Our long-term objective is to understand the signaling mechanisms and functions of heterotrimeric G proteins and G protein-coupled receptors. Recently we have discovered that G protein Gas can directly stimulate the activity of Src-family tyrosine kinases, and that tyrosine kinase Csk plays a critical role in linking signals from G proteins and G protein-coupled receptors to actin cytoskeletal reorganization. Yet, the relative contribution of Src-family tyrosine kinases and adenylyl cyclases to the physiology of Gs in animals is not clear. The mechanism by which Csk relays heterotrimeric G protein signals to Rho GTPases is not defined. In this grant application, we have proposed experiments to answer these questions.
The specific aims are: 1. Cellular physiological studies of Gas regulation of Src. We focus on the role of the Gs-Src link in Gs-coupled f32-admergic receptor desensitization! internalization in cells. 2. Mouse genetic study of the physiological role of Gs-Src signaling. We will use two approaches to examine Gs-Src function in mouse. One is to generate knock-in mice with different Gas mutants. Another is to rescue the Gas-knock-out mice with different Gas mutants to investigate the rescue of specific phenotypes of the Gas knockout mice. 3. Signaling mechanism from G proteins to actin cytoskeletal reorganization. We will test a specific hypothesis that, downstream of Csk, Src and p190 RhoGAP are signal transducers leading to Rho in this G protein pathway. We will extend the cytoskeletal reorganization study in fibroblast cells to clinically relevant breast cancer cell migration. This research is directly related to human health. Mutations of G proteins, G protein-coupled receptors, and tyrosine kinases can lead to many human diseases such as cancers and heart diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Pharmacology A Study Section (PHRA)
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Dunsmore, Sarah
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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