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

被引：51

作者：

Hashimoto, Ari ^{[1
,2
]}

Hashimoto, Shigeru ^{[1
,2
]}

Ando, Ryo ^{[3
]}

Noda, Kosuke ^{[3
]}

Ogawa, Eiji ^{[2
,4
,5
]}

Kotani, Hirokazu ^{[5
,6
]}

Hirose, Mayumi ^{[7
]}

Menju, Toshi ^{[2
,5
]}

Morishige, Masaki ^{[2
,8
]}

Manabe, Toshiaki ^{[4
]}

Toda, Yoshinobu ^{[6
]}

Ishida, Susumu ^{[3
]}

Sabe, Hisataka ^{[1
,2
]}

机构：

[1] Hokkaido Univ, Dept Mol Biol, Grad Sch Med, Sapporo, Hokkaido, Japan

[2] Osaka Biosci Inst, Dept Mol Biol, Suita, Osaka 565, Japan

[3] Hokkaido Univ, Grad Sch Med, Dept Ophthalmol, Sapporo, Hokkaido, Japan

[4] Kyoto Univ, Fac Med, Lab Diagnost Pathol, Kyoto, Japan

[5] Kyoto Univ, Fac Med, Dept Thorac Surg, Kyoto, Japan

[6] Kyoto Univ, Grad Sch Med, Ctr Anat Studies, Kyoto, Japan

[7] Osaka Univ, Inst Prot Res, Lab Supramol Crystallog, Osaka, Japan

[8] Oita Univ, Sch Med, Dept Neurosurg, Oita 87011, Japan

来源：

PLOS ONE | 2011年 / 6卷 / 08期

关键词：

VASCULAR ENDOTHELIAL-CADHERIN; IN-VIVO; CHOROIDAL NEOVASCULARIZATION; SIGNALING PROMOTES; DRUG-RESISTANCE; VE-CADHERIN; ARF6; GROWTH; CELLS; PERMEABILITY;

D O I：

10.1371/journal.pone.0023359

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

共 49 条

[21] Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition [J].