Abstract

The overall goal of this application is to establish the mechanisms controlling the activity of Dbl-related guanine nucleotide exchange factors, a highly conserved family of GEFs specific for Rho GTPases. The investigator will utilize biochemical and genetic approaches to attain the following five specific aims: 1) To determine whether Src-related kinases can phosphorylate and modulate GEF activity of Dbl-related molecules. 2) To examine the functional role of PH domains of Dbl-related GEFs. 3) To investigate the significance of the interaction of Vav, a Dbl-related GEF, with components of the Ras signal transduction pathways. 4) To examine the structural basis underlying the specificity of recognition of Rho GTPases by Dbl-related GEFs. 5) To identify residues in Dbl-related GEFs which are critical for interaction with Rho GTPases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA050261-13
Application #
6341921
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Program Officer
Spalholz, Barbara A
Project Start
1989-07-01
Project End
2003-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
13
Fiscal Year
2001
Total Cost
$317,843
Indirect Cost

  Institution

Name
University of Southern California
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Wu, Weicheng; Mosteller, Raymond D; Broek, Daniel (2004) Sphingosine kinase protects lipopolysaccharide-activated macrophages from apoptosis. Mol Cell Biol 24:7359-69
Hassanieh, Loubna; Rodriguez, Dorothy; Xu, Jinsong et al. (2003) Generation of a monoclonal antibody to a cryptic site common to both integrin beta1 as well as gelatinase MMP9. Hybrid Hybridomics 22:285-92
Wu, Weicheng; Shu, Xiaodong; Hovsepyan, Harut et al. (2003) VEGF receptor expression and signaling in human bladder tumors. Oncogene 22:3361-70
Shu, Xiaodong; Wu, Weicheng; Mosteller, Raymond D et al. (2002) Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol Cell Biol 22:7758-68
Han, Jaewon; Das, Balaka; Broek, Daniel (2002) In vitro, Vav is a regulated guanine nucleotide dissociation inhibitor for Ras. Immunol Lett 80:1-2
Das, B; Shu, X; Day, G J et al. (2000) Control of intramolecular interactions between the pleckstrin homology and Dbl homology domains of Vav and Sos1 regulates Rac binding. J Biol Chem 275:15074-81
Day, G J; Mosteller, R D; Broek, D (1998) Distinct subclasses of small GTPases interact with guanine nucleotide exchange factors in a similar manner. Mol Cell Biol 18:7444-54
Han, J; Luby-Phelps, K; Das, B et al. (1998) Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science 279:558-60
Park, W; Mosteller, R D; Broek, D (1997) Identification of a dominant-negative mutation in the yeast CDC25 guanine nucleotide exchange factor for Ras. Oncogene 14:831-6
Quilliam, L A; Hisaka, M M; Zhong, S et al. (1996) Involvement of the switch 2 domain of Ras in its interaction with guanine nucleotide exchange factors. J Biol Chem 271:11076-82

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