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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Polycystin-1 regulates STAT activity by a dual mechanism
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Polycystin-1 regulates STAT activity by a dual mechanism

机译：Polycystin-1通过双重机制调节STAT活性

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摘要

Mutations in polycystin-1 (PC1) lead to autosomal-dominant poly-cystic kidney disease (ADPKD), a leading cause of renal failure for which no treatment is available. PC1 is an integral membrane protein, which has been implicated in the regulation of multiple signaling pathways including the JAK/STAT pathway. Here we show that membrane-anchored PC1 activates STAT3 in a JAK2-dependent manner, leading to tyrosine phosphorylation and transcriptional activity. The C-terminal cytoplasmic tail of PC1 can undergo pro-teolytic cleavage and nuclear transfocation. Tail-cleavage abolishes the ability of PC1 to directly activate STAT3 but the cleaved PC1 tail now coactivates STAT3 in a mechanism requiring STAT phosphorylation by cytokines or growth factors. This leads to an exaggerated cytokine response. Hence, PC1 can regulate STAT activity by a dual mechanism. In ADPKD kidneys PC1 tail fragments are over-expressed, including a unique ~15-kDa fragment (P15). STAT3 is strongly activated in cyst-lining epithelial cells in human ADPKD, and orthologous and nonorthologous polycystic mouse models. STAT3 is also activated in developing, postnatal kidneys but inactivated in adult kidneys. These results indicate that STAT3 signaling is regulated by PC1 and is a driving factor for renal epithelial proliferation during normal renal development and during cyst growth.
机译：polycystin-1（PC1）中的突变会导致常染色体显性遗传的多囊性肾病（ADPKD），这是无法进行治疗的肾衰竭的主要原因。 PC1是必不可少的膜蛋白，已参与包括JAK / STAT途径在内的多种信号途径的调控。在这里，我们显示膜锚定的PC1以JAK2依赖的方式激活STAT3，从而导致酪氨酸磷酸化和转录活性。 PC1的C末端胞质尾巴可以进行蛋白水解切割和核转录。尾部切割消除了PC1直接激活STAT3的能力，但现在，已切割的PC1尾部以需要通过细胞因子或生长因子使STAT磷酸化的机制共激活STAT3。这导致细胞因子反应过度。因此，PC1可以通过双重机制调节STAT活性。在ADPKD肾脏中，PC1尾部片段过度表达，包括一个独特的〜15-kDa片段（P15）。 STAT3在人ADPKD以及直系和非直系多囊小鼠模型中的囊壁上皮细胞中被强烈激活。 STAT3在发育中的出生后肾脏中也被激活，但在成年肾脏中被灭活。这些结果表明STAT3信号传导受PC1调节，并且是正常肾脏发育和囊肿生长期间肾上皮细胞增殖的驱动因素。

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    Jeffrey J. Talbot; Jonathan M. Shillingford; Shivakumar Vasanth; Nicholas Doerr; Sambuddho Mukherjee; Mike T. Kinter; Terry Watnick; Thomas Weimbs;

  • 作者单位

    Department of Molecular, Cellular, and Developmental Biology,Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9610;

    Department of Molecular, Cellular, and Developmental Biology,Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9610;

    Department of Molecular, Cellular, and Developmental Biology,Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9610;

    Department of Molecular, Cellular, and Developmental Biology,Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9610;

    Department of Molecular, Cellular, and Developmental Biology,Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9610;

    Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104;

    Division of Nephrology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;

    Department of Molecular, Cellular, and Developmental Biology,Neuroscience Research Institute, University of California, Santa Barbara, CA 93106-9610;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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