GEP100-Arf6-AMAP1-cortactin pathway frequently used in cancer invasion is activated by VEGFR2 to promote angiogenesis.
GEP100-Arf6-AMAP1-cortactin pathway frequently used in cancer invasion is activated by VEGFR2 to promote angiogenesis.
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DOI：
10.1371/journal.pone.0023359
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Sabe H
中科院分区：
文献类型：
--
作者：
Hashimoto A;Hashimoto S;Ando R;Noda K;Ogawa E;Kotani H;Hirose M;Menju T;Morishige M;Manabe T;Toda Y;Ishida S;Sabe H
血管生成和肿瘤侵袭性是肿瘤恶性的重要因素。Arf 6及其效应子AMAP 1在乳腺癌中频繁过表达，并构成诱导浸润和转移的中心途径。在该途径中，Arf 6通过GEP 100被EGFR激活。Arf 6也在人脐静脉内皮细胞（HUVEC）中高度表达，并参与血管生成。在这里，我们发现HUVECs也高度表达AMAP 1，并且血管内皮生长因子受体2（VEGFR 2）招募GEP 100来激活Arf 6。AMAP 1通过与corneumen结合在癌症侵袭和转移中发挥作用。我们证明了相同的GEP 100-Arf 6-AMAP 1-corneumen途径对于血管生成活动是必不可少的，包括细胞迁移和肾小管形成，以及对于VEGF刺激的HUVECs的细胞通透性和VE-钙粘蛋白内吞的增强。该途径的组分在病理性血管生成中高度表达，阻断该途径可有效抑制VEGF或肿瘤诱导的血管生成和脉络膜新生血管形成。GEP 100-Arf 6-AMAP 1-corneumen通路由受体酪氨酸激酶激活，在血管生成和肿瘤侵袭和转移中似乎是常见的，并提供了新的治疗靶点。
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.
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影响因子：
21.3
作者：
Jones CA;Nishiya N;London NR;Zhu W;Sorensen LK;Chan AC;Lim CJ;Chen H;Zhang Q;Schultz PG;Hayallah AM;Thomas KR;Famulok M;Zhang K;Ginsberg MH;Li DY
通讯作者：
Li DY
影响因子：
5.3
作者：
Fukuhara, S;Sakurai, A;Mochizuki, N
通讯作者：
Mochizuki, N
影响因子：
3.2
作者：
MADRI, JA;PRATT, BM
通讯作者：
PRATT, BM
影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
Hanahan, D
影响因子：
6
作者：
Guedez, L;Rivera, AM;Stetler-Stevenson, WG
通讯作者：
Stetler-Stevenson, WG