The overall goal is to elucidate mechanisms of signal transduction through growth factor receptors. Previous results showed that stimulation of the platelet derived growth factor (PDGF) receptor with PDGF triggers the physical binding of a number of cell proteins to the receptor. Two of these proteins are phosphatidylinositol (PI) 3 kinase and the Ras GTPase activator protein (GAP). Mapping of tyrosine phosphorylation sites in the PDGF receptor, mutagenesis, and in vitro biochemical studies have provided evidence that binding of GAP and PI3 kinase involves receptor phosphorylation, activated by PDGF. These results lead to the hypothesis that binding and phosphorylation of PI3 kinase, GAP and the other cell proteins by the PDGF receptor is involved in initiating signalling events within the cells, culminating in a mitogenic response. The work will be extended in three directions: (1) Investigation of other sequences in the PDGF receptor, besides the identified phosphorylation sites, that are important for binding reactions. The results should contribute to the design of molecules that may inhibit the binding and phosphorylation reactions, and may inhibit signal transduction through the PDGF receptor. (2) Test whether results obtained with the PDGF receptor extend to another receptor tyrosine kinase, Kit, a protein of general interest because of its role in hematopoiesis. (3) Perform experiments with GAP to try to understand how its binding to the receptor occurs and how binding and phosphorylation of GAP may be involved in signal transduction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA054786-04
Application #
2096152
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1991-09-01
Project End
1995-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Chantry, D; Vojtek, A; Kashishian, A et al. (1997) p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem 272:19236-41

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