title: GEP100-Arf6-AMAP1-cortactin pathway frequently used in cancer invasion is activated by VEGFR2 to promote angiogenesis.
abstract: Angiogenesis and cancer invasiveness greatly contribute to cancer malignancy.Arf6 and its effector, AMAP1, are frequently overexpressed in breast cancer, and constitute a central pathway to induce the invasion and metastasis. In this pathway, Arf6 is activated by EGFR via GEP100. Arf6 is highly expressed also in human umbilical vein endothelial cells (HUVECs) and is implicated in angiogenesis. Here, we found that HUVECs also highly express AMAP1, and that vascular endothelial growth factor receptor-2 (VEGFR2) recruits GEP100 to activate Arf6. AMAP1 functions by binding to cortactin in cancer invasion and metastasis. We demonstrate that the same GEP100-Arf6-AMAP1-cortactin pathway is essential for angiogenesis activities, including cell migration and tubular formation, as well as for the enhancement of cell permeability and VE-cadherin endocytosis of VEGF-stimulated HUVECs. Components of this pathway are highly expressed in pathologic angiogenesis, and blocking of this pathway effectively inhibits VEGF- or tumor-induced angiogenesis and choroidal neovascularization. The GEP100-Arf6-AMAP1-cortactin pathway, activated by receptor tyrosine kinases, appears to be common in angiogenesis and cancer invasion and metastasis, and provides their new therapeutic targets.
authors.affiliation: Department of Molecular Biology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Ari
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Ando
authors.forename: Kosuke
authors.initials: K
authors.lastname: Noda
authors.forename: Eiji
authors.initials: E
authors.lastname: Ogawa
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kotani
authors.forename: Mayumi
authors.initials: M
authors.lastname: Hirose
authors.forename: Toshi
authors.initials: T
authors.lastname: Menju
authors.forename: Masaki
authors.initials: M
authors.lastname: Morishige
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Manabe
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Toda
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
authors.forename: Hisataka
authors.initials: H
authors.lastname: Sabe
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000089982:ADP-Ribosylation Factor 6; C117891:ASAP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C495868:CTTN protein, human; D051356:Cortactin; D020662:Guanine Nucleotide Exchange Factors; C504483:IQSEC1 protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse