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.

项目总结/文摘