TGF Beta Receptor Dynamics

描述（由申请人提供）：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诱导生长刺激（即间充质细胞）和生长抑制（即上皮细胞）等不同的反应？考虑到tgf - β在许多正常和病理条件中的关键作用，如果我们希望制定具体的干预策略，解决这个问题是至关重要的。为此，在之前的资助周期中，我们已经确定(i) tgf - β受体运输到极化上皮细胞的基底外侧区域，在空间上与顶端分泌的配体分离；（ii） AP2 β 2亚基直接结合tgf - β受体复合物；（iii） c-Abl非受体酪氨酸激酶作为tgf - β作用的关键促纤维化介质发挥作用。后一点是非常令人兴奋的，因为它导致研究者启动了II期临床试验，测试甲酸伊马替尼（格列卫）与安慰剂治疗特发性肺纤维化的疗效。在竞争更新中，我们希望扩展这些发现，并测试一般假设，即细胞对tgf - β的反应依赖于运输和信号机制的综合作用。这一假设将通过各种生化、生物学和形态学的方法来解决。首先，我们将定义途径并表征控制极化tgf - β受体运输的受体元件；其次，将确定β 2适应蛋白和Rin1适应蛋白在调节tgf - β受体内化、网格蛋白组装/拆卸以及与信号机制耦合中的作用；第三，将定义tgf - β受体复合物以细胞类型特异性方式激活c-Abl激酶的方法。如果要阐明介导tgf - β诱导的各种细胞表型的过程，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.