TGF Beta Receptor Dynamics

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，即细胞对转化生长因子？有赖于贩运和信号机制的综合行动。为了支持这一提议，我们提供了证据：(I)II型转化生长因子-？受体(T2R)通过非规范机制调节基底膜的传递；(Ii)分类连接蛋白9(SNX9)区分Smad3依赖的反应和Smad2；(Iii)ErbB家族成员的诱导对转化生长因子-β调节的间充质细胞表型至关重要。在这场竞争性的更新中，我们将使用各种生化、生物和形态方法来扩展这些概念。首先，我们将确定哺乳动物逆转聚体复合体在调节转化生长因子受体运输中的作用。由于许多疾病是由于蛋白质分类或运输到特定细胞位置的能力缺陷所致，确定可操作的反式作用因子为改变细胞对转化生长因子β的反应提供了潜在的机制。其次，对SNX9调控Smad3转录活性的机制(S)进行了研究。鉴于大多数Smad依赖的转录是通过Smad3介导的，这些研究提出了可以开发干预策略来增强或减弱Smad3特异性反应的可能性。第三，EGF家族成员在促肝纤维化中的作用？将定义信令。自从转化生长因子？是由直接和间接介质的协同作用调节的，我们发现ErbB配体是添加转化生长因子-β后出现的促纤维化表型的基础。为组织纤维化的发生提出了新的范式。 公共卫生相关性：转化生长因子？是一种对人类健康有益或有害的蛋白质。虽然它刺激细胞生长的能力对正常的伤口愈合很重要，但如果不加以控制，许多器官的功能可能会因疤痕(即纤维化)的形成而受到破坏。相反，转化生长因子-β的生长抑制作用。对预防癌症至关重要。拟议的研究将确定/表征可用于增加或减少这些反应的目标。

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 the cellular response to TGF-? is dependent upon an integrated action of the trafficking and signaling machinery. In support of that proposal, we provide evidence that (i) a unique motif in the type II TGF-? receptor (T2R) regulates basolateral membrane delivery via a non-canonical mechanism; (ii) sorting nexin 9 (SNX9) distinguishes Smad3-dependent responses from Smad2; and (iii) the induction of ErbB family members is critical to the mesenchymal cell phenotype regulated by TGF-?. In this competing renewal we will extend these concepts using a variety of biochemical, biological, and morphologic approaches. First, we will determine the role of the mammalian retromer complex in regulating TGF-?R trafficking. As a number of diseases result from defects in the ability to sort or transport proteins to defined cellular locales, characterizing the operative trans-acting factors provides potential mechanisms to alter the cellular response to TGF-?. Second, the mechanism(s) by which SNX9 controls Smad3 transcriptional activity will be characterized. Given that the majority of Smad-dependent transcription is mediated via Smad3, these studies raise the possibility that intervention strategies can be developed to enhance or diminish Smad3-specific responses. Third, the role of EGF family members in pro-fibrotic TGF-? signaling will be defined. Since TGF-? is regulated by the concerted action of both direct and indirect mediators, our finding that ErbB ligands are fundamental for the pro-fibrotic phenotype seen following addition of TGF-? suggests new paradigms to the genesis of tissue fibrosis. PUBLIC HEALTH RELEVANCE: TGF-? is a protein which can be either helpful or harmful to human health. While its ability to stimulate cell growth is important for normal wound healing, when unchecked the function of many organs can be disrupted by scar (i.e., fibrosis) formation. Conversely, the growth inhibitory actions of TGF-? are critical in preventing cancer. The proposed studies will identify/characterize targets which can be used to either increase or decrease these responses.