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Anti‐angiogenic Peptide Derived from Kinesin KIF13B Inhibits Trafficking of VEGFR2 to Endothelial Cell surface
Author(s) -
Yamada Kaori,
Malik Asrar B.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.990.8
Subject(s) - angiogenesis , microbiology and biotechnology , kinesin , chemistry , peptide , phosphorylation , endothelial stem cell , neovascularization , in vitro , cancer research , microtubule , biology , biochemistry
Trafficking of VEGFR2 to the endothelial cell (EC) surface is required for VEGF‐induced angiogenesis. We found that the kinesin‐family plus‐end motor KIF13B transports VEGFR2 to the EC surface. VEGF induced phosphorylation on KIF13B, and activated KIF13B by increasing binding of KIF13B to VEGFR2, and KIF13B‐VEGFR2 complex to microtubule tracks. KIF13B depletion shunted VEGFR2 towards the lysosomal degradation pathway. KIF13B depletion also prevented VEGF‐mediated endothelial migration, capillary tube formation, and neo‐vascularization in mice, suggesting blockade of trafficking as a potential anti‐angiogenesis strategy. We developed a bioactive peptide based on VEGFR2‐binding domain of KIF13B, which competes specifically with VEGFR2‐binding of KIF13B, and thereby inhibits angiogenesis. The peptide termed a kinesin‐derived angiogenesis inhibitor (KAI) is a cell‐permeable, water‐soluble peptide, inhibiting EC migration, capillary network formation, and EC sprouting, in vitro. KAI also inhibited 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. Support or Funding Information This work was supported by PPG HL060678, R01 HL045638, P01 HL077806, R01 HL090152, R01 HL118068, and R01 HL125350 to ABM, R56 HL128342 and 13SDG14680053 to KHY.