title: Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation.
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.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, California 92130, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhou
authors.forename: Myung-Shin
authors.initials: MS
authors.lastname: Jeon
authors.forename: Dmytro
authors.initials: D
authors.lastname: Demydenko
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Harada
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhou
authors.forename: Yun-Cai
authors.initials: YC
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D014443:Tyrosine; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; D051076:Proto-Oncogene Proteins c-fyn