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: 7096518
• 负责人: Panagiotis Z. Anastasiadis
• 金额: $ 27.02万
• 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/7096518
• 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近膜结构域相互作用来影响细胞间粘附，并且在细胞质和细胞核中具有额外的作用。最近的三份报告表明，细胞质 p​​120 可以调节 RhoA、Rac 和 Cdc42 的活性，从而改变细胞形态并增加运动性。钙粘蛋白结合阻断了这些细胞质 p​​120 效应，这表明了一种优雅且先前意想不到的调节粘附和运动细胞表型之间平衡的机制。这些观察结果还为失去 E-钙粘蛋白表达的癌细胞显示的转移表型提供了潜在的解释。我们的长期目标是了解、预防或开发肿瘤转移的治疗方法。具体来说，在这个项目中，我们寻求 (1) 阐明 p120 影响不同 Rho GTPases 的机制，(2) 检验细胞质 p​​120 可以促进体外和体内侵袭性的假设，以及 (3) 阐明 p120 影响不同 Rho GTPases 的机制。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 Cdc42。在目标 2 中，我们将在体外测试未结合钙粘蛋白的 p120 是否会促进细胞运动并诱导侵袭性。将细胞注射到裸鼠体内后，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 Aim3 中，我们将测试 p120-驱动蛋白关联在 Rho GTPases 活性、钙粘蛋白功能、细胞骨架动力学和细胞运动中的作用。通过探索 p120 连环蛋白在钙粘蛋白和 Rho 信号级联整合中的作用，我们期望确定 p120 是否充当细胞接触敏感开关，介导运动的接触抑制和钙粘蛋白介导的侵袭性抑制。我们期望阐明 p120 的功能和物理相互作用域将允许下一代针对特定 p120 功能的化合物，作为新型癌症治疗的基础。我们认为，由于 p120 在正常细胞中与钙粘蛋白结合，因此选择性靶向促进钙粘蛋白未偶联状态下侵袭性的 p120 功能对于钙粘蛋白缺陷的恶性细胞将具有独特的效果。