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The role and regulation of mTORC2 in cell migration

mTORC2在细胞迁移中的作用和调控

基本信息

批准号：
10583572
负责人：
Pascale G Charest
金额：
$ 30.09万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583572
关键词：
Actins Address Advanced Development Autoimmune Diseases Binding Biochemical 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 Genetic Guanosine Triphosphate Phosphohydrolases Human Immune Inflammatory Invaded 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 Proto-Oncogene Proteins c-akt Public Health RAS genes RIPK3 gene Regulation Research Role Signal Pathway Signal Transduction Signaling Protein Testing Work 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 protein purification ras Proteins recruit response therapeutic development therapy development tumor

项目摘要

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一种重要的细胞行为，是正常生理和解除调节的关键。疾病，包括癌症。然而，细胞如何引导它们的运动以响应迁移线索并不清楚。明白雷帕霉素复合物2的机制靶点（mTORC 2）在进化上是保守的。在调节肌动蛋白细胞骨架和控制细胞迁移中的作用。mTORC 2是两种由mTOR激酶形成的多蛋白信号复合物。mTORC 1是细胞生长的关键调节因子，增殖及其调节和信号传导途径得到了很好的描述。对mTORC 2的了解要少得多，但最近的研究揭示了mTORC 2在促进癌细胞迁移和肿瘤扩散中的作用。然而，在癌症治疗中靶向mT 0 RC 2途径的能力受到缺乏靶向mT 0 RC 2途径的能力的极大阻碍。 mTORC 2如何被激活，调节和信号传递给细胞运动机制的机制见解。我们旨在通过确定指导mTORC 2活性的关键分子机制来解决这一知识缺口并在细胞迁移中起作用。最近，我们发现两个Ras家族的GTP酶Ras和Rap 1， mTOR和mTORC 2组分RIP 3/SIN 1，并控制mTORC 2活性。实验模型盘基网柄藓重要的是，我们的初步数据表明，这些mTORC 2 调节机制在人类细胞中是保守的。我们的总体目标是确定以及Ras和Rap 1介导的mTORC 2活性和功能调节在细胞迁移中的作用。我们的中央假设Ras和Rap 1独立地调节mTORC 2以响应迁移信号，通过与mTORC 2组分的不同相互作用，从而控制mTORC 2在细胞内的信号传导功能，迁移，并在促进癌细胞迁移中发挥关键作用。我们将在三个具体的实验中验证我们的假设。目标。在目标1中，我们将利用mTOR与网骨藻Ras蛋白RasC的相互作用，我们已经确定了Ras介导的mTORC 2调节在细胞迁移中的机制和作用，以网骨藻为实验模型。在目标2中，我们将确定Rap 1在调节mTORC 2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。在目标3中，我们定义控制乳腺癌细胞迁移的mTORC 2通路，应用我们在在目标1和目标2中进行的机制研究，以具体询问Ras-和Rap 1-的作用，调节mTORC 2促进乳腺癌细胞的迁移。总之，拟议的工作将导致描述参与调节mTORC 2和细胞迁移的新分子机制，包括这将为开发治疗策略提供创新机会，抑制癌细胞在转移中的迁移。此外，我们的研究结果也将推动开发涉及细胞病理性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通路发挥重要作用。