title: VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis.
abstract: 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.
authors.affiliation: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Lanahan
authors.forename: Karlien
authors.initials: K
authors.lastname: Hermans
authors.forename: Filip
authors.initials: F
authors.lastname: Claes
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Kerley-Hamilton
authors.forename: Zhen W
authors.initials: ZW
authors.lastname: Zhuang
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Giordano
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
mesh_terms: 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
chemical_list: 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