Table 1.

Summary of the identified ubiquitin substrates for ITCH.

Substrate	Linkage	Role ITCH plays	Mechanism summary	Ref#
BCL10	K48?	PKC or T-cell receptor (TCR)/CD28 signaling results in the downregulation of BCL10 protein levels by Itch and NEDD4, thereby attenuating NF-κB transcriptional activity.	ITCH, together with NEDD4, targets the BCL10 for proteolysis, downmodulating CD3/ CD28-induced activation of NF-κB.	[135]
BRAF	K27	ITCH facilitates BRAF/MEK/ERK signaling pathway activation.	BRAF is ubiquitinated by the ITCH E3 ligase in response to JNK-mediated phosphorylation abolishes 14–3–3-mediated suppression of BRAF kinase activity, leading to sustained BRAF/MEK/ERK signaling.	[103]
c-FLIP	K48?	ITCH facilitates TNFα-induced cell death.	TNFα activates JNK to phosphorylate ITCH, which then ubiquitinates c-FLIP and induces its proteasomal degradation.	[104]
c-JUN	K48	ITCH antagonizes AP-1 function upon JNK pathway activation.	Ubiqui tination of c-JUN and JUNB by ITCH results in their proteasomal degradation.	[71]
CXCR4, Hrs	Unknown	ITCH facilitates the sorting of CXCR4 to lysosomal degradation.	ITCH facilitates the lysosomal degradation of chemokine receptor CXCR4 by ubiquitination of the endosomal protein Hrs.	[91]
cytoplasmic misfolded proteins	Unknown	ITCH targets misfolded proteins to ensure the protein quality control (QC) system which protects cells against cellular toxicity.	ITCH mediates the degradation of thermally denatured misfolded luciferase proteins.	[174]
Deltex	K29	ITCH may restrain NOTCH signaling.	ITCH promotes Deltex degradation through catalyzing K29-linked poly ubiqui tin chains on Deltex.	[81]
DVL	K48?	ITCH inhibits WNT pathway activation.	Phosphorylation of DVL leads to its proteolytic ubiquitination by the E3 ligase ITCH.	[76]
Endophilin A1	Unknown	ITCH regulates ubiquitin-mediated endosomal sorting.	ITCH promotes endophilin A1 ubiquitination by the interaction of proline-rich domain of ITCH and SH3 domain of endophilin Al.	[90]
ERBB3	K48?		ITCH engages a HER3 antibody to induce the proteasomal degradation of HER3 in cancer cells.	[175]
ERBB4	mono, K63	ITCH facilitates the sorting and degradation of the ERBB4 CYT-1 isoform, which suppresses EGF-dependent transcriptional activation.	ITCH catalyzes mono-ubiquitination and K63 polyubiquitination of ERBB4 CYT-1, promoted its localization to intracellular vesicles for subsequent degradation.	[97,98,176]
FOXO1	K48	ITCH is essential for the differentiation of Tfh cells, germinal center responses and IgG responses to acute viral infection.	FOXOl is ubiquitinated by ITCH for proteasomal degradation.	[156]
GLI1	K48	ITCH suppresses Hedgehog pathway activation.	GLI1 is ubiquitinated by ITCH with the assistance from the adaptor protein Numb, which suppresses the Hedgehog signals.	[42]
GLI-Similar 3	K48?	ITCH functions as a negative regulator of Glis3-mediated transcriptional activity.	ITCH targets GLIS3 transcription factor for ubiquitination and proteolysis.	[59]
HEF1/NEDD9	K48	ITCH may suppress TGF-β signaling.	TGF-β promotes ITCH, SMAD3 and HEF1 to form a complex to catalyze HEF1 ubiquitination and subsequent degradation.	[67]
histone H1.2	K48, K63	ITCH suppresses cellular DNA damage response.	ITCH-mediated polyubiqui tination of HI. 2 suppressed RNF8/RNF 168-dependent formation of 53BP 1 foci, which plays an important role in DNA damage response.	[31]
influenza A virus A1 protein	K48?	ITCH suppresses influenza A virus cell entrance.	ITCH interacts with viral Ml protein to facilitates its ubiquitination.	[177]
ITCH	K63	K6 3-linked ITCH auto ubiqui tination may stabilize ITCH.	ITCH auto ubiquitination is an inter molecular reaction that promotes K6 3-linked, but not K48-linked polyubiqui tin chains.	[43]
ITSN1	mono and K48?	ITCH regulates endocytosis.	ITSN1 is regulated differentially by ITCH depending on which of its isoform is modified. The major isoform ITSNl-s is monoubiquitinated, while the minor isoform, ITSNl-22a, undergoes a combination of mono- and oligo ubiqui tination. The mono ubiquitination stabilizes ITSNl-s, whereas the oligo ubiquitination of the minor isoform leads to its proteasomal degradation.	[92]
JUNB	K48	ITCH antagonizes AP-1 function upon JNK pathway activation.	Ubiquitination of c-JUN and JUNB by ITCH results in their proteasomal degradation.	[70,71]
LATS1	K48	ITCH promotes YAP signaling in tumor cells.	ITCH-mediated degradation of LATS1 reduces YAP phosphorylation and leads to the accumulation of nuclear YAP, ITCH enhances transcriptional coactivation function of YAP to promote tumorigenicity.	[49]
LRP6	Unknown	ITCH promotes LRP6-mediated WNT signaling function	ITCH interacts with and ubiquitinates wild type LRP6 but not the LDLR repeat mutants.	[77]
MAVS	K48	ITCH suppresses antiviral innate immunity.	Expression of PCBP2 is induced after viral infection, which recruits ITCH to catalyze K48-linked polyubiquitination and degradation of MAVS.	[178]
MKK4/SEK1	K48?	ITCH degrades MKK4 as a negative feedback regulation of the JNK/p38 pathways.	ITCH binds to MKK4 to promote the ubiquitination of MKK4 at K140 and K143, which leads to MKK4 degradation.	[105]
Notch	K29	ITCH may restrain NOTCH signaling.	ITCH promotes the ubiquitination of NOTCH, and likely in a ligand-independent	[79,80]
Occludin	Unknown	ITCH regulates tight junction in epithelial cells	manner. ITCH promotes the degradation of tight junction-specific protein occludin.	[179]
p45/NF-E2	K63	ITCH may regulate NF-E2 function during the development of hematopoietic cell lineages.	ITCH suppresses the transactivation activity of p45/NF-E2 via K63-linked polyubiquitination of p45/NF-E2.	[180]
p63	K48?	ITCH may modulate keratinocyte function, where p63 plays a role.	ITCH binds, ubiquitinates, and promotes the degradation of p63.	[83]
p73	K48?	ITCH suppresses DNA damage responses through p73.	ITCH binds to p73 and promotes its ubiquitination and proteasome-dependent degradation in basal conditions. In response to DNA damage, ITCH is rapidly degraded, reducing p73 turnover. TAp73 levels increase.	[87]
PI4KIIα	Unknown		ITCH has been shown to form a functional complex with the phosphatidylinositol (PI) 4-kinase type Ila (PI4KIIα) through which ITCH promotes the non-proteolytic ubiquitination of PI4KIIα.	[93]
PLC-γ1	K48?	Sustained Ca2+ and calcineurin signaling engage ITCH and NEDD4 to destabilizes PLC-γ1 and thereby inhibiting T cell anergy.	NEDD4 and ITCH promote PLC-γ1 ubiquitination and degradation.	[136]
PTCH1	K48?	ITCH suppresses SHH-independent Hedgehog pathway activation.	C-terminal domain (CTD) of PTCH1 interacts with and is ubiquitinated on K1413 by ITCH.	[60]
RASSF5/NORE1	K48?	ITCH suppresses RASSF5-mediated growth inhibition.	RASSF5 is poly-ubiquitinated by ITCH, a process that is inhibited by the acetylation of RASSF5, which suppress the binding between ITCH and RASSF5.	[181]
RIP 2	K63	ITCH inhibits NOD 2/RIP 2-induced NF-κB activation and suppresses inflammatory responses at mucosal surfaces.	The NOD2 signaling partner, RIP2, is directly K63-polyubiquitinated by ITCH.	[182]
ROR-γt	K48	ITCH regulates IL-17-mediated colonic inflammation and carcinogenesis.	ITCH negatively controls Thl7 differentiation through ubiquitination and degradation of transcription factor RORγt, which is the regulator of Thl7 differentiation.	[153]
SHP-1	K27	Mice lacking ITCH and WWP2 showed signs of autoimmunity and lung inflammation due to biased differentiation toward the Th2 lineage and hypo-responsiveness after TCR stimulation.	ITCH and WWP2 form a complex to catalyze K27-linked ubiquitination of the phosphatase SHP-1, which disrupts the interaction between SHP-1 and the tyrosine kinase Lck, and therefore promoting TCR signaling.	[137]
SIRT6	K48?	ITCH promotes hepatic lipid infiltration through reduced fatty acid oxidation.	ITCH ubiquitinates SIRT6, leading to its proteolysis.	[183]
Smad2	Unknown	ITCH enhances TGF-β-induced transcription.	ITCH promotes the ubiquitination of SMAD2 and augments SMAD2 phosphorylation and activation. ITCH facilitates complex formation between TGF-β receptor and SMAD2 and enhances TGF-β-induced transcription.	[63]
Smad7	K48?	ITCH facilitates TGF-β-induced transcription.	ITCH is an E3 ubiquitin ligase that specifically targets SMAD7 for ubiquitin-dependent degradation.	[64]
STAM-1	Unknown	Depletion of ITCH and STAM-1 by siRNA caused significant inhibition of CXCR4-induced ERK-1/2 activation.	ITCH-mediated ubiquitination of STAM-1 in caveolae coordinates activation of ERK-1/2 signaling.	[91]
SUFU	K63	ITCH suppresses Hedgehog pathway activation.	β-Arrestin 2 forms a complex with ITCH to promote K63-linked polyubiquitination of the Hedgehog pathway tumor suppressor SUFU, which inhibits the GLI-dependent transcription program.	[40]
TAB1	K48	ITCH suppresses skin inflammation in the mouse.	ITCH ubiquitinates TAB1 for proteolysis to suppress p38a activation.	[184]
TAK1	K48	ITCH suppresses TNF-mediated inflammatory signaling.	The ITCH-CYLD complex sequentially cleaved K63-linked ubiquitin chains and catalyzed K48-linked ubiquitination on the kinase TAK1 to terminate inflammatory signaling via tumor necrosis factor.	[69]
TCR-ζ	K33	In mice deficient in the E3 ubiquitin ligases Cbl-b and Itch, T cell activation was augmented, accompanied by spontaneous auto immunity.	ITCH and Cbl-b promote TCR-ζ polyubiquitination via a K33-linkage, which affects its phosphorylation and association with the ζ chain-associated protein kinase Zap-70, to control T cell activation and auto immunity.	[134]
TIEG1	K27	ITCH facilitates Treg cell function and contributes to T cell anergy in the mouse.	ITCH catalyzes the K27-linked poly-ubiquitination of TIEG1, which facilitates its transcriptional activation to boost Foxp3 expression.	[65,66]
TRPV4	K27	ITCH suppresses TRPV4-mediated Ca2+ entry to the cells.	ITCH promotes the ubiquitination of the transient receptor potential (TRP) family protein TRPV4 to terminate TRPV4-mediated Ca2+ uptake.	[39,185]
TXNIP	Unknown	ITCH suppresses TXNIP-mediated cardiomyocyte apoptosis	TXNIP is ubiquitinated and degraded by ITCH in cardiomyocytes to reduce cardiotoxicity.	[186]
vFLIP	K48?	ITCH antagonizes Kaposi’s sarcoma herpesvirus vFLIP-mediated NFkB signaling and viral latency.	ITCH is involved in the ubiquitination and degradation of vFLIP, a process that is induced by KSHV RTA.	[187]
YAP	K48?	ITCH, with Amotl 30 engaged, suppresses YAP signaling.	Atoml30 repurposes ITCH from its previously described role in degrading LATS1 to the inhibition of YAP.	[188]