J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/05/1877/06 $2.00
Volume 185, Number 10, May 19, 1997 1877-1882

BRIEF DEFINITIVE REPORT:
The Vav Binding Site (Y315) in ZAP-70 Is Critical for Antigen Receptor-mediated Signal Transduction

By Jun Wu,^* Qihong Zhao,^§ Tomohiro Kurosaki, and Arthur Weiss^*§

From the ^* Department of Microbiology and Immunology, and the  Department of Medicine and the ^§ Howard Hughes Medical Institute, University of California, San Francisco, California 94143, and  Department of Molecular Genetics, Institute of Hepatic Research, Kansai Medical School, Moriguchi 570, Japan

Stimulation of antigen receptors in T and B cells leads to the activation of the Src and Syk families of protein tyrosine kinases (PTK). These PTKs subsequently phosphorylate numerous intracellular substrates, including the 95-kD protooncogene product Vav. Vav is essential for both T and B cell development and T and B cell antigen receptor-mediated signal transduction. After receptor ligation, Vav associates with phosphorylated Syk and ZAP-70 PTKs, an interaction that depends upon its SH2 domain. Here we demonstrate that a point mutation of tyrosine 315 (Y315F) in ZAP-70, a putative Vav SH2 domain binding site, eliminated the Vav- ZAP-70 interaction. Moreover, the Y315 mutation impaired the function of ZAP-70 in antigen receptor signaling. Surprisingly, this mutation also resulted in marked reduction in the tyrosine phosphorylation of ZAP-70, Vav, SLP-76, and Shc. These data demonstrate that the Vav binding site in ZAP-70 plays a critical role in antigen receptor-mediated signal transduction.

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