The Shc gene encodes three proteins that are widely expressed and that contribute to signal transduction by a wide variety of protein-tyrosine kinases. Both cytoplasmic and receptor protein-tyrosine kinases can become oncogenically activated and Shc is highly tyrosine-phosphorylated in cells that express oncogenically activated protein-tyrosine kinases. Shc proteins lack catalytic activity and are thought to function as a scaffold for protein-protein interactions. Two phosphotyrosine-binding modules and several tyrosine phosphorylation sites enable Shc to mediate several protein-protein interactions at the same time. Shc becomes tyrosine phosphorylated upon association with activated growth factor receptors. Tyrosine phosphorylated Shc associates with the Grb2-Sos complex and is thought to play a role in Ras activation. However, Shc's precise contribution to Ras activation remains poorly understood. It also remains unclear whether Shc performs functions independent of Ras. Their long-term goal is to understand Shc's function during normal and malignant signal transduction. To reach that goal, they propose to characterize the signaling abilities of a collection of Shc mutants in Shc-deficient cells. In addition, they will determine the differences in signaling between Shc and Grb2 following growth factor receptor activation and they propose to purify a Shc-binding protein from Src-transformed fibroblasts.
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