PUBLICATION
VEGF Receptor 2 Endocytic Trafficking Regulates Arterial Morphogenesis
- Authors
- Lanahan, A.A., Hermans, K., Claes, F., Kerley-Hamilton, J.S., Zhuang, Z.W., Giordano, F.J., Carmeliet, P., and Simons, M.
- ID
- ZDB-PUB-100504-20
- 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
Citation
Lanahan, A.A., Hermans, K., Claes, F., Kerley-Hamilton, J.S., Zhuang, Z.W., Giordano, F.J., Carmeliet, P., and Simons, M. (2010) VEGF Receptor 2 Endocytic Trafficking Regulates Arterial Morphogenesis. Developmental Cell. 18(5):713-724.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping