In this proposal we plan to further define the roles of the adapter proteins Shc and Cbl, and their associated molecules, in T cell signaling. They plan to develop a better understanding of these proteins by employing biochemical approaches, studying the function of these proteins in transformed T cells and finally studying their function in animals. I. The role of Shc in T cell activation and T cell development. They have observed that dominant negative mutants of Shc, when introduced into the murine T cell hybridoma DO. I 1, can disrupt T cell receptor (TCR) mediated IL-2 production and antigen induced cell death (AICD). They will define the Shc signaling-pathwgys by defining the proteins upstream and downstream of Shc. They will also introduce the dominant negative forms of Shc as transgenes into bone marrow stem cells to determine their effect on T cell development and T cell effector function in vivo. II. The role of Cbl in T cell activation and T cell development. Cbl appears to play a role as a negative regulator of T cell signaling. They will use a variant Jurkat cell, Jl16, which lacks ZAP-70 and Syk to define the mechanism by which Cbl inhibits T cell signaling. They will introduce mutant forms of Cbl into c-Cbl-/- mice to define its role in vivo. III. The role of SLAP and TSAD in T cell signaling. Usin2 Cbl-N as bait in the modified yeast two hybrid system they have isolated CDNA clones encoding two adapter proteins, SLAP and TSAD. They propose to study their role in T cell signaling.
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