Dynamics of Transforming Growth Factor Beta Receptors

描述(由申请者提供)：转变增长的核心悖论 β因子(转化生长因子-b)生物学研究的是相同的生长因子如何诱导 作为生长刺激(例如，间充质细胞)和生长的不同反应 抑制(例如，上皮细胞)。考虑到转化生长因子-β在 一些正常和病态的情况，解决这个问题是 如果我们希望能够制定具体的干预策略，这是至关重要的。 为此，在之前的资金周期中，我们已经确定了受体 元件和活性对转化生长因子-β受体的差异性调节 内吞作用取决于细胞类型。然而，目前还不清楚如何 这种内吞反应与受体信号相耦合，随后 细胞表型。两种两极分化的观点认为：(I)内吞作用仅仅是一种 抑制响应的手段-所有信令都在 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。而当 这些极端的观点使讨论变得生动，更加恰当 问题是：这些模式是相互排斥的吗，还是有可能 在不同的细胞类型和/或受体系统中都有各自的特点吗？ 在这场相互竞争的更新中，我们希望检验一个普遍的假设 转化生长因子受体的内吞和/或转运受特定受体控制 元素和调节与不同信号中间体的关联 极化和非极化细胞。初步数据以文件形式提供 TGFbRs与AP2的b2亚基的特定结合，要求 Smad2磷酸化过程中转化生长因子受体内化和极化转化生长因子受体 贩卖和发信号。我们将进一步扩展这一整合的概念 不同细胞类型中内吞和信号传递机制的作用(I) 转化生长因子受体与受体相互作用及其功能意义的研究 成纤维细胞和上皮细胞的质膜AP2复合体；(Ii)定义 不同细胞内转化生长因子受体内吞作用与信号转导的关系 类型；以及(Iii)确定调节基底外侧的受体元件 转化生长因子-BR的分类和测定这种极化膜的位置 不同地参与信号和内吞机制。

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.