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

Shin S, Wolgamott L, Yoon SO. Regulation of endothelial cell morphogenesis by the protein kinase d (PKD)/glycogen synthase kinase 3 (GSK3)beta pathway. Am J Physiol Cell Physiol 303: C743-C756, 2012. First published August 1, 2012; doi:10.1152/ajpcell.00442.2011.-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 3 beta (GSK3 beta). Further mechanistic studies revealed that GSK3 beta activity is regulated by protein kinase D (PKD). PKD inhibited GSK3 beta activity, which was required for collagen I-induced endothelial tube morphogenesis. We also found that GSK3 beta regulated trafficking of integrin alpha(2)beta(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 GSK3 beta activity and integrin alpha(2)beta(1) trafficking.