TGF Beta Receptor Dynamics

描述(申请人提供)：转化生长因子β(TGF-β)生物学中的一个中心悖论是，相同的生长因子如何引起不同的反应，如生长刺激(即，间充质细胞)和生长抑制(即，上皮细胞)？考虑到转化生长因子-β在许多正常和病理条件下的关键作用，如果我们希望制定具体的干预策略，解决这个问题是根本的。为此，在之前的资金周期中，我们已经确定：(I)转化生长因子-β受体在空间上与顶端分泌的配体分离，进入极化上皮细胞的基底外侧区域；(Ii)AP2-β2亚单位直接与转化生长因子-β受体复合体结合；(Iii)c-Ab1非受体酪氨酸激酶作为转化生长因子-β作用的关键促纤维化介质发挥作用。后一点非常令人兴奋，因为它导致一名研究人员启动了第二阶段临床试验，测试甲磺酸伊马替尼(格列卫)与安慰剂治疗特发性肺纤维化的疗效。在竞争性更新中，我们希望扩展这些发现，并检验一般假设，即细胞对转化生长因子-β的反应依赖于运输和信号机制的综合作用。这一假说将通过各种生化、生物学和形态学方法加以解决。首先，我们将确定控制极化的转化生长因子-β受体转运的受体元件的特征；其次，将确定β2适配素和Rin1接头在调节转化生长因子-β受体内化、网状蛋白组装/分解以及与信号机制的偶联中的作用(S)；第三，将确定转化生长因子-β受体复合体以特定细胞类型的方式激活c-Abl激酶的方式。如果要阐明转化生长因子-β诱导的各种细胞表型的调节过程，这些问题的答案是至关重要的。

DESCRIPTION (provided by applicant): A central paradox in transforming growth factor beta (TGF-beta) biology is how the same growth factor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells)? Considering the pivotal role TGF-beta has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, during the previous funding cycle we have determined that (i) TGF-beta receptors traffic to the basolateral domain of polarized epithelial cells, spatially separate from apically secreted ligand; (ii) the AP2 beta2 subunit directly binds the TGF-beta receptor complex; and (iii) the c-Abl nonreceptor tyrosine kinase functions as a crucial profibrogenic mediator of TGF-beta action. This latter point is extremely exciting as it has led to an investigator initiated Phase II clinical trial testing the efficacy of imatinib mesylate (Gleevec) vs. placebo in the treatment of idiopathic pulmonary fibrosis. In the competing renewal we wish to extend these findings and test the general hypothesis that the cellular response to TGF-beta is dependent upon an integrated action of the trafficking and signaling machinery. This hypothesis will be addressed through a variety of biochemical, biological, and morphologic approaches. First, we will define the route and characterize the receptor elements controlling polarized TGF-beta receptor trafficking; second, the role(s) of beta2 adaptin and the Rin1 adaptor in regulating TGF-beta receptor internalization, clathrin assembly/disassembly, and coupling to the signaling machinery will be determined; and third, the means by which the TGF-beta receptor complex activates the c-Abl kinase in a cell type-specific manner will be defined. Answers to these questions are critical if the processes mediating the various cellular phenotypes induced by TGF-beta are to be elucidated.