This application proposes studies on the role of the small GTPase R-ras in regulating integrin activity in cells. We recently discovered that R-ras regulates the ability of integrins to mediate cell adhesion. Given the central role of integrin-mediated cell adhesion in a variety of cellular functions and pathological conditions, it is important to elucidate the significance and molecular mechanisms Of this new regulatory pathway. Results from this laboratory have revealed several potential molecular links between R-ras and integrins, providing clues to the workings of the integrin regulating pathway: 1) R-ras binds to filamin, which also binds to integrin cytoplasmic domains. It is possible that filamin directly affects integrin activity, and R-ras could regulate filamin's ability to do so. 2) R-ras binds to the adapter protein Nck through an SH3 domain interaction. This interaction may bring R-ras into a subcellular localization suitable for integrin regulation. 3) R-ras is phosphorylated on tyrosine in cells that have been transfected with an activated Eph receptor tyrosine kinase, EphB2. The EphB2 transfection causes loss of cell adhesion, as does transfection of an R-ras variant designed to mimic phoshorylated R-ras. Thus, the R-ras-integrin pathway may be controlled by kinases within the cell. In this proposal, we will elucidate further the R-ras-integrin regulatory pathway. Protein interaction analyses and transfection of cells with various mutated forms of R-ras, filamin and Nck will be the main methods to be used. These studies will provide important information on how cells regulate their adhesion in response to external signals. They may also explain how malignant cells down-regulate their adhesiveness and increase their ability to migrate and invade. As the R-ras interactions we have uncovered are novel for the Ras protein superfamily, new information on this important family of cellular regulators and oncoproteins will ensue.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079984-03
Application #
6342130
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Mohla, Suresh
Project Start
1999-01-11
Project End
2002-12-31
Budget Start
2001-01-17
Budget End
2001-12-31
Support Year
3
Fiscal Year
2001
Total Cost
$273,254
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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