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（由申请人提供）：细胞彼此以及细胞外基质之间的粘附是所有多细胞生物体的基本特征。最近的研究表明，施加到细胞粘附受体（包括钙粘蛋白和整合素）的机械力可以影响 Rho 家族 GTPases 的活性，从而影响细胞骨架的组织和细胞的刚度。该资助旨在了解钙粘蛋白的信号如何产生细胞硬化所需的细胞骨架重排，重点是了解细胞从何处获得支持细胞硬化所需的能量。在我们的初步研究中，我们发现对 E-钙粘蛋白施加力会刺激葡萄糖摄取并增加质膜上的葡萄糖转运蛋白。目标 1 将使用分子、生物化学和细胞生物学方法来定义 E-钙粘蛋白如何刺激葡萄糖摄取的分子机制。目标 2 将确定增加的葡萄糖摄取如何促进硬化所需的细胞骨架重排。在这里，我们的目标是确定 RhoA 激活剂和所涉及的信号通路。使用磁镊子和涂有 E-钙粘蛋白胞外域的珠子，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的加强。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。将采用乳腺癌小鼠模型来探索促进 E-钙粘蛋白介导的力传递对疾病的影响。当该提案中的工作完成后，我们期望建立一个新的范例，说明如何通过武力刺激葡萄糖摄取并促进细胞硬化。该范例可用于更好地理解其他蛋白质的力传递，并将为理解 E-钙粘蛋白力传递是否以及如何防止癌症的发展奠定基础。