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首页> 外文期刊>Cell biology international. >Evidence that TMEM67 causes polycystic kidney disease through activation of JNK/ERK-dependent pathways.
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Evidence that TMEM67 causes polycystic kidney disease through activation of JNK/ERK-dependent pathways.

机译：TMEM67通过激活JNK / ERK依赖性途径导致多囊肾的证据。

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TMEM67 mutations are associated with severe autosomal recessive polycystic kidney disease (ARPKD) in both humans and animals. However, the molecular mechanisms underlying the pathogenesis of PKD caused by TMEM67 mutations remain to be determined. We have investigated the possible signalling pathways involved in the pathogenesis of PKD. Overexpression of TMEM67 in human embryonic kidney (HEK293) cells triggered the activation of overall tyrosine phosphorylated proteins, extracellular signal-regulated kinase (ERK) and c-jun N-terminal KINASE (JNK). Activation was suppressed by pharmacological inhibitors of ERK or JNK. Activation of the mammalian target of rapamycin (mTOR) or p70s kinase (S6K) did not occur, although elevated phosphorylation of eIF4E-binding protein 1 (4E-BP1), a target of S6K, was seen. In animal studies, activation of a variety of signalling molecules was linked to ERK, JNK and 4E-BP1. Significant induction of phosphorylation of tyrosine phosphorylated proteins, ERK and 4E-BP1, at different postnatal ages was detected in mutant kidneys of B6C3Fe a/a-bpck mice, a cystic renal disease mouse model caused by TMEM67 loss of function mutation. Based on these in vitro and in vivo observations, we propose that TMEM67 mutations cause PKD through ERK- and JNK-dependent signalling pathways, which may provide novel insight into the therapy of polycystic kidney diseases.
机译：TMEM67突变与人类和动物的严重常染色体隐性隐性多囊肾病（ARPKD）有关。然而，由TMEM67突变引起的PKD发病机理的分子机制尚待确定。我们已经研究了PKD发病机制中可能的信号通路。 TMEM67在人类胚胎肾脏（HEK293）细胞中的过表达触发了整体酪氨酸磷酸化蛋白，细胞外信号调节激酶（ERK）和c-jun N端激酶（JNK）的激活。激活被ERK或JNK的药理抑制剂抑制。尽管看到了作为S6K靶标的eIF4E结合蛋白1（4E-BP1）的磷酸化水平升高，但并未激活哺乳动物雷帕霉素靶标（mTOR）或p70s激酶（S6K）。在动物研究中，多种信号分子的激活与ERK，JNK和4E-BP1相关。在B6C3Fe a / a-bpck小鼠的突变肾脏中检测到了明显的酪氨酸磷酸化蛋白ERK和4E-BP1磷酸化诱导，这是一种由TMEM67功能丧失突变引起的囊性肾脏疾病小鼠模型。基于这些体外和体内观察，我们建议TMEM67突变通过ERK和JNK依赖性信号通路引起PKD，这可能为多囊肾疾病的治疗提供新的见识。

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