This grant seeks to better understand the regulatory mechanisms of G protein regulation of nonreceptor tyrosine kinases, which comprise two major groups of cellular proteins playing important roles in signal transduction. Our laboratory has genetically demonstrated that Gq- and Gi-coupled receptors activate mitogen-activated protein kinase pathways requiring nonreceptor tyrosine kinases. Gs-coupled receptors initiate a tyrosine kinase-dependent, but cAMP-PKA independent, apoptotic pathway in thymocytes. To provide a biochemical mechanism for the dependence of G protein signals on tyrosine kinases in these physiological processes, we have shown biochemically that: 1) purified Gaq subunits can directly stimulate the kinase activity of Bruton's tyrosine kinase (Btk); 2) purified Ga12 subunits can directly stimulate the kinase activity of Btk, and a Ras-GAP (GTPase-activating-protein) through a conserved PHJBM domain present on both Btk and Ras-GAP; 3) purified Gas and Gai subunits can directly stimulate the kinase activity of another tyrosine kinase, Src. We plan to characterize these regulatory mechanisms by which G proteins regulate these tyrosine kinases in order to better understand G protein signaling and the biological functions of G proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014563-06
Application #
6509823
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Bellino, Francis
Project Start
1996-09-26
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
6
Fiscal Year
2002
Total Cost
$381,375
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Physiology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
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