The goal of the proposed studies will be to understand the regulation of the small GTPases, Rho, Rac, and Cdc42 by receptor tyrosine kinases and by integrins.
One aim of these studies will be to use assays that have been developed by the applicant and others for the cellular activation of Rho, Rac, and Cdc42 to delineate the contributions of integrins and growth factors to the function of these small GTPases.
A second aim will be to identify the guanine nucleotide exchange factors that are responsible for the integrin dependent activation of these GTPases, with a particular emphasis being the Vav2 protein.
The third aim will involve studies of the effects of the phosphatidylinositol 4 phosphate 5 kinase (PIP 5 kinase) on the actin cytoskeleton.
This aim will extend the important discovery made by the applicant's laboratory regarding the ability of Rho to stimulate the PIP 5 kinase. Taking advantage of the fact that members of this kinase family have been cloned, the applicant proposes to identify the PIP 5 kinase that binds to Rho and/or Rac and thereby identify small regions of the kinase(s) responsible for these interactions. The idea is to use these fragments as competitive inhibitors to determine whether the blockade of the activation of the PIP 5 kinase by Rho and/or Rac inhibits specific effects by these GTPases on the actin cytoskeleton.
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