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矛盾是相同的生长因子如何诱导诸如生长刺激（即，间充质细胞）和生长抑制（即，上皮细胞）？考虑到TGF-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，解决这个问题是至关重要的。为此，在前一个资助周期中，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结构域，与顶端分泌的配体在空间上分离;（ii）AP 2 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。这后一点是非常令人兴奋的，因为它导致了研究人员启动的II期临床试验测试伊马替尼甲磺酸盐（格列卫）与安慰剂在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，并检验细胞对TGF-β的反应依赖于运输和信号机制的综合作用的一般假设。这一假说将通过各种生物化学，生物学和形态学的方法来解决。首先，我们将确定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 adaptin和Rin 1 adaptor在调节TGF-β受体内化、网格蛋白组装/拆卸以及与信号传导机制偶联中的作用;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TGF-β诱导的各种细胞表型的介导过程，这些问题的答案至关重要。

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.