VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis.
VEGF is the key growth factor regulating arterial morphogenesis. However, molecular events involved in this process have not been elucidated. Synectin null mice demonstrate impaired VEGF signaling and a marked reduction in arterial morphogenesis. Here, we show that this occurs due to delayed trafficking of VEGFR2-containing endosomes that exposes internalized VEGFR2 to selective dephosphorylation by PTP1b on Y(1175) site. Synectin involvement in VEGFR2 intracellular trafficking requires myosin-VI, and myosin-VI knockout in mice or knockdown in zebrafish phenocopy the synectin null phenotype. Silencing of PTP1b restores VEGFR2 activation and significantly recovers arterial morphogenesis in myosin-VI(-/-) knockdown zebrafish and synectin(-/-) mice. We conclude that activation of the VEGF-mediated arterial morphogenesis cascade requires phosphorylation of the VEGFR2 Y(1175) site that is dependent on trafficking of internalized VEGFR2 away from the plasma membrane via a synectin-myosin-VI complex. This key event in VEGF signaling occurs at an intracellular site and is regulated by a novel endosomal trafficking-dependent process.
Lanahan
Anthony A
AA
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Hermans
Karlien
K
Claes
Filip
F
Kerley-Hamilton
Joanna S
JS
Zhuang
Zhen W
ZW
Giordano
Frank J
FJ
Carmeliet
Peter
P
Simons
Michael
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001158:Arteries / Q000196:embryology* / Q000254:growth & development; D002352:Carrier Proteins / Q000235:genetics; D002462:Cell Membrane / Q000502:physiology; D004705:Endocytosis; D004730:Endothelium, Vascular / Q000196:embryology / Q000502:physiology*; D020868:Gene Silencing; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009479:Neuropeptides / Q000172:deficiency* / Q000235:genetics; D010766:Phosphorylation; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*; D015027:Zebrafish
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C115271:Gipc1 protein, mouse; D009479:Neuropeptides; D042461:Vascular Endothelial Growth Factor A; C089785:myosin VI; D040301:Vascular Endothelial Growth Factor Receptor-2; D018995:Myosin Heavy Chains