Cadherin-p120 signaling in motility and invasiveness

钙粘蛋白-p120 运动性和侵袭性信号传导

• 批准号: 6922806
• 负责人: Panagiotis Z. Anastasiadis
• 金额: $ 27.68万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922806
• 关键词: athymic mouse; biological signal transduction; cadherins; cell adhesion; cell migration; cell motility; cytoplasm; cytoskeleton; enzyme activity; gene deletion mutation; gene delivery system; gene expression; guanine nucleotide binding protein; guanosinetriphosphatases; intercellular connection; intracellular transport; kinesin; mutant; neoplasm /cancer invasiveness; point mutation; protein localization; protein protein interaction; protein structure function; protein transport; tissue /cell culture

DESCRIPTION (provided by applicant): p120 catenin affects cell-cell adhesion by interacting with the highly conserved juxtamembrane domain of classical cadherins, and has additional roles in both the cytoplasm and the nucleus. Three recent reports indicate that cytoplasmic p120 can modulate the activities of RhoA, Rac, and Cdc42, leading to altered cell morphology and increased motility. Cadherin binding blocks these cytoplasmic p120 effects, suggesting an elegant and previously unexpected mechanism for regulating the balance between adhesive and motile cellular phenotypes. These observations also provide a potential explanation for the metastatic phenotype shown by cancer cells that have lost E-cadherin expression. Our long-term goal is to understand, and prevent or develop treatments for, tumor metastasis. Specifically, in this project, we seek to (1) elucidate the mechanism(s) by which p120 affects different Rho GTPases, (2) test the hypothesis that cytoplasmic p120 can promote invasiveness in vitro and in vivo, and (3) clarify the role of kinesin in p120 function. In Aim 1 structure-function analysis and selective uncoupled mutants of p120 will be used, and specific protein-protein interactions tested, to determine whether p120 affects RhoA, Rac and Cdc42 via the same or distinct mechanisms. In Aim 2, we will test in vitro whether cadherin-unbound p120 promotes cell motility and induces invasiveness. Treatments that affect p120 localization or function in cultured cells will also be tested for their effects on invasiveness, after injection of the cells into nude mice. Finally, in Aim3 we will test the role of the p120-kinesin association in the activity of Rho GTPases, cadherin function, cytoskeletal dynamics and cell motility. By exploring the role of p120 catenin in the integration of cadherin and Rho signaling cascades, we expect to determine whether p120 acts as a cell contact-sensitive switch, mediating contact inhibition of motility, and cadherin-mediated suppression of invasiveness. We expect that elucidating p120's functional and physical interaction domains will allow the future generation of compounds that target particular p120 functions, as the basis of novel cancer treatments. We believe that because p120 is bound to cadherins in normal cells, selectively targeting the p120 functions that promote invasiveness in the cadherin-uncoupled state would be uniquely effective in cadherin-deficient malignant cells.

描述（由申请人提供）：p120连环蛋白通过与经典钙粘蛋白的高度保守的跨膜结构域相互作用影响细胞-细胞粘附，并在细胞质和细胞核中具有额外的作用。三个最近的报告表明，细胞质p120可以调节RhoA，Rac和Cdc 42的活动，导致改变细胞形态和运动性增加。钙粘蛋白结合阻断这些细胞质p120的影响，这表明一个优雅的和以前意想不到的机制，调节粘附和运动细胞表型之间的平衡。这些观察结果也提供了一个潜在的解释转移表型所示的癌细胞已经失去了E-钙粘蛋白的表达。我们的长期目标是了解、预防或开发肿瘤转移的治疗方法。具体而言，在本项目中，我们试图（1）阐明p120影响不同Rho GTP酶的机制，（2）验证细胞质p120可以促进体外和体内侵袭的假设，（3）阐明驱动蛋白在p120功能中的作用。在目标1中，将使用p120的结构-功能分析和选择性解偶联突变体，并测试特定的蛋白质-蛋白质相互作用，以确定p120是否通过相同或不同的机制影响RhoA，Rac和Cdc 42。在目标2中，我们将在体外测试钙粘蛋白未结合的p120是否促进细胞运动并诱导侵袭性。在将细胞注射到裸鼠中后，还将测试影响培养细胞中p120定位或功能的治疗对侵袭性的影响。最后，在Aim 3中，我们将测试p120-驱动蛋白联合在Rho GTP酶活性、钙粘蛋白功能、细胞骨架动力学和细胞运动性中的作用。通过探索p120连环蛋白在整合钙粘蛋白和Rho信号级联中的作用，我们希望确定p120是否作为细胞接触敏感开关，介导运动的接触抑制，以及钙粘蛋白介导的侵袭抑制。我们希望阐明p120的功能和物理相互作用域将允许未来一代的化合物，针对特定的p120功能，作为新的癌症治疗的基础。我们相信，因为p120是绑定到正常细胞中的钙粘蛋白，选择性地针对p120的功能，促进在钙粘蛋白解偶联状态的侵袭性将是唯一有效的钙粘蛋白缺陷的恶性细胞。