 164
Lamin B1 p38α Enhances lamin B1 accumulation Barascu A et al., EMBO J, 2012 165
Paxillin p38α Required for NGF-induced neurite
extension of PC-12 cells
Huang C et al., J Cell Biol, 2004 166
Stathmin p38δ N/D Parker CG et al., Biochem Biophys Res
Commun, 1998 167
SAP97 p38γ Modulating the association of this
protein with other cytoskeleton proteins
Sabio G et al., EMBO J, 2005 168
Tau p38α, p38γ, p38δ Enhances formation of paired helical
filaments
Inhibits amyloid-β toxicity in Alzheimer's
mice
Reynolds CH et al., J Neurochem,1997 169
Ittner A et al., Science, 2016 170
Tensin1 p38α Regulates the binding specificity of
tensin1 to different proteins
Hall EH et al. , Mol Cell Proteomics, 2010 171
Others DEPTOR p38γ, p38δ Enhances degradation and mTOR
hyperactivation
González-Terán B et al. , Nat Commun, 2016 114
GS p38β Required for subsequent
phosphorylation to inhibit enzyme activity
Kuma Y et al. , Biochem J, 2004 172
LAMP2A p38α Activates chaperone-mediated
autophagy
Li W et al., Nat Commun, 2017 117
Parkin p38α Decreases its interaction with PINK1
and suppresses mitophagy
Chen J et al., Cell Death Dis, 2018 173
p47 phox p38α Promotes NADPH oxidase activation
and superoxide production
Makni-Maalej K et al. , J Immunol, 2012 174
p62 p38γ, p38δ Enhances mTORC1 activity Linares JF et al., Cell Rep, 2015 175
Koh A et al., Cell, 2018 176
Raptor p38β Enhances mTORC1 activity in response
to arsenite stress
Wu X-N et al. , J Biol Chem, 2011 113
Rpn2 p38α Inhibits proteasome activity Lee SH et al. , J Biol Chem, 2010 177
Siah2 p38α Increases Siah2-mediated degradation
of PHD3
Khurana A et al. , J Biol Chem, 2006 178

CDK, cyclin-dependent kinase; EGFR, epidermal growth factor receptor; FBP1, far upstream binding protein; FGF1, fibroblast growth factor 1; FGFR1, fibroblast growth factor receptor 1; FRS2, fibroblast growth factor receptor substrate 2; GDI, GDP dissociation inhibitor; KSRP, hnRNPK-homology type splicing regulatory protein; MAPK, mitogen-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; NADPH, nicotinamide adenine dinucleotide phosphate; NGF, nerve growth factor; NHE1, Na +/H + exchanger isoform 1; PHD3, prolyl hydroxylase 3; PLA2, phospholipase A2; SAP97, synapse-associated protein 97; TAB, transforming growth factor-β-activated protein kinase-1-binding protein; TACE, tumor necrosis factor-alpha-converting enzyme; TAK1, transforming growth factor β-activated kinase 1; TGF, transforming growth factor.

Biological functions of the p38 pathway

Embryo development

p38α is required for embryo development, since the mouse Mapk14 –/– embryo dies between embryonic days (E) 10.5 and 12.5 118121. Mutant mice with a single Thr 180 to Ala mutation or with the double T180A Y182F mutation are also embryonic lethal 122, 123. Surprisingly, given the importance of the dual phosphorylation for complete p38 activation, substitution of Tyr 182 with Phe results in mice that have reduced p38 signaling but are nevertheless viable 123, although this is consistent with previous studies showing that the p38 phosphorylated on Thr 180 alone retains some activity in vitro 37. Histological analysis demonstrates that p38α is required for placental angiogenesis, but not embryonic cardiovascular development, and tetraploid rescue of the placental defect in Mapk14 –/– embryos confirmed that p38α is essential for extraembryonic development 120, 121. Given the important role that p38 and MK2 plays in regulating TNF-induced cell death 179182, it is intriguing that the Mapk14 –/– embryonic lethal phenotype is very similar to that observed in other mice with defects in the TNF death pathway. Caspase-8, FADD, and cFLIP knock-out mice also die at E10.5, and this is due to TNF-dependent endothelial cell death and disruption of the vasculature in the yolk sac 183, 184. Other p38 isoforms are not necessary for embryo development, but p38α and p38β have overlapping functions, as Mapk14 loxp/loxpMapk11 –/–Sox2-Cre embryos die before E16.5 with spina bifida that correlates with neural hyperproliferation and increased apoptosis in the liver, which was not observed in Mapk14 ∆/∆ Sox2-Cre embryos 185. Remarkably, p38α appears to have a very specific function during embryogenesis because when p38α was replaced by p38β in the Mapk14 chromosomal locus, which thereby placed p38β under the control of the endogenous p38α promoter, it was unable to rescue the embryonic lethality induced by loss of p38α 185.

Immune responses

p38 is activated by many inflammatory stimuli, and its activity is important for inflammatory responses. Macrophage-specific deletion of Mapk14 inhibits inflammatory cytokine production and protects mice from CLP-induced sepsis 186. p38α controls the production of inflammatory cytokines, such as TNF and IL-6, at many levels. It directly phosphorylates transcription factors, such as MEF2C 62, 186, and regulators of mRNA stability, such as hnRNPK-homology (KH) type splicing regulatory protein (KSRP) 187. MEF2C appears to play an anti-inflammatory role in endothelial cells in vivo 188. Via MK2/MK3, p38 also upregulates cytokine mRNA transcription by the serum response transcription factor (SRF) 189, and similarly, via MK2/MK3, p38 regulates mRNA stability by phosphorylating and inactivating TTP/Zfp36, a protein that promotes rapid turnover of AU-rich mRNAs, many of which are cytokine mRNAs 187, 190. p38 activation also induces the expression of inflammatory mediators such as COX-2, MMP9, iNOS, and VCAM-1, which are involved in tissue remodeling and oxidation regulation 191194. The p38 pathway also regulates adaptive immunity. p38α participates in antigen processing in CD8 + cDCs 195, and ZAP70-mediated p38α/β activation is important for T cell homeostasis and function 18. In B cells, p38α is important for CD40-induced gene expression and proliferation of B cells 196, and the p38α–MEF2c axis is believed to be necessary for germinal center B (GCB) cell proliferation and survival 197, 198. Excessive activation of p38α has been observed in many inflammatory diseases, such as inflammatory bowel disease (IBD), asthma, rheumatoid arthritis, and steatohepatitis 199201. The other members of the p38 family also play roles in immune responses. For example, p38γ and p38δ are required for neutrophil migration to damaged liver in non-alcoholic fatty liver disease 202 and inhibition of eukaryotic elongation factor 2 in LPS-induced liver damage 203. p38δ is required for neutrophil accumulation in acute lung injury 204. These observations, and the role that p38s play in TNF production, led to enormous pharmaceutical efforts to develop p38 inhibitors to treat chronic inflammatory diseases. However, unfortunately, these drugs were not efficacious in these diseases 205.

Cell cycle

p38 has been implicated in G1 and G2/M phases of the cell cycle in several studies. The addition of activated recombinant p38α caused mitotic arrest in vitro, and an inhibitor of p38α/β suppressed activation of the checkpoint by nocodazole in NIH3T3 cells 206. G1 arrest caused by Cdc42 overexpression is also dependent on p38α in NIH3T3 cells 207. Besides, p38γ is specially required for gamma-irradiation-induced G2 arrest 208. The link between p38 and cell cycle control has been proposed through the regulation of several p38 substrates. Both p38α and p38γ regulate cell cycle progression via Rb but in opposite directions 14, 209. HBP1 represses the expression of cell cycle regulatory genes during cell cycle arrest in a p38-dependent manner 210; p53 and p21 activation by p38α prevented G1 progression through blockade of CDK activity 211, 212. The p38 pathway is also involved in cell cycle progress, as it is essential for self-renewal of mouse male germline stem cells 213 and its regulation of G1-length plays a role in cell size uniformity 214.

Cell differentiation

Participation of p38 in cell differentiation has been reported in certain cell types. p38α activity is essential for neuronal differentiation in PC-12 cells and EPO-induced differentiation in SKT6 cells 20, 215. Treatment of 3T3-L1 fibroblasts with specific p38α/β inhibitors prevents their differentiation into adipocytes by reducing C/EBPβ phosphorylation 83, and p38α-dependent phosphorylation of MEF2C and BAF60 is critical for myogenic differentiation 110, 216. Intestinal epithelial cell-specific deletion of p38α also influences goblet cell differentiation in a Notch-dependent manner 200.

Cell metabolism

p38 group members participate in many cellular events related to metabolism. The p38β–PRAK axis specifically phosphorylates Rheb and suppresses mTORC1 activity under energy depletion conditions 22. DEPTOR, an inhibitor of mTORC, can be phosphorylated by p38γ and p38δ, leading to its degradation 123. Meanwhile, p38δ directly phosphorylated p62 to enhance mTORC1 activity in response to amino acids 175. In brown adipocytes, p38α functions as a central mediator in β-adrenergic-induced UCP1 expression 217, 218, while in white adipocytes, p38α inactivation leads to elevated white-to-beige adipocyte reprogramming and resistance to diet-induced obesity 219, 220. In hepatocytes, p38α controls lipolysis and protects against nutritional steatohepatitis. Thus, mice with hepatocyte-specific loss of p38α developed more severe steatohepatitis than wild type mice when fed high-fat or -cholesterol diets. Intriguingly, macrophage specific deletion of p38 had the opposite effect in the same high-fat diets and resulted in less steatohepatitis than in wild type mice, which probably reflects the inflammatory role of p38 in macrophages 199. p38α also directly phosphorylates Xbp1s to enhance its nuclear migration for maintaining glucose homeostasis in obesity 75. However, p38α also functions as a negative regulator of AMPK signaling in maintaining gluconeogenesis, and hepatic p38α could be a drug target for hyperglycemia 221. It was also reported that p38γ directly phosphorylated p62 under imidazole propionate stimulation to promote mTORC1 activity in hepatocytes 176. Interestingly, AMPK also triggers the recruitment of p38α to scaffold protein TAB1 for p38α autoactivation in human T cells 222.

Cell senescence

p38α appears to play a pivotal role in senescence. Constitutive activation of the p38 pathway by active MKK3 or MKK6 induces senescence in several cell types 223, 224, and p38α activity is responsible for senescence induced by multiple stimuli, such as telomere shortening 225, 226, H 2O 2 exposure 227, 228, and chronic oncogene activation 19, 223, 229. p38α/β-specific inhibitors have been successfully used to prevent cellular senescence in cultivated human corneal endothelial cells 230. Since cellular senescence is considered a defense strategy against oncogene activation, the p38 pathway plays important roles in tumorigenesis 231. Meanwhile, p38α activity is important for senescence-associated secretory phenotype (SASP), and its inhibition markedly reduces the secretion of most SASP factors, suggesting multiple roles for the p38 pathway in senescence 232235.

Cell survival and death

The role of the p38 pathway in cell fate is cell type and stimulus dependent. For example, p38α becomes activated upon NGF withdrawal in PC-12 cells, and p38α activated by overexpression of MKK3 induced apoptosis in NGF differentiated PC-12 cells 211. Similarly, inhibition of p38 with PD169316 blocked NGF withdrawal-induced apoptosis in PC-12 cells 236, 237. The interplay between the p38 pathway and caspases, the central regulators/executors of apoptosis, is complicated because p38α activity can be elevated in a caspase-dependent manner in death stimulus treated cells 238, 239, and caspase activity can also be elevated in MKK6E (dominant active form) overexpressed cells 239, 240. In contrast, inhibition of caspase-8 and caspase-3 by p38α-mediated phosphorylation in neutrophils was also reported 140. Recent studies show that p38-activated MK2 directly phosphorylates RIPK1 in TNF-treated cells or pathogen-infected cells, limiting TNF-induced cell death 180182. This represents an interesting link between cytokine production induced by TNF and cell death because TNF-induced MK2/MK3 phosphorylation of tristetraprolin/Zfp36 inactivates it and leads to increased stability of cytokine mRNAs 190. Aberrant p38α activity is observed in many tumor cells, and inhibition of p38α/β enhances cell death in these cells 241, 242.

Perspectives

p38 is one of the most researched of all proteins, let alone kinases, and a search in PubMed for p38 MAPK or p38 kinase returns more than 36,000 publications, which is a higher number than some proteins listed in a review of the "top 10" most studied genes 243. By contrast, searches for the kinases Raf and Src return about 17,000 and 25,000 hits, respectively. In 2018, there were more than 2,000 publications that mention p38, and it is clearly impractical to summarize such a vast amount of literature. As might be surmised from the preceding commentary, the studies are on a wide range of topics; however, the publications are more concentrated in some areas than others. The role of the p38 pathway in cancers (>10,000) 244246, inflammation (>8,000) 247249, and infections (>3,600) 250, 251 was intensively studied. About 1,600 publications include the specific term "p38 inhibitor". This reflects the previously mentioned enormous interest of the pharmaceutical industry in developing p38 inhibitors to treat chronic inflammatory diseases, such as rheumatoid arthritis. Yet other publications report natural products that can activate or inhibit p38, with the ultimate aim of using them clinically 252258. In 2011, the European Commission approved Esbriet (pirfenidone), which was described as a p38γ inhibitor, for the treatment of idiopathic pulmonary fibrosis 259. However, when this drug was approved by the FDA in 2014 for treating the same disease, it was described as a compound that acts on multiple pathways. In 2008, there were 27 clinical trials listed testing the use of p38 inhibitors in inflammatory disease settings 205, while a search today for p38 inhibitors in clinicaltrials.gov returns 44 studies for conditions as diverse as pain, asthma, cognitive impairment, rheumatoid arthritis, cancer, myelodysplastic syndrome, and depression ( Table 5). This indicates that there remains clinical interest in targeting the pathway and that there is therefore a need for more specific inhibitors of each of the p38 group members and more basic research to fully understand how the pathway, especially how each member of the p38 family, is utilized and regulated.

Table 5. Clinical trials of p38 inhibitors.

Drug Target Condition or disease Status NCT number
ARRY-371797 p38 Ankylosing spondylitis Phase 2 NCT00811499
ARRY-371797 p38 Dental pain Phase 2 NCT00542035
NCT00663767
ARRY-371797 p38 Healthy Phase 1 NCT00790049
ARRY-371797 p38 LMNA-related dilated cardiomyopathy Phase 2 NCT02351856
NCT02057341
ARRY-371797 p38 Osteoarthritis of the knee Phase 2 NCT01366014
ARRY-371798 p38 Rheumatoid arthritis Phase 1 NCT00729209
ARRY-614 p38 and
Tie2
Myelodysplastic syndromes Phase 1 NCT01496495
NCT00916227
AZD7624 p38 Corticosteroid-resistant asthma Phase 2 NCT02753764
BIRB 796 BS p38 Healthy Phase 1 NCT02211170
BMS-582949 p38α Rheumatoid arthritis Phase 2 NCT00605735
BMS-582949 p38α Vascular diseases (atherosclerosis) Phase 2 NCT00570752
CHF6297 p38α Chronic obstructive pulmonary
disease
Phase 1/2 NCT02815488
Losmapimod
(GS856553)
p38α/β Acute coronary syndrome Phase
1/2/3
NCT01756495
NCT02145468
NCT00910962
Losmapimod
(GS856553)
p38α/β Chronic obstructive pulmonary
disease
Phase 2 NCT00642148
NCT01541852
Losmapimod
(GS856553)
p38α/β Depressive disorder, major Phase 2 NCT00976560
NCT00569062
Losmapimod
(GS856553)
p38α/β Glomerulosclerosis, focal segmental Phase 2 NCT02000440
Losmapimod
(GS856553)
p38α/β Pain, neuropathic Phase 2 NCT01110057
NCT00969059
LY3007113 p38 Metastatic cancer Phase 1 NCT01463631
Neflamapimod
(VX-745)
p38α Alzheimer’s disease Phase 2 NCT03402659
NCT02423200
NCT02423122
Neflamapimod
(VX-745)
p38α Dementia with Lewy bodies Recruiting NCT04001517
P38 inhibitor
(4)
p38 Rheumatoid arthritis Phase 2 NCT00303563
NCT00316771
PF-03715455 p38α Asthma Phase 2 NCT02219048
PF-03715455 p38α Chronic obstructive pulmonary
disease
Phase 2 NCT02366637
PF-03715455 p38α Healthy Phase 1 NCT01226693
PH-797804 p38α/β Rheumatoid arthritis Phase 2 NCT00383188
NCT00620685
Ralimetinib
(LY2228820)
p38α/β Adult glioblastoma Phase 1/2 NCT02364206
Ralimetinib
(LY2228820)
p38α/β Advanced cancer Phase 1 NCT01393990
Ralimetinib
(LY2228820)
p38α/β Epithelial ovarian cancer Fallopian
tube cancer Primary peritoneal cancer
Phase 1/2 NCT01663857
Ralimetinib
(LY2228820)
p38α/β Postmenopausal metastatic breast
cancer
Phase 2 NCT02322853
SB-681323 p38 Acute lung injury Phase 2 NCT00996840
SB-681323 p38 Coronary heart disease Phase 2 NCT00291902
SB-681323 p38 Chronic obstructive pulmonary
disease
Phase 1/2 NCT00564746
NCT00144859
SB-681323 p38 Pain, neuropathic Phase 2 NCT00390845
SB-681323 p38 Rheumatoid arthritis Inflammation Phase 1/2 NCT00419809
NCT00439881
NCT00134693
Talmapimod
(SCIO-469)
p38α Bone marrow diseases
Myelodysplastic syndromes
Hematologic diseases Bone marrow
neoplasms
Phase 2 NCT00113893
Talmapimod
(SCIO-469)
p38α Multiple myeloma Phase 2 NCT00095680
NCT00087867
Talmapimod
(SCIO-469)
p38α Rheumatoid arthritis Phase 2 NCT00043732
NCT00089921
VX-702 p38α Rheumatoid arthritis Phase 2 NCT00395577
NCT00205478

One consequence of the massive pharmaceutical effort over the last 20 years is a large number of very specific, well-tolerated, and readily bioavailable drugs that can enable such basic research. For example, one study using a boutique panel of kinase inhibitors was able to demonstrate that 11 potent and specific p38 inhibitors synergized with Smac-mimetic drugs to kill a subset of AML leukemias, providing the strongest evidence implicating p38 in Smac-mimetic-induced killing 179. Since several of these p38 inhibitors had already been clinically trialed, this presents an opportunity to fast-track such combinations into the clinic. In our opinion, it is likely that this is where the future of p38 research and p38 inhibitors lies, in revealing the intricate web of inter-connections and inter-dependencies of this core and central regulator of cell stress. We also believe that greater efforts to genetically assess the role of p38 and p38 isoforms in the pathophysiology of inflammatory and other diseases need to be made in order to push forward the clinical application of our burgeoning knowledge.

Acknowledgments

We thank Peipei Zhang and Ye-hsuan Sun (School of Life Sciences, Xiamen University, China) for their help in preparing this manuscript.

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).

The referees who approved this article are:

  • Guadalupe Sabio, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

  • Jonathan Ashwell, Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

Funding Statement

This work was supported by the National Natural Science Foundation of China (81788101, 31420103910 and 81630042 to J.H.), the 111 Project (B12001 to J.H.) and by an NHMRC fellowship (1107149) to JS.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

[version 1; peer review: 2 approved]

References

  • 1. Han J, Lee JD, Tobias PS, et al. : Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14. J Biol Chem. 1993;268(33):25009–25014. [PubMed] [Google Scholar]
  • 2. Han J, Lee JD, Bibbs L, et al. : A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 1994;265(5173):808–811. 10.1126/science.7914033 [DOI] [PubMed] [Google Scholar]
  • 3. Rouse J, Cohen P, Trigon S, et al. : A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell. 1994;78(6):1027–1037. 10.1016/0092-8674(94)90277-1 [DOI] [PubMed] [Google Scholar]
  • 4. Freshney NW, Rawlinson L, Guesdon F, et al. : Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell. 1994;78(6):1039–1049. 10.1016/0092-8674(94)90278-x [DOI] [PubMed] [Google Scholar]
  • 5. Lee JC, Laydon JT, McDonnell PC, et al. : A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372(6508):739–746. 10.1038/372739a0 [DOI] [PubMed] [Google Scholar]
  • 6. Jiang Y, Chen C, Li Z, et al. : Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem. 1996;271(30):17920–17926. 10.1074/jbc.271.30.17920 [DOI] [PubMed] [Google Scholar]
  • 7. Lechner C, Zahalka MA, Giot JF, et al. : ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A. 1996;93(9):4355–4359. 10.1073/pnas.93.9.4355 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Li Z, Jiang Y, Ulevitch RJ, et al. : The primary structure of p38 gamma: a new member of p38 group of MAP kinases. Biochem Biophys Res Commun. 1996;228(2):334–340. 10.1006/bbrc.1996.1662 [DOI] [PubMed] [Google Scholar]
  • 9. Jiang Y, Gram H, Zhao M, et al. : Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J Biol Chem. 1997;272(48):30122–30128. 10.1074/jbc.272.48.30122 [DOI] [PubMed] [Google Scholar]
  • 10. Kumar S, McDonnell PC, Gum RJ, et al. : Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles. Biochem Biophys Res Commun. 1997;235(3):533–538. 10.1006/bbrc.1997.6849 [DOI] [PubMed] [Google Scholar]
  • 11. Raingeaud J, Gupta S, Rogers JS, et al. : Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995;270(13):7420–7426. 10.1074/jbc.270.13.7420 [DOI] [PubMed] [Google Scholar]
  • 12. Lanna A, Gomes DC, Muller-Durovic B, et al. : A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat Immunol. 2017;18(3):354–363. 10.1038/ni.3665 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Obata T, Brown GE, Yaffe MB: MAP kinase pathways activated by stress: the p38 MAPK pathway. Crit Care Med. 2000;28(4 Suppl):N67–77. 10.1097/00003246-200004001-00008 [DOI] [PubMed] [Google Scholar]
  • 14. Tomas-Loba A, Manieri E, Gonzalez-Teran B, et al. : p38γ Is Essential for Cell Cycle Progression and Liver Tumorigenesis. Nature. 2019;568(7753):557–560. 10.1038/s41586-019-1112-8 [DOI] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 15. Gong X, Liu A, Ming X, et al. : UV-induced interaction between p38 MAPK and p53 serves as a molecular switch in determining cell fate. FEBS Lett. 2010;584(23):4711–4716. 10.1016/j.febslet.2010.10.057 [DOI] [PubMed] [Google Scholar]
  • 16. Zauberman A, Zipori D, Krupsky M, et al. : Stress activated protein kinase p38 is involved in IL-6 induced transcriptional activation of STAT3. Oncogene. 1999;18(26):3886–3893. 10.1038/sj.onc.1202738 [DOI] [PubMed] [Google Scholar]
  • 17. Foltz IN, Lee JC, Young PR, et al. : Hemopoietic growth factors with the exception of interleukin-4 activate the p38 mitogen-activated protein kinase pathway. J Biol Chem. 1997;272(6):3296–3301. 10.1074/jbc.272.6.3296 [DOI] [PubMed] [Google Scholar]
  • 18. Salvador JM, Mittelstadt PR, Guszczynski T, et al. : Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat Immunol. 2005;6(4):390–395. 10.1038/ni1177 [DOI] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 19. Sun P, Yoshizuka N, New L, et al. : PRAK is essential for ras-induced senescence and tumor suppression. Cell. 2007;128(2):295–308. 10.1016/j.cell.2006.11.050 [DOI] [PubMed] [Google Scholar]
  • 20. Nagata Y, Takahashi N, Davis RJ, et al. : Activation of p38 MAP kinase and JNK but not ERK is required for erythropoietin-induced erythroid differentiation. Blood. 1998;92(6):1859–1869. 10.1182/blood.V92.6.1859 [DOI] [PubMed] [Google Scholar]
  • 21. Zarubin T, Han J: Activation and signaling of the p38 MAP kinase pathway. Cell Res. 2005;15(1):11–18. 10.1038/sj.cr.7290257 [DOI] [PubMed] [Google Scholar]
  • 22. Zheng M, Wang YH, Wu XN, et al. : Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nat Cell Biol. 2011;13(3):263–272. 10.1038/ncb2168 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Raingeaud J, Whitmarsh AJ, Barrett T, et al. : MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996;16(3):1247–1255. 10.1128/mcb.16.3.1247 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Derijard B, Raingeaud J, Barrett T, et al. : Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995;267(5198):682–685. 10.1126/science.7839144 [DOI] [PubMed] [Google Scholar]
  • 25. Han J, Lee JD, Jiang Y, et al. : Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem. 1996;271(6):2886–2891. 10.1074/jbc.271.6.2886 [DOI] [PubMed] [Google Scholar]
  • 26. Enslen H, Raingeaud J, Davis RJ: Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem. 1998;273(3):1741–1748. 10.1074/jbc.273.3.1741 [DOI] [PubMed] [Google Scholar]
  • 27. Moriguchi T, Kuroyanagi N, Yamaguchi K, et al. : A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem. 1996;271(23):13675–13679. 10.1074/jbc.271.23.13675 [DOI] [PubMed] [Google Scholar]
  • 28. Ichijo H, Nishida E, Irie K, et al. : Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997;275(5296):90–94. 10.1126/science.275.5296.90 [DOI] [PubMed] [Google Scholar]
  • 29. Hirai S, Katoh M, Terada M, et al. : MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase. J Biol Chem. 1997;272(24):15167–15173. 10.1074/jbc.272.24.15167 [DOI] [PubMed] [Google Scholar]
  • 30. Takekawa M, Posas F, Saito H: A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. EMBO J. 1997;16(16):4973–4982. 10.1093/emboj/16.16.4973 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Bagrodia S, Derijard B, Davis RJ, et al. : Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. J Biol Chem. 1995;270(47):27995–27998. 10.1074/jbc.270.47.27995 [DOI] [PubMed] [Google Scholar]
  • 32. Martin GA, Bollag G, McCormick F, et al. : A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20. EMBO J. 1995;14(9):1970–1978. 10.1002/j.1460-2075.1995.tb07189.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Ge B, Gram H, Di Padova F, et al. : MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science. 2002;295(5558):1291–1294. 10.1126/science.1067289 [DOI] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 34. Thapa D, Nichols C, Bassi R, et al. : TAB1-Induced Autoactivation of p38alpha Mitogen-Activated Protein Kinase Is Crucially Dependent on Threonine 185. Mol Cell Biol. 2018;38(5):e00409-17. 10.1128/MCB.00409-17 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 35. Ohkusu-Tsukada K, Tominaga N, Udono H, et al. : Regulation of the maintenance of peripheral T-cell anergy by TAB1-mediated p38 alpha activation. Mol Cell Biol. 2004;24(16):6957–6966. 10.1128/MCB.24.16.6957-6966.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Tanno M, Bassi R, Gorog DA, et al. : Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation: evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia. Circ Res. 2003;93(3):254–261. 10.1161/01.RES.0000083490.43943.85 [DOI] [PubMed] [Google Scholar]
  • 37. Mittelstadt PR, Yamaguchi H, Appella E, et al. : T cell receptor-mediated activation of p38{alpha} by mono-phosphorylation of the activation loop results in altered substrate specificity. J Biol Chem. 2009;284(23):15469–15474. 10.1074/jbc.M901004200 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Jirmanova L, Sarma DN, Jankovic D, et al. : Genetic disruption of p38alpha Tyr323 phosphorylation prevents T-cell receptor-mediated p38alpha activation and impairs interferon-gamma production. Blood. 2009;113(10):2229–2237. 10.1182/blood-2008-04-153304 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Jirmanova L, Giardino Torchia ML, et al. : Lack of the T cell-specific alternative p38 activation pathway reduces autoimmunity and inflammation. Blood. 2011;118(12):3280–3289. 10.1182/blood-2011-01-333039 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 40. Alam MS, Gaida MM, Debnath S, et al. : Unique properties of TCR-activated p38 are necessary for NFAT-dependent T-cell activation. PLoS Biol. 2018;16(1):e2004111. 10.1371/journal.pbio.2004111 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Giardino Torchia ML, Dutta D, et al. : Intensity and duration of TCR signaling is limited by p38 phosphorylation of ZAP-70 T293 and destabilization of the signalosome. Proc Natl Acad Sci U S A. 2018;115(9):2174–2179. 10.1073/pnas.1713301115 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 42. Sun H, Charles CH, Lau LF, et al. : MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell. 1993;75(3):487–493. 10.1016/0092-8674(93)90383-2 [DOI] [PubMed] [Google Scholar]
  • 43. Nunes-Xavier C, Roma-Mateo C, Rios P, et al. : Dual-specificity MAP kinase phosphatases as targets of cancer treatment. Anticancer Agents Med Chem. 2011;11(1):109–132. 10.2174/187152011794941190 [DOI] [PubMed] [Google Scholar]
  • 44. Cho SSL, Han J, James SJ, et al. : Dual-Specificity Phosphatase 12 Targets p38 MAP Kinase to Regulate Macrophage Response to Intracellular Bacterial Infection. Front Immunol. 2017;8:1259. 10.3389/fimmu.2017.01259 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Tanoue T, Yamamoto T, Maeda R, et al. : A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs. J Biol Chem. 2001;276(28):26629–26639. 10.1074/jbc.M101981200 [DOI] [PubMed] [Google Scholar]
  • 46. Manetsch M, Che W, Seidel P, et al. : MKP-1: a negative feedback effector that represses MAPK-mediated pro-inflammatory signaling pathways and cytokine secretion in human airway smooth muscle cells. Cell Signal. 2012;24(4):907–913. 10.1016/j.cellsig.2011.12.013 [DOI] [PubMed] [Google Scholar]
  • 47. Topolska-Wos AM, Rosinska S, Filipek A: MAP kinase p38 is a novel target of CacyBP/SIP phosphatase. Amino Acids. 2017;49(6):1069–1076. 10.1007/s00726-017-2404-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Liu G, Hu X, Sun B, et al. : Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1. Blood. 2013;121(3):519–529. 10.1182/blood-2012-05-432674 [DOI] [PubMed] [Google Scholar]
  • 49. Takekawa M, Maeda T, Saito H: Protein phosphatase 2Calpha inhibits the human stress-responsive p38 and JNK MAPK pathways. EMBO J. 1998;17(16):4744–4752. 10.1093/emboj/17.16.4744 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Maeda T, Wurgler-Murphy SM, Saito H: A two-component system that regulates an osmosensing MAP kinase cascade in yeast. Nature. 1994;369(6477):242–245. 10.1038/369242a0 [DOI] [PubMed] [Google Scholar]
  • 51. Qi X, Pohl NM, Loesch M, et al. : p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem. 2007;282(43):31398–31408. 10.1074/jbc.M703857200 [DOI] [PubMed] [Google Scholar]
  • 52. Chen YW, Ko WC, Chen CS, et al. : RIOK-1 Is a Suppressor of the p38 MAPK Innate Immune Pathway in Caenorhabditis elegans. Front Immunol. 2018;9:774. 10.3389/fimmu.2018.00774 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 53. Bird TA, Schule HD, Delaney P, et al. : The interleukin-1-stimulated protein kinase that phosphorylates heat shock protein hsp27 is activated by MAP kinase. FEBS Lett. 1994;338(1):31–36. 10.1016/0014-5793(94)80111-8 [DOI] [PubMed] [Google Scholar]
  • 54. McLaughlin MM, Kumar S, McDonnell PC, et al. : Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem. 1996;271(14):8488–8492. 10.1074/jbc.271.14.8488 [DOI] [PubMed] [Google Scholar]
  • 55. New L, Jiang Y, Zhao M, et al. : PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J. 1998;17(12):3372–3384. 10.1093/emboj/17.12.3372 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Deak M, Clifton AD, Lucocq LM, et al. : Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 1998;17(15):4426–4441. 10.1093/emboj/17.15.4426 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Waskiewicz AJ, Flynn A, Proud CG, et al. : Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 1997;16(8):1909–1920. 10.1093/emboj/16.8.1909 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Fukunaga R, Hunter T: MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J. 1997;16(8):1921–1933. 10.1093/emboj/16.8.1921 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Thornton TM, Pedraza-Alva G, Deng B, et al. : Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science. 2008;320(5876):667–670. 10.1126/science.1156037 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 60. Bikkavilli RK, Feigin ME, Malbon CC: p38 mitogen-activated protein kinase regulates canonical Wnt-beta-catenin signaling by inactivation of GSK3beta. J Cell Sci. 2008;121(Pt 21):3598–3607. 10.1242/jcs.032854 [DOI] [PubMed] [Google Scholar]
  • 61. Sumara G, Formentini I, Collins S, et al. : Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis. Cell. 2009;136(2):235–248. 10.1016/j.cell.2008.11.018 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 62. Han J, Jiang Y, Li Z, et al. : Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature. 1997;386(6622):296–299. 10.1038/386296a0 [DOI] [PubMed] [Google Scholar]
  • 63. Tan Y, Rouse J, Zhang A, et al. : FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J. 1996;15(17):4629–4642. [PMC free article] [PubMed] [Google Scholar]
  • 64. Barsyte-Lovejoy D, Galanis A, Sharrocks AD: Specificity determinants in MAPK signaling to transcription factors. J Biol Chem. 2002;277(12):9896–9903. 10.1074/jbc.M108145200 [DOI] [PubMed] [Google Scholar]
  • 65. Hazzalin CA, Cano E, Cuenda A, et al. : p38/RK is essential for stress-induced nuclear responses: JNK/SAPKs and c-Jun/ATF-2 phosphorylation are insufficient. Curr Biol. 1996;6(8):1028–1031. 10.1016/s0960-9822(02)00649-8 [DOI] [PubMed] [Google Scholar]
  • 66. Whitmarsh AJ, Yang SH, Su MS, et al. : Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors. Mol Cell Biol. 1997;17(5):2360–2371. 10.1128/mcb.17.5.2360 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67. Janknecht R, Hunter T: Convergence of MAP kinase pathways on the ternary complex factor Sap-1a. EMBO J. 1997;16(7):1620–1627. 10.1093/emboj/16.7.1620 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Wang XZ, Ron D: Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science. 1996;272(5266):1347–1349. 10.1126/science.272.5266.1347 [DOI] [PubMed] [Google Scholar]
  • 69. Bulavin DV, Saito S, Hollander MC, et al. : Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J. 1999;18(23):6845–6854. 10.1093/emboj/18.23.6845 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70. Huang C, Ma WY, Maxiner A, et al. : p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. J Biol Chem. 1999;274(18):12229–12235. 10.1074/jbc.274.18.12229 [DOI] [PubMed] [Google Scholar]
  • 71. Galibert MD, Carreira S, Goding CR: The Usf-1 transcription factor is a novel target for the stress-responsive p38 kinase and mediates UV-induced Tyrosinase expression. EMBO J. 2001;20(17):5022–5031. 10.1093/emboj/20.17.5022 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Gomez del Arco P, Martinez-Martinez S, Maldonado JL, et al. : A role for the p38 MAP kinase pathway in the nuclear shuttling of NFATp. J Biol Chem. 2000;275(18):13872–13878. 10.1074/jbc.275.18.13872 [DOI] [PubMed] [Google Scholar]
  • 73. Rampalli S, Li L, Mak E, et al. : p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation. Nat Struct Mol Biol. 2007;14(12):1150–1156. 10.1038/nsmb1316 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 74. Ramsauer K, Sadzak I, Porras A, et al. : p38 MAPK enhances STAT1-dependent transcription independently of Ser-727 phosphorylation. Proc Natl Acad Sci U S A. 2002;99(20):12859–12864. 10.1073/pnas.192264999 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Lee J, Sun C, Zhou Y, et al. : p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis. Nat Med. 2011;17(10):1251–1260. 10.1038/nm.2449 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 76. Lin KC, Moroishi T, Meng Z, et al. : Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. Nat Cell Biol. 2017;19(8):996–1002. 10.1038/ncb3581 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77. Pierrat B, Correia JS, Mary JL, et al. : RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen-activated protein kinase (p38alphaMAPK). J Biol Chem. 1998;273(45):29661–29671. 10.1074/jbc.273.45.29661 [DOI] [PubMed] [Google Scholar]
  • 78. Kaur R, Liu X, Gjoerup O, et al. : Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase. J Biol Chem. 2005;280(5):3323–3330. 10.1074/jbc.M406701200 [DOI] [PubMed] [Google Scholar]
  • 79. Jones DR, Bultsma Y, Keune WJ, et al. : Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta. Mol Cell. 2006;23(5):685–695. 10.1016/j.molcel.2006.07.014 [DOI] [PubMed] [Google Scholar]
  • 80. Saurin AT, Durgan J, Cameron AJ, et al. : The regulated assembly of a PKCepsilon complex controls the completion of cytokinesis. Nat Cell Biol. 2008;10(8):891–901. 10.1038/ncb1749 [DOI] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 81. Cuenda A, Cohen P, Buee-Scherrer V, et al. : Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J. 1997;16(2):295–305. 10.1093/emboj/16.2.295 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82. Qiao L, MacDougald OA, Shao J: CCAAT/enhancer-binding protein alpha mediates induction of hepatic phosphoenolpyruvate carboxykinase by p38 mitogen-activated protein kinase. J Biol Chem. 2006;281(34):24390–24397. 10.1074/jbc.M603038200 [DOI] [PubMed] [Google Scholar]
  • 83. Engelman JA, Lisanti MP, Scherer PE: Specific inhibitors of p38 mitogen-activated protein kinase block 3T3-L1 adipogenesis. J Biol Chem. 1998;273(48):32111–32120. 10.1074/jbc.273.48.32111 [DOI] [PubMed] [Google Scholar]
  • 84. Williamson EA, Williamson IK, Chumakov AM, et al. : CCAAT/enhancer binding protein epsilon: changes in function upon phosphorylation by p38 MAP kinase. Blood. 2005;105(10):3841–3847. 10.1182/blood-2004-09-3708 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85. Morillo SM, Abanto EP, Roman MJ, et al. : Nerve growth factor-induced cell cycle reentry in newborn neurons is triggered by p38 MAPK-dependent E2F4 phosphorylation. Mol Cell Biol. 2012;32(14):2722–2737. 10.1128/MCB.00239-12 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86. Lee H, Bai W: Regulation of estrogen receptor nuclear export by ligand-induced and p38-mediated receptor phosphorylation. Mol Cell Biol. 2002;22(16):5835–5845. 10.1128/mcb.22.16.5835-5845.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87. Tanos T, Marinissen MJ, Leskow FC, et al. : Phosphorylation of c-Fos by members of the p38 MAPK family. Role in the AP-1 response to UV light. J Biol Chem. 2005;280(19):18842–18852. 10.1074/jbc.M500620200 [DOI] [PubMed] [Google Scholar]
  • 88. Ho KK, McGuire VA, Koo CY, et al. : Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin. J Biol Chem. 2012;287(2):1545–1555. 10.1074/jbc.M111.284224 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89. Miller AL, Webb MS, Copik AJ, et al. : p38 Mitogen-activated protein kinase (MAPK) is a key mediator in glucocorticoid-induced apoptosis of lymphoid cells: correlation between p38 MAPK activation and site-specific phosphorylation of the human glucocorticoid receptor at serine 211. Mol Endocrinol. 2005;19(6):1569–1583. 10.1210/me.2004-0528 [DOI] [PubMed] [Google Scholar]
  • 90. Macfarlane WM, Smith SB, James RF, et al. : The p38/reactivating kinase mitogen-activated protein kinase cascade mediates the activation of the transcription factor insulin upstream factor 1 and insulin gene transcription by high glucose in pancreatic beta-cells. J Biol Chem. 1997;272(33):20936–20944. 10.1074/jbc.272.33.20936 [DOI] [PubMed] [Google Scholar]
  • 91. Katz S, Aronheim A: Differential targeting of the stress mitogen-activated protein kinases to the c-Jun dimerization protein 2. Biochem J. 2002;368(Pt 3):939–945. 10.1042/BJ20021127 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92. Humar M, Loop T, Schmidt R, et al. : The mitogen-activated protein kinase p38 regulates activator protein 1 by direct phosphorylation of c-Jun. Int J Biochem Cell Biol. 2007;39(12):2278–2288. 10.1016/j.biocel.2007.06.013 [DOI] [PubMed] [Google Scholar]
  • 93. Sii-Felice K, Pouponnot C, Gillet S, et al. : MafA transcription factor is phosphorylated by p38 MAP kinase. FEBS Lett. 2005;579(17):3547–3554. 10.1016/j.febslet.2005.04.086 [DOI] [PubMed] [Google Scholar]
  • 94. Zhao M, New L, Kravchenko VV, et al. : Regulation of the MEF2 family of transcription factors by p38. Mol Cell Biol. 1999;19(1):21–30. 10.1128/mcb.19.1.21 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95. Mansky KC, Sankar U, Han J, et al. : Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling. J Biol Chem. 2002;277(13):11077–11083. 10.1074/jbc.M111696200 [DOI] [PubMed] [Google Scholar]
  • 96. Suelves M, Lluis F, Ruiz V, et al. : Phosphorylation of MRF4 transactivation domain by p38 mediates repression of specific myogenic genes. EMBO J. 2004;23(2):365–375. 10.1038/sj.emboj.7600056 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97. Matsumoto M, Kogawa M, Wada S, et al. : Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. J Biol Chem. 2004;279(44):45969–45979. 10.1074/jbc.M408795200 [DOI] [PubMed] [Google Scholar]
  • 98. Yang TT, Xiong Q, Enslen H, et al. : Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases. Mol Cell Biol. 2002;22(11):3892–3904. 10.1128/mcb.22.11.3892-3904.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99. Sekine Y, Takagahara S, Hatanaka R, et al. : p38 MAPKs regulate the expression of genes in the dopamine synthesis pathway through phosphorylation of NR4A nuclear receptors. J Cell Sci. 2011;124(Pt 17):3006–3016. 10.1242/jcs.085902 [DOI] [PubMed] [Google Scholar]
  • 100. Li L, Liu Y, Chen HZ, et al. : Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation. Nat Chem Biol. 2015;11(5):339–346. 10.1038/nchembio.1788 [DOI] [PubMed] [Google Scholar]
  • 101. Ortuno MJ, Ruiz-Gaspa S, Rodriguez-Carballo E, et al. : p38 regulates expression of osteoblast-specific genes by phosphorylation of osterix. J Biol Chem. 2010;285(42):31985–31994. 10.1074/jbc.M110.123612 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102. Mikkola I, Bruun JA, Bjorkoy G, et al. : Phosphorylation of the transactivation domain of Pax6 by extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. J Biol Chem. 1999;274(21):15115–15126. 10.1074/jbc.274.21.15115 [DOI] [PubMed] [Google Scholar]
  • 103. Barger PM, Browning AC, Garner AN, et al. : p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response. J Biol Chem. 2001;276(48):44495–44501. 10.1074/jbc.M105945200 [DOI] [PubMed] [Google Scholar]
  • 104. Hayes SA, Huang X, Kambhampati S, et al. : p38 MAP kinase modulates Smad-dependent changes in human prostate cell adhesion. Oncogene. 2003;22(31):4841–4850. 10.1038/sj.onc.1206730 [DOI] [PubMed] [Google Scholar]
  • 105. Ryu KJ, Park SM, Park SH, et al. : p38 Stabilizes Snail by Suppressing DYRK2-Mediated Phosphorylation That Is Required for GSK3beta-betaTrCP-Induced Snail Degradation. Cancer Res. 2019;79(16):4135–4148. 10.1158/0008-5472.CAN-19-0049 [DOI] [PubMed] [Google Scholar]
  • 106. Kovarik P, Stoiber D, Eyers PA, et al. : Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. Proc Natl Acad Sci U S A. 1999;96(24):13956–61. 10.1073/pnas.96.24.13956 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107. Visconti R, Gadina M, Chiariello M, et al. : Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood. 2000;96(5):1844–52. [PubMed] [Google Scholar]
  • 108. Hong J, Zhou J, Fu J, et al. : Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res. 2011;71(11):3980–90. 10.1158/0008-5472.CAN-10-2914 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109. Simone C, Forcales SV, Hill DA, et al. : p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci. Nat Genet. 2004;36(7):738–43. 10.1038/ng1378 [DOI] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 110. Forcales SV, Albini S, Giordani L, et al. : Signal-dependent incorporation of MyoD-BAF60c into Brg1-based SWI/SNF chromatin-remodelling complex. EMBO J. 2012;31(2):301–16. 10.1038/emboj.2011.391 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111. Anwar T, Arellano-Garcia C, Ropa J, et al. : p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis. Nat Commun. 2018;9(1):2801. 10.1038/s41467-018-05078-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112. Seong KH, Li D, Shimizu H, et al. : Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell. 2011;145(7):1049–1061. 10.1016/j.cell.2011.05.029 [DOI] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 113. Wu XN, Wang XK, Wu SQ, et al. : Phosphorylation of Raptor by p38beta participates in arsenite-induced mammalian target of rapamycin complex 1 (mTORC1) activation. J Biol Chem. 2011;286(36):31501–31511. 10.1074/jbc.M111.233122 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114. Gonzalez-Teran B, Lopez JA, Rodriguez E, et al. : p38gamma and delta promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation. Nat Commun. 2016;7:10477. 10.1038/ncomms10477 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 115. Zheng H, Seit-Nebi A, Han X, et al. : A posttranslational modification cascade involving p38, Tip60, and PRAK mediates oncogene-induced senescence. Mol Cell. 2013;50(5):699–710. 10.1016/j.molcel.2013.04.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116. Xu Y, Liao R, Li N, et al. : Phosphorylation of Tip60 by p38alpha regulates p53-mediated PUMA induction and apoptosis in response to DNA damage. Oncotarget. 2014;5(24):12555–12572. 10.18632/oncotarget.2717 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117. Li W, Zhu J, Dou J, et al. : Phosphorylation of LAMP2A by p38 MAPK couples ER stress to chaperone-mediated autophagy. Nat Commun. 2017;8(1):1763. 10.1038/s41467-017-01609-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118. Allen M, Svensson L, Roach M, et al. : Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells. J Exp Med. 2000;191(5):859–870. 10.1084/jem.191.5.859 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119. Tamura K, Sudo T, Senftleben U, et al. : Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell. 2000;102(2):221–231. 10.1016/s0092-8674(00)00027-1 [DOI] [PubMed] [Google Scholar]
  • 120. Adams RH, Porras A, Alonso G, et al. : Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell. 2000;6(1):109–116. 10.1016/S1097-2765(05)00014-6 [DOI] [PubMed] [Google Scholar]
  • 121. Mudgett JS, Ding J, Guh-Siesel L, et al. : Essential role for p38alpha mitogen-activated protein kinase in placental angiogenesis. Proc Natl Acad Sci U S A. 2000;97(19):10454–10459. 10.1073/pnas.180316397 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122. Wong ES, Le Guezennec X, Demidov ON, et al. : p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age. Dev Cell. 2009;17(1):142–149. 10.1016/j.devcel.2009.05.009 [DOI] [PubMed] [Google Scholar]
  • 123. Brichkina A, Bertero T, Loh HM, et al. : p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis. Genes Dev. 2016;30(23):2623–2636. 10.1101/gad.290346.116 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 124. Rao PS, Satelli A, Zhang S, et al. : RNF2 is the target for phosphorylation by the p38 MAPK and ERK signaling pathways. Proteomics. 2009;9(10):2776–2787. 10.1002/pmic.200800847 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 125. Ma H, Liu Z, Zhong CQ, et al. : Inactivation of Cyclic AMP Response Element Transcription Caused by Constitutive p38 Activation Is Mediated by Hyperphosphorylation-Dependent CRTC2 Nucleocytoplasmic Transport. Mol Cell Biol. 2019;39(9):e00554–18. 10.1128/MCB.00554-18 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126. Page JL, Wang X, Sordillo LM, et al. : MEKK1 signaling through p38 leads to transcriptional inactivation of E47 and repression of skeletal myogenesis. J Biol Chem. 2004;279(30):30966–30972. 10.1074/jbc.M402224200 [DOI] [PubMed] [Google Scholar]
  • 127. Lluis F, Ballestar E, Suelves M, et al. : E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription. EMBO J. 2005;24(5):974–84. 10.1038/sj.emboj.7600528 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 128. Xiu M, Kim J, Sampson E, et al. : The transcriptional repressor HBP1 is a target of the p38 mitogen-activated protein kinase pathway in cell cycle regulation. Mol Cell Biol. 2003;23(23):8890–901. 10.1128/mcb.23.23.8890-8901.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 129. Cuadrado A, Lafarga V, Cheung PCF, et al. : A new p38 MAP kinase-regulated transcriptional coactivator that stimulates p53-dependent apoptosis. EMBO J. 2007;26(8):2115–26. 10.1038/sj.emboj.7601657 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 130. Puigserver P, Rhee J, Lin J, et al. : Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol Cell. 2001;8(5):971–82. 10.1016/s1097-2765(01)00390-2 [DOI] [PubMed] [Google Scholar]
  • 131. Delston RB, Matatall KA, Sun Y, et al. : p38 phosphorylates Rb on Ser567 by a novel, cell cycle-independent mechanism that triggers Rb-Hdm2 interaction and apoptosis. Oncogene. 2011;30(5):588–99. 10.1038/onc.2010.442 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 132. Gianni M, Parrella E, Raska I, Jr, et al. : P38MAPK-dependent phosphorylation and degradation of SRC-3/AIB1 and RARalpha-mediated transcription. EMBO J. 2006;25(4):739–751. 10.1038/sj.emboj.7600981 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 133. Goloudina A, Yamaguchi H, Chervyakova DB, et al. : Regulation of human Cdc25A stability by Serine 75 phosphorylation is not sufficient to activate a S phase checkpoint. Cell Cycle. 2003;2(5):473–478. 10.4161/cc.2.5.482 [DOI] [PubMed] [Google Scholar]
  • 134. Lemaire M, Froment C, Boutros R, et al. : CDC25B phosphorylation by p38 and MK-2. Cell Cycle. 2006;5(15):1649–1653. 10.4161/cc.5.15.3006 [DOI] [PubMed] [Google Scholar]
  • 135. Casanovas O, Miro F, Estanyol JM, et al. : Osmotic stress regulates the stability of cyclin D1 in a p38SAPK2-dependent manner. J Biol Chem. 2000;275(45):35091–35097. 10.1074/jbc.M006324200 [DOI] [PubMed] [Google Scholar]
  • 136. Casanovas O, Jaumot M, Paules AB, et al. : P38SAPK2 phosphorylates cyclin D3 at Thr-283 and targets it for proteasomal degradation. Oncogene. 2004;23(45):7537–7544. 10.1038/sj.onc.1208040 [DOI] [PubMed] [Google Scholar]
  • 137. Joaquin M, Gubern A, Gonzalez-Nunez D, et al. : The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress. EMBO J. 2012;31(13):2952–64. 10.1038/emboj.2012.122 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 138. Min H, Ghatnekar GS, Ghatnekar AV, et al. : 2-Methoxyestradiol induced Bax phosphorylation and apoptosis in human retinoblastoma cells via p38 MAPK activation. Mol Carcinog. 2012;51(7):576–85. 10.1002/mc.20825 [DOI] [PubMed] [Google Scholar]
  • 139. Cai B, Chang SH, Becker EBE, et al. : p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. J Biol Chem. 2006;281(35):25215–22. 10.1074/jbc.M512627200 [DOI] [PubMed] [Google Scholar]
  • 140. Alvarado-Kristensson M, Melander F, Leandersson K, et al. : p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils. J Exp Med. 2004;199(4):449–58. 10.1084/jem.20031771 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 141. Seifert A, Clarke PR: p38alpha- and DYRK1A-dependent phosphorylation of caspase-9 at an inhibitory site in response to hyperosmotic stress. Cell Signal. 2009;21(11):1626–33. 10.1016/j.cellsig.2009.06.009 [DOI] [PubMed] [Google Scholar]
  • 142. Chandrasekaran S, Tan TX, Hall JR, et al. : Stress-stimulated mitogen-activated protein kinases control the stability and activity of the Cdt1 DNA replication licensing factor. Mol Cell Biol. 2011;31(22):4405–16. 10.1128/MCB.06163-11 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 143. Yang Q, Li W, She H, et al. : Stress induces p38 MAPK-mediated phosphorylation and inhibition of Drosha-dependent cell survival. Mol Cell. 2015;57(4):721–734. 10.1016/j.molcel.2015.01.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 144. Danckwardt S, Gantzert AS, Macher-Goeppinger S, et al. : p38 MAPK controls prothrombin expression by regulated RNA 3' end processing. Mol Cell. 2011;41(3):298–310. 10.1016/j.molcel.2010.12.032 [DOI] [PubMed] [Google Scholar]
  • 145. Lu C, Shi Y, Wang Z, et al. : Serum starvation induces H2AX phosphorylation to regulate apoptosis via p38 MAPK pathway. FEBS Lett. 2008;582(18):2703–8. 10.1016/j.febslet.2008.06.051 [DOI] [PubMed] [Google Scholar]
  • 146. Zhong SP, Ma WY, Dong Z: ERKs and p38 kinases mediate ultraviolet B-induced phosphorylation of histone H3 at serine 10. J Biol Chem. 2000;275(28):20980–4. 10.1074/jbc.M909934199 [DOI] [PubMed] [Google Scholar]
  • 147. Lafarga V, Cuadrado A, Lopez de Silanes I, et al. : p38 Mitogen-activated protein kinase- and HuR-dependent stabilization of p21 Cip1 mRNA mediates the G 1/S checkpoint. Mol Cell Biol. 2009;29(16):4341–4351. 10.1128/MCB.00210-09 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 148. Briata P, Forcales SV, Ponassi M, et al. : p38-dependent phosphorylation of the mRNA decay-promoting factor KSRP controls the stability of select myogenic transcripts. Mol Cell. 2005;20(6):891–903. 10.1016/j.molcel.2005.10.021 [DOI] [PubMed] [Google Scholar]
  • 149. Knight JD, Tian R, Lee RE, et al. : A novel whole-cell lysate kinase assay identifies substrates of the p38 MAPK in differentiating myoblasts. Skelet Muscle. 2012;2:5. 10.1186/2044-5040-2-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 150. Al-Ayoubi AM, Zheng H, Liu Y, et al. : Mitogen-activated protein kinase phosphorylation of splicing factor 45 (SPF45) regulates SPF45 alternative splicing site utilization, proliferation, and cell adhesion. Mol Cell Biol. 2012;32(14):2880–2893. 10.1128/MCB.06327-11 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 151. Mace G, Miaczynska M, Zerial M, et al. : Phosphorylation of EEA1 by p38 MAP kinase regulates mu opioid receptor endocytosis. EMBO J. 2005;24(18):3235–3246. 10.1038/sj.emboj.7600799 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 152. Cavalli V, Vilbois F, Corti M, et al. : The stress-induced MAP kinase p38 regulates endocytic trafficking via the GDI:Rab5 complex. Mol Cell. 2001;7(2):421–432. 10.1016/s1097-2765(01)00189-7 [DOI] [PubMed] [Google Scholar]
  • 153. Kelkar N, Standen CL, Davis RJ: Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways. Mol Cell Biol. 2005;25(7):2733–2743. 10.1128/MCB.25.7.2733-2743.2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 154. Cheung PC, Campbell DG, Nebreda AR, et al. : Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. EMBO J. 2003;22(21):5793–5805. 10.1093/emboj/cdg552 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 155. Mendoza H, Campbell DG, Burness K, et al. : Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex. Biochem J. 2008;409(3):711–722. 10.1042/BJ20071149 [DOI] [PubMed] [Google Scholar]
  • 156. Zakrzewska M, Opalinski L, Haugsten EM, et al. : Crosstalk between p38 and Erk 1/2 in Downregulation of FGF1-Induced Signaling. Int J Mol Sci. 2019;20(8):1826. 10.3390/ijms20081826 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 157. Winograd-Katz SE, Levitzki A: Cisplatin induces PKB/Akt activation and p38 MAPK phosphorylation of the EGF receptor. Oncogene. 2006;25(56):7381–7390. 10.1038/sj.onc.1209737 [DOI] [PubMed] [Google Scholar]
  • 158. Sørensen V, Zhen Y, Zakrzewska M, et al. : Phosphorylation of fibroblast growth factor (FGF) receptor 1 at Ser777 by p38 mitogen-activated protein kinase regulates translocation of exogenous FGF1 to the cytosol and nucleus. Mol Cell Biol. 2008;28(12):4129–4141. 10.1128/MCB.02117-07 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 159. Gasser A, Cheng X, Gilmore ES, et al. : Two Nedd4-binding motifs underlie modulation of sodium channel Na v1.6 by p38 MAPK. J Biol Chem. 2010;285(34):26149–26161. 10.1074/jbc.M109.098681 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 160. Khaled AR, Moor AN, Li A, et al. : Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization. Mol Cell Biol. 2001;21(22):7545–7557. 10.1128/MCB.21.22.7545-7557.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 161. Börsch-Haubold AG, Bartoli F, Asselin J, et al. : Identification of the phosphorylation sites of cytosolic phospholipase A2 in agonist-stimulated human platelets and HeLa cells. J Biol Chem. 1998;273(8):4449–4458. 10.1074/jbc.273.8.4449 [DOI] [PubMed] [Google Scholar]
  • 162. Xu P, Derynck R: Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol Cell. 2010;37(4):551–566. 10.1016/j.molcel.2010.01.034 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 163. Hedges JC, Yamboliev IA, Ngo M, et al. : p38 mitogen-activated protein kinase expression and activation in smooth muscle. Am J Physiol. 1998;275(2):C527–534. 10.1152/ajpcell.1998.275.2.C527 [DOI] [PubMed] [Google Scholar]
  • 164. Ku NO, Azhar S, Omary MB: Keratin 8 phosphorylation by p38 kinase regulates cellular keratin filament reorganization: modulation by a keratin 1-like disease causing mutation. J Biol Chem. 2002;277(13):10775–10782. 10.1074/jbc.M107623200 [DOI] [PubMed] [Google Scholar]
  • 165. Barascu A, Le Chalony C, Pennarun G, et al. : Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation. EMBO J. 2012;31(5):1080–1094. 10.1038/emboj.2011.492 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 166. Huang C, Borchers CH, Schaller MD, et al. : Phosphorylation of paxillin by p38MAPK is involved in the neurite extension of PC-12 cells. J Cell Biol. 2004;164(4):593–602. 10.1083/jcb.200307081 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 167. Parker CG, Hunt J, Diener K, et al. : Identification of stathmin as a novel substrate for p38 delta. Biochem Biophys Res Commun. 1998;249(3):791–796. 10.1006/bbrc.1998.9250 [DOI] [PubMed] [Google Scholar]
  • 168. Sabio G, Arthur JS, Kuma Y, et al. : p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J. 2005;24(6):1134–1145. 10.1038/sj.emboj.7600578 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 169. Reynolds CH, Nebreda AR, Gibb GM, et al. : Reactivating kinase/p38 phosphorylates tau protein in vitro. J Neurochem. 1997;69(1):191–198. 10.1046/j.1471-4159.1997.69010191.x [DOI] [PubMed] [Google Scholar]
  • 170. Ittner A, Chua SW, Bertz J, et al. : Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice. Science. 2016;354(6314):904–908. 10.1126/science.aah6205 [DOI] [PubMed] [Google Scholar]
  • 171. Hall EH, Balsbaugh JL, Rose KL, et al. : Comprehensive analysis of phosphorylation sites in Tensin1 reveals regulation by p38MAPK. Mol Cell Proteomics. 2010;9(12):2853–2863. 10.1074/mcp.M110.003665 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 172. Kuma Y, Campbell DG, Cuenda A: Identification of glycogen synthase as a new substrate for stress-activated protein kinase 2b/p38beta. Biochem J. 2004;379(Pt 1):133–139. 10.1042/BJ20031559 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 173. Chen J, Ren Y, Gui C, et al. : Phosphorylation of Parkin at serine 131 by p38 MAPK promotes mitochondrial dysfunction and neuronal death in mutant A53T α-synuclein model of Parkinson's disease. Cell Death Dis. 2018;9(6):700. 10.1038/s41419-018-0722-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 174. Makni-Maalej K, Boussetta T, Hurtado-Nedelec M, et al. : The TLR7/8 agonist CL097 primes N-formyl-methionyl-leucyl-phenylalanine-stimulated NADPH oxidase activation in human neutrophils: critical role of p47phox phosphorylation and the proline isomerase Pin1. J Immunol. 2012;189(9):4657–4665. 10.4049/jimmunol.1201007 [DOI] [PubMed] [Google Scholar]
  • 175. Linares JF, Duran A, Reina-Campos M, et al. : Amino Acid Activation of mTORC1 by a PB1-Domain-Driven Kinase Complex Cascade. Cell Rep. 2015;12(8):1339–1352. 10.1016/j.celrep.2015.07.045 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 176. Koh A, Molinaro A, Stahlman M, et al. : Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. Cell. 2018;175(4):947–961.e917. 10.1016/j.cell.2018.09.055 [DOI] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 177. Lee SH, Park Y, Yoon SK, et al. : Osmotic stress inhibits proteasome by p38 MAPK-dependent phosphorylation. J Biol Chem. 2010;285(53):41280–41289. 10.1074/jbc.M110.182188 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 178. Khurana A, Nakayama K, Williams S, et al. : Regulation of the ring finger E3 ligase Siah2 by p38 MAPK. J Biol Chem. 2006;281(46):35316–35326. 10.1074/jbc.M606568200 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 179. Lalaoui N, Hanggi K, Brumatti G, et al. : Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. Cancer Cell. 2016;30(3):499–500. 10.1016/j.ccell.2016.08.009 [DOI] [PubMed] [Google Scholar]
  • 180. Jaco I, Annibaldi A, Lalaoui N, et al. : MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death. Mol Cell. 2017;66(5):698–710.e5. 10.1016/j.molcel.2017.05.003 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 181. Dondelinger Y, Delanghe T, Rojas-Rivera D, et al. : MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. Nat Cell Biol. 2017;19(10):1237–1247. 10.1038/ncb3608 [DOI] [PubMed] [Google Scholar]
  • 182. Menon MB, Gropengiesser J, Fischer J, et al. : p38 MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. Nat Cell Biol. 2017;19(10):1248–1259. 10.1038/ncb3614 [DOI] [PubMed] [Google Scholar]
  • 183. Silke J, Rickard JA, Gerlic M: The diverse role of RIP kinases in necroptosis and inflammation. Nat Immunol. 2015;16(7):689–697. 10.1038/ni.3206 [DOI] [PubMed] [Google Scholar]
  • 184. Dillon CP, Tummers B, Baran K, et al. : Developmental checkpoints guarded by regulated necrosis. Cell Mol Life Sci. 2016;73(11-12):2125–2136. 10.1007/s00018-016-2188-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 185. del Barco Barrantes I, Coya JM, Maina F, et al. : Genetic analysis of specific and redundant roles for p38alpha and p38beta MAPKs during mouse development. Proc Natl Acad Sci U S A. 2011;108(31):12764–12769. 10.1073/pnas.1015013108 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 186. Kang YJ, Chen J, Otsuka M, et al. : Macrophage deletion of p38alpha partially impairs lipopolysaccharide-induced cellular activation. J Immunol. 2008;180(7):5075–5082. 10.4049/jimmunol.180.7.5075 [DOI] [PubMed] [Google Scholar]
  • 187. Tiedje C, Holtmann H, Gaestel M: The role of mammalian MAPK signaling in regulation of cytokine mRNA stability and translation. J Interferon Cytokine Res. 2014;34(4):220–232. 10.1089/jir.2013.0146 [DOI] [PubMed] [Google Scholar]
  • 188. Xu Z, Yoshida T, Wu L, et al. : Transcription factor MEF2C suppresses endothelial cell inflammation via regulation of NF-kappaB and KLF2. J Cell Physiol. 2015;230(6):1310–1320. 10.1002/jcp.24870 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 189. Ronkina N, Menon MB, Schwermann J, et al. : Stress induced gene expression: a direct role for MAPKAP kinases in transcriptional activation of immediate early genes. Nucleic Acids Res. 2011;39(7):2503–2518. 10.1093/nar/gkq1178 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 190. Ronkina N, Shushakova N, Tiedje C, et al. : The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3. J Immunol. 2019;203(8):2291–2300. 10.4049/jimmunol.1801221 [DOI] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 191. Guan Z, Buckman SY, Pentland AP, et al. : Induction of cyclooxygenase-2 by the activated MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway. J Biol Chem. 1998;273(21):12901–8. 10.1074/jbc.273.21.12901 [DOI] [PubMed] [Google Scholar]
  • 192. Badger AM, Cook MN, Lark MW, et al. : SB 203580 inhibits p38 mitogen-activated protein kinase, nitric oxide production, and inducible nitric oxide synthase in bovine cartilage-derived chondrocytes. J Immunol. 1998;161(1):467–73. [PubMed] [Google Scholar]
  • 193. Da Silva J, Pierrat B, Mary JL, et al. : Blockade of p38 mitogen-activated protein kinase pathway inhibits inducible nitric-oxide synthase expression in mouse astrocytes. J Biol Chem. 1997;272(45):28373–80. 10.1074/jbc.272.45.28373 [DOI] [PubMed] [Google Scholar]
  • 194. Wiehler S, Cuvelier SL, Chakrabarti S, et al. : p38 MAP kinase regulates rapid matrix metalloproteinase-9 release from eosinophils. Biochem Biophys Res Commun. 2004;315(2):463–70. 10.1016/j.bbrc.2004.01.078 [DOI] [PubMed] [Google Scholar]
  • 195. Zhou Y, Wu J, Liu C, et al. : p38alpha has an important role in antigen cross-presentation by dendritic cells. Cell Mol Immunol. 2018;15(3):246–259. 10.1038/cmi.2016.49 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 196. Craxton A, Shu G, Graves JD, et al. : p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes. J Immunol. 1998;161(7):3225–36. [PubMed] [Google Scholar]
  • 197. Khiem D, Cyster JG, Schwarz JJ, et al. : A p38 MAPK-MEF2C pathway regulates B-cell proliferation. Proc Natl Acad Sci U S A. 2008;105(44):17067–72. 10.1073/pnas.0804868105 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 198. Wilker PR, Kohyama M, Sandau MM, et al. : Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation. Nat Immunol. 2008;9(6):603–12. 10.1038/ni.1609 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 199. Zhang X, Fan L, Wu J, et al. : Macrophage p38α promotes nutritional steatohepatitis through M1 polarization. J Hepatol. 2019;71(1):163–174. 10.1016/j.jhep.2019.03.014 [DOI] [PubMed] [Google Scholar]
  • 200. Otsuka M, Kang YJ, Ren J, et al. : Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease. Gastroenterology. 2010;138(4):1255–65.1265.e1-9. 10.1053/j.gastro.2010.01.005 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 201. Liang L, Li F, Bao A, et al. : Activation of p38 mitogen-activated protein kinase in ovalbumin and ozone-induced mouse model of asthma. Respirology. 2013;18 Suppl 3:20–29. 10.1111/resp.12189 [DOI] [PubMed] [Google Scholar]
  • 202. Gonzalez-Teran B, Matesanz N, Nikolic I, et al. : p38γ and p38δ Reprogram Liver Metabolism by Modulating Neutrophil Infiltration. EMBO J. 2016;35(5):536–552. 10.15252/embj.201591857 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 203. Gonzalez-Teran B, Cortes JR, Manieri E, et al. : Eukaryotic Elongation Factor 2 Controls TNF-α Translation in LPS-induced Hepatitis. J Clin Invest. 2013;123(1):164–178. 10.1172/JCI65124 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 204. Ittner A, Block H, Reichel CA, et al. : Regulation of PTEN Activity by p38δ-PKD1 Signaling in Neutrophils Confers Inflammatory Responses in the Lung. J Exp Med. 2012;209(12):2229–2246. 10.1084/jem.20120677 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 205. Genovese MC: Inhibition of p38: has the fat lady sung? Arthritis Rheum. 2009;60(12):317–320. 10.1002/art.24264 [DOI] [PubMed] [Google Scholar]
  • 206. Takenaka K, Moriguchi T, Nishida E: Activation of the protein kinase p38 in the spindle assembly checkpoint and mitotic arrest. Science. 1998;280(5363):599–602. 10.1126/science.280.5363.599 [DOI] [PubMed] [Google Scholar]
  • 207. Molnar A, Theodoras AM, Zon LI, et al. : Cdc42Hs, but not Rac1, inhibits serum-stimulated cell cycle progression at G 1/S through a mechanism requiring p38/RK. J Biol Chem. 1997;272(20):13229–13235. 10.1074/jbc.272.20.13229 [DOI] [PubMed] [Google Scholar]
  • 208. Wang X, McGowan CH, Zhao M, et al. : Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol. 2000;20(13):4543–4552. 10.1128/mcb.20.13.4543-4552.2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 209. Gubern A, Joaquin M, Marquès M, et al. : The N-Terminal Phosphorylation of RB by p38 Bypasses Its Inactivation by CDKs and Prevents Proliferation in Cancer Cells. Mol Cell. 2016;64(1):25–36. 10.1016/j.molcel.2016.08.015 [DOI] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 210. Yee AS, Paulson EK, McDevitt MA, et al. : The HBP1 transcriptional repressor and the p38 MAP kinase: unlikely partners in G1 regulation and tumor suppression. Gene. 2004;336(1):1–13. 10.1016/j.gene.2004.04.004 [DOI] [PubMed] [Google Scholar]
  • 211. Kumari G, Ulrich T, Gaubatz S: A role for p38 in transcriptional elongation of p21 CIP1 in response to Aurora B inhibition. Cell Cycle. 2013;12(13):2051–2060. 10.4161/cc.25100 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 212. Saha K, Adhikary G, Kanade SR, et al. : p38δ regulates p53 to control p21 Cip1 expression in human epidermal keratinocytes. J Biol Chem. 2014;289(16):11443–11453. 10.1074/jbc.M113.543165 [DOI] [PMC free article] [PubMed] [Google Scholar] [Research Misconduct Found]
  • 213. Niu Z, Mu H, Zhu H, et al. : p38 MAPK pathway is essential for self-renewal of mouse male germline stem cells (mGSCs). Cell Prolif. 2017;50(1):e12314. 10.1111/cpr.12314 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 214. Liu S, Ginzberg MB, Patel N, et al. : Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length. eLife. 2018;7:e26947. 10.7554/eLife.26947 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 215. Morooka T, Nishida E: Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells. J Biol Chem. 1998;273(38):24285–24288. 10.1074/jbc.273.38.24285 [DOI] [PubMed] [Google Scholar]
  • 216. Li Y, Jiang B, Ensign WY, et al. : Myogenic differentiation requires signalling through both phosphatidylinositol 3-kinase and p38 MAP kinase. Cell Signal. 2000;12(11–12):751–757. 10.1016/s0898-6568(00)00120-0 [DOI] [PubMed] [Google Scholar]
  • 217. Cao W, Medvedev AV, Daniel KW, et al. : β-Adrenergic activation of p38 MAP kinase in adipocytes: cAMP induction of the uncoupling protein 1 (UCP1) gene requires p38 MAP kinase. J Biol Chem. 2001;276(29):27077–27082. 10.1074/jbc.M101049200 [DOI] [PubMed] [Google Scholar]
  • 218. Cao W, Daniel KW, Robidoux J, et al. : p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol Cell Biol. 2004;24(7):3057–3067. 10.1128/mcb.24.7.3057-3067.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 219. Matesanz N, Nikolic I, Leiva M, et al. : p38α blocks brown adipose tissue thermogenesis through p38δ inhibition. PLoS Biol. 2018;16(7):e2004455. 10.1371/journal.pbio.2004455 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 220. Zhang S, Cao H, Li Y, et al. : Metabolic benefits of inhibition of p38α in white adipose tissue in obesity. PLoS Biol. 2018;16(5):e2004225. 10.1371/journal.pbio.2004225 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 221. Jing Y, Liu W, Cao H, et al. : Hepatic p38α regulates gluconeogenesis by suppressing AMPK. J Hepatol. 2015;62(6):1319–1327. 10.1016/j.jhep.2014.12.032 [DOI] [PubMed] [Google Scholar]
  • 222. Lanna A, Henson SM, Escors D, et al. : The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol. 2014;15(10):965–972. 10.1038/ni.2981 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 223. Wang W, Chen JX, Liao R, et al. : Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol. 2002;22(10):3389–3403. 10.1128/mcb.22.10.3389-3403.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 224. Haq R, Brenton JD, Takahashi M, et al. : Constitutive p38HOG mitogen-activated protein kinase activation induces permanent cell cycle arrest and senescence. Cancer Res. 2002;62(17):5076–5082. [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 225. Tivey HS, Brook AJ, Rokicki MJ, et al. : p38 MAPK stress signalling in replicative senescence in fibroblasts from progeroid and genomic instability syndromes. Biogerontology. 2013;14(1):47–62. 10.1007/s10522-012-9407-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 226. Naka K, Tachibana A, Ikeda K, et al. : Stress-induced premature senescence in hTERT-expressing ataxia telangiectasia fibroblasts. J Biol Chem. 2004;279(3):2030–2037. 10.1074/jbc.M309457200 [DOI] [PubMed] [Google Scholar]
  • 227. Dimozi A, Mavrogonatou E, Sklirou A, et al. : Oxidative stress inhibits the proliferation, induces premature senescence and promotes a catabolic phenotype in human nucleus pulposus intervertebral disc cells. Eur Cell Mater. 2015;30:89–102. 10.22203/ecm.v030a07 [DOI] [PubMed] [Google Scholar]
  • 228. Borodkina AV, Shatrova AN, Nikolsky NN, et al. : Role of P38 Map-Kinase in the Stress-Induced Senescence Progression of Human Endometrium-Derived Mesenchymal Stem Cells. Tsitologiia. 2016;58(6):429–435. [PubMed] [Google Scholar]
  • 229. Harada G, Neng Q, Fujiki T, et al. : Molecular mechanisms for the p38-induced cellular senescence in normal human fibroblast. J Biochem. 2014;156(5):283–290. 10.1093/jb/mvu040 [DOI] [PubMed] [Google Scholar]
  • 230. Hongo A, Okumura N, Nakahara M, et al. : The Effect of a p38 Mitogen-Activated Protein Kinase Inhibitor on Cellular Senescence of Cultivated Human Corneal Endothelial Cells. Invest Ophthalmol Vis Sci. 2017;58(9):3325–3334. 10.1167/iovs.16-21170 [DOI] [PubMed] [Google Scholar]
  • 231. Han J, Sun P: The pathways to tumor suppression via route p38. Trends Biochem Sci. 2007;32(8):364–371. 10.1016/j.tibs.2007.06.007 [DOI] [PubMed] [Google Scholar]
  • 232. Freund A, Patil CK, Campisi J: p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011;30(8):1536–1548. 10.1038/emboj.2011.69 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 233. Zhang B, Fu D, Xu Q, et al. : The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nat Commun. 2018;9(1):1723. 10.1038/s41467-018-04010-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 234. Alimbetov D, Davis T, Brook AJ, et al. : Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2. Biogerontology. 2016;17(2):305–315. 10.1007/s10522-015-9610-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 235. Coppe JP, Desprez PY, Krtolica A, et al. : The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118. 10.1146/annurev-pathol-121808-102144 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 236. Xia Z, Dickens M, Raingeaud J, et al. : Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995;270(5240):1326–1331. 10.1126/science.270.5240.1326 [DOI] [PubMed] [Google Scholar]
  • 237. Kummer JL, Rao PK, Heidenreich KA: Apoptosis induced by withdrawal of trophic factors is mediated by p38 mitogen-activated protein kinase. J Biol Chem. 1997;272(33):20490–20494. 10.1074/jbc.272.33.20490 [DOI] [PubMed] [Google Scholar]
  • 238. Cahill MA, Peter ME, Kischkel FC, et al. : CD95 (APO-1/Fas) induces activation of SAP kinases downstream of ICE-like proteases. Oncogene. 1996;13(10):2087–2096. [PubMed] [Google Scholar]
  • 239. Huang S, Jiang Y, Li Z, et al. : Apoptosis signaling pathway in T cells is composed of ICE/Ced-3 family proteases and MAP kinase kinase 6b. Immunity. 1997;6(6):739–749. 10.1016/s1074-7613(00)80449-5 [DOI] [PubMed] [Google Scholar]
  • 240. Cardone MH, Salvesen GS, Widmann C, et al. : The regulation of anoikis: MEKK-1 activation requires cleavage by caspases. Cell. 1997;90(2):315–323. 10.1016/s0092-8674(00)80339-6 [DOI] [PubMed] [Google Scholar]
  • 241. Tan W, Yu HG, Luo HS: Inhibition of the p38 MAPK pathway sensitizes human gastric cells to doxorubicin treatment in vitro and in vivo. Mol Med Rep. 2014;10(6):3275–3281. 10.3892/mmr.2014.2598 [DOI] [PubMed] [Google Scholar]
  • 242. Slawinska-Brych A, Zdzisinska B, Mizerska-Dudka M, et al. : Induction of apoptosis in multiple myeloma cells by a statin-thalidomide combination can be enhanced by p38 MAPK inhibition. Leuk Res. 2013;37(5):586–594. 10.1016/j.leukres.2013.01.022 [DOI] [PubMed] [Google Scholar]
  • 243. Dolgin E: The most popular genes in the human genome. Nature. 2017;551(7681):427–431. 10.1038/d41586-017-07291-9 [DOI] [PubMed] [Google Scholar]
  • 244. Alam MS, Gaida MM, Bergmann F, et al. : Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression. Nat Med. 2015;21(11):1337–1343. 10.1038/nm.3957 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 245. Luk ST, Ng KY, Zhou L, et al. : Deficiency in Embryonic Stem Cell Marker Reduced Expression 1 Activates Mitogen-Activated Protein Kinase Kinase 6-Dependent p38 Mitogen-Activated Protein Kinase Signaling to Drive Hepatocarcinogenesis. Hepatology. 2019. 10.1002/hep.31020 [DOI] [PubMed] [Google Scholar]
  • 246. Salome M, Magee A, Yalla K, et al. : A Trib2-p38 axis controls myeloid leukaemia cell cycle and stress response signalling. Cell Death Dis. 2018;9(5):443. 10.1038/s41419-018-0467-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 247. Gibbs KL, Kalmar B, Rhymes ER, et al. : Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS. Cell Death Dis. 2018;9(6):596. 10.1038/s41419-018-0624-8 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 248. Fang C, Wu B, Le NTT, et al. : Prions activate a p38 MAPK synaptotoxic signaling pathway. PLoS Pathog. 2018;14(9): e1007283. 10.1371/journal.ppat.1007283 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 249. Obergasteiger J, Frapporti G, Pramstaller PP, et al. : A new hypothesis for Parkinson's disease pathogenesis: GTPase-p38 MAPK signaling and autophagy as convergence points of etiology and genomics. Mol Neurodegener. 2018;13(1):40. 10.1186/s13024-018-0273-5 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 250. Wang PY, Hsu PI, Wu DC, et al. : SUMOs Mediate the Nuclear Transfer of p38 and p-p38 during Helicobacter Pylori Infection. Int J Mol Sci. 2018;19(9):2482. 10.3390/ijms19092482 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 251. Zhang F, Zhao Q, Tian J, et al. : Effective Pro-Inflammatory Induced Activity of GALT, a Conserved Antigen in A. Pleuropneumoniae, Improves the Cytokines Secretion of Macrophage via p38, ERK1/2 and JNK MAPKs Signal Pathway. Front Cell Infect Microbiol. 2018;8:337. 10.3389/fcimb.2018.00337 [DOI] [PMC free article] [PubMed] [Google Scholar]; Faculty Opinions Recommendation
  • 252. Zhu J, Yu W, Liu B, et al. : Escin induces caspase-dependent apoptosis and autophagy through the ROS/p38 MAPK signalling pathway in human osteosarcoma cells in vitro and in vivo. Cell Death Dis. 2017;8(10):e3113. 10.1038/cddis.2017.488 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 253. Fan H, Gao Z, Ji K, et al. : The in vitro and in vivo anti-inflammatory effect of osthole, the major natural coumarin from Cnidium monnieri (L.) Cuss, via the blocking of the activation of the NF-kappaB and MAPK/p38 pathways. Phytomedicine. 2019;58:152864. 10.1016/j.phymed.2019.152864 [DOI] [PubMed] [Google Scholar]
  • 254. Li Y, Xu B, Xu M, et al. : 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-kappaB signalling. Pharmacol Res. 2017;119:137–148. 10.1016/j.phrs.2017.01.026 [DOI] [PubMed] [Google Scholar]
  • 255. Zhang X, Wang X, Wu T, et al. : Isoliensinine induces apoptosis in triple-negative human breast cancer cells through ROS generation and p38 MAPK/JNK activation. Sci Rep. 2015;5:12579. 10.1038/srep12579 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 256. Bachegowda L, Morrone K, Winski SL, et al. : Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancer Res. 2016;76(16):4841–4849. 10.1158/0008-5472.CAN-15-3062 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 257. O'Donoghue ML, Glaser R, Aylward PE, et al. : Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial. Am Heart J. 2015;169(5):622–630.e6. 10.1016/j.ahj.2015.02.012 [DOI] [PubMed] [Google Scholar]
  • 258. Emami H, Vucic E, Subramanian S, et al. : The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial. Atherosclerosis. 2015;240(2):490–496. 10.1016/j.atherosclerosis.2015.03.039 [DOI] [PubMed] [Google Scholar]
  • 259. Moran N: p38 kinase inhibitor approved for idiopathic pulmonary fibrosis. Nat Biotechnol. 2011;29(4):301. 10.1038/nbt0411-301 [DOI] [PubMed] [Google Scholar]

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