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Article

Dapeng Qian^*, Sima Lev, Nicolai S.C. van Oers^*, Ivan Dikic, Joseph Schlessinger, and Arthur Weiss^*

From the ^* Howard Hughes Medical Institute, Departments of Medicine and of Microbiology and Immunology, University of California, San Francisco, California 94143; SUGEN, Redwood City, California 94063; and the Department of Pharmacology, New York University Medical Center, New York 10016

The Src family protein tyrosine kinases (PTKs), Lck and Fyn, are coexpressed in T cells and perform crucial functions involved in the initiation of T cell antigen receptor (TCR) signal transduction. However, the mechanisms by which Lck and Fyn regulate TCR signaling are still not completely understood. One important question is whether Lck and Fyn have specific targets or only provide functional redundancy during TCR signaling. We have previously shown that Lck plays a major role in the tyrosine phosphorylation of the TCR- chain and the ZAP-70 PTK. In an effort to identify the targets that are specifically regulated by Fyn, we have studied the tyrosine phosphorylation of Pyk2, a recently discovered new member of the focal adhesion kinase family PTK. We demonstrated that Pyk2 was rapidly tyrosine phosphorylated following TCR stimulation. TCR-induced tyrosine phosphorylation of Pyk2 was selectively dependent on Fyn but not Lck. Moreover, in heterologous COS-7 cells, coexpression of Pyk2 with Fyn but not Lck resulted in substantial increases in Pyk2 tyrosine phosphorylation. The selective regulation of Pyk2 tyrosine phosphorylation by Fyn in vivo correlated with the preferential phosphorylation of Pyk2 by Fyn in vitro. Our results demonstrate that Pyk2 is a specific target regulated by Fyn during TCR signaling.

D. Qian is an associate, N.S.C. van Oers is a research associate, and A. Weiss is an investigator of the Howard Hughes Medical Institute. This work is supported in part by a grant from SUGEN (to J. Schlessinger).

¹Abbreviations used in this paper: FAK, focal adhesion kinase; PTK, protein tyrosine kinase; ZAP-70, -associated protein 70.

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