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- signaling途径代表正常上皮细胞中的主要生长抑制途径，并且矛盾地促进了间充质起源细胞的增殖。这是TGF-◎是一把双边剑，既是早期肿瘤中肿瘤抑制剂又是肿瘤侵袭和癌中转移的重要启动子。尽管TGF-◎损失是癌症的标志，但超过TGF-signaling已与肿瘤转移，纤维化，自身免疫和心血管疾病有关。改善这些疾病的前景可以从对控制TGF-信号途径激活和终止的分子机制的更好理解中受益。我们提出的研究是专注于通过耦合dephosphosphorylationnuclear导出步骤终止TGF-信号的分子机制。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光晶酶。现在，我们首次证明了PPM1A的去磷酸化SMAD2/3的去磷酸化SMAD2/3已准备好通过依赖于RAN结合蛋白RANBP3的途径从核us出口。基于这些发现，当前建议的统一假设是ppm1a和ranbp3的联合作用终止了核us中的tgf- signaling。为了检验该假设，我们已经开始生化和细胞生物学研究，以确定RANBP3如何调节TGF-介导的下游信号通路和物理反应的激活。提出了两个具体目标：1。充分了解Ranbp3如何控制SMAD2/3的核出口； 2。阐明RANBP3如何特异性调节正常和癌细胞中的TGF响应。拟议的研究不仅应了解在生理条件下TGF-◎◎的机制和RANBP3作用的洞察力，而且还提供了有关靶向TGF-◎◎在癌症预防和治疗方面的宝贵信息。