Vav1 Acidic Region Tyrosine 174 Is Required for the Formation of T Cell Receptor-induced Microclusters and Is Essential in T Cell Development and Activation
著者
和文:
Ana V. Miletic,
十川 久美子,
Michio Hiroshima,
Michael J. Hamann,
Timothy S. Gomez,
Naruhisa Ota,
Tracie Kloeppel,
Osami Kanagawa,
徳永 万喜洋,
Daniel D. Billadeau,
Wojciech Swat.
英文:
Ana V. Miletic,
Kumiko Sakata-Sogawa,
Michio Hiroshima,
Michael J. Hamann,
Timothy S. Gomez,
Naruhisa Ota,
Tracie Kloeppel,
Osami Kanagawa,
Makio Tokunaga,
Daniel D. Billadeau,
Wojciech Swat.
言語
English
掲載誌/書名
和文:
英文:
J Biol Chem.
巻, 号, ページ
Vol. 281
No. 50
pp. 38257-38265
出版年月
2006年12月
出版者
和文:
英文:
会議名称
和文:
英文:
開催地
和文:
英文:
アブストラクト
Vav proteins are multidomain signaling molecules critical for mediating signals downstream ofseveral surface receptors, including the antigen receptors of T and B lymphocytes. The catalyticguanine nucleotide exchange factor (GEF) activity of the Vav Dbl homology (DH) domain is thoughtto be controlled by an intramolecular autoinhibitory mechanism involving an N-terminal extensionand phosphorylation of tyrosine residues in the acidic region (AC). Here, we report that the sequencessurrounding the Vav1 AC: Tyr142, Tyr160, and Tyr174 are evolutionarily conserved, conform toconsensus SH2 domain binding motifs, and bind several proteins implicated in TCR signaling,including Lck, PI3K p85α, and PLCγ1, through direct interactions with their SH2 domains. Inaddition, the AC tyrosines regulate tyrosine phosphorylation of Vav1. We also show that Tyr174 isrequired for the maintenance of TCR-signaling microclusters and for normal T cell development andactivation. In this regard, our data demonstrate that while Vav1 Tyr174 is essential for maintainingthe inhibitory constraint of the DH domain in both developing and mature T cells, constitutivelyactivated Vav GEF disrupts TCR-signaling microclusters and leads to defective T cell developmentand proliferation.
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