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T Cell Activation-Induced CrkII Binding to the Zap70 Protein Tyrosine Kinase Is Mediated by Lck-Dependent Phosphorylation of Zap70 Tyrosine 315¹

Sigal Gelkop^*,, Gerrald D. Gish, Yael Babichev^*, Tony Pawson and Noah Isakov^2,*

^* Department of Microbiology and Immunology, Faculty of Health Sciences, and the Cancer Research Center, Ben Gurion University of the Negev, Beer Sheva, Israel; and Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada

The Zap70 protein tyrosine kinase controls TCR-linked signal transduction pathways and is critical for T cell development and responsiveness. Following engagement of TCR, the Zap70 undergoes phosphorylation on multiple tyrosine residues that are implicated in the regulation of its catalytic activity and interaction with signaling effector molecules downstream of the TCR. We have shown previously that the CT10 regulator of kinase II (CrkII) adapter protein interacts with tyrosine-phosphorylated Zap70 in TCR-engaged T cells, and now extend these studies to show that Tyr³¹⁵ in the Zap70 interdomain B region is the site of interaction with CrkII. A point mutation of Tyr³¹⁵ (Y315F) eliminated the CrkII-Zap70 interaction capacity. Phosphorylation of Tyr³¹⁵ and Zap70 association with CrkII were both dependent upon the Lck protein tyrosine kinase. Previous studies demonstrated the Tyr³¹⁵ is the Vav-Src homology 2 (SH2) binding site, and that replacement of Tyr³¹⁵ by Phe impaired the function of Zap70 in TCR signaling. However, fluorescence polarization-based binding studies revealed that the CrkII-SH2 and the Vav-SH2 bind a phosphorylated Tyr³¹⁵-Zap70-derived peptide with affinities of a similar order of magnitude (K_d of 2.5 and 1.02 µM, respectively). The results suggest therefore that the biological functions attributed to the association of Zap70 with Vav following T cell activation may equally reflect the association of Zap70 with CrkII, and further support a regulatory role for CrkII in the TCR-linked signal transduction pathway.

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