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J. Biol. Chem., Vol. 281, Issue 50, 38257-38265, December 15, 2006

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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^*

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^¶, and Wojciech Swat¹

From the Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, the Research Unit for Single Molecule Immunoimaging, RIKEN Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan, the ^¶Department of Immunology and Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, the ^||Laboratory for Autoimmune Regulation, RIKEN Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan, and the ^**Structural Biology Center, National Institute of Genetics, and Department of Genetics, Graduate University for Advanced Studies, Mishima, Shizuoka 411-8540, Japan

Vav proteins are multidomain signaling molecules critical for mediating signals downstream of several surface receptors, including the antigen receptors of T and B lymphocytes. The catalytic guanine nucleotide exchange factor (GEF) activity of the Vav Dbl homology (DH) domain is thought to be controlled by an intramolecular autoinhibitory mechanism involving an N-terminal extension and phosphorylation of tyrosine residues in the acidic region (AC). Here, we report that the sequences surrounding the Vav1 AC: Tyr¹⁴², Tyr¹⁶⁰, and Tyr¹⁷⁴ are evolutionarily conserved, conform to consensus SH2 domain binding motifs, and bind several proteins implicated in TCR signaling, including Lck, PI3K p85, and PLC1, through direct interactions with their SH2 domains. In addition, the AC tyrosines regulate tyrosine phosphorylation of Vav1. We also show that Tyr¹⁷⁴ is required for the maintenance of TCR-signaling microclusters and for normal T cell development and activation. In this regard, our data demonstrate that while Vav1 Tyr¹⁷⁴ is essential for maintaining the inhibitory constraint of the DH domain in both developing and mature T cells, constitutively activated Vav GEF disrupts TCR-signaling microclusters and leads to defective T cell development and proliferation.

Received for publication, September 8, 2006 , and in revised form, October 6, 2006.

^* This work was supported by Grants P30-AR048335, R01-AI061077 (to W. S.) and R01-AI065447 (to D. D. B.) from the National Institutes of Health, NEDO, and MEXT Adv. Innov. Res. Program (to M. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Table S1.

¹ To whom correspondence should be addressed: Dept. of Pathology and Immunology, WA University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-747-8886; Fax: 314-362-4096; E-mail: swat{at}pathology.wustl.edu.

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