KDR stimulates endothelial cell migration through heterotrimeric G protein Gq/11-mediated activation of a small GTPase RhoA.

Content Provider	Semantic Scholar
Author	Zeng, Huiyan Zhao, Dezheng Mukhopadhyay, Debabrata
Copyright Year	2002
Abstract	Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) functions by activating two receptor tyrosine kinases, Flt-1 (VEGFR-1) and KDR (VEGFR-2), both of which are selectively expressed on the primary vascular endothelium. KDR is responsible for VPF/VEGF-stimulated endothelial cell (EC) proliferation and migration, whereas Flt-1 down-modulates KDR-mediated EC proliferation. Flt-1 mediates down-regulation of EC proliferation through pertussis toxin-sensitive G proteins, betagamma subunits, small GTPase CDC42, and partly by Rac-1. However, the molecular mechanism by which KDR mediates EC migration is not clear yet. Here we show for the first time that activation of RhoA and Rac1 is fully and partially required for KDR-mediated human umbilical vein endothelial cell (HUVEC) migration, respectively, and that CDC42, however, is not involved. Furthermore, overexpression of the RhoA dominant negative mutant RhoA-19N does not affect VPF/VEGF-stimulated KDR phosphorylation, intracellular Ca(2+) mobilization, and mitogen-activated protein kinase phosphorylation. Utilizing the receptor chimeras (EGDR and EGLT) in which the extracellular domain of the epidermal growth factor receptor (EGFR) was fused to the transmembrane domain and the intracellular domains of KDR and Flt-1, respectively, we demonstrate that RhoA activation is mediated by EGDR, not by EGLT, and that EGDR mediates activation of Rac1, not CDC42. Furthermore, the EGDR-mediated RhoA and Rac1 activation is regulated by G proteins Gq/11, Gbetagamma, and phospholipase C independent of phosphatidylinositol 3-kinase and intracellular Ca(2+) mobilization. Interestingly, the RhoA activation can be partially inhibited by overexpression of Rac1-17N, but overexpression of RhoA-19N has no effect on Rac1 activation. Finally, Gq/11 and Gbetagamma subunits are also required for VPF/VEGF-stimulated HUVEC migration. Taken together, our results indicate that KDR stimulates endothelial cell migration through a heterotrimeric G protein Gq/11 and Gbetagamma-mediated RhoA pathway.
Starting Page	294
Ending Page	301
Page Count	8
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://www.jbc.org/content/early/2002/09/19/jbc.M206133200.full.pdf
PubMed reference number	12244099v1
Volume Number	277
Issue Number	48
Journal	The Journal of biological chemistry
Language	English
Access Restriction	Open
Subject Keyword	1-Phosphatidylinositol 3-Kinase Chimera organism Dominant-Negative Mutation Down-Regulation Endothelial Cells Endothelial Growth Factors Endothelium, Vascular Growth Factor Receptors Guanosine Triphosphate Phosphohydrolases Hippocampus (Brain) Migration, Cell Mitogen-Activated Protein Kinases Mitogens Pertussis Toxin Phospholipase RAC1 gene Receptor Protein-Tyrosine Kinases Tyrosine Umbilical vein Umbilicus (Anatomy) Vascular Endothelial Growth Factor Receptor 2, human Vascular Endothelial Growth Factor Receptor-1 rhoA GTP-Binding Protein
Content Type	Text
Resource Type	Article