Regulation of endothelial cell morphogenesis by the protein kinase D (PKD)/glycogen synthase kinase 3 (GSK3)ß pathway.

ABSTRACT

Vascular morphogenesis is a key process for development, reproduction, and pathogenesis. Thus understanding the mechanisms of this process is of pathophysiological importance. Despite the fact that collagen I is the most abundant and potent promorphogenic molecule known, the molecular mechanisms by which this protein regulates endothelial cell tube morphogenesis are still unclear. Here we provide strong evidence that collagen I induces tube morphogenesis by inhibiting glycogen synthase kinase 3ß (GSK3ß). Further mechanistic studies revealed that GSK3ß activity is regulated by protein kinase D (PKD). PKD inhibited GSK3ß activity, which was required for collagen I-induced endothelial tube morphogenesis. We also found that GSK3ß regulated trafficking of integrin α(2)ß(1) in a Rab11-dependent manner. Taken together, our studies highlight the important role of PKD in the regulation of collagen I-induced vascular morphogenesis and show that it is mediated by the modulation of GSK3ß activity and integrin α(2)ß(1) trafficking.