PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism.
PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism.
复制标题
DOI：
10.1371/journal.pgen.1001377
复制
发表时间：
2011-04
期刊：
影响因子：
4.5
通讯作者：
Tissenbaum HA
中科院分区：
文献类型：
--
作者：
Narasimhan SD;Yen K;Bansal A;Kwon ES;Padmanabhan S;Tissenbaum HA
胰岛素/IGF-1信号通路（IIS）是长寿、发育和代谢的保守调节因子。在秀丽隐杆线虫中，IIS涉及激活胰岛素/IGF-1受体酪氨酸激酶、AGE-1（PI 3-激酶）和其他下游丝氨酸/苏氨酸激酶，这些激酶最终磷酸化并负调节单个FOXO转录因子同系物β-16。磷酸酶通过平衡激酶活性来帮助维持细胞信号稳态。然而，很少有磷酸酶已被确定为负调节IIS途径。在这里，我们确定和表征的IIS途径的一种新的负调制器的ESTA-1。我们发现，PDP-1调节IIS的多种输出，如寿命，脂肪储存和dauer滞育。此外，PDP-1还促进β-16的核定位和转录活性。有趣的是，遗传上位性分析将PDP-1置于β 7/TGF-β信号通路中，处于R-SMAD蛋白β 14和β 8的水平。对TGF-β信号传导的组分如何影响IIS/TGF-β-16的多个输出的进一步研究揭示了这两个高度保守的信号传导途径之间的广泛串扰。我们发现PDP-1调节几种胰岛素基因的表达，这些基因可能进入IIS途径以调节β-16活性。重要的是，IIS和TGF-β信号传导失调与2型糖尿病、肥胖和癌症等疾病有关。我们的研究结果可能会提供一个新的视角，在正常条件下，在疾病的情况下，这些途径的调节的理解。身体中的细胞对以限定的空间和时间方式传递的各种开/关信号做出响应。这些信号影响几个过程，如生长，脂肪储存和受损分子的修复。随着人类年龄的增长，2型糖尿病、肥胖症和癌症等疾病的发生往往是由于细胞中开/关信号水平的不平衡。胰岛素/IGF-1信号通路是整个生育期长寿、发育和代谢的重要调节因子。虽然激活这一通路的蛋白激酶已经得到了很好的研究，但对下调信号的蛋白磷酸酶知之甚少。蛔虫C. elegans已经成为研究胰岛素/IGF-1信号在衰老过程中的作用的极好模型系统。在这里，我们确定了一种新的磷酸酶，负调节胰岛素/IGF-1途径，以提高寿命和抗应激能力。有趣的是，磷酸酶通过下调保守的TGF-β途径（一种对发育很重要的途径）的活性来实现这一功能。通过降低TGF-β途径活性，这种磷酸酶降低可能刺激胰岛素/IGF-1途径的胰岛素分子的表达。我们的研究不仅揭示了这些通路的新调节因子，还指出了它们之间的联系比以前认为的更紧密。胰岛素/IGF-1和TGF-β信号传导都与年龄相关疾病有关，了解它们的联系将为我们提供潜在的治疗途径。
The insulin/IGF-1 signaling (IIS) pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase), AGE-1 (PI 3-kinase), and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway. Here we identify and characterize pdp-1 as a novel negative modulator of the IIS pathway. We show that PDP-1 regulates multiple outputs of IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptional activity. Interestingly, genetic epistasis analyses place PDP-1 in the DAF-7/TGF-β signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-β signaling affects multiple outputs of IIS/DAF-16, revealed extensive crosstalk between these two well-conserved signaling pathways. We find that PDP-1 modulates the expression of several insulin genes that are likely to feed into the IIS pathway to regulate DAF-16 activity. Importantly, dysregulation of IIS and TGF-β signaling has been implicated in diseases such as Type 2 Diabetes, obesity, and cancer. Our results may provide a new perspective in understanding of the regulation of these pathways under normal conditions and in the context of disease. Cells in the body respond to a variety of on/off signals that are relayed in a defined spatial and temporal manner. These signals influence several processes such as growth, fat storage, and the repair of damaged molecules. As humans age, the onset of diseases such as Type 2 Diabetes, obesity, and cancer often results from an imbalance in the levels of on/off signals in the cell. The insulin/IGF-1 signaling pathway is an important regulator of longevity, development, and metabolism across phylogeny. While the protein kinases that activate this pathway have been well studied, less is known about the protein phosphatases that tune down the signals. The roundworm C. elegans has been an excellent model system to study the role of insulin/IGF-1 signaling in the aging process. Here, we identify a new phosphatase that negatively regulates the insulin/IGF-1 pathway to enhance longevity and stress-resistance. Interestingly, the phosphatase achieves this function by tuning down the activity of a conserved TGF-β pathway, a pathway important for development. By reducing TGF-β pathway activity, this phosphatase decreases expression of insulin molecules that may stimulate the insulin/IGF-1 pathway. Our studies not only unravel a new regulator of these pathways, but also point to how they are more linked than previously thought. Both insulin/IGF-1 and TGF-β signaling have been implicated in age-associated diseases, and understanding their connection will provide us with potential therapeutic avenues.
登录
查看更多内容
影响因子：
9.9
作者：
通讯作者：
--
影响因子：
64.5
作者：
Kao, Gautam;Nordenson, Cecilia;Naredi, Peter
通讯作者：
Naredi, Peter
影响因子：
56.9
作者：
Garsin, DA;Villanueva, JM;Ausubel, FM
通讯作者：
Ausubel, FM
DOI：
10.1073/pnas.0605333103
发表时间：
2006-08-22
影响因子：
11.1
作者：
Gomis, Roger R.;Alarcon, Claudio;Massague, Joan
通讯作者：
Massague, Joan
影响因子：
4.6
作者：
da Graca, LS;Zimmerman, KK;Patterson, GI
通讯作者：
Patterson, GI