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: 9105649
• 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/9105649
• 关键词: Adaptor Signaling Protein; Apical; Binding; Breast Carcinoma; 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; Human; Immunohistochemistry; Intercellular Junctions; Invaded; Lead; Learning; 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; base; cancer cell; cancer stem cell; cell behavior; cell motility; coated pit; differential expression; epithelial to mesenchymal transition; 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.

 描述（由应用提供）：TGF-β信号传导控制细胞生理，增殖和分化，其放松管制在癌症的进展和纤维化中显着起作用。在癌中，增加的TGF-信号传导促进了上皮可塑性响应，该反应可以发展为上皮 - 间质转变（EMT），这是由基因表达重编程的驱动，并通过上皮细胞 - 细胞 - 细胞连接的丧失和顶端 - 基本 - 基本 - 层状和胞质骨骼重新构成的质量增强性，并提高了正面的极性，并提高了灵活性。由于TGF-β信号的增加，部分或完整的EMT与细胞浸润和癌症传播增加，并与癌通过癌的干细胞产生相关联。 TGF-β结合两种类型的跨膜双特异性激酶受体的TGF-β激活了“ I型受体”TβRI，这又激活了SMAD信号传导，但也启动了ERK MAPK和PI3K-AKT途径信号。 SMAD介导的基因表达变化，ERK MAPK和PI3K-AKT途径信号对于通过EMT的进展至关重要。募集衔接蛋白SHCA募集为两种功能形式，即p52SHCA和p66SHCA，以激活的TβRI，而TβRI启用了SHCA的磷酸化。然而，TβRI主要在SER上磷酸化SHCA，但TGF-β诱导的SER磷酸化的作用尚不清楚。解剖TGF-β诱导的EMT的控制，我们发现SHCA的下调主要以p52SHCA表示，导致EMT通过增加的自分泌TGF-β/SMAD信号传导而导致EMT。此外，p52SHCA与SMAD3竞争与TβRI结合，并有助于定义与网状蛋白相关的SMAD激活复合物和Caveolol复合物之间TGF-β受体的分布，以及P52SHCA募集TGF-β受体在后来的p52SHCA。因此，通过反映自分泌TGF-β/SMAD反应的能力，SHCA可以保护上皮细胞免受EMT的影响，并有助于维持上皮完整性。现在，我们提出了一个旨在定义SHCA在平衡TGF-β接收器空间分布中的核心作用的程序 复合物和差异TGF-β信号反应，通过TGF-β信号传导对SHCA功能的控制，并通过控制其通过控制TGF-β信号传导来欣赏其在控制上皮可塑性，细胞入侵，癌症干细胞产生和癌症发展中的作用。朝向这些目标，我们建议（1）定义p52SHCA和p66SHCA在TGF-β受体的差分分布和信号传导中的作用，TβRI稳定性和Sumoylation（（）定义SHCA Ser磷酸化在TGF-β诱导信号反应中的作用TGF-β信号传导的性质和肿瘤进展。我们的结果将有助于了解SHCA在控制TGF-β信号传导，癌细胞行为和癌症进展中的作用，这可能导致稳定上皮表型的方法，并防止上皮可塑性反应，从而促进癌症的进展和传播。