| The EGF receptor (EGFR) kinase is "transactivated" by a number of stimuli (G-protein receptor activation, UV, H202 and other cell signals)(4). What differentiates this from a typical signal (i.e. EGF) is that it is either ligand- independent or involves proteolytic release of EGF-like ligands from the cell surface. Our recent studies demonstrated that an important class of compounds used for the treatment of type II diabetes (peroxisome proliferators (PPAR) agonists- glitazones), induced EGFR transactivation in rat liver epithelial cells. In addition these compounds caused the rapid activation of the ERK and p38 MAPK's by both EGFR-dependent and independent mechanisms (5). Importantly, these studies suggested that PPAR agonists elicited "non-genomic"events that could influence cellular responses to these compounds. Thus the objectives of this project are to investigate the mechanisms by which glitazones stimulate EGFR "transactivation" and the consequences of MAP kinase activation (or inhibition) on regulating responses to insulin signaling and the development of diabetes. In a related project, we are studying the influence of Zinc on EGFR receptor signaling in human airway epithelial cells (6-8). |