The role and regulation of mTORC2 in cell migration

mTORC2在细胞迁移中的作用和调控

• 批准号: 9900031
• 负责人: Pascale G Charest
• 金额: $ 30.53万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900031
• 关键词: Actins; Address; Advanced Development; Autoimmune Diseases; Binding; Biochemical Genetics; Breast Cancer Cell; Cardiovascular system; Catalytic Domain; Cell Proliferation; Cell membrane; Cell model; Cells; Complex; Cues; Cytoskeleton; Data; Development; Dictyostelium; Dictyostelium discoideum; Disease; ERBB2 gene; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial Cells; Experimental Models; F-Actin; FRAP1 gene; Family; Focal Adhesions; Future; Guanosine Triphosphate Phosphohydrolases; Human; Immune; Inflammatory; Knowledge; Literature; MCF10A cells; Malignant Neoplasms; Mediating; Molecular; Movement; Mutate; Neoplasm Metastasis; Oncogenes; PH Domain; Pathologic; Pathway interactions; Phosphotransferases; Physiology; Play; Protein Family; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Public Health; RAS genes; RIPK3 gene; Regulation; Research; Role; Signal Pathway; Signal Transduction; Testing; Work; base; cancer cell; cancer therapy; cell behavior; cell growth; cell motility; drug development; innovation; insight; interest; mammary epithelium; migration; novel; novel therapeutics; phosphoinositide-3,4,5-triphosphate; ras Proteins; recruit; response; therapeutic development; therapy development; tumor

PROJECT SUMMARY The directed migration of cells is an important cellular behavior key to normal physiology and deregulated in disease, including cancer. Yet, how cells direct their movements in response to migration cues is not understood. The mechanistic Target of Rapamycin Complex 2 (mTORC2) plays an evolutionarily conserved role in regulating the actin cytoskeleton and controlling the migration of cells. mTORC2 is one of two multiprotein signaling complexes formed by the mTOR kinase. mTORC1 is a key regulator of cell growth and proliferation, and its regulation and signaling pathway are well described. Much less is known about mTORC2, but recent research revealed a role for mTORC2 in promoting cancer cell migration and tumor dissemination. The ability to target the mTORC2 pathway in cancer therapy, however, is greatly hampered by a lack of mechanistic insight into how mTORC2 is activated, regulated, and signals to the cell motility machinery. We aim to address this knowledge gap by identifying the key molecular mechanisms that direct mTORC2 activity and function in cell migration. Recently, we discovered that two Ras family GTPases, Ras and Rap1, bind mTOR and the mTORC2 component RIP3/SIN1, respectively, and control mTORC2 activity in the experimental model Dictyostelium discoideum. Importantly, our preliminary data indicate that these mTORC2 regulatory mechanisms are conserved in human cells. Our overall objective is to determine the mechanism and role of Ras and Rap1-mediated regulation of mTORC2 activity and function in cell migration. Our central hypothesis is that Ras and Rap1 independently regulate mTORC2 in response to a migration signal through distinct interactions with components of mTORC2, thereby controlling mTORC2's signaling functions in cell migration and playing a key role in promoting cancer cell migration. We will test our hypothesis in three specific aims. In Aim 1, we will take advantage of the mTOR interaction with the Dictyostelium Ras protein RasC that we have identified to define the mechanism and role of Ras-mediated mTORC2 regulation in cell migration, using Dictyostelium as experimental model. In Aim 2, we will identify the role of Rap1 in regulating mTORC2 function in cell migration, using prototypical human epithelial cells as experimental model. In Aim 3, we will define the mTORC2 pathway controlling breast cancer cell migration, applying our findings from the mechanistic studies performed in Aim 1 and Aim 2 to specifically interrogate the role of Ras- and Rap1- regulated mTORC2 in promoting the migration of breast cancer cells. Altogether, the proposed work will lead to the description of novel molecular mechanisms involved in regulating mTORC2 and cell migration, including that of cancer cells, which will provide innovative opportunities for the development of therapeutic strategies for inhibiting the migration of cancer cells in metastasis. Furthermore, our findings will also advance the development of treatments for other diseases that involve the pathological migration of cells, including cardiovascular, inflammatory and autoimmune disorders, in which mTOR pathways play important roles.

项目摘要 细胞的定向迁移是正常生理的重要细胞行为关键并放松管制 疾病，包括癌症。但是，细胞如何指导其动作以响应迁移提示而不是 理解。雷帕霉素复合物2（MTORC2）的机械目标扮演着进化保守的 在调节肌动蛋白细胞骨架和控制细胞迁移方面的作用。 mtorc2是两个 MTOR激酶形成的多蛋白信号传导复合物。 MTORC1是细胞生长和 增殖及其调节和信号通路得到很好的描述。关于mtorc2的知之甚少， 但是最近的研究表明，MTORC2在促进癌细胞迁移和肿瘤传播中的作用。 然而，由于缺乏 关于如何激活，调节MTORC2的机械洞察力和细胞运动机制的信号。我们 旨在通过识别导致MTORC2活性的关键分子机制来解决这一知识差距 和在细胞迁移中的功能。最近，我们发现两个RAS家族GTPases RAS和RAP1 BIND MTOR和MTORC2分量RIP3/SIN1和控制MTORC2活性 实验模型迪斯特尔迪斯特尔。重要的是，我们的初步数据表明这些MTORC2 调节机制在人类细胞中是保守的。我们的总体目标是确定机制 RAS和RAP1介导的MTORC2活性和功能在细胞迁移中的作用的作用。我们的中心 假设是RAS和RAP1通过响应通过 与MTORC2组件的不同相互作用，从而控制MTORC2的信号函数 迁移并在促进癌细胞迁移方面发挥关键作用。我们将在三个特定的特定方面检验我们的假设 目标。在AIM 1中，我们将利用MTOR与Dictyostelium Ras蛋白RASC的相互作用 我们已经确定要定义RAS介导的MTORC2调节在细胞迁移中的机制和作用， 使用dictyostelium作为实验模型。在AIM 2中，我们将确定RAP1在调节MTORC2中的作用 在细胞迁移中的功能，使用原型人类上皮细胞作为实验模型。在AIM 3中，我们将 定义控制乳腺癌细胞迁移的MTORC2途径，应用我们的发现 在AIM 1中进行的机械研究和AIM 2进行了专门询问RAS和RAP1-的作用。 调节MTORC2促进乳腺癌细胞的迁移。总共提出的工作将导致 对调节MTORC2和细胞迁移的新型分子机制的描述，包括 癌细胞将为制定治疗策略的创新机会 抑制癌细胞在转移中的迁移。此外，我们的发现也将推进 开发涉及细胞病理迁移的其他疾病的治疗方法，包括 心血管，炎症和自身免疫性疾病，其中mTOR途径在其中起重要作用。