J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/04/1253/08 $2.00
Volume 185, Number 7, April 7, 1997 1253-1260

Tyrosine Phosphorylation of Pyk2 Is Selectively Regulated by Fyn During TCR Signaling

By 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.

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• al-Ramadi, B. K., Zhang, H., Bothwell, A. L. M. (1998). Cell-cycle arrest and apoptosis hypersusceptibility as a consequence of Lck deficiency in nontransformed T lymphocytes. Proc. Natl. Acad. Sci. USA 95: 12498-12503 [Abstract] [Full Text]  
• Sunder-Plassmann, R., Reinherz, E. L. (1998). A p56lck-independent Pathway of CD2 Signaling Involves Jun Kinase. J. Biol. Chem. 273: 24249-24257 [Abstract] [Full Text]  
• Lin, H., Hutchcroft, J. E., Andoniou, C. E., Kamoun, M., Band, H., Bierer, B. E. (1998). Association of p59fyn with the T Lymphocyte Costimulatory Receptor CD2. BINDING OF THE Fyn Src HOMOLOGY (SH) 3 DOMAIN IS REGULATED BY THE Fyn SH2 DOMAIN. J. Biol. Chem. 273: 19914-19921 [Abstract] [Full Text]  
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• Li, X., Hunter, D., Morris, J., Haskill, J. S., Earp, H. S. (1998). A Calcium-dependent Tyrosine Kinase Splice Variant in Human Monocytes. ACTIVATION BY A TWO-STAGE PROCESS INVOLVING ADHERENCE AND A SUBSEQUENT INTRACELLULAR SIGNAL. J. Biol. Chem. 273: 9361-9364 [Abstract] [Full Text]  
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• Majeti, R., Bilwes, A. M., Noel, J. P., Hunter, T., Weiss, A. (1998). Dimerization-Induced Inhibition of Receptor Protein Tyrosine Phosphatase Function Through an Inhibitory Wedge. Science 279: 88-91 [Abstract] [Full Text]  
• van Oers, N. S. C., Love, P. E., Shores, E. W., Weiss, A. (1998). Regulation of TCR Signal Transduction in Murine Thymocytes by Multiple TCR {zeta}-Chain Signaling Motifs. J. Immunol. 160: 163-170 [Abstract] [Full Text]  
• Okazaki, H., Zhang, J., Hamawy, M. M., Siraganian, R. P. (1997). Activation of Protein-tyrosine Kinase Pyk2 Is Downstream of Syk in Fcepsilon RI Signaling. J. Biol. Chem. 272: 32443-32447 [Abstract] [Full Text]  
• Liao, X. C., Littman, D. R., Weiss, A. (1997). Itk and Fyn Make Independent Contributions to T Cell Activation. J. Exp. Med. 186: 2069-2073 [Abstract] [Full Text]  
• da Silva, A. J., Li, Z., de Vera, C., Canto, E., Findell, P., Rudd, C. E. (1997). Cloning of a novel T-cell protein FYB that binds FYN and SH2-domain-containing leukocyte protein 76 and modulates interleukin 2 production. Proc. Natl. Acad. Sci. USA 94: 7493-7498 [Abstract] [Full Text]  
• Ganju, R. K., Brubaker, S. A., Chernock, R. D., Avraham, S., Groopman, J. E. (2000). beta -Chemokine Receptor CCR5 Signals through SHP1, SHP2, and Syk. J. Biol. Chem. 275: 17263-17268 [Abstract] [Full Text]  
• Linseman, D. A., Heidenreich, K. A., Fisher, S. K. (2001). Stimulation of M3 Muscarinic Receptors Induces Phosphorylation of the Cdc42 Effector Activated Cdc42Hs-associated Kinase-1 via a Fyn Tyrosine Kinase Signaling Pathway. J. Biol. Chem. 276: 5622-5628 [Abstract] [Full Text]  
• Watson, J. M., Harding, T. W., Golubovskaya, V., Morris, J. S., Hunter, D., Li, X., Haskill, J. S., Earp, H. S. (2001). Inhibition of the Calcium-dependent Tyrosine Kinase (CADTK) Blocks Monocyte Spreading and Motility. J. Biol. Chem. 276: 3536-3542 [Abstract] [Full Text]  
• Anfosso, F., Bardin, N., Vivier, E., Sabatier, F., Sampol, J., Dignat-George, F. (2001). Outside-in Signaling Pathway Linked to CD146 Engagement in Human Endothelial Cells. J. Biol. Chem. 276: 1564-1569 [Abstract] [Full Text]  
• Ulivieri, C., Peter, A., Orsini, E., Palmer, E., Baldari, C. T. (2001). Defective Signaling to Fyn by a T Cell Antigen Receptor Lacking the alpha -Chain Connecting Peptide Motif. J. Biol. Chem. 276: 3574-3580 [Abstract] [Full Text]  
• Sorokin, A., Kozlowski, P., Graves, L., Philip, A. (2001). Protein-tyrosine Kinase Pyk2 Mediates Endothelin-induced p38 MAPK Activation in Glomerular Mesangial Cells. J. Biol. Chem. 276: 21521-21528 [Abstract] [Full Text]  
• Katagiri, T., Takahashi, T., Sasaki, T., Nakamura, S., Hattori, S. (2000). Protein-tyrosine Kinase Pyk2 Is Involved in Interleukin-2 Production by Jurkat T Cells via Its Tyrosine 402. J. Biol. Chem. 275: 19645-19652 [Abstract] [Full Text]  
• Gamero, A. M., Larner, A. C. (2000). Signaling via the T Cell Antigen Receptor Induces Phosphorylation of Stat1 on Serine 727. J. Biol. Chem. 275: 16574-16578 [Abstract] [Full Text]  

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