Drugs that inhibit the renin angiotensin system have enormous clinical benefit assessed by reduction in cardiovascular events including stroke and myocardial infarction. The mechanisms by which angiotensin II (AII) mediates harmful effects in the vasculature remains unclear. The intracellular signal mediators activated by AII provide oppommities for new therapies, which is the topic for this renewal of RO1 HL63462. The major goals of the previous grant were to understand how AII couples to tyrosine kinases in the absence of its receptor being a tyrosine kinase. We identified transactivation of the PDGF and EGF receptors as one pathway. We also discovered a novel protein GIT1 (G protein coupled receptor kinase (GRK) interacting protein 1) that is phosphorylated by c-Src in response to All, and binds to PLC-gamma and MEK1. The major hypothesis of this proposal is that GIT1 is a scaffold that organizes signal mediators spatially and temporally to generate specificity and amplification of AII signal transduction.
Three aims are proposed. 1) Elucidate the scaffolding function of GIT1 by defining the specific domains of GIT1 that interact with specific domains of MEK1; 2) Define the components of the AII-stimulated GITl-associated MAP kinase module, focusing on identifying the MEK1 kinase; and 3) Define the biological importance of GIT1 in AII signal transduction by examining changes in AII function in transgenic mice deficient in GIT1 and mice that overexpress dominant negative mutants of GIT1. The proposed studies will provide insight into a novel scaffold protein that should be important both for AII signal transduction and MAP kinase function.
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