Blocking angiogenesis by targeting PP-2A pathways

描述（由申请方提供）：肿瘤刺激的血管生成涉及内皮细胞迁移和重组为血管结构，这是一个受激酶和磷酸酶之间平衡调节的过程。我们已经表明，几种肿瘤产生的主要运动刺激因子是PGE 2和TGF β，反过来，它们抑制丝氨酸/苏氨酸蛋白磷酸酶PP-2A的活性。PP-2A的药理学抑制增加细胞运动性。 我们的假设是，通过产生运动刺激因子PGE 2和TGF β，肿瘤抑制内皮细胞PP-2A活性，PP-2A活性通过两个相互关联的途径刺激内皮细胞运动：（i）桩蛋白的丝氨酸/苏氨酸磷酸化，其使FAK/Src/桩蛋白复合物不稳定并触发p130（Cas）/Crk和PI 3 K运动性刺激途径的Src活化，从而抑制其限制PI 3 K和p130（Cas）/Crk途径活化的能力。定义这些运动刺激途径还将确定可以靶向中断内皮细胞运动的信号传导组分，进而中断肿瘤生长所需的新血管形成。 我们的假设将在体外和体内在鼠刘易斯肺癌（LLC）模型中通过评估PGE 2/TGF β对PP-2A的抑制是否刺激：（i）桩蛋白的丝氨酸/苏氨酸磷酸化，FAK/Src/桩蛋白复合物的溶解和Src作为运动刺激途径的一个分支的活化;（ii）丝氨酸/苏氨酸磷酸化以及因此PTEN的失活是运动性刺激途径的第二臂;（iii）通过产生活性Src和失活PTEN的级联的两个臂激活运动刺激性p130（Cas）/Crk和PI 3 K途径。 完成后，这些研究将确定PP-2A的肿瘤抑制如何增加内皮细胞运动性，这是血管生成过程的一个要求。这些研究还将确定可以靶向阻断运动刺激通路的信号传导成分。虽然在LLC模型中进行，但所提出的研究一般适用于实体癌，因为它们的生长依赖于血管生成。

DESCRIPTION (provided by applicant): Tumor-stimulated angiogenesis involves endothelial cell migration and reorganization into vessel structures, a process that is regulated by the balance between kinases and phosphatases. We have shown that the principal motility-stimulatory factors produced by several tumors are PGE2 and TGFbeta which, in turn, inhibit the activity of the serine/threonine protein phosphatase PP-2A. Pharmacological inhibition of PP-2A increases cellular motility. Our hypothesis is that by producing the motility-stimulatory factors PGE2 and TGFbeta, tumors inhibit endothelial cell PP-2A activity, which stimulates endothelial cell motility through two interconnected pathways: (i) serine/threonine phosphorylation of paxillin, which destabilizes FAK/Src/paxillin complexes and triggers Src activation of the p130(Cas)/Crk and PI3K motility-stimulatory pathways, (ii) serine/threonine phosphorylation of PTEN, thus inhibiting its ability to limit activation of the PI3K and p130(Cas)/Crk pathways. Defining these motility-stimulatory pathways will also identify signaling components that can be targeted to interrupt endothelial cell motility and, in turn, the neovascularization that is required for tumor growth. Our hypothesis will be tested in vitro and in vivo in a murine Lewis lung carcinoma (LLC) model by assessing if the inhibition of PP-2A by PGE2/TGFbeta stimulates: (i) serine/threonine phosphorylation of paxillin, dissolution of FAK/Src/paxillin complexes and activation of Src as one arm of a motility-stimulatory pathway; (ii) serine/threonine phosphorylation and, consequently, inactivation of PTEN is the second arm of a motility-stimulatory pathway; (iii) activation of the motility-stimulatory p130(Cas)/Crk and PI3K pathways by the two arms of the of the cascade that yield active Src and inactive PTEN. Upon completion, these studies will identify how tumor inhibition of PP-2A increases endothelial cell motility, a requirement for the process of angiogenesis. These studies will also identify signaling components that can be targeted to block the motility-stimulatory pathways. Although being conducted in the LLC model, the proposed studies are applicable to solid cancers in general, as their growth is dependent on angiogenesis.