Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Department II of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
J Cell Mol Med. 2020 Dec;24(24):14633-14638. doi: 10.1111/jcmm.16014. Epub 2020 Oct 28.
Autosomal recessive polycystic kidney disease (ARPKD) is mainly caused by variants in the PKHD1 gene, encoding fibrocystin (FC), a large transmembrane protein of incompletely understood cellular function. Here, we show that a C-terminal fragment of human FC can suppress a signalling module of the kinase SRC and signal transducer and activator of transcription 3 (STAT3). Consistently, we identified truncating genetic variants specifically affecting the cytoplasmic tail in ARPKD patients, found SRC and the cytoplasmic tail of fibrocystin in a joint dynamic protein complex and observed increased activation of both SRC and STAT3 in cyst-lining renal epithelial cells of ARPKD patients.
常染色体隐性多囊肾病 (ARPKD) 主要由 PKHD1 基因突变引起，该基因编码纤连蛋白 (FC)，一种细胞功能尚不完全清楚的大型跨膜蛋白。在这里，我们表明人 FC 的 C 末端片段可以抑制 SRC 激酶和信号转导子和转录激活子 3 (STAT3) 的信号模块。一致地，我们在 ARPKD 患者中鉴定出专门影响细胞质尾巴的截断遗传变异，在联合动态蛋白复合物中发现 SRC 和纤连蛋白的细胞质尾巴，并观察到 ARPKD 患者的囊泡衬里肾上皮细胞中 SRC 和 STAT3 的激活增加。
