Simultaneous EGF receptor and thrombin receptor activation synergistically induces pro‐angiogenic immediate early genes in endothelial cells

Abstract

Signaling interactions between G‐protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) function in a number of pathophysiological processes, including cellular proliferation, invasion, and acquired resistance to chemotherapeutic agents. Here, we examine the consequences of simultaneous EGF receptor (EGFR) and thrombin receptor (protease‐activated receptor‐1, PAR‐1) activation in human endothelial cells (EC). We observe that concurrent EGFR and PAR‐1 activation causes the synergistic induction of at least six pro‐angiogenic immediate early genes (IEGs), including the transcription factor early growth response‐1 (EGR‐1). In contrast to other cell types, matrix metalloprotease‐mediated transactivation of EGFR by PAR‐1 does not appear to be a major signaling mechanism in EC. Instead, an intracellular mechanism involving glycogen synthase kinase‐3 (GSK‐3α/β) mediates receptor crosstalk by integrating signals from EGFR and PAR‐1. These findings provide a mechanistic basis for how cells integrate information of concurrent receptor activation to enhance EGR‐1 expression in EC.This study was supported by grant HL29582 from the National Institutes of Health (Dr. DiCorleto).