Cadherins and Cell Stiffening

钙粘蛋白和细胞硬化

• 批准号: 9303401
• 负责人: Kris A DeMali
• 金额: $ 30.12万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303401
• 关键词: 5' -AMP-activated protein kinase; Actins; Actomyosin; Adhesions; Affect; Binding; Biochemical; Biological; Biology; Breast Cancer Cell; Breast Cancer Model; Breast cancer metastasis; Cadherins; Cancer Etiology; Cancer Model; Cell Adhesion; Cell Nucleus; Cell membrane; Cell surface; Cells; Cessation of life; Characteristics; Complex; Couples; Cytoskeleton; Data; Development; Disease; E-Cadherin; Event; Extracellular Domain; Extracellular Matrix; Family; Glucose; Glucose Transporter; Goals; Grant; Gray unit of radiation dose; Growth; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Integrins; Knowledge; Lead; Link; Magnetism; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Molecular; Neoplasm Metastasis; Oranges; Organism; Pathway interactions; Phosphorylation; Physiological; Process; Production; Protein Kinase; Proteins; Recruitment Activity; Regulation; STK11 gene; Signal Pathway; Signal Transduction; Supporting Cell; Testing; Vinculin; Warburg Effect; Woman; Work; adhesion receptor; base; beta catenin; cancer cell; cell growth; cell growth regulation; glucose metabolism; glucose uptake; improved; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; mechanical force; mouse model; neoplastic cell; novel; polymerization; prevent; public health relevance; response; rho; transmission process; tumor growth; tumorigenesis; uptake

 DESCRIPTION (provided by applicant): Adhesion of cells to one another and the extracellular matrix is a fundamental characteristic of all multicellular organisms. Recent work has shown that mechanical force applied to cell adhesion receptors, including the cadherins and integrins, can affect the activities of Rho family GTPases, thereby influencing the organization of the cytoskeleton and the stiffness of cells. This grant is aimed at understanding how signals from cadherins produce the cytoskeletal rearrangements necessary for cell stiffening, with an emphasis on understanding where the cell derives the energy required to support cell stiffening. In our preliminary studies, we discovered that application of force to E-cadherin stimulates glucose uptake and increases glucose transporters on the plasma membrane. Using molecular, biochemical and cell biological approaches, Aim 1 will define the molecular mechanism for how E-cadherin stimulates glucose uptake. Aim 2 will determine how increased glucose uptake facilitates the cytoskeletal rearrangements required for stiffening. Here we aim to identify the RhoA activator and signaling pathways involved. Using magnetic tweezers and beads coated with the extracellular domain of E-cadherin we will determine how force-induced glucose uptake leads to the strengthening of cadherin-mediated adhesions. The final aim will investigate how the force-induced glucose impacts the actin cytoskeleton and its regulation of cell growth and metastasis in vivo. Mouse models of breast cancer will be employed to explore the consequence that promoting E-cadherin mediated force transmission has on disease. When the work in this proposal is complete, we expect to establish a new paradigm for how glucose uptake is stimulated by force and facilitates cell stiffening. This paradigm can be applied to better understand force transmission by other proteins and will lay the groundwork for understanding if and how E- cadherin force transmission protects against the development of cancer.

 描述（由适用提供）：细胞彼此粘附，细胞外矩阵是所有多细胞组织的基本特征。最近的工作表明，应用于包括钙粘蛋白和整联蛋白在内的细胞粘附受体的机械力会影响Rho家族GTPase的活性，从而影响细胞骨架的组织和细胞的僵硬。该赠款旨在了解钙粘蛋白的信号如何产生细胞僵硬所需的细胞骨架重排，并强调了解细胞在何处得出支持细胞僵硬所需的能量。在我们的初步研究中，我们发现将力在e-钙黏着蛋白上的应用刺激葡萄糖摄取，并增加质膜上的葡萄糖转运蛋白。使用分子，生化和细胞生物学方法，AIM 1将定义E-钙粘蛋白如何刺激葡萄糖摄取的分子机制。 AIM 2将确定增加的葡萄糖摄取如何促进僵硬所需的细胞骨架重排。在这里，我们旨在确定涉及的RhoA激活剂和信号通路。使用带有E-钙粘蛋白细胞外域的磁镊子和珠子，我们将确定力诱导的葡萄糖摄取如何导致钙粘蛋白介导的粘附力的增强。最终目标将研究力诱导的葡萄糖如何影响肌动蛋白细胞骨架及其对体内细胞生长和转移的调节。将采用乳腺癌的小鼠模型来探索促进e-钙粘蛋白介导的力对疾病的影响。当该提案中的工作完成后，我们希望建立一个新的范式，以通过力刺激葡萄糖摄取并促进细胞僵硬。该范式可以应用于更好地理解其他蛋白质的力传播，并将为理解E-钙粘蛋白力传递如何保护癌症的发展奠定基础。