Hood John D, Frausto Ricardo, Kiosses William B, Schwartz Martin A, Cheresh David A
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Cell Biol. 2003 Sep 1;162(5):933-43. doi: 10.1083/jcb.200304105.
Antagonists of alphavbeta3 and alphavbeta5 disrupt angiogenesis in response to bFGF and VEGF, respectively. Here, we show that these alphav integrins differentially contribute to sustained Ras-extracellular signal-related kinase (Ras-ERK) signaling in blood vessels, a requirement for endothelial cell survival and angiogenesis. Inhibition of FAK or alphavbeta5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin alphavbeta3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation. Furthermore, retroviral delivery of active Ras or c-Raf promoted ERK activity and angiogenesis, which anti-alphavbeta5 blocked upstream of Ras, whereas anti-alphavbeta3 blocked downstream of Ras, but upstream of c-Raf. The activation of c-Raf by bFGF/alphavbeta3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak. Thus, integrins alphavbeta3 and alphavbeta5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.
αvβ3和αvβ5拮抗剂分别响应碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子（VEGF）破坏血管生成。在此，我们表明这些αv整合素对血管中持续的Ras-细胞外信号调节激酶（Ras-ERK）信号传导有不同贡献，这是内皮细胞存活和血管生成所必需的。抑制黏着斑激酶（FAK）或αvβ5会破坏VEGF介导的鸡胚绒毛尿囊膜上的Ras和c-Raf活性，而阻断FAK或整合素αvβ3对bFGF介导的Ras活性没有影响，但确实会抑制c-Raf激活。此外，逆转录病毒递送活性Ras或c-Raf可促进ERK活性和血管生成，抗αvβ5在Ras上游阻断，而抗αvβ3在Ras下游但在c-Raf上游阻断。bFGF/αvβ3介导的c-Raf激活不仅依赖于FAK，还需要p21激活激酶依赖的c-Raf丝氨酸338磷酸化，而VEGF介导的c-Raf磷酸化/激活依赖于Src，而非Pak。因此，整合素αvβ3和αvβ5对Ras-ERK途径有不同调节作用，这解释了血管生成两条途径中不同的血管反应。
