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: 8788692
• 负责人: RIK M DERYNCK
• 金额: $ 35.61万
• 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/8788692
• 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; Health; 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; rab GTP-Binding Proteins; receptor; response; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): 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 surfae 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.

描述（由申请人提供）：随着上皮细胞进展为癌症，自分泌 TGF-¿ 信号传导的增加通过诱导可导致上皮间质转化 (EMT) 的上皮可塑性反应，在癌症进展中发挥重要作用。 EMT 导致细胞脱粘附并增加细胞运动和侵袭，这是癌细胞的先决条件 传播，并且越来越多地被视为癌干细胞的一个不可或缺的特性。由于 TGF-¿ 信号驱动 EMT，而 TGF-¿ 反应性有助于癌症进展，因此我们一直在研究 TGF-¿ 信号的调节，因为它与上皮可塑性有关。 经过充分研究的 Smad 信号通路可响应 TGF-β 调节基因表达，但 TGF-β 诱导的上皮可塑性反应不能仅用基因调节的变化来解释。因此，TGF-β诱导的非Smad信号传导已受到越来越多的重视。在这笔资金的支持下，我们一直在研究 TGF-β 诱导的 Erk MAPK 和 PI3K-Akt-mTOR 通路激活，并开始研究它们在 EMT 中的作用。 TGF-β诱导的任一途径激活在上皮可塑性反应中的具体作用仍有待进一步确定。我们还发现，细胞通过调节细胞表面的细胞内储存的 TGF-β 受体水平来调节其对 TGF-β 的反应性。葡萄糖水平和胰岛素升高会激活细胞表面 TGF-β 受体的上调，这似乎是由 Akt 激活和 Rab GTPase 激活蛋白 AS160（Akt 磷酸化的直接靶标）介导的。我们假设，Akt 激活的增加（如癌症中常见的那样，或由于葡萄糖或胰岛素刺激增加而导致）增强了细胞的 TGF-¿ 反应性，以及癌细胞对 EMT 的敏感性和易感性，因此可能通过增强 TGF-¿ 反应性来促进癌症进展。 我们现在寻求继续我们的研究计划，旨在表征非 Smad 信号传导机制在控制细胞表面 TGF-β 受体水平、由此产生的 TGF-β 反应性以及 TGF-β 诱导的 EMT 中的作用。我们将当前和未来的研究分为三个目标：（1）研究葡萄糖或胰岛素对 TGF-¿ 信号传导、上皮间质转化、癌症干细胞生成和 EMT 依赖性癌症进展的影响； (2) 定义响应 Akt 激活调节 TGF-β 受体细胞表面呈递的分子机制； (3) 明确TGF-β诱导的Erk MAPK和PI3K-Akt通路激活在上皮-间质转化和癌症干细胞生成中的作用。 我们的研究应该为 TGF-¿ 反应性的调节以及 TGF-¿ 诱导的非 Smad 信号在细胞 TGF-¿ 反应中的作用，特别是在 EMT 和癌症干细胞生成中的作用提供新的机制见解。这些见解可能通过增加 TGF-¿ 反应性将高血糖或胰岛素治疗与癌症进展联系起来，并揭示了癌症中常见的 Akt 信号增加的新作用，从而通过增强 TGF-¿ 反应性促进癌症进展。