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首页> 外文学位 >Positive and negative modulatory roles of Platelet Endothelial Cell Adhesion Molecule-1 signaling in endothelial cell migration: Coordination of Rho signaling and targeting of SHP-2 tyrosine phosphatase activity.
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Positive and negative modulatory roles of Platelet Endothelial Cell Adhesion Molecule-1 signaling in endothelial cell migration: Coordination of Rho signaling and targeting of SHP-2 tyrosine phosphatase activity.

机译：血小板内皮细胞粘附分子1信号在内皮细胞迁移中的正负调节作用：Rho信号的协调和SHP-2酪氨酸磷酸酶活性的靶向。

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摘要

Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), an immunoglobulin family adhesion molecule, is involved in endothelial migration and angiogenesis. We found that PECAM-1 deficient endothelial cells exhibit enhanced nondirected single cell motility and extension formation at the expense of wound-healing migration. These in vitro endothelial behaviors model aspects of highly developmentally and pathophysiologically relevant processes. Wound healing migration may model the reendothelialization of denuded vasculature following balloon angioplasty or the remodeling of vascular endothelium under variant flow conditions, while single cell motility is prominently involved in developmental processes such as endocardial-mesenchymal transition within the cardiac cushion. A specific deficiency of RhoGTP in PECAM-1 deficient endothelial cells accounted for their migratory phenotype. The serum sphingolipid sphingosine-1-phosphate (S1P) drives Rho-dependent migration and angiogenesis. Indeed PECAM-1 was necessary for an appropriate wound healing response to S1P. We have found that PECAM-1 localizes to rafts, and that in its absence heterotrimeric G protein components are differentially recruited to rafts, providing a potential mechanism for PECAM-1-mediated coordination of S1P signaling.; PECAM-1 activates the tyrosine phosphatase SHP-2 via its phosphorylated immunoreceptor tyrosine-based inhibitory motif (ITIM). ITIM signaling is not required for the positive Rho-activating role of PECAM-1. Instead we found that ITIM signaling retards wound healing migration, and that during migration the second ITIM tyrosine becomes selectively dephosphorylated. The second ITIM tyrosine proved important for recruitment but not activation of SHP-2. Any SHP-2 that remains transiently associated with partially dephosphorylated PECAM-1 could amplify the migration signal by dephosphorylating adjacent PECAM-1 ITIMs. We found that PECAM-1 helps localize SHP-2 to the actin cytoskeleton, and to a subset of phosphoproteins. In fact, interfering with PECAM-1 ITIM signaling not only increased wound healing migration but decreased dephosphorylation of β-catenin and focal adhesion kinase. SHP-2 targetting is instrumental in controlling endothelial wound healing migration, potentially via effects on adherens junction stability and focal contact dynamics.
机译：血小板内皮细胞粘附分子1（PECAM-1），一种免疫球蛋白家族粘附分子，参与内皮迁移和血管生成。我们发现缺乏PECAM-1的内皮细胞表现出增强的非定向单细胞运动性和延伸形成，但以伤口愈合迁移为代价。这些体外内皮行为模拟了高度发育和病理生理相关过程的各个方面。伤口愈合迁移可以模拟在不同的血流条件下球囊血管成形术或血管内皮重塑后裸露的血管系统的重新内皮化，而单细胞运动主要参与发展过程，例如心垫内心内膜-间质转化。在缺乏PECAM-1的内皮细胞中，RhoGTP的一种特定缺陷解释了它们的迁移表型。血清鞘脂-1-磷酸鞘氨醇（S1P）驱动Rho依赖性迁移和血管生成。确实，PECAM-1对于适当的S1P伤口愈合反应是必需的。我们已经发现PECAM-1定位于筏，并且在不存在的情况下，异三聚G蛋白成分被差异地募集到筏上，从而为PECAM-1介导的S1P信号传导提供了潜在的机制。 PECAM-1通过其磷酸化的免疫受体基于酪氨酸的抑制性基序（ITIM）激活酪氨酸磷酸酶SHP-2。 PECAM-1的正Rho激活作用不需要ITIM信号传导。相反，我们发现ITIM信号传导阻碍了伤口的愈合迁移，并且在迁移过程中，第二个ITIM酪氨酸被选择性地去磷酸化。事实证明，第二个ITIM酪氨酸对募集很重要，但对SHP-2的激活并不重要。保持与部分去磷酸化PECAM-1瞬时相关的任何SHP-2都可以通过使相邻的PECAM-1 ITIM去磷酸化来放大迁移信号。我们发现，PECAM-1有助于将SHP-2定位于肌动蛋白的细胞骨架，以及一部分磷蛋白。实际上，干扰PECAM-1 ITIM信号不仅增加伤口愈合迁移，而且减少β-连环蛋白和粘着斑激酶的去磷酸化。 SHP-2靶向可能通过对粘附连接稳定性和局部接触动力学的影响来控制内皮伤口愈合的迁移。

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  • 作者

    Gratzinger, Dita.;

  • 作者单位

    Yale University.;

  • 授予单位 Yale University.;
  • 学科 Biology Cell.; Health Sciences Pathology.; Biology Molecular.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 143 p.
  • 总页数 143
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;病理学;分子遗传学;
  • 关键词

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