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 Catenin通过与经典钙粘着蛋白的高度保守的近膜结构域相互作用来影响细胞细胞的粘附，并且在细胞质和细胞核中都具有附加作用。最近的三个报告表明，细胞质P120可以调节RhoA，RAC和CDC42的活性，从而导致细胞形态改变并增加运动性。钙粘着蛋白结合阻断了这些细胞质P120的影响，这表明了一种优雅而出乎意料的机制，可用于调节粘合剂和动感细胞表型之间的平衡。这些观察结果还为丧失E-钙粘蛋白表达的癌细胞所示的转移性表型提供了潜在的解释。我们的长期目标是了解和预防或开发肿瘤转移的治疗方法。具体而言，在这个项目中，我们试图（1）阐明p120影响不同的Rho GTPases的机制，（2）检验了细胞质p120可以在体外和体内促进侵入性的假设，以及（3）阐明球的作用在P120功能中的作用。在AIM 1结构功能分析和选择性的p120的选择性取消耦合突变体中，测试了特定的蛋白质 - 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AIM 2中，我们将在体外测试cadherin-unbound P120是否促进细胞运动并诱导侵入性。在将细胞注射到裸鼠中后，影响P120定位或功能的治疗也将测试其对侵袭性的影响。最后，在AIM3中，我们将测试p120基因蛋白关联在Rho GTPases，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 catenin在钙粘蛋白和Rho信号级联反应中的作用，我们希望确定P120是否充当细胞接触敏感性开关，介导了运动的接触抑制以及钙粘蛋白介导的侵袭性抑制。我们预计，阐明P120的功能和物理相互作用域将允许以未来的靶向特定P120功能的化合物，这是新型癌症治疗的基础。我们认为，由于P120与正常细胞中的钙粘蛋白注定，因此有选择地靶向促进cadherin脉络脉络态侵入性的P120功能将在缺乏cadherin的缺陷型恶性细胞中有效。