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 #
5R01AG014563-08
Application #
6760103
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Sierra, Felipe
Project Start
1996-09-26
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
8
Fiscal Year
2004
Total Cost
$381,375
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Physiology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Guo, Dagang; Tan, Ying-cai; Wang, Dawei et al. (2007) A Rac-cGMP signaling pathway. Cell 128:341-55
Madhusoodanan, K S; Guo, Dagang; McGarrigle, Deirdre K et al. (2006) Csk mediates G-protein-coupled lysophosphatidic acid receptor-induced inhibition of membrane-bound guanylyl cyclase activity. Biochemistry 45:3396-403
McGarrigle, Deirdre; Shan, Dandan; Yang, Shengyu et al. (2006) Role of tyrosine kinase Csk in G protein-coupled receptor- and receptor tyrosine kinase-induced fibroblast cell migration. J Biol Chem 281:10583-8
Ma, Yong Chao; Huang, Xin Yun (2002) Novel signaling pathway through the beta-adrenergic receptor. Trends Cardiovasc Med 12:46-9
Zheng, B; Ma, Y C; Ostrom, R S et al. (2001) RGS-PX1, a GAP for GalphaS and sorting nexin in vesicular trafficking. Science 294:1939-42
Cvejic, S; Jiang, Y; Huang, X (2000) Signaling of G(alpha)(12) family of G proteins through a tyrosine kinase and a Ras-GAP. Trends Cardiovasc Med 10:160-5
Ma, Y C; Huang, J; Ali, S et al. (2000) Src tyrosine kinase is a novel direct effector of G proteins. Cell 102:635-46