Regulatory non-Smad signaling in TGF-b-induced epithelial-mesenchymal transition

TGF-b 诱导的上皮间质转化中的调节性非 Smad 信号传导

• 批准号: 8632683
• 负责人: RIK M DERYNCK
• 金额: $ 35.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632683
• 关键词: Address; Adhesions; Affect; Behavior; Carcinoma; Cell Line; Cell Nucleus; Cell surface; Cells; Complex; Data; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; GTPase-Activating Proteins; Gene Expression; Gene Expression Regulation; Generations; Genes; Glucose; Grant; Growth; Hyperglycemia; Incidence; Insulin; Invaded; Lead; Learning; Light; Link; MAP Kinase Gene; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mesenchymal; Molecular; Names; Organ; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Plastics; Play; Population Study; Predisposition; Property; Proteins; Receptor Protein-Tyrosine Kinases; Refractory; Regulation; Repression; Research; Role; Signal Pathway; Signal Transduction; Specificity; Stem cells; Surface; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Up-Regulation; autocrine; base; cancer cell; cancer stem cell; cell motility; epithelial to mesenchymal transition; human FRAP1 protein; insight; mutant; novel; programs; public health relevance; rab GTP-Binding Proteins; receptor; response; transcription factor; tumor; tumor progression

Project Summary/Abstract As epithelial cells progress to carcinomas, increased autocrine TGF-¿ signaling acquires a prominent role in cancer progression, by inducing an epithelial plasticity response that can lead to epithelial-mesenchymal transition (EMT). EMT results in cell de-adhesion and increased cell motility and invasion, a prerequisite of cancer cell dissemination, and is increasingly seen as an integral property of carcinoma stem cells. As TGF-¿ signaling drives EMT, and TGF-¿ responsiveness contributes to cancer progression, we have been studying the regulation of TGF-¿ signaling, as it pertains to epithelial plasticity. The well-studied Smad signaling pathway regulates gene expression in response to TGF-¿, but the TGF-¿- induced epithelial plasticity response cannot be explained merely by changes in gene regulation. Accordingly, TGF-¿-induced non-Smad signaling has received increasing appreciation. Supported by this grant, we have been studying the TGF-¿-induced activation of the Erk MAPK and PI3K-Akt-mTOR pathways, and have started addressing their roles in EMT. The specific roles of TGF-¿-induced activation of either pathway in the epithelial plasticity response remain to be further defined. We also found that cells regulate their responsiveness to TGF- ¿, by regulating the TGF-¿ receptor levels at the cell surface from intracellular stores. Increased glucose levels and insulin activate this upregulation of cell surface TGF-¿ receptors, which appears to be mediated by Akt activation and the Rab GTPase activating protein AS160, a direct target of Akt phosphorylation. We hypothesize that increased Akt activation, as commonly seen in carcinomas, or resulting from increased glucose or insulin stimulation, enhances the cell's TGF-¿ responsiveness, and the sensitivity and susceptibility of cancer cells to EMT, and thus may promote cancer progression by enhancing TGF-¿ responsiveness. We now seek to continue our research program aimed at characterizing the roles of non-Smad signaling mechanisms in the control of the cell surface TGF-¿ receptor levels, and resulting TGF-¿ responsiveness, and in TGF-¿-induced EMT. We organized our current and future research in three Aims: (1) To study the effects of glucose or insulin on TGF-¿ signaling, epithelial-mesenchymal transition, cancer stem cell generation and EMT-dependent cancer progression; (2) To define the molecular mechanisms regulating the cell surface presentation of the TGF-¿ receptors in response to Akt activation; (3) To define the roles of TGF-¿-induced Erk MAPK and PI3K-Akt pathway activation in epithelial-mesenchymal transition, and cancer stem cell generation. Our studies should provide novel mechanistic insights into the regulation of TGF-¿ responsiveness and the roles of TGF-¿-induced non-Smad signaling in the cellular TGF-¿ response, in particular in EMT and cancer stem cell generation. These insights may link hyperglycemia or insulin treatment with cancer progression, through increased TGF-¿ responsiveness, and reveal a new role for the increased Akt signaling that is commonly seen in carcinomas, thus contributing to cancer progression by enhancing TGF-¿ responsiveness.

项目摘要/摘要 随着上皮细胞发展为癌，增加的自分泌TGF-信号传导在 癌症进展，通过诱导上皮可塑性反应，该反应可能导致上皮 - 间质 过渡（EMT）。 EMT导致细胞去粘附并增加细胞的运动性和侵袭，这是 癌细胞传播，越来越被视为癌干细胞的整体特性。作为tgf- 信号传导驱动EMT，TGF-¿响应性有助于癌症的发展，我们一直在研究 与上皮可塑性有关的TGF-€信号传导的调节。 经过良好研究的SMAD信号通路可调节对TGF-的响应基因表达，但TGF- - - 诱导的上皮可塑性反应不能仅通过基因调节的变化来解释。根据 TGF-诱导的非SMAD信号已获得越来越多的欣赏。在这笔赠款的支持下，我们有 我们正在研究tgf-the诱导的ERK MAPK和PI3K-AKT-MTOR途径的激活，并已开始 解决他们在EMT中的角色。 TGF-诱导的上皮中任一途径的激活的特定作用 塑性响应仍有待进一步定义。我们还发现细胞调节其对TGF-的反应性 通过调节细胞内存储的细胞表面的TGF-€受体水平。葡萄糖水平升高 胰岛素激活细胞表面TGF-接收器的上调，该接收器似乎是由Akt介导的 激活和RAB GTPase激活蛋白AS160，这是Akt磷酸化的直接靶标。我们 假设增加了Akt激活的增加，如在癌中所见，或者是由于增加而引起的 葡萄糖或胰岛素刺激，增强细胞的TGF- - 响应性以及敏感性和敏感性 癌细胞的EMT，因此可能通过增强TGF-tgf-temants促进癌症进展。 现在，我们试图继续我们的研究计划，以表征非SMAD信号的作用 控制细胞表面TGF-受体水平的机制，以及由此产生的TGF-反应性和 在TGF -¿诱导的EMT中。我们以三个目的组织了当前和未来的研究：（1）研究 TGF-信号传导，上皮间质转变，癌症干细胞的产生和葡萄糖或胰岛素 EMT依赖性癌症进展； （2）定义调节细胞表面的分子机制 响应Akt激活的TGF-oo接收器的呈现； （3）定义TGF-诱导的ERK的作用 上皮间质转变和癌症干细胞产生的MAPK和PI3K-AKT途径激活。 我们的研究应提供对TGF-响应性调节和 TGF-诱导的非SMAD信号在细胞TGF-反应中的作用，特别是在EMT和癌症中 干细胞产生。这些见解可能会将高血糖或胰岛素治疗与癌症的进展联系起来， 通过提高TGF-响应性，并揭示了增加的Akt信号的新作用，即 通常在癌中出现，因此通过增强TGF-®反应性来促进癌症的进展。