. The c-Cbl proto- oncogene product is tyrosine-phosphorylated upon stimulation of a wide range of receptors, including the T-cell antigen receptor (TCR). Both Fyn and ZAP-70 contribute to the phosphorylation of Cbl in T cells, and the tyrosine phosphorylation of Cbl induces its interaction with a number of important signaling molecules, including Grb2, PI 3-kinase, CrkL, and 14-3-3 proteins. However, whether Cbl plays a positive or a negative role in signal transduction through the TCR remains unclear. The applicant proposes that abnormal Cbl phosphorylation and function contributes to the pathogenesis of certain autoimmune diseases, a relevant example being the syndrome manifested by the autoimmune nonobese diabetic (NOD) mouse. The specific aims of this proposal are: (1) to define the interactions between the Fyn and ZAP-70 tyrosine kinases and Cbl, (2) to define the downstream targets of Cbl in activated T cells, and (3) to determine whether altered Cbl function contributes to the hypo-responsive status of T cells in NOD mice.