E3 ubiquitin ligases mediate the final step of an enzymatic cascade that results in the conjugation of ubiquitin to a protein substrate. New data published in Molecular Cell indicate that the function of the E3 ubiquitin ligase itchy (ITCH) is negatively regulated by FYN-mediated tyrosine phosphorylation.
Previous studies indicate that some SRC-family tyrosine kinases are targeted for degradation following ubiquitylation by HECT (homologous to the E6-associated protein carboxy terminus)-type E3 ubiquitin ligases. So, Yang et al. set out to investigate whether the SRC-family tyrosine kinase FYN is a target of the HECT-type E3 ubiquitin ligase ITCH in T cells. Surprisingly, ectopic co-expression of ITCH and FYN by a fibroblast-cell line did not result in ITCH-mediated ubiquitylation of FYN but resulted in tyrosine phosphorylation of ITCH. Consistent with this, FYN was shown to phosphorylate ITCH in an in vitro kinase assay. And, in wild-type T cells, T-cell receptor (TCR) crosslinking induced rapid tyrosine phosphorylation of ITCH, but this was not observed in FYN-deficient T cells. Further analysis showed that FYN phosphorylates Tyr371, which is found in the third WW domain (a domain that contains two conserved tryptophan residues) of ITCH.
In T cells, the absence of FYN, or the presence of a mutant form of ITCH in which Tyr371 was substituted with phenylalanine, resulted in an increased association of ITCH with its substrate JUNB. Furthermore, TCR-induced ubiquitylation of JUNB was also increased, resulting in increased degradation of the protein.
These data indicate that FYN-mediated phosphorylation of ITCH Tyr371 negatively regulates substrate recruitment by the E3 ubiquitin ligase ITCH. This is in contrast to the positive effect of phosphorylation by the serine/threonine kinase JUN amino-terminal kinase 1 (JNK1) on the E3-ubiquitin-ligase activity of ITCH.
References
ORIGINAL RESEARCH PAPER
Yang, C. et al. Negative regulation of the E3 ubiquitin ligase Itch via Fyn-mediated tyrosine phosphorylation. Mol. Cell 21, 135–141 (2006)
FURTHER READING
Liu, Y.-C., Penninger, J. & Karin, M. Immunity by ubiquitylation: a reversible process of modification. Nature Rev. Immunol. 5, 941–952 (2005)
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Honey, K. FYN keeps ITCH under control. Nat Rev Immunol 6, 90 (2006). https://doi.org/10.1038/nri1798
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DOI: https://doi.org/10.1038/nri1798