Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
PLoS Genet. 2011 Apr;7(4):e1001377. doi: 10.1371/journal.pgen.1001377. Epub 2011 Apr 21.
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.
胰岛素/胰岛素样生长因子-1 信号通路（IIS）是一种保守的长寿、发育和代谢调节剂。在秀丽隐杆线虫中，IIS 涉及 DAF-2（胰岛素/胰岛素样生长因子-1 受体酪氨酸激酶）、AGE-1（PI 3-激酶）和其他下游丝氨酸/苏氨酸激酶的激活，这些激酶最终磷酸化并负调控单一的 FOXO 转录因子同源物 DAF-16。磷酸酶通过平衡激酶活性有助于维持细胞信号转导的内稳态。然而，只有少数磷酸酶被鉴定为负调控 IIS 途径。在这里，我们鉴定并表征了 pdp-1 作为 IIS 途径的一种新的负调节剂。我们表明，PDP-1 调节 IIS 的多种输出，如寿命、脂肪储存和 dauer 休眠。此外，PDP-1 促进 DAF-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 DAF-7/TGF-β 信号通路中，位于 R-SMAD 蛋白 DAF-14 和 DAF-8 的水平。进一步研究 TGF-β 信号通路的一个组成部分如何影响 IIS/DAF-16 的多个输出，揭示了这两个高度保守的信号通路之间的广泛串扰。我们发现 PDP-1 调节了几种胰岛素基因的表达，这些基因可能会进入 IIS 途径来调节 DAF-16 的活性。重要的是，IIS 和 TGF-β 信号转导的失调与 2 型糖尿病、肥胖和癌症等疾病有关。我们的研究结果可能为理解这些通路在正常情况下和疾病背景下的调节提供了新的视角。
