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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053660-09
Application #
6603827
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Anderson, Richard A
Project Start
1996-03-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
9
Fiscal Year
2003
Total Cost
$380,250
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Sun, Yingqing; Yuan, Jing; Liu, Houqi et al. (2004) Role of Gab1 in UV-induced c-Jun NH2-terminal kinase activation and cell apoptosis. Mol Cell Biol 24:1531-9
Zhang, Eric E; Chapeau, Emilie; Hagihara, Kazuki et al. (2004) Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc Natl Acad Sci U S A 101:16064-9
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Zhao, Chunmei; Ma, Hong; Bossy-Wetzel, Ella et al. (2003) GC-GAP, a Rho family GTPase-activating protein that interacts with signaling adapters Gab1 and Gab2. J Biol Chem 278:34641-53