PMID:16387660

Citation	Yang, C, Zhou, W, Jeon, MS, Demydenko, D, Harada, Y, Zhou, H and Liu, YC (2006) Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation. Mol. Cell 21:135-41
Abstract	Conjugation of ubiquitin (Ub) to a protein substrate targets the substrate for degradation or functional modification, which is tightly controlled by diverse mechanisms including phosphorylation of the substrate. An emerging mechanism involves regulation of the E3 Ub ligase, for example, the JNK-dependent phosphorylation and activation of Itch E3 ligase, which controls the turnover of Jun proteins and T cell differentiation. Here we show that Itch is also modulated by an Src kinase Fyn via tyrosine phosphorylation at the Tyr371 residue. Fyn associates with Itch, and loss of Fyn results in reduced Itch phosphorylation. Importantly, tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB. The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation. Thus, in contrast to the activation pathway mediated by serine/threonine phosphorylation, tyrosine phosphorylation of Itch plays a negative role in modulating Itch-promoted ubiquitination.
Links	PubMed Online version:10.1016/j.molcel.2005.11.014
Keywords	Amino Acid Sequence; Animals; Cell Line; Humans; Mice; Molecular Sequence Data; Phosphorylation; Proto-Oncogene Proteins c-fyn/genetics; Proto-Oncogene Proteins c-fyn/metabolism; Proto-Oncogene Proteins c-jun/metabolism; Sequence Alignment; T-Lymphocytes/cytology; T-Lymphocytes/physiology; Tyrosine/metabolism; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:ITCH		GO:2000060: positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process	ECO:0000315:		P		Figure 4EFGHI	complete CACAO 10985

References

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