A primary pathological feature of polycystic kidney disease (PKD) is the hyperproliferation of epithelial cells in renal tubules, resulting in formation of fluid-filled cysts. The proliferative aspects of the two major forms of PKD-autosomal dominant PKD (ADPKD), which arises from mutations in the polycystins PKD1 and PKD2, and autosomal recessive PKD (ARPKD), which arises from mutations in PKHD1-has encouraged investigation into protein components of the core cell proliferative machinery as potential drivers of PKD pathogenesis. In this review, we examine the role of signaling by ERBB proteins and their effectors, with a primary focus on ADPKD. The ERBB family of receptor tyrosine kinases (EGFR/ERBB1, HER2/ERBB2, ERBB3, and ERBB4) are activated by extracellular ligands, inducing multiple pro-growth signaling cascades; among these, activation of signaling through the RAS GTPase, and the RAF, MEK1/2, and ERK1/2 kinases enhance cell proliferation and restrict apoptosis during renal tubuloepithelial cyst formation. Characteristics of PKD include overexpression and mislocalization of the ERBB receptors and ligands, leading to enhanced activation and increased activity of downstream signaling proteins. The altered regulation of ERBBs and their effectors in PKD is influenced by enhanced activity of SRC kinase, which is promoted by the loss of cytoplasmic Ca2+ and an increase in cAMP-dependent PKA kinase activity that stimulates CFTR, driving the secretory phenotype of ADPKD. We discuss the interplay between ERBB/SRC signaling, and polycystins and their depending signaling, with emphasis on thes changes that affect cell proliferation in cyst expansion, as well as the inflammation-associated fibrogenesis, which characterizes progressive disease. We summarize the current progress of preclinical and clinical trials directed at inhibiting this signaling axis, and discuss potential future strategies that may be productive for controlling PKD.

中文翻译：

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ERBB蛋白和RAF / MEK / ERK效应子在多囊肾疾病中的增殖信号转导。

多囊性肾病（PKD）的主要病理特征是肾小管中上皮细胞过度增殖，导致形成充满液体的囊肿。PKD-常染色体显性PKD（ADPKD）的两种主要形式的增生方面是由多囊藻蛋白PKD1和PKD2的突变引起的，而常染色体隐性PKD（ARPKD）则是由PKHD1的突变引起的，这鼓励了对蛋白质成分的研究。作为PKD发病机理的潜在驱动因素的核心细胞增殖机制。在这篇综述中，我们研究了ERBB蛋白及其效应子的信号传导作用，主要侧重于ADPKD。受体酪氨酸激酶的ERBB家族（EGFR / ERBB1，HER2 / ERBB2，ERBB3和ERBB4）被细胞外配体激活，诱导了多个促生长信号级联反应。在这些当中，RAS GTPase和RAF，MEK1 / 2和ERK1 / 2激酶激活信号传导增强细胞增殖，并在肾小管上皮囊肿形成过程中限制细胞凋亡。PKD的特征包括ERBB受体和配体的过表达和错位，导致下游信号传导蛋白的激活增强和活性增强。ERBBs及其效应子在PKD中的调节改变受SRC激酶活性增强的影响，SRC激酶活性增强由细胞质Ca2 +的丧失和刺激CFTR的cAMP依赖性PKA激酶活性增加所推动，从而驱动ADPKD的分泌表型。我们讨论了ERBB / SRC信号与多囊蛋白及其依赖性信号之间的相互作用，重点讨论了影响囊肿扩展中细胞增殖的变化，以及与炎症相关的纤维化，这是进行性疾病的特征。我们总结了旨在抑制该信号轴的临床前和临床试验的当前进展，并讨论了可能对控制PKD有用的潜在未来策略。