This application outlines the research and career planproposed by Dr. Peter P. Sayeski concerning the mechanisms by which the non-receptor tyrosine kinase, Jak2, binds the angiotensin II type AT1 receptor and subsequently mediates the angiotensin 11-dependent nuclear accumulation of Stat 1. Angiotensin II is the effector molecule of the renin-angiotensin-aldosterone system which maintains hemodynamic and electrolyte homeostasis. The binding of angiotensin II to the AT1 receptor initiates tyrosine phosphorylation signaling cascades that end with increased vasoconstrictive and mitogenic growth responses. The pharmacological inhibition of this system has been advantageous in a variety of common diseases including hypertension, heart failure and diabetic nephropathy. In response to angiotensin II, Jak2 forms a physical co-association with the AT1 receptor. Previous work by Dr. Sayeski and others suggest that Jak2 plays a critical role in mediating these tyrosine phosphorylation growth responses. The idea that the growth promoting effects of angiotensin II are dependent on Jak2 tyrosine kinase and not heterotrimeric G proteins is a novel concept. Thus, defining the proximal biochemical and cellular events that allow Jak2 to bind the AT1 receptor and subsequently facilitate the translocation of Stat 1 into the nucleus where it modulates gene transcription, will greatly advance this concept. Furthermore, the results of these experiments will be of great interest to the signal transduction community as a whole, at it addresses the fundamental question of how cell surface receptors activate the JakI STAT signaling pathway. The proposed experiments in this application are based on preliminary data using newly created recombinant DNA molecules and novel cell lines. Completion of the proposed Specific Aims will provide a better understanding of (1) the biochemical nature of the AT1/Jak2 physical co-association and (2) the specific role of Jak2 in mediating the angiotensin TI-dependent nuclear accumulation of Stat 1. The research will be performed at the University of Florida, which contains state of the art facilities and programs that foster the development of young scientific investigators.
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