Dynamics of Transforming Growth Factor Beta Receptors

描述（由申请人提供）：转型增长中的一个核心悖论 因子β（TGF-β）生物学是如何相同的生长因子可以诱导这种 作为生长刺激的不同反应（例如，间充质细胞）和生长 抑制（例如，上皮细胞）。考虑到TGF-b在肿瘤生长中的关键作用， 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战略，这是根本性的。 为此，在上一个供资周期，我们已确定该受体 元件和活性差异调节TGF-β受体（TGF-β R） 内吞作用取决于细胞类型。然而，目前尚不清楚如何 这种内吞反应与受体信号传导偶联， 细胞表型两种两极分化的观点认为：（i）内吞作用只是一个简单的过程， 抑制响应的方法-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 这些极端的观点引起了热烈的讨论， 问题是：这些模式是相互排斥的，还是有可能 每个方面都发生在不同的细胞类型和/或受体系统？ 在这种竞争性的更新中，我们希望测试一般假设， TGF-bRs的内吞和/或运输由确定的受体控制 元素和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， TGF β R与AP 2的b2亚基的特异性结合， TGF-β R在Smad2磷酸化中的内化和极化TGF-β R 贩运和信号。我们将进一步扩大这一概念， 内吞和信号传导机制在不同细胞类型中的作用：（i） 表征TGF-bRs与肿瘤细胞的相互作用和功能意义 成纤维细胞和上皮细胞中的质膜AP2复合物;（ii）定义 不同细胞内TGF-bR内吞与信号转导关系 类型;和（iii）识别调节基底外侧的受体元件 TGF-bR分选和确定这种极化膜的位置 差异地接合信号传导和内吞机制。

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.