Table 1.
Nuclear substrates of p38α/β and their role in cancer and inflammation. More than 120 substrates of p38α/β were found in several reviews [27,43,86,87,88,89], and the translocation of each one of them was inspected in various databases. Substrates with constant (> 80%) nuclear localization in all cell lines described are shown under “Mostly Nuclear Proteins”, while proteins that are mostly nuclear in resting cells but are exported to the cytoplasm after stimulation are shown under “Nuclear Export”. The role of the p38α/β phosphorylation, as well as their general involvement in cancer or inflammation (independent of the phosphorylation in the nucleus) is described for each nuclear substrate. ND—not determined.
| Localization | p38-phosphorylated Protein | Role of Phosphorylation | Involvement in Cancer | Involvement in Inflammation |
|---|---|---|---|---|
| Cyclin D3 | Targets cyclin D3 for proteasomal degradation [124]. | Together with CDK6 regulates cell metabolism to promote cancer [125]. | Together with CDK6 phosphorylates NFκB to induce inflammatory gene expression [126]. | |
| Mostly Nuclear Proteins | E47 | Promotes MyoD/E47 association and muscle-gene transcription [127]. | Induces EMT and therefore may facilitate tumor formation [128]. | Required for the efficient recruitment of GR (anti-inflammatory) to chromatin [129]. |
| FBP2 (KSRP) | Controls stability of myogenic transcripts [130]. | Regulates c-Fos RNA stability and therefore cancers [131]. | Induce pro-inflammatory genes upon resveratrol treatment [132]. | |
| FBP3 | Controls prothrombin expression [133]. | May regulate Myc expression [134]. | May be involved in thrombin-induced inflammation [133]. | |
| H2AX | Chromatin remodeling. Involved in G2 checkpoint that protects cells from DNA breaks [135]. | Phosphorylation of Ser139 by RSK (the same site phosphorylated by p38) inhibits cell transformation [136]. | Colonocytes from ulcerative colitis patients showed an increase in H2AX content. Not necessarily related to phosphorylation [137]. | |
| H3 | Related to chromatin remodeling and chromosome condensation [138]. | p38 phosphorylation of Ser10 causes aggressive gastric cancer [139]. | p38-dependent H3 phosphorylation may mark promoters for increased NFκB recruitment and inflammation [140]. | |
| HBP1 | Stabilizes the proteins that leads to cell cycle inhibition [141]. | Inhibits cell cycle and functions as a tumor suppressor [78]. | Promote vascular inflammation in atherogenesis [142]. | |
| Id2 | Regulates transcription, cell cycle, and differentiation [143]. | Participate in VHL inactivation in cancer [144]. | Maintains regulatory T cell to suppress inflammatory diseases [145]. | |
| IWS1 | Likely regulates RNA processing and export [89]. | Regulates trimethylation of Histone H3 that may lead to cancer [146]. | ND | |
| JDP2 | Phosphorylation at Thr148 likely leads to proteasomal degradation (as with JNK [147]). | Implicated in progression and suppression of different cancers [148]. | Involved in liver inflammation [149]. | |
| MEF2d | Regulates recruitment of proteins to specific genes [150]. | Enhances proliferation migration and invasion in pancreatic cancer [151]. | Regulates IL-10 production in microglia to protect neuronal cells from inflammation-induced death [152]. | |
| Mnk2b | Induces activation [153]. | Mnk2b is oncogenic, by enhancing eIF4E phosphorylation [154]. | MNK2 is involved in adipose tissue inflammation (possibly both isoforms) [155]. | |
| MSK1 | Induces activation [156]. | Induces the transcription of immediate-early oncogenes [32]. | Activation of the pro-inflammatory NF-κB signaling pathway through MSK1 in microglial cells [157]. | |
| MSK2 | Induces activation [158]. | Induces the transcription of immediate-early oncogenes [32]. | Plays a role in limiting Toll-like receptor-driven inflammation [159]. | |
| P18Hamlet (Znhit1) | Stimulates p53-dependent apoptosis [160]. | Regulates p53 and therefore cancer [160]. | May affect p53-dependent inflammation [160,161]. | |
| P53 | Regulates apoptosis [162]. | Tumor suppressor [161]. | Suppressor of inflammation and autoimmunity [161]. | |
| PGC-1α | Regulates cytokine-induced energy expenditure [163]. | PGC-1α expression is altered in tumors and metastasis in relation to modifications in cellular metabolism [164]. | Connects oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome [165]. | |
| PPARalpha | Plays a role in cardiac metabolic stress response [166]. | Modulates metabolic pathways and attenuates kidney tumor growth [167]. | Exerts a major anti-inflammatory action in human liver [168]. | |
| Ranbp2 | Probably regulates SUMOylation and myotube formation [89]. | Involved in inflammatory myofibroblastic tumor formation [169]. | Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement [169]. | |
| Rb1 | Mediates Fas-effects on inactivation of Rb1, independent of CDKs [170]. | Functions as a tumor suppressor. Inactivation induces retinoblastoma and other cancers [171]. | RB inactivation enhances pro-inflammatory signaling that can lead to cancer [172]. | |
| RNF2 | Modulates the expression of transcription factors and histone 2B acetylation [173]. | Monoubiquitinates H2AK119 at the promoter of LTBP2, thus regulates TGFβ signaling to induce melanoma [174]. | Inhibit interferon-dependent responses that may include inflammation [175]. | |
| Rpn2 | Negatively regulates proteasome activity [40]. | Promotes metastasis of hepatocellular carcinoma [176]. | Downregulated the inflammatory-associated JAK1/STAT3 pathway [177]. | |
| RUNX2 | Increases transcriptional activity [178]. | Abnormally expressed in prostatecancerand associates with metastatic disease [179]. | May have a role in the inflammatory remodeling of the collagen matrix [180]. | |
| SPF45 | Regulates alternative splicing site utilization [181], which may lead to multidrug resistance phenotypes [182]. | The phosphorylation inhibits proliferation and therefore may block cancer [181]. | Highly expressed in lung’s inflammatory cells, which might be involved in their function [182]. | |
| SRC3 | Controls the dynamics of interactions with RARalpha to facilitate gene activation [183]. | Promotes breast and prostate cancer cell proliferation and survival [184]. | Regulates inflammation during wound healing [185]. | |
| AHNAK | Probably induces its differentiation-related activity [89]. | Promotes metastasis through TGF-β-mediated EMT [186]. | Silencing of AHNAK in dental pulp cells led to reduced inflammation-related proteins [187]. | |
| Nuclear Export | c/EBPalpha | Inhibits enhancer activity [188]. | Suppresses tumor metastasis and growth in gastric cancer [189]. | Interacts with NF-κB to regulate inflammation [190]. |
| c/EBPbeta | Activates enhancer activity [191]. | Regulates tumor progression [192]. | Induces inflammation and ER stress [193]. | |
| ERalpha | Induces activation and nuclear export [55]. | Functions as an oncogene in breast cancer [194]. | Abnormal ERalpha signaling leads to inflammation [195]. | |
| MK2 | Induces activation [196]. | Plays a role in the induction of lung cancer [197]. Activates cancer-related proteins (Cdc25B/C, Plk1, and TSC2) [198]. | Plays a role in inflammatory pulmonary diseases [197]. Regulates inflammatory cytokines, transcript stability, and critical cellular processes [69]. | |
| MK3 | Induces activation [199]. | Leads to pancreatic cancer growth [200]. | Induces TNF biosynthesis and inflammation [201]. | |
| MK5 | Induces activation [202]. | Induces breast cancer [203]. | Phosphorylates HSP27 to induce inflammation [204]. | |
| MRF4 | Reduces transcriptional activity [205]. | May regulate hairy cell leukemia (HCL) [206]. | ND | |
| NFATc4 | Activation and nuclear export [207]. | Correlates with decreased proliferation and poor prognosis of ovarian cancer [208]. | Involved in the secretion of inflammatory factors [209]. | |
| NR4A | Regulates dopamine synthesis genes [210]. | Has both tumor suppressor and oncogenic functions in different cells [211]. | May contribute to the cellular processes that control inflammation [212]. | |
| Pax6 | Elevates transcriptional activity [213]. | Induces cell proliferation in lung cancer [214]. | ND |