Regulation of the T cell cytoskeleton by the assembly of a tri-molecular complex consisting of nck, VAv and SLP-76

The ZAP-70 protein tyrosine kinase is required for T cell receptor (TCR)-mediated mobilization of calcium, ras activation, cytokine secretion, and cytoskeletal reorganization. While much is known about the mechanisms by which the TCR regulates the ras and calcium pathways, less is known about how the TCR controls cytoskeletal reorganization. We have previously demonstrated that phosphorylation of the SLP-76 linker protein by ZAP-70 is required for IL-2 gene upregulation. We demonstrate here that the assembly of a tri-molecular complex consisting of SLP-76, the nck adaptor protein, and the Vav guanine nucleotide exchange factor is required for a functional T cell cytoskeleton. Disruption of the ability of either nck or Vav to interact with phosphorylated SLP-76 abrogates TCR-mediated actin polymerization. Hence, phosphorylation of SLP-76 by ZAP-70 provides a scaffold to colocalize Vav and nck and likely permits the integration of rho-GTPases with nck-bound p21-activated kinases and the Wiskott-Aldrich Syndrome Protein to mediate reorganization of the T cell cytoskeleton.