SIGNAL TRANSDUCTION FROM THE T-CELL ANTIGEN RECEPTOR

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DESCRIPTION (Adapted from applicant's abstract): The cascade of molecular events that link cell surface ligand-receptor interactions to regulated changes in cellular functions are only partially understood. The T-cell antigen receptor (TCR) is a multimeric complex, which includes the CD3 complex that serves as the primary recognition and signal-transducing element during specific T-cell activation. Triggering of the TCR by activating ligands stimulates a pleiotropic activation response culminating in cell growth and differentiation. A prototypical early (minutes) response to TCR ligation is the exocytosis of cytoplasmic granules from cytolytic T-lymphocytes (CTL). The long-term goals of this project are to define the mechanisms of transmembrane signal generation and propagation initiated by TCR ligation. Recent studies indicate that an undefined protein tyrosine kinase serves as the proximal signal-transducing element from ligand-bound TCR.A critical substrate for this TCR-coupled protein tyrosine kinase is phosphoinositide- specific phospholipase C (PLC-gamma1). The specific aims of this proposal are the following: (1) To identify the protein tyrosine kinase that couples TCR-ligation to the tyrosine phosphorylation of PLC-gamma1; (2) to determine the effect of altered PLC-gamma1 isozyme expression on signal transduction through the TCR; and (3) to examine the role of protein tyrosine kinase activation and p21ras in TCR-dependent granule exocytosis in cytolytic T-cells. The investigator indicates that the results of this study should offer novel insights into transmembrane signalling mechanisms involved in both normal cell growth and cellular transformation.