[PDF][PDF] VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis
AA Lanahan, K Hermans, F Claes, JS Kerley-Hamilton… - Developmental cell, 2010 - cell.com
AA Lanahan, K Hermans, F Claes, JS Kerley-Hamilton, ZW Zhuang, FJ Giordano…
Developmental cell, 2010•cell.comVEGF 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 …
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 …
Summary
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 Y1175 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 Y1175 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.
cell.com