Abstract

This proposal focuses on the relation between the cell biology (localization,targeting) of trimeric G proteins and their ability to transduce signals. Experiments will: 1) Elucidate key steps in the localization mechanisms that target G protein alpha and beta-gamma subunits to the plasma membrane and determine where and when they become capable of transducing signals from the receptor to the effector. 2) Assess the role of G-alpha palmitoylation, a lipid modification that may serve to retain these subunits at the plasma membranes and determine how these mechanisms modulate G protein mediated signals inintiated by receptor agonists. 3) Identify cellular proteins that associate with G-beta-gamma subunits and mediate cellular proliferation and (potentially) neoplastic transformation via activation of the MAPK/ERK pathway. 4) Define interactions of the G-alpha with three proteins - actin, caveolin and members of the G-alpha-interacting protein (GAIP) family-that may inhibit G protein signaling by interacting with and sequestering G-alpha subunit.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA054427-19
Application #
2871759
Study Section
Molecular Cytology Study Section (CTY)
Program Officer
Spalholz, Barbara A
Project Start
1991-08-01
Project End
2002-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
19
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Wang, Fei; Herzmark, Paul; Weiner, Orion D et al. (2002) Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils. Nat Cell Biol 4:513-8
Servant, G; Weiner, O D; Herzmark, P et al. (2000) Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science 287:1037-40
Fishburn, C S; Pollitt, S K; Bourne, H R (2000) Localization of a peripheral membrane protein: Gbetagamma targets Galpha(Z). Proc Natl Acad Sci U S A 97:1085-90
Neptune, E R; Iiri, T; Bourne, H R (1999) Galphai is not required for chemotaxis mediated by Gi-coupled receptors. J Biol Chem 274:2824-8
Servant, G; Weiner, O D; Neptune, E R et al. (1999) Dynamics of a chemoattractant receptor in living neutrophils during chemotaxis. Mol Biol Cell 10:1163-78
Apanovitch, D M; Iiri, T; Karasawa, T et al. (1998) Second site suppressor mutations of a GTPase-deficient G-protein alpha-subunit. Selective inhibition of Gbeta gamma-mediated signaling. J Biol Chem 273:28597-602
Neptune, E R; Bourne, H R (1997) Receptors induce chemotaxis by releasing the betagamma subunit of Gi, not by activating Gq or Gs. Proc Natl Acad Sci U S A 94:14489-94
Onrust, R; Herzmark, P; Chi, P et al. (1997) Receptor and betagamma binding sites in the alpha subunit of the retinal G protein transducin. Science 275:381-4
Yan, Y; Chi, P P; Bourne, H R (1997) RGS4 inhibits Gq-mediated activation of mitogen-activated protein kinase and phosphoinositide synthesis. J Biol Chem 272:11924-7
Wedegaertner, P B; Bourne, H R; von Zastrow, M (1996) Activation-induced subcellular redistribution of Gs alpha. Mol Biol Cell 7:1225-33

Showing the most recent 10 out of 25 publications