Reversible tyrosine phosphorylation, a major biochemical event in cell regulation, is controlled by the opposing activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). However, relatively little is known about the mechanism for regulation and functions of PTPs, as compared to the extensive attention received for PTKs. The goal of this project is to determine the role of Shp-2, a PTP with two src-homology 2 (SH2) domains, in intracellular signal transduction. Work from this laboratory and others implicates the involvement of Shp-2 in different signaling pathways as a positive or a negative regulator in the control of cell growth, differentiation, migration and death. In particular, Shp-2 acts to promote growth factor stimulation of extracellular signal regulated kinase (ERK) activity. However, it remains a mystery how a PTP can act positively downstream of a receptor PTK to enhance the induction of ERK activity. Our most recent data present a fresh view that Shp-2 works in concert with Gab1 scaffold protein in a multimeric protein complex, in promoting the activation of the Ras-Raf-MEK-ERK cascade by epidermal growth factor. In this competitive renewal of the previously funded R29 grant, we propose to determine the biochemical basis for Shp-2 function in Ras-ERK activation by identifying its specific substrate(s). We will further investigate the physiological role of Shp-2 in cytoplasmic signaling, particularly in the modulation of information flow along the Ras pathway, and we will also determine the phosphatase-dependent and independent activities of the Shp-2 protein. Finally, we will define the biological function of Shp-2 in different cell types. Results from this study will allow us understand better how PTPs are regulated and how PTP activities are executed during intracellular signal relay in general.
