Antiangiogenic Therapeutic Potential of Peptides Derived from the Molecular Motor KIF13B that Transports VEGFR2 to Plasmalemma in Endothelial Cells

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR2) localized on the surface of endothelial cells (ECs) is a key determinant of the magnitude and duration of angiogenesis induced by vascular endothelial growth factor (VEGF). The kinesin family plus-end motor KIF13B transports VEGFR2 to the EC surface, and as such, specific inhibition of polarized VEGFR2 trafficking prevents angiogenesis. We designed a series of bioactive peptides based on deep analysis of VEGFR2-binding domain of KIF13B that compete specifically with VEGFR2 binding of KIF13B and thereby potently inhibit angiogenesis. Expression of these peptides by lentivirus prevents VEGF-induced capillary network formation in Matrigel plugs and neovascularization in vivo. A synthetic soluble, cell-permeable, 23-amino acid peptide termed kinesin-derived angiogenesis inhibitor (KAI) not only prevents interaction of VEGFR2 with KIF13B but also trafficking of VEGFR2 in the plus-end direction to the EC plasmalemma. Kinesin-derived angiogenesis inhibitor also inhibits VEGF-induced EC migration and tumor growth in human lung carcinoma xenografted in immunodeficient mice. Thus, we describe a novel class of peptides derived from the site of interaction of KIF13B with VEGFR2 that inhibit VEGFR2 trafficking and thereby starve cancer of blood supply.

Isomangiferin, a Novel Potent Vascular Endothelial Growth Factor Receptor 2 Kinase Inhibitor, Suppresses Breast Cancer Growth, Metastasis and Angiogenesis

“…The VEGFR-2 kinase assay was performed to investigate whether isomangiferin is a potential VEGFR-2 inhibitor for breast cancer therapy. SU5408, the classical cell-permeable inhibitor of VEGFR-2 kinase, had an IC 50 of 72.42 nM, which was consistent with previous reports [ 22 ]. Isomangiferin also inhibited VEGFR-2 kinase activity with an IC 50 of 820.67 nM ( Supplementary Table 1 , available online).…”

Palmitoylation of δ-catenin promotes kinesin-mediated membrane trafficking of Na v 1.6 in sensory neurons to promote neuropathic pain

“…Our data also suggest a critical role for the motor protein KIF3A in this mechanism. Previous studies demonstrated that various motor proteins of the KIFs exhibit differential function to form intracellular cargo apparatus and regulate protein trafficking, including that of the vascular endothelial growth factor receptor 2 in endothelial cells (34), the glutamate receptor in the ventral nerve cord of Caenorhabditis elegans (worms) (35), and voltage-gated potassium (K v ) channels in mouse hippocampal neurons (36). Specifically, KIF3A mediates the polarized trafficking of K v 1.2 channel to axons (37,38) and the transport of vesicles containing -catenin toward the plasma membrane in the developing neuroepithelium (39).…”

ATF4 selectively regulates heat nociception and contributes to kinesin-mediated TRPM3 trafficking

“…Previous evidence has demonstrated that various subtypes of KIFs exhibit differential functions to form intracellular cargo apparatuses and regulate protein trafficking 13 . For example, upon binding with its target protein, KIF13B promotes the membrane translocation of vascular endothelial growth factor receptor 2 to the surface of endothelial cells 49 . Kinesin KIF13 also serves as a key regulator of anterograde glutamate receptor trafficking in the ventral nerve cord of Caenorhabditis elegans 50 .…”