首页> 外文期刊>Molecular cancer research: MCR >Anastellin, the angiostatic fibronectin peptide, is a selective inhibitor of lysophospholipid signaling.
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Anastellin, the angiostatic fibronectin peptide, is a selective inhibitor of lysophospholipid signaling.

机译:Anastellin是一种血管抑制性纤连蛋白肽,是溶血磷脂信号传导的选择性抑制剂。

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Angiogenesis is regulated by integrin-dependent cell adhesion and the activation of specific cell surface receptors on vascular endothelial cells by angiogenic factors. Lysophosphatidic acid (LPA) and sphingosine-1 phosphate (S1P) are bioactive lysophospholipids that activate G protein-coupled receptors that stimulate phosphatidylinositol 3-kinase (PI3K), Ras, and Rho effector pathways involved in vascular cell survival, proliferation, adhesion, and migration. Previous studies have shown that anastellin, a fragment of the first type III module of fibronectin, functions as an antiangiogenic peptide suppressing tumor growth and metastasis. We have previously shown that anastellin blocks serum-dependent proliferation of microvessel endothelial cells (MVEC) by affecting extracellular signal-regulated kinase (ERK)-dependent G(1)-S transition. However, the mechanism by which anastellin regulates endothelial cell function remains unclear. In the present study, we mapped several lysophospholipid-mediated signaling pathways in MVEC and examined the effects of anastellin on LPA- and S1P-induced MVEC proliferation, migration, and cytoskeletal organization. Both LPA and S1P activated PI3K, Ras/ERK, and Rho/Rho kinase pathways, leading to migration, G(1)-S cell cycle progression, and stress fiber formation, respectively. Stimulation of proliferation by LPA/S1P occurred through a G(i)-dependent Ras/ERK pathway, which was independent of growth factor receptors and PI3K and Rho/Rho kinase signaling. Although LPA and S1P activated both PI3K/Akt and Ras/ERK signaling through G(i), anastellin inhibited only the Ras/ERK pathway. Stress fiber formation in response to LPA was dependent on Rho/Rho kinase but independent of G(i) and unaffected by anastellin. These results suggest that lysophospholipid mediators of G(i) activation leading to PI3K/Akt and Ras/ERK signaling bifurcate downstream of G(i) and that anastellin selectively inhibits the Ras/ERK arm of the pathway.
机译:血管生成受整联蛋白依赖性细胞粘附和血管生成因子对血管内皮细胞上特定细胞表面受体的激活的调节。溶血磷脂酸(LPA)和Sphingosine-1磷酸(S1P)是具有生物活性的溶血磷脂,可激活G蛋白偶联受体,从而刺激参与血管细胞存活,增殖,黏附和移民。先前的研究表明,astastinin是纤连蛋白的第一个III型模块的片段,起抑制肿瘤生长和转移的抗血管生成肽的作用。我们以前已经表明,阿那斯通通过影响细胞外信号调节激酶(ERK)依赖的G(1)-S转换来阻止微血管内皮细胞(MVEC)的血清依赖性增殖。但是,阿那列汀调节内皮细胞功能的机制仍不清楚。在本研究中,我们在MVEC中绘制了几个溶血磷脂介导的信号通路,并检查了Alastellin对LPA和S1P诱导的MVEC增殖,迁移和细胞骨架组织的影响。 LPA和S1P均激活PI3K,Ras / ERK和Rho / Rho激酶途径,分别导致迁移,G(1)-S细胞周期进程和应力纤维形成。 LPA / S1P通过G(i)依赖性Ras / ERK途径刺激增殖,该途径独立于生长因子受体,PI3K和Rho / Rho激酶信号传导。尽管LPA和S1P通过G(i)激活了PI3K / Akt和Ras / ERK信号传导,但阿那列汀仅抑制Ras / ERK途径。响应LPA的应激纤维形成取决于Rho / Rho激酶,但独立于G(i),不受阿那列汀的影响。这些结果表明,导致PI3K / Akt和Ras / ERK信号转导的G(i)的溶血磷脂介体在G(i)的下游分叉,并且阿那曲林选择性地抑制该途径的Ras / ERK臂。

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