KIF13B regulates angiogenesis through golgi-plasma membrane trafficking of VEGFR2

Abstract

Although the trafficking of newly synthesized VEGFR2 to the plasma membrane is a key determinant of angiogenesis, the molecular mechanisms of Golgi to plasma membrane trafficking are unknown. Here, we have identified a key role of the kinesin family plus-end molecular motor KIF13B in delivering VEGFR2 cargo from the Golgi to the endothelial cell surface. KIF13B is shown to interact directly with VEGFR2 on microtubules. We also observed that overexpression of truncated versions of KIF13B containing the binding domains that interact with VEGFR2 inhibited VEGF-induced capillary tube formation. KIF13B depletion prevented VEGFmediated endothelial migration, capillary tube formation and neovascularization in mice. Impairment in trafficking induced by knockdown of KIF13B shunted VEGFR2 towards the lysosomal degradation pathway. Thus, KIF13B is an essential molecular motor required for the trafficking of VEGFR2 from the Golgi, and its delivery to the endothelial cell surface mediates angiogenesis.

The Golgi apparatus in neurorestoration

“…Meanwhile, lack of YAP/TAZ results in impaired Golgi-to-plasma membrane trafficking of VEGFR2 [63]. The kinesin-3 protein KIF13B can bind to VEGFR2 at the Golgi apparatus and initiate its trafficking to the endothelial cell surface [64]. Although previous studies confirmed that the above molecules contribute to VEGFR2 trafficking from the Golgi apparatus, the associations among syntaxin 6, Myo1c, YAP/TAZ, and KIF13B warrant further exploration.…”

Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins

“…Based on Refs. . (B) Live fluorescence image of a ciliated hTERT ‐ RPE 1 cell coexpressing the ciliary membrane marker Tag RFP ‐T‐ RAB 8 (red) and GFP ‐ KIF 13B (green).…”

“…Similarly, KIF13B also binds the MAGUKs DLG4, PALS1 and CARD11 . Other reported binding partners or cargoes of KIF13B include CENTA1 , a phosphatidylinositol 3,4,5‐triphosphate (PIP3)‐binding protein that functions as a GTPase activating protein (GAP) for ARF6 ; the endothelial cell RTK VEGFR2 and neuronal TRPV1 channels .…”

“…Similarly, KIF13B also binds the MAGUKs DLG4, PALS1 [299] and CARD11 [300]. Other reported binding partners or cargoes of KIF13B include CENTA1 [301,302], a phosphatidylinositol 3,4,5-triphosphate (PIP3)-binding protein that functions as a GTPase activating protein (GAP) for ARF6 [303]; the endothelial cell RTK VEGFR2 [304] and neuronal TRPV1 channels [305]. A recent study using conditional Kif13b knockout mice showed how KIF13B through its interaction with DLG1 affects myelination positively in the peripheral nervous system but negatively in the central nervous system [306].…”

Kinesins in cell migration

“…The exposure of the receptor at the endothelial cell surface is required for VEGF-induced endothelial cell migration [52]. In vascular smooth muscle cells, in response to vascular endothelial growth factor (VEGF) stimulation, the kinesin-3 KIF13B transports vesicles containing newly synthesized VEGF receptor 2 (VEGFR2) from the Golgi to the plasma membrane.…”