Table 2.

Summary of the identified regulations for ITCH.

Upstream regulator	Mechanism summary	Ref#
AKT	AKT-mediated S257 phosphorylation of ITCH activates its function.	[31]
ATM	ATM positively modulates ITCH E3-ubiquitin ligase activity by phosphorylating ITCH on S161.	[30]
FYN	Tyrosine phosphorylation of ITCH at Y420 by FYN inhibits ITCH activity.	[32]
Herpes simplex virus UL56	UL56 interacts with Itch, independent of additional viral proteins, and mediates degradation of Itch.	[189]
IKKα, IKKβ	ITCH is phosphorylated on S687 by IKKs, which suppresses ITCH activity	[190]
JNK	JNK phosphorylates ITCH at S240, S263, and T273 to promote ITCH-mediated JUNB ubiquitination and subsequent degradation	[29]
LRAD3	LRAD3 contains two PPxY and functions similarly as NDFIPs to alter ITCH inhibitory conformation	[37]
miR-106b	hsa-miR-106b, which itself is down regulated in metastatic pancreatic cancer, directly interacts and inhibit ITCH expression	[191,192]
N4BP1	N4BP1 association with the second WW domain (WW2) of ITCH interferes with E3 binding to its substrates, hence suppresses Itch activity	[175]
NDFIP1, NDFIP2	WW domains 2 and 3 of Itch bind to the HECT domain, mediating autoinhibition. NDFIPs bind multiple WW domains through its PY motifs and relieve this autoinhibition, leaving other WW domains available to recruit substrate.	[25,26,27,36]
NF-κB p65	Overexpression of NF-κB p65 increased ITCH expression, and RANKL promoted the binding of p65 onto the NF-κB binding sites in the ITCH promoter.	[193]
SGK3/CISK	SGK3 phosphorylates ITCH at T385 and S450 to suppress ITCH acitivity.	[33]
Spartin	Spartin acts as an adaptor protein that activates and recruits ITCH to lipid droplets and by this means regulates the level of ubiquitination of adipophilin and potentially other lipid-associated proteins.	[194]
USP9X	Functions as the DUB to antagonize the proteolytic ITCH autoubiquitination	[44]
YOD1	Functions as the DUB to antagonize the proteolytic ITCH autoubiquitination	[45]