Structure and Mechanism of G-proteins and cell adhesion proteins in regulation of cell growth and motility

联系PD/PI：坎贝尔、Sharon 摘要 本项目主要研究两个主题：1）阐明鸟嘌呤核苷酸的新的驱动机制 结合（G）-蛋白信号传导和肿瘤发生; 2）研究细胞的个体和协调作用 粘附蛋白在调节细胞形态、力传递和细胞运动中的作用。我们对G蛋白的研究 以RAS和异源三聚体G蛋白为中心。我们实验室最近的发现挑战了一个长期以来的教条 G蛋白的致癌激活主要由核苷酸循环中的缺陷驱动。然而，在这方面， 越来越清楚的是，G蛋白中的密码子和残基特异性激活突变可以驱动 通过不同的机制引起肿瘤。换句话说，并非所有的激活突变都是平等的。我们 提出旨在了解残基特异性激活突变如何独特地改变G蛋白的研究 结构，核苷酸循环，蛋白质识别和信号传导，这可能是发展精度的关键 拮抗G蛋白介导的肿瘤发生的药物途径。我们的实验室还发现了 通过翻译后修饰和pH调节的G蛋白活化机制。我们建议高度 综合多学科的结构，生物化学和细胞生物学的方法来询问这些作用， 信号转导和肿瘤发生中的新型翻译后修饰。我们的第二个主题是细胞 粘附蛋白，粘着斑蛋白和后粘着斑蛋白。这些细胞粘附蛋白是同种型，在细胞粘附中起关键作用。 调节细胞形态、分化、力传递和定向细胞迁移。我们提出 实验性检查黏着斑蛋白和metavinculin介导的丝状肌动蛋白的新模型的研究 组装和膜插入，进行细胞研究，以阐明metavinculin如何协调 调节黏着斑蛋白的功能，并阐明metavinculin心肌病突变如何失调收缩， 心脏病的力量我们还将研究黏着斑蛋白和后黏着斑蛋白如何参与丝状肌动蛋白的表达。 力依赖的方式来调节定向细胞运动。 第6页 项目总结/摘要

Contact PD/PI: Campbell, Sharon Abstract This project focuses on two themes: 1) elucidation of novel mechanisms that drive guanine nucleotide binding (G)-protein signaling and tumorigenesis and 2) investigation of individual and coordinated roles of cell adhesion proteins in regulating cell morphology, force transmission and cell motility. Our work on G-proteins is centered on RAS and heterotrimeric G-proteins. Recent findings from our lab challenge a long-held dogma in the field that oncogenic activation of G-proteins is primarily driven by defects in nucleotide cycling. However, it is becoming increasingly clear that codon and residue specific activating mutations in G-proteins can drive tumorigenesis by distinct mechanisms. In other words, not all activating mutations are created equal. We propose studies aimed at understanding how residue specific activating mutations uniquely alter G-protein structure, nucleotide cycling, protein recognition and signaling, that may be key to developing precision medicine approaches to antagonize G-protein mediated tumorigenesis. Our lab has also uncovered novel mechanisms of G-protein activation by post-translational modification and pH regulation. We propose highly integrated multidisciplinary structural, biochemical and cell biology approaches to interrogate the role of these novel posttranslational modifications in signaling and tumorigenesis. Our second theme is focused on the cell adhesion proteins, vinculin and metavinculin. These cell adhesion proteins are isoforms that play a key role in regulation of cell morphology, differentiation, force transmission and directed cell migration. We propose studies to experimentally examine new models for vinculin and metavinculin-mediated filamentous actin assembly and membrane insertion, conduct cellular studies to elucidate how metavinculin coordinately regulates vinculin function, and elucidate how metavinculin cardiomyopathy mutations dysregulate contractile force in heart disease. We will also investigate how vinculin and metavinculin engage filamentous actin in a force dependent manner to regulate directed cell motility. Page 6 Project Summary/Abstract