Abstract 15705: Novel Epsin-VEGFR2 Interactions Facilitated by c-Cbl Ubiquitination of Epsin and VEGFR2 Regulate VEGFR2 Signaling and Physiological and Pathological Angiogenesis

Angiogenesis is the process of developing new vasculature from pre-existing vasculature to ensure adequate oxygen and nutrient delivery to growing or damaged tissues. VEGF is a key pro-angiogenic growth factor that promotes new vessel sprouting via enhanced endothelial cell (EC) survival, proliferation and migration. VEGF signaling is regulated, in part, by the activation and degradation of VEGFR2. We recently reported that ubiquitin-interacting endocytic adaptor protein, epsin, binds ubiquitinated VEGFR2 via its ubiquitin interacting motif (UIM) and is required for degradation and signaling attenuation of activated VEGFR2. However, the molecular mechanism for epsin-dependent regulation of VEGFR2 activity is not understood. In this study, we report that activated VEGFR2 is ubiquitinated by E3 ligase, c-Cbl. Epsin UIM binds to the ubiquitin moieties on VEGFR2 which triggers ubiquitination of epsin by c-Cbl and facilitates the interaction of epsin with a novel ubiquitin-binding surface on VEGFR2. Additional...