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pp56^Lck Mediates TCR -Chain Binding to the Microfilament Cytoskeleton¹

Moshe M. Rozdzial^*, Chris M. Pleiman^2,*, John C. Cambier^*, and Terri H. Finkel3^,

^* Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206; Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80262; and Departments of Pediatrics and Biochemistry & Molecular Genetics, University of Colorado Health Sciences Center, Denver, CO 80262

The TCR -chain () on mature murine T lymphocytes binds to the microfilament cytoskeleton in response to Ag receptor ligation. Here, we report the role of Src family kinases in -cytoskeletal binding, using mutant mice and a cell-free model system. Binding of to actin in the cell-free system has a specific requirement for ATP and divalent cations, with an apparent Michaelis-Menton constant for ATP in the millimolar range, and can be disrupted by either EDTA or the microfilament poison, cytochalasin D, suggesting that microfilaments provide the structural framework for an active process involving cellular kinases. Indeed, tyrosine-phosphorylated is a predominant form of the -chain bound to polymerized actin, while challenge with alkaline phosphatase prevents -chain association in solution and releases -chain from the bound state. Phosphorylated Src-family kinase pp56^Lck also associates with membrane skeleton upon TCR engagement and is a component of the reconstituted cytoskeletal pellet. -Chain phosphorylation and -cytoskeletal binding are abrogated in cell lysates with reduced levels of pp56^Lck and in activated mutant murine T cells lacking pp56^Lck, implicating pp56^Lck as the kinase involved in -chain tyrosine phosphorylation and -cytoskeletal binding. Finally, recombinant Lck Src homology 2 domain preferentially inhibits reconstituted -cytoskeleton association, suggesting that -microfilament binding is dependent on interactions between phosphorylated tyrosine residues in -chain activation motifs and the Src homology 2 domain of the Lck protein tyrosine kinase.

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