Mechanisms of TGF-B/Smad Signaling

描述(由申请人提供)：这项建议的主要目标有两个方面：测试由多功能细胞因子TGF-(由T(Ri(Alk5)-Smad2/3)和其他途径(如涉及Alk1-Smad1/5的通路)的组合介导的多种生物反应的假设；以及测试这样的假设，即不同细胞环境中的信号的特异性和强度也由SMAD3的基础水平预先决定，因为存在一个由Axin-GSK3组成的调控机构，它在缺乏TGF-α信号的情况下调节SMAD3的周转。如初步研究部分所示，我们已经生成了大量的初步数据，以支持主题的生理意义和研究计划的可行性。因此，目标1将确定转化生长因子-1通过非规范的骨形态发生因子相关受体I/Smad1/5信号通路引起特异性生物反应的功能和机制，如抑制B淋巴细胞增殖和刺激细胞迁移。这一假说的验证将挑战目前该领域的范式，即Smad1/5主要作为BMP信号通路的效应器，只有极少数介导内皮细胞中的转化生长因子-β信号。目的2确定Axin-GSK3(复合体)翻转Smad3基础水平的功能意义和机制。我们将研究GSK3(激酶)对Smad3上特定残基进行磷酸化的生化和生物学性质。由于APC和CKI被定义为(-连环蛋白破坏复合体的组成部分)，我们还将研究这两个蛋白是否参与SMAD3的周转。虽然主要的转化生长因子信号通路的范式已经建立，但关于非规范通路在特定细胞环境中调节不同生物反应的贡献还需要更多的了解。这些特定目标的实现将使人们更好地理解这一重要因素在细胞内稳态、发育和疾病过程中的作用和机制。作为一种多功能的细胞因子，转化生长因子-β参与了多种生理和病理过程的调节。更好地了解转化生长因子-()的作用机制可能有助于开发治疗许多人类疾病的新疗法，包括癌症和纤维化。

DESCRIPTION (provided by applicant): The primary objectives of this proposal are two folds: test the hypothesis that the diverse biological responses elicited by the multifunctional cytokine TGF-( are mediated by a combination of the canonical pathway of T(RI(Alk5)-Smad2/3 and other pathways such as those involving Alk1- Smad1/5; and test the hypothesis that the specificity and intensity of TGF-( signaling in different cellular context are also predetermined by the basal level of Smad3 due to the presence of a regulatory apparatus consisting of Axin-GSK3( that mediates the turnover of Smad3 in the absence of TGF-( signal. As shown in the section of Preliminary Studies, we have generated substantial amount of preliminary data to support the physiological significance of the topics and the feasibility of the research plan. Thus, Aim 1 will determine the function and mechanism by which TGF-( elicits specific biological responses, such as inhibition of B lymphocyte proliferation and stimulation of cell migration, via the non-canonical bone morphogenetic factor associated receptor I/Smad1/5 signaling pathway. Validation of this hypothesis would challenge the current paradigm in the field that Smad1/5 function primarily as effectors for the BMP signaling pathway and only very rarely mediate TGF-( signal as in endothelial cells. Aim 2 will determine the functional significance of and mechanism underlying the turnover of basal level of Smad3 by the Axin-GSK3( complex. We will study the biochemical and biological nature of phosphorylation of specific residues on Smad3 by the GSK3( kinase. Since APC and CKI have been defined as integral parts of the (-catenin destruction complex, we will also investigate whether these two proteins are involved in Smad3 turnover. While the paradigm for the primary TGF-( signaling pathway has been well established, much more needs to be learned on the contributions of non-canonical pathways to the mediation of diverse biological responses in specific cellular contexts. Accomplishment of these specific aims will lead to a better understanding on the actions and mechanisms of this important factor in cell homeostasis, development, and disease processes. As a multifunctional cytokine, TGF-( is involved in the regulation of many physiological and pathological processes. A better understanding of the mechanisms underlying the actions of TGF-( could help the development of novel therapeutics for many human diseases, including cancer and fibrosis.