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Mechanism of TGF-beta Signaling Termination

TGF-β信号传导终止机制

基本信息

批准号：
7895079
负责人：
XIN-HUA FENG
金额：
$ 30.78万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2013-08-31
项目状态：
已结题

项目摘要

The TGF-􀀁signaling pathway represents a major growth inhibitory pathway in normal epithelial cells, and paradoxically, it promotes proliferation in cells of mesenchymal origins. Thus, TGF-􀀁 is a double-edge sword acting as both a tumor suppressor in early tumors and as a significant promoter of tumor invasion and metastasis in carcinomas. Whilst loss of TGF-􀀁growth inhibitory actions is a hallmark in cancer, excess of TGF-􀀁signaling has been associated with tumor metastasis, fibrotic, autoimmune and cardiovascular diseases. Improving the outlook for these diseases can benefit from a better understanding of the molecular mechanisms that govern the activation and termination of TGF-􀀁signaling pathway. Our proposed research is to focus on the molecular mechanisms underlying the termination of TGF-􀀁signaling by coupled dephosphorylationnuclear export steps. As a first step, we recently identified PPM1A as a critical protein phosphatase that initiates the TGF-􀀁signal termination step. Now we demonstrated, for the first time, that the dephosphorylated Smad2/3 by PPM1A is ready to be exported out of the nucleus through a pathway dependent of Ran-binding protein RanBP3. Based on these discoveries, the unifying hypothesis of the current proposal is that the combined actions of PPM1A and RanBP3 terminate TGF-􀀁signaling in the nucleus. To test this hypothesis, we have begun biochemical and cell biological studies to determine how RanBP3 regulates TGF-􀀁-mediated activation of downstream signaling pathways and physiological responses. Two specific aims are proposed: 1. To fully understand how RanBP3 controls the nuclear export of Smad2/3; 2. To elucidate how RanBP3 specifically regulates TGF􀀁responses in normal and cancer cells. The proposed studies should not only gain insights into the mechanisms of TGF-􀀁and RanBP3 actions under physiological conditions, but also provide invaluable information on targeting TGF-􀀁in cancer prevention and treatment.

TGF-信号通路代表正常上皮细胞中的主要生长抑制通路，但矛盾的是，它促进间充质来源的细胞增殖。因此，TGF-是一把双刃剑，既可以作为早期肿瘤的肿瘤抑制因子，又可以作为癌症中肿瘤侵袭和转移的重要促进剂。虽然 TGF-生长抑制作用的丧失是癌症的一个标志，但 TGF-信号传导过多与肿瘤转移、纤维化、自身免疫和心血管疾病有关。更好地了解控制 TGF-信号通路激活和终止的分子机制可以改善这些疾病的前景。我们提出的研究重点是通过耦合去磷酸化核输出步骤终止 TGF-信号传导的分子机制。作为第一步，我们最近将 PPM1A 确定为启动 TGF-信号终止步骤的关键蛋白磷酸酶。现在，我们首次证明，PPM1A 去磷酸化的 Smad2/3 已准备好通过 Ran 结合蛋白 RanBP3 依赖的途径从细胞核输出。基于这些发现，当前提议的统一假设是 PPM1A 和 RanBP3 的联合作用终止细胞核中的 TGF-信号传导。为了检验这一假设，我们已经开始进行生化和细胞生物学研究，以确定 RanBP3 如何调节 TGF-β 介导的下游信号通路激活和生理反应。提出了两个具体目标： 1. 充分了解 RanBP3 如何控制 Smad2/3 的核输出； 2. 阐明 RanBP3 如何特异性调节正常细胞和癌细胞中的 TGF 反应。拟议的研究不仅应该深入了解 TGF- 和 RanBP3 在生理条件下的作用机制，而且还可以提供有关靶向 TGF- 在癌症预防和治疗中的宝贵信息。