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.

 描述(申请人提供)：转化生长因子-β信号控制细胞的生理、增殖和分化，其去调控在癌症进展和纤维化中起重要作用。在癌症中，转化生长因子-信号的增加促进了上皮的可塑性反应，该反应可以进展到上皮-间充质转化，这是由基因表达的重新编程驱动的，其特征是上皮细胞-细胞连接的丧失和顶端-基底极性的丧失，细胞骨架的重组，前后极性和增加的运动性，从而通常使侵袭成为可能。由于转化生长因子-β信号的增加，部分或全部内皮细胞转移与细胞侵袭和癌症扩散增加有关，并与癌症产生的癌症干细胞有关。转化生长因子-β与两种类型的跨膜双特异性受体组成的细胞表面复合体结合后，可激活“I型受体”T-βRI，进而激活Smad信号，同时也启动ERK-MAPK和PI3K-Akt信号通路。Smad介导的基因表达变化以及Erk MAPK和PI3K-Akt信号通路在EMT过程中起着至关重要的作用。以两种功能形式(即p52ShcA和p66ShcA)产生的适配蛋白SHCA被募集到激活的TβRI上，并被TβRI磷酸化以启动TYR启动转化生长因子-β诱导的ERK MAPK激活。然而，TβRI主要在Ser上磷酸化ShcA，但β诱导Shca的Ser磷酸化的作用尚不清楚。分析转化生长因子-β诱导的子宫内膜转化的调控，我们发现主要表达为p52ShcA的SHCA的下调通过增加自分泌转化生长因子-β/Smad信号而导致子宫内膜转化。此外，p52ShcA与Smad3竞争结合TβRI，有助于确定转化生长因子-β受体在分子筛相关的Smad激活复合体和空泡复合体之间的分布，p52ShcA将转化生长因子-β受体募集到后者。因此，通过抑制自分泌的转化生长因子-β/SMAD反应，SHCA保护上皮细胞免受EMT的影响，并有助于维持上皮细胞的完整性。我们现在提出一个计划，旨在确定SHCA在平衡转化生长因子-β受体的空间分布中的核心作用 本研究的目的是通过研究转化生长因子-β复合体和不同的转化生长因子-β信号反应，通过转化生长因子-β信号调控SHCA的功能，从而认识其通过控制转化生长因子-DNA信号，在控制上皮可塑性、细胞侵袭、肿瘤干细胞生成和癌症进展中的作用。为此，我们建议(1)明确p52ShcA和p66ShcA在转化生长因子-β受体的差异分布和信号转导中的作用，以及T-βRI的稳定性和总摩化；(3)研究SHCA丝氨酸磷酸化在转化生长因子-β诱导的信号反应中的作用；(3)研究转化生长因子-β信号在上皮可塑性、细胞侵袭、肿瘤干细胞特性和肿瘤进展中的调控作用。我们的结果将有助于理解SHCA在控制转化生长因子-β信号、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和防止导致癌症进展和扩散的上皮可塑性反应的方法。