TGF beta Receptors and Cell Proliferation

描述(申请人提供)：转化生长因子β(TGF-？)的一个中心悖论生物学是指相同的生长因子如何引起刺激生长(即间充质细胞)和抑制生长(即上皮细胞)等不同反应？考虑到转化生长因子的关键作用？在一些正常和病理情况下，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，我们一直在研究一种普遍的假设，即转化生长因子？信号转导受近端细胞膜和胞核的协同作用所调控。受体(转化生长因子受体)活性。为了支持这一提议，我们提供的证据表明：(I)FAK(粘着斑激酶)在促纤维化的转化生长因子？它通过将配体激活的I型转化生长因子受体偶联到PI3K的P85亚基上的信号转导途径，PI3K是调节非Smad通路的最上游成分，如PAK2/c-Abl和Akt/mTOR；以及(Ii)质膜定位的I型和II型转化生长因子-β受体在添加配体后经历逆行运输和核输入。在这场竞争性的更新中，我们将使用各种生化、遗传和形态方法来扩展这些概念。首先，我们将确定FAK如何调控非Smad转化生长因子？由于器官纤维化的有效治疗策略的数量有限，定义这种相互作用为解偶联转化生长因子-β受体的纤维增殖作用提供了潜在的途径。其次，将确定转化生长因子-β受体从细胞表面向细胞核转运的机制和靶点。这些结果扩展了细胞环境指导不同的转化生长因子-β信号反应的范式。此外，由于在开发转化生长因子-β作用的抑制剂方面具有显著的活性，核转化生长因子-β受体的活性可能会影响这些治疗的疗效。

DESCRIPTION (provided by applicant): A central paradox in transforming growth factor beta (TGF-?) 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-? 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, we have been investigating the general hypothesis that TGF-? signaling is regulated by the coordinate action of membrane proximal and nuclear TGF-? receptor (TGF-?R) activity. In support of that proposal, we provide evidence that (i) FAK (focal adhesion kinase) has an obligate scaffolding function in profibrotic TGF-? signaling whereby it couples the ligand-activated type I TGF-?R to the p85 subunit of PI3K, the most upstream component regulating non-Smad pathways such as PAK2/c-Abl and Akt/mTOR; and (ii) plasma membrane localized type I and type II TGF-?Rs undergo retrograde trafficking and nuclear import following addition of ligand. In this competing renewal we will extend these concepts using a variety of biochemical, genetic, and morphologic approaches. First, we will determine how FAK regulates non-Smad TGF-? signaling through cell type-specific binding with the type I TGF-?R. As the number of effective therapeutic strategies for organ fibrosis is limited, defining this interaction provides potential approaches to uncouple TGF-?'s fibroproliferative actions. Second, the mechanism and targets of TGF-?R trafficking from the cell surface to the nucleus will be defined. These results extend the paradigm whereby the cellular environment directs distinct TGF-? signaling responses. Moreover, as there is significant activity in developing inhibitors to TGF-? action, nuclear TGF-?R activity might impact the efficacy of these treatments.