VEGF Receptor 2 Endocytic Trafficking Regulates Arterial Morphogenesis

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. [Display omitted] ► Synectin/myosin-VI complex regulates VEGF receptor 2 (VEGFR2) endosome trafficking ► Loss of the complex disrupts activation of VEGFR2 Y 1175 and arterial development ► PTP1b inhibition restores activation of VEGFR2 Y 1175 site and rescues morphogenesis ► VEGF receptor 2 trafficking is required to relieve PTP1b-dependent VEGFR2 inhibition