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GEP100-Arf6-AMAP1-Cortactin Pathway Frequently Used in Cancer Invasion Is Activated by VEGFR2 to Promote Angiogenesis

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Title: GEP100-Arf6-AMAP1-Cortactin Pathway Frequently Used in Cancer Invasion Is Activated by VEGFR2 to Promote Angiogenesis
Authors: Hashimoto, Ari Browse this author
Hashimoto, Shigeru Browse this author
Ando, Ryo Browse this author
Noda, Kosuke Browse this author
Ogawa, Eiji Browse this author
Kotani, Hirokazu Browse this author
Hirose, Mayumi Browse this author
Menju, Toshi Browse this author
Morishige, Masaki Browse this author
Manabe, Toshiaki Browse this author
Toda, Yoshinobu Browse this author
Ishida, Susumu Browse this author
Sabe, Hisataka Browse this author →KAKEN DB
Issue Date: 15-Aug-2011
Publisher: Public Library of Science
Journal Title: PLoS One
Volume: 6
Issue: 8
Start Page: e23359
Publisher DOI: 10.1371/journal.pone.0023359
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.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 佐邊 壽孝

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