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

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 3β (GSK3β). Further mechanistic studies revealed that GSK3β activity is regulated by protein kinase D (PKD). PKD inhibited GSK3β activity, which was required for collagen I-induced endothelial tube morphogenesis. We also found that GSK3β regulated trafficking of integrin α(2)β(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 GSK3β activity and integrin α(2)β(1) trafficking.