Angiotensin II is critical in the control of blood pressure through its interactions with the seven transmembrane AT1 receptor. During the previous grant period, my group studied early signaling events initiated by this receptor. Specifically, we focused on understanding the biochemistry and the functional significance of angiotensin II initiated intracellular tyrosine signaling cascades, particularly the Jak-STAT pathway. The highlights of the previous grant period are: 1) the identification of the AT1 receptor motif 319YIPP as critical for angiotensin II mediated Jak2 activation, 2) the identification of the Jak2 protein motif 231YRFRR as critical for Jak2-AT1 receptor association, and perhaps most importantly, 3) the realization that Jak2 acts as both an intracellular kinase and as a phosphotyrosine donor bridge molecule in the assembly of a ligand dependent signaling complex at the AT1 receptor. The 1st and 2nd Specific Aims for the next grant period continue these investigations. The 3rd Specific Aim proposes to study angiotensin II mediated STAT nuclear translocation. It expands a remarkable observation, that angiotensin II activation of the mutant Jak2 receptor 231FAAAA induces STAT I tyro sine phosphorylation, but results in the failure of STAT 1 to translocate into the nucleus. The ultimate goal of this work is to understand the role of angiotensin II stimulated phosphorylation cascades in health and disease.
Showing the most recent 10 out of 44 publications
