RECEPTORS FOR TRANSFORMING GROWTH FACTOR-BETA

转化生长因子-β受体

• 批准号: 2088719
• 负责人: JOAN MASSAGUE
• 金额: $ 25.57万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-05-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2088719
• 关键词: SDS polyacrylamide gel electrophoresis; affinity chromatography; animal tissue; antibody; biological signal transduction; cell membrane; chemical binding; complementary DNA; extracellular matrix; fluorescent dye /probe; genetic library; genetic promoter element; genetically modified animals; growth factor receptors; human genetic material tag; inhibitor /antagonist; laboratory mouse; laboratory rabbit; membrane proteins; molecular cloning; mutant; protein sequence; protein structure function; proteoglycan; site directed mutagenesis; tissue /cell culture; transfection; transforming growth factors

Transforming growth factor-beta (TGF-beta) is prototypic of a large family of paracrine polypeptides that are present in organisms from insects to humans and involved in processes ranging from embryogenic pattern formation and morphogenesis to regulation of endocrine systems. Their mechanism of action is unknown. Our appreciation of the complexity of the TGF-beta system has escalated dramatically in the last five years. TGF-beta exists in multiple isoforms that regulate cell growth, differentiation, adhesion, migration and extracellular matrix deposition. TGF-beta is thought to play crucial roles in organismal development and tissue repair processes. Excess of TGF-beta activity can lead to fibrotic disorders and immunosuppression. Failure of TGF-beta to inhibit cell proliferation can promote or contribute to oncogenesis. The wealth of information that has accumulated during recent years on the structure, distribution and activity of the TGF-betas contrasts with the scanty understanding of its mechanism of action. The intracellular components known to play some role in mediating TGF-beta action are very few. The membrane receptors implicated in TGF-beta signal transduction have been identified only recently, and their mode of signaling is completely unknown. The long-term goal of this project is to elucidate the mechanisms that initiate and mediate TGF-beta signal transduction. To achieve this goal, I propose to molecularly clone TGF-beta receptor components I and II by taking advantage of their known properties and of a panel of cell mutants that have specific defects in these receptor components. The cloning of these cDNAs will allow a structural and functional analysis of the TGF-beta receptor and should lead to identification of the TGF-beta signaling mechanism. It should also assist in identifying analogous receptors for other members of the TGF-beta superfamily. To complement this approach, I also propose to clone cDNAs whose products suppress cellular responsiveness to TGF-beta. Such antagonists or negative regulators of TGF-beta action will be important as indicators of the nature of the signaling pathway. Finally, I propose to molecularly clone and functionally characterize betaglycan, and integral membrane proteoglycan whose core protein binds TGF-beta with high affinity and whose carbohydrate chains may bind to specific proteins in cell membranes and extracellular matrices. Betaglycan, which may function as a major pericellular reservoir and/or regulator of TGF-beta presentation to the signaling receptors, has been purified to homogeneity in our laboratory to characterize its function and as a step towards cloning its cDNA. Future progress towards the aims set forth in this proposal should clarify important gaps in our current understanding of fundamental mechanisms that control animal cell growth and phenotype.

转化生长因子β（TGF-beta）是一个大家族的原型 从昆虫到生物中存在的旁分泌多肽 人类，参与胚胎模式形成的过程 和对内分泌系统调节的形态发生。 他们的机制 动作是未知的。 我们对TGF-beta的复杂性的欣赏 在过去的五年中，系统急剧升级。 TGF-beta存在 在调节细胞生长，分化，粘附的多种同工型中， 迁移和细胞外基质沉积。 TGF-beta被认为玩 在有机体发育和组织修复过程中至关重要的作用。 过多的TGF-β活性会导致纤维化疾病，并且 免疫抑制。 TGF-β无法抑制细胞增殖可以 促进或有助于肿瘤发生。 拥有的丰富信息 近年来在结构，分布和活动上积累 TGF-betas与对其机制的理解形成鲜明对比 行动。 已知在 介导TGF-β动作很少。 涉及膜受体 在TGF-β信号转导中，仅最近才确定，并且 他们的信号传导方式是完全未知的。 这个长期目标 项目是为了阐明启动和介导TGF-beta的机制 信号转导。 为了实现这一目标，我建议分子克隆 TGF-β受体成分I和II通过利用其已知的优势 特性和一组具有特定缺陷的细胞突变体 这些受体成分。 这些cDNA的克隆将允许 TGF-beta受体的结构和功能分析，应引导 识别TGF-β信号传导机制。 它也应该 协助识别TGF-beta其他成员的类似受体 超家族。 为了补充这种方法，我还建议克隆cDNA 其产品抑制了对TGF-β的细胞反应性。 这样的 TGF-beta作用的拮抗剂或负调节剂将很重要 信号通路性质的指标。 最后，我建议 分子克隆并在功能上表征βlycan和积分 膜蛋白聚糖的核心蛋白与高亲和力结合TGF-β 并且其碳水化合物链可能与细胞中的特定蛋白结合 膜和细胞外矩阵。 betaglycan，可能充当 TGF-beta演示的主要细胞周围储层和/或调节器 信号受体已被纯化为我们的实验室的同质性 表征其功能，并作为克隆cDNA的一步。 未来朝着本提案中规定的目标的进步应澄清 在我们当前对基本机制的理解中的重要差距 控制动物细胞的生长和表型。