Mechanisms of TGF-B/Smad Signaling

描述（由申请人提供）：本提案的主要目的有两个方面：检验由多功能细胞因子TGF-β 1引起的多种生物学应答的假设。（由T（RI）（Alk 5）-Smad 2/3的经典途径和其它途径如涉及Alk 1-Smad 1/5的那些途径的组合介导;并检验以下假设：由于存在由Axin-GSK 3（其在TGF-β信号不存在的情况下介导Smad 3的周转。如初步研究部分所示，我们已经产生了大量的初步数据，以支持主题的生理意义和研究计划的可行性。因此，目的1将确定TGF-β 1通过非经典骨形态发生因子相关受体I/Smad 1/5信号通路产生特异性生物学反应，如抑制B淋巴细胞增殖和刺激细胞迁移的功能和机制。该假设的验证将挑战本领域的当前范例，即Smad 1/5主要作为BMP信号传导途径的效应物起作用，并且仅非常罕见地如在内皮细胞中介导TGF-β信号。目的2：探讨Axin-GSK 3复合物对Smad 3基础水平转换的功能意义和机制。我们将研究GSK 3（激酶）对Smad 3上特定残基磷酸化的生物化学和生物学性质。由于APC和CKI已被定义为β-连环蛋白破坏复合物的组成部分，我们也将研究这两种蛋白质是否参与Smad 3周转。虽然已经很好地建立了主要TGF-β信号传导途径的范例，但是需要了解更多关于非经典途径在特定细胞环境中介导多种生物反应的贡献。这些具体目标的实现将导致更好地理解这一重要因素在细胞稳态，发育和疾病过程中的作用和机制。作为一种多功能细胞因子，TGF-β参与多种生理和病理过程的调节。更好地了解TGF-β的作用机制可以帮助开发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.