Over-activation of the PI3K/Akt/mTOR network is a well-known pathogenic event that leads to hyper-proliferation. Pharmacological targeting of this pathway has been developed for the treatment of multiple diseases, including cancer. In polycystic kidney disease (PKD), the mTOR cascade promotes cyst growth by boosting proliferation, size and metabolism of kidney tubule epithelial cells. Therefore, mTOR inhibition has been tested in pre-clinical and clinical studies, but only the former showed positive results. This review reports recent discoveries describing the activity and molecular mechanisms of mTOR activation in tubule epithelial cells and cyst formation and discusses the evidence of an upstream regulation of mTOR by the PI3K/Akt axis. In particular, the complex interconnections of the PI3K/Akt/mTOR network with the principal signaling routes involved in the suppression of cyst formation are dissected. These interactions include the antagonism and the reciprocal negative regulation between mTOR complex 1 and the proteins whose deletion causes Autosomal Dominant PKD, the polycystins. In addition, the emerging role of phopshoinositides, membrane components modulated by PI3K, will be presented in the context of primary cilium signaling, cell polarization and protection from cyst formation. Overall, studies demonstrate that the activity of various members of the PI3K/Akt/mTOR network goes beyond the classical transduction of mitogenic signals and can impact several aspects of kidney tubule homeostasis and morphogenesis. These properties might be useful to guide the establishment of more effective treatment protocols to be tested in clinical trials.

中文翻译：

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多囊性肾脏疾病中的PI3K / Akt / mTOR途径：与多囊藻毒素和原发纤毛的复杂相互作用。

PI3K / Akt / mTOR网络的过度激活是导致过度增殖的众所周知的致病事件。已经开发出该途径的药理学靶向，用于治疗多种疾病，包括癌症。在多囊肾疾病（PKD）中，mTOR级联通过促进肾小管上皮细胞的增殖，大小和代谢来促进囊肿生长。因此，mTOR抑制作用已在临床前和临床研究中进行了测试，但只有前者显示出阳性结果。这篇综述报告了最近的发现，这些发现描述了小管上皮细胞中mTOR活化和囊肿形成的活性和分子机制，并讨论了PI3K / Akt轴上游调节mTOR的证据。特别是，剖析了PI3K / Akt / mTOR网络与抑制囊肿形成的主要信号传导途径之间的复杂互连。这些相互作用包括mTOR复合物1与缺失导致常染色体显性PKD的蛋白（多囊蛋白）之间的拮抗作用和相互负调控。此外，磷脂酰肌醇（由PI3K调节的膜成分）的新兴作用将在主要纤毛信号传导，细胞极化和保护免受囊肿形成的背景下呈现。总体而言，研究表明，PI3K / Akt / mTOR网络各个成员的活动超出了有丝分裂信号的经典转导范围，并可能影响肾小​​管稳态和形态发生的多个方面。