Vascular Endothelial Growth Factor A (VEGF-A) Induces Endothelial and Cancer Cell Migration through Direct Binding to Integrin α9β1 IDENTIFICATION OF A SPECIFIC α9β1 BINDING SITE
Vascular Endothelial Growth Factor A (VEGF-A) Induces Endothelial and Cancer Cell Migration through Direct Binding to Integrin α9β1 IDENTIFICATION OF A SPECIFIC α9β1 BINDING SITE
复制标题
DOI：
10.1074/jbc.m110.175158
复制
发表时间：
2011-01-14
影响因子：
4.8
通讯作者：
Vlahakis, Nicholas E.
中科院分区：
文献类型：
--
作者：
Oommen, Saji;Gupta, Shiv K.;Vlahakis, Nicholas E.
整合素α9β1通过与多种不同的细胞外配体相互作用，促进细胞的黏附和迁移。我们以前已经证明，它直接与血管内皮生长因子(VEGF)A、C和D结合，并在血管生成和淋巴管生成中发挥作用。到目前为止，血管内皮细胞生长因子中的α9β1结合位点还没有确定。在此，我们报道了由血管内皮生长因子-A外显子3编码的三个氨基酸序列EYP是血管内皮生长因子与整合素α9β1结合所必需的，并诱导内皮细胞和癌细胞的黏附和迁移。EYP专用于α9β1结合，既不需要也不激活VEGFR-2，VEGFR-2是血管内皮生长因子-A的同源受体。在与EYP结合后，整合素α9β1通过直接激活整合素信号中间产物Src和粘着斑激酶来转导细胞迁移。这种相互作用在生物学上很重要，因为它在体外介导内皮细胞管的形成、伤口愈合和癌细胞侵袭。这些新的发现确定EYP是一个潜在的定向药物治疗地点。
Integrin alpha 9 beta 1 mediates accelerated cell adhesion and migration through interactions with a number of diverse extracellular ligands. We have shown previously that it directly binds the vascular endothelial growth factors (VEGF) A, C, and D and contributes to VEGF-induced angiogenesis and lymphangiogenesis. Until now, the alpha 9 beta 1 binding site in VEGF has not been identified. Here, we report that the three-amino acid sequence, EYP, encoded by exon 3 of VEGF-A is essential for binding of VEGF to integrin alpha 9 beta 1 and induces adhesion and migration of endothelial and cancer cells. EYP is specific for alpha 9 beta 1 binding and neither requires nor activates VEGFR-2, the cognate receptor for VEGF-A. Following binding to EYP, integrin alpha 9 beta 1 transduces cell migration through direct activation of the integrin signaling intermediates Src and focal adhesion kinase. This interaction is biologically important because it mediates in vitro endothelial cell tube formation, wound healing, and cancer cell invasion. These novel findings identify EYP as a potential site for directed pharmacotherapy.