Regulation of Hippo pathway signaling by mechanical forces

机械力对 Hippo 通路信号的调节

• 批准号: 9352344
• 负责人: DANNEL MCCOLLUM
• 金额: $ 44.07万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352344
• 关键词: AMOT gene; Actins; Adherens Junction; Affect; Artificial Membranes; Binding; Cell Death; Cell Density; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cell Survival; Cell membrane; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Crowding; Cytoplasm; Cytoskeleton; Epithelial; F-Actin; Family; Goals; Growth; Homeostasis; Intercellular Junctions; LATS1 gene; LIM Domain Protein; Lead; MAP4K4 gene; Malignant Neoplasms; Mechanics; Mediating; Membrane; Modeling; Molecular; Monitor; Nuclear; Oncogenes; Pathway interactions; Pattern; Phosphotransferases; Process; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Stem cells; Stimulus; Stretching; Structure; Tertiary Protein Structure; Testing; Therapeutic; Tissue Engineering; Transcription Coactivator; Translating; Tumor Suppression; Tumor Suppressor Proteins; Tumor Tissue; Ubiquitin family; Work; alpha catenin; cancer therapy; density; direct application; improved; insight; mechanical force; response; sensor; stem cell differentiation; stem cell therapy; therapeutic target; tissue regeneration; tissue repair; treatment response; ubiquitin ligase; upstream kinase

Project Summary The long term goal of this project is to uncover the regulatory networks that control the Hippo signaling pathway in response to mechanical stimuli, which could lead to better treatments for cancer, and improved stem cell therapies. The canonical Hippo pathway consists of two tumor suppressor kinases called MST1/2 and LATS1/2. MST1/2 activate LATS1/2, which in turn phosphorylates and inhibits the transcriptional co-activator and oncogene YAP, causing it to relocalize from the nucleus to the cytoplasm. When in the nucleus, the YAP promotes cell survival and proliferation. YAP nuclear localization is regulated by diverse mechanical stimuli such as substrate stiffness, cell detachment, cell crowding, and stretch to control density dependent inhibition of growth, tissue repair and stem cell proliferation and differentiation. Although these mechanical stimuli appear to affect Hippo signaling through effects on the F-actin cytoskeleton, the molecular mechanism for how F-actin perturbations are translated into changes in Hippo pathway signaling is largely unknown. Here we will identify how mechanical forces act on the core Hippo pathway. In Specific Aim 1, we will determine how LATS1/2 activating kinases are regulated to turn on LATS1/2 in response to mechanical forces. In Specific Aim 2, we will test various models for how angiomotin proteins act as sensors to regulate multiple aspects of Hippo signaling in response to mechanical stimuli that affect F-actin levels. We will determine in Specific Aim 3 how TRIP6 regulates LATS1/2 activity in response to cellular tension across sheets of cells. Overall these studies will reveal key molecular pathways controling Hippo signaling in response to mechanical forces. These studies will have an important impact on our understanding of tumor suppression and tissue regeneration and may lead to ways to manipulate these important processes.

项目摘要 该项目的长期目标是发现控制河马的监管网络 响应机械刺激的信号通路，这可能会导致更好的癌症治疗 并改善了干细胞疗法。规范的河马途径由两个肿瘤抑制剂组成 激酶称为MST1/2和LATS1/2。 MST1/2激活LATS1/2，进而磷酸化和 抑制转录共激活因子和癌基因YAP，使其从核重新定位到 细胞质。在细胞核中，YAP促进细胞的存活和增殖。 yap核 定位受不同的机械刺激调节，例如底物刚度，细胞脱离， 细胞拥挤，并伸展以控制密度依赖于生长，组织修复和干细胞的抑制 增殖和分化。尽管这些机械刺激似乎会影响河马信号传导 通过对F-肌动蛋白细胞骨架的作用，F-肌动蛋白如何扰动的分子机制 被翻译成河马途径信号传导的变化是未知的。在这里，我们将确定如何 机械力作用于核心河马途径。在特定目标1中，我们将确定LATS1/2的方式 激活激活的激酶对机械力响应于机械力而打开LATS1/2。在特定目标中 2，我们将测试各种模型，以了解血管蛋白蛋白如何作为调节多个方面的传感器 响应影响F-肌动蛋白水平的机械刺激的河马信号传导。我们将确定 特定目标3 Trip6如何调节LATS1/2的活性，以应对跨的细胞张力 细胞。总体而言，这些研究将揭示控制河马信号的关键分子途径。 到机械力。这些研究将对我们对肿瘤的理解产生重要影响 抑制和组织再生，可能导致操纵这些重要过程的方法。