GEP100-Arf6-AMAP1-cortactin pathway frequently used in cancer invasion is activated by VEGFR2 to promote angiogenesis

Ari Hashimoto; Shigeru Hashimoto; Ryo Ando; Kosuke Noda; Eiji Ogawa; Hirokazu Kotani; Mayumi Hirose; Toshi Menju; Masaki Morishige; Toshiaki Manabe; Yoshinobu Toda; Susumu Ishida; Hisataka Sabe

doi:10.1371/journal.pone.0023359

GEP100-Arf6-AMAP1-cortactin pathway frequently used in cancer invasion is activated by VEGFR2 to promote angiogenesis

PLoS One. 2011;6(8):e23359. doi: 10.1371/journal.pone.0023359. Epub 2011 Aug 15.

Authors

Ari Hashimoto¹, Shigeru Hashimoto, Ryo Ando, Kosuke Noda, Eiji Ogawa, Hirokazu Kotani, Mayumi Hirose, Toshi Menju, Masaki Morishige, Toshiaki Manabe, Yoshinobu Toda, Susumu Ishida, Hisataka Sabe

Affiliation

¹ Department of Molecular Biology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADP-Ribosylation Factor 6
ADP-Ribosylation Factors / genetics
ADP-Ribosylation Factors / metabolism*
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
COS Cells
Cell Line, Tumor
Chlorocebus aethiops
Cortactin / genetics
Cortactin / metabolism*
Female
Guanine Nucleotide Exchange Factors / genetics
Guanine Nucleotide Exchange Factors / metabolism*
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / metabolism
Human Umbilical Vein Endothelial Cells / physiology
Humans
Immunoblotting
Male
Mice
Mice, Inbred C57BL
Mice, Nude
Neoplasm Invasiveness
Neoplasms / blood supply
Neoplasms / metabolism
Neoplasms / pathology
Neovascularization, Pathologic / genetics
Neovascularization, Physiologic / genetics
Protein Binding
RNA Interference
Signal Transduction / drug effects
Vascular Endothelial Growth Factor A / pharmacology
Vascular Endothelial Growth Factor Receptor-2 / genetics
Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

ADP-Ribosylation Factor 6
ASAP1 protein, human
Adaptor Proteins, Signal Transducing
CTTN protein, human
Cortactin
Guanine Nucleotide Exchange Factors
IQSEC1 protein, human
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
ADP-Ribosylation Factors
ARF6 protein, human
Arf6 protein, mouse