Dynamics of Transforming Growth Factor Beta Receptors

转化生长因子β受体的动力学

• 批准号: 6636234
• 负责人: EDWARD B LEOF
• 金额: $ 25.4万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6636234
• 关键词: cell component structure /function; clathrin; growth factor receptors; immunoprecipitation; intermolecular interaction; intracellular transport; laboratory rabbit; membrane proteins; molecular asymmetry; molecular site; phosphorylation; protein degradation; protein kinase; protein localization; protein protein interaction; protein structure function; protein transport; radiotracer; receptor binding; receptor coupling; receptor expression; receptor mediated endocytosis; tissue /cell culture; transforming growth factors; western blottings

DESCRIPTION (provided by applicant): A central paradox in transforming growth factor beta (TGF-b) biology is how the same growth factor can induce such divergent responses as growth stimulation (e.g., mesenchymal cells) and growth inhibition (e.g., epithelial cells). Considering the pivotal role TGF-b has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to be able to develop specific intervention strategies. To that end, during the previous funding cycle we have determined that receptor elements and activity differentially regulate TGF-b receptor (TGF-bR) endocytosis depending upon the cell type. However, it is presently unclear how this endocytic response is coupled to receptor signaling and subsequently cellular phenotypes. Two polarized views state that (i)endocytosis is simply a means to dampen the response - all signaling is initiated and completed at the plasma membrane; or (ii) the endocytic system is required to promote the association of activated receptors with downstream signaling molecules. While these extreme viewpoints make for lively discussion, a more appropriate question would be: are these models mutually exclusive or is it possible to have aspects of each occurring in various cell types and/or receptor systems? In this competing renewal we wish to test the general hypothesis that the endocytosis and/or trafficking of TGF-bRs is controlled by defined receptor elements and regulates association with distinct signaling intermediaries in polarized and nonpolarized cells. Preliminary data is presented documenting specific association of TGFbRs with the b2 subunit ofAP2, a requirement for TGF-bR internalization in Smad2 phsosphorylation, and polarized TGF-bR trafficking and signaling. We will further extend this concept of an integrated action of the endocytic and signaling machineries in distinct cell types by (i) characterizing the interaction and functional significance of TGF-bRs with the plasma membrane AP2 complex in fibroblasts and epithelial cells; (ii) defining the relationship between TGF-bR endocytosis and signaling in various cell types; and (iii) identifying the receptor elements regulating basolateral TGF-bR sorting and determining whether this polarized membrane location differentially engages the signaling and endocytic machinery.

描述（由申请人提供）：转变增长的核心悖论 β因子（TGF-b）生物学是相同的生长因子如何诱导这种 生长刺激（例如间充质细胞）和生长的不同反应 抑制（例如上皮细胞）。考虑到 TGF-b 在 一些正常和病理条件，解决这个问题是 如果我们希望能够制定具体的干预策略，这一点至关重要。 为此，在上一个资助周期中，我们确定了受体 元素和活性差异调节 TGF-b 受体 (TGF-bR) 内吞作用取决于细胞类型。但目前尚不清楚如何 这种内吞反应与受体信号传导耦合，随后 细胞表型。两种两极分化的观点认为（i）内吞作用只是 抑制响应的手段 - 所有信令均在 质膜；或 (ii) 需要内吞系统来促进 激活的受体与下游信号分子的关联。尽管 这些极端的观点引起了热烈的讨论，一个更合适的 问题是：这些模型是否相互排斥或者是否有可能 每种细胞类型和/或受体系统中都有不同的方面吗？ 在这种竞争性更新中，我们希望检验以下一般假设： TGF-bR 的内吞作用和/或运输由特定受体控制 元素并调节与不同信号中介的关联 极化和非极化细胞。提供初步数据并记录 TGFbR 与 AP2 的 b2 亚基的特异性关联，这是 Smad2 磷酸化中的 TGF-bR 内化和极化 TGF-bR 贩运和信号传递。我们将进一步拓展这种一体化的理念 内吞和信号传导机制在不同细胞类型中的作用： (i) 表征 TGF-bR 与 成纤维细胞和上皮细胞中的质膜 AP2 复合物； (二) 定义 不同细胞中TGF-bR内吞作用与信号传导的关系 类型； (iii) 识别调节基底外侧的受体元件 TGF-bR分选并确定该极化膜是否定位 差异性地参与信号传导和内吞机制。