Central role of ShcA in differential TGF-beta signaling, epithelial plasticity and carcinoma cell behavior

ShcA 在差异 TGF-β 信号传导、上皮可塑性和癌细胞行为中的核心作用

• 批准号: 9237246
• 负责人: RIK M DERYNCK
• 金额: $ 36.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237246
• 关键词: AKT Signaling Pathway; Adaptor Signaling Protein; Alpha Cell; Apical; Binding; Breast Carcinoma; Cancer Control; Carcinoma; Caveolae; Cell Culture Techniques; Cell Line; Cell Maintenance; Cell physiology; Cell surface; Cells; Clathrin; Complex; Cytoskeletal Modeling; Development; Differentiation and Growth; Disease; Down-Regulation; Epithelial; Epithelial Cells; Equilibrium; Family; Fibrosis; Funding; Gene Activation; Gene Expression; Generations; Goals; Growth Factor; Human; Immunohistochemistry; Intercellular Junctions; Invaded; Lead; Light; Link; MAP Kinase Gene; Malignant Epithelial Cell; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mesenchymal; Mutation Analysis; Names; Organ; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Property; Proteins; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Regulation; Research; Role; Signal Pathway; Signal Transduction; Spatial Distribution; Specificity; Surface; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; autocrine; cancer cell; cancer stem cell; cell behavior; cell motility; coated pit; epithelial to mesenchymal transition; mouse ShcA protein; prevent; programs; prototype; public health relevance; receptor; response; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): TGF-β signaling controls cell physiology, proliferation and differentiation, and its deregulation acts prominently in cancer progression and fibrosis. In carcinomas, increased TGF- signaling promotes an epithelial plasticity response that can progress to epithelial-mesenchymal transition (EMT), which is driven by reprogramming of gene expression and marked by loss of epithelial cell-cell junctions and apical-basal polarity, cytoskeletal reorganization, frontal-rear polarity and increased motility that often enables invasion. Partial or complete EMT, as a result of increased TGF-β signaling, associates with increased cell invasion and cancer dissemination, and with cancer stem cell generation by carcinomas. TGF-β binding to a cell surface complex of two types of transmembrane dual-specificity kinase receptors activates the "type I receptor" TβRI, which in turn activates Smad signaling, yet also initiates Erk MAPK and PI3K-Akt pathway signaling. Smad-mediated changes in gene expression and Erk MAPK and PI3K-Akt pathway signaling are essential for progression through EMT. Recruitment of the adaptor protein ShcA, which is generated as two functional forms, i.e. p52ShcA and p66ShcA, to the activated TβRI, and phosphorylation of ShcA by TβRI on Tyr initiate TGF-β-induced Erk MAPK activation. However, TβRI phosphorylates ShcA predominantly on Ser, but the role of TGF-β-induced Ser phosphorylation of ShcA is unknown. Dissecting the control of TGF-β-induced EMT, we found that downregulation of ShcA, expressed primarily as p52ShcA, leads to EMT through increased autocrine TGF-β/Smad signaling. Furthermore, p52ShcA competes with Smad3 for binding to TβRI and helps define the distribution of TGF-β receptors between clathrin-associated Smad activating complexes, and caveolar complexes, with p52ShcA recruiting TGF-β receptors to the latter. Thus, through its ability to repress autocrine TGF-β/Smad responses, ShcA protects epithelial cells against EMT, and helps maintain epithelial integrity. We now propose a program aimed at defining the central role of ShcA in balancing the spatial distribution of TGF-β receptor complexes and differential TGF-β signaling responses, the control of ShcA function by TGF-β signaling, and to consequently appreciate its role in controlling epithelial plasticity, cell invason, cancer stem cell generation and cancer progression, through its control of TGF-β signaling. Toward these goals, we propose (1) to define the roles of p52ShcA and p66ShcA in the differential distribution and signaling of TGF-β receptors, and TβRI stability and sumoylation, () to define the roles of ShcA Ser phosphorylation in TGF-β-induced signaling responses, (3) to study the role of ShcA in the regulation of epithelial plasticity, cell invasion, cancer stem cell properties and tumor progression by TGF-β signaling. Our results will help understand the role of ShcA in the control of TGF-β signaling, cancer cell behavior and cancer progression, which may lead to approaches to stabilize the epithelial phenotype and prevent epithelial plasticity responses that enable cancer progression and dissemination.