Protein Kinase D Regulates Kinesin-Mediated VEGFR2 Trafficking and Influences Retinal Endothelial Permeability.

Vascular endothelial growth factor (VEGF) induces angiogenesis and vascular leakage by binding to cell surface receptor VEGFR2. KIF13B, a kinesin 3 family cellular motor, regulates VEGF/VEGFR2 signaling by bringing VEGFR2 to the cell surface. Regulating the trafficking of VEGFR2 could be a potential therapeutic target in pathogenesis originating from abnormal angiogenesis. However, the regulation mechanism of VEGFR2 trafficking is not fully understood. Here, we show that protein kinase D (PKD) phosphorylates KIF13B. The phosphorylation of KIF13B by PKD is required for KIF13B-VEGFR2 interaction and KIF13B-microtubule interaction. Live cell imaging using VEGFR2-mCherry revealed that the PKD inhibitor reduced the mean speed and total distance of VEGFR2 vesicular trafficking. Finally, inhibition of PKD also mitigated VEGF-induced permeability measured by trans-endothelial electrical resistance (TEER). Our results demonstrate how VEGFR2 trafficking is regulated by the phosphorylation of kinesin motor KIF13B by protein kinase PKD. We anticipate that elucidating the underlying mechanism of VEGFR2 trafficking can help progress the therapy development of the target diseases related to abnormal angiogenesis.