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
Keywords: CELLBIO, DEVBIO
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
FIGURES
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.
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