ZFIN ID: ZDB-PUB-100504-20
VEGF Receptor 2 Endocytic Trafficking Regulates Arterial Morphogenesis
Lanahan, A.A., Hermans, K., Claes, F., Kerley-Hamilton, J.S., Zhuang, Z.W., Giordano, F.J., Carmeliet, P., and Simons, M.
Date: 2010
Source: Developmental Cell   18(5): 713-724 (Journal)
Registered Authors: Simons, Michael
MeSH Terms:
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Arteries/embryology*
  • Arteries/growth & development
  • Carrier Proteins/genetics
  • Cell Membrane/physiology
  • Endocytosis
  • Endothelium, Vascular/embryology
  • Endothelium, Vascular/physiology*
  • Gene Silencing
  • Mice
  • Mice, Knockout
  • Morphogenesis/physiology*
  • Myosin Heavy Chains/deficiency
  • Myosin Heavy Chains/genetics
  • Myosin Heavy Chains/physiology
  • Neuropeptides/deficiency*
  • Neuropeptides/genetics
  • Phosphorylation
  • Vascular Endothelial Growth Factor A/physiology
  • Vascular Endothelial Growth Factor Receptor-2/physiology*
  • Zebrafish
PubMed: 20434959 Full text @ Dev. Cell
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.