title: 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.
authors.affiliation: Department of Pharmacology, The University of Illinois College of Medicine, Chicago, Illinois; Center of Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, Illinois. Electronic address: horiguch@uic.edu.
authors.forename: Kaori H
authors.initials: KH
authors.lastname: Yamada
authors.affiliation: Department of Pharmacology, The University of Illinois College of Medicine, Chicago, Illinois; Center of Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, Illinois.
authors.forename: Hojin
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, The University of Illinois College of Medicine, Chicago, Illinois; Center of Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, Illinois. Electronic address: abmalik@uic.edu.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D016547:Kinesins / Q000737:chemistry* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D020409:Molecular Motor Proteins / Q000737:chemistry*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D000072417:Protein Domains; D021381:Protein Transport; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D020409:Molecular Motor Proteins; D010455:Peptides; D040301:Vascular Endothelial Growth Factor Receptor-2; C513406:KIF13B protein, human; D016547:Kinesins