Department of Medical and Molecular Genetics, Centre for Rare Diseases and Personalized Medicine, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental Sciences, Edgbaston, Birmingham, UK.
Hum Mol Genet. 2012 Dec 15;21(24):5268-79. doi: 10.1093/hmg/dds378. Epub 2012 Sep 10.
Inherited mutations in the folliculin (FLCN) gene cause the Birt-Hogg-Dubé syndrome of familial hair follicle tumours (fibrofolliculomas), lung cysts and kidney tumours. Though folliculin has features of a tumour suppressor, the precise function of the FLCN gene product is not well characterized. We identified plakophilin-4 (p0071) as a potential novel folliculin interacting protein by yeast two-hybrid analysis. We confirmed the interaction of folliculin with p0071 by co-immunoprecipitation studies and, in view of previous studies linking p0071 to the regulation of rho-signalling, cytokinesis and intercellular junction formation, we investigated the effect of cell folliculin status on p0071-related functions. Folliculin and p0071 partially co-localized at cell junctions and in mitotic cells, at the midbody during cytokinesis. Previously, p0071 has been reported to regulate RhoA signalling during cytokinesis and we found that folliculin deficiency was associated with increased expression and activity of RhoA and evidence of disordered cytokinesis. Treatment of folliculin-deficient cells with a downstream inhibitor of RhoA signalling (the ROCK inhibitor Y-27632) reversed the increased cell migration phenotype observed in folliculin-deficient cells. Deficiency of folliculin and of p0071 resulted in tight junction defects and mislocalization of E-cadherin in mouse inner medullary collecting duct-3 renal tubular cells. These findings suggest that aspects of folliculin tumour suppressor function are linked to interaction with p0071 and the regulation of RhoA signalling.
滤泡素（FLCN）基因突变导致家族性毛囊肿瘤（纤维毛囊瘤）、肺囊肿和肾肿瘤的 Birt-Hogg-Dubé 综合征。尽管滤泡素有肿瘤抑制因子的特征，但 FLCN 基因产物的确切功能尚未得到很好的描述。我们通过酵母双杂交分析鉴定出桥粒斑蛋白-4（p0071）是潜在的新的滤泡素相互作用蛋白。我们通过共免疫沉淀研究证实了滤泡素与 p0071 的相互作用，并且鉴于先前的研究将 p0071 与 rho 信号转导、胞质分裂和细胞间连接形成的调节联系起来，我们研究了细胞滤泡素状态对 p0071 相关功能的影响。滤泡素和 p0071 部分在细胞连接处和有丝分裂细胞中、在胞质分裂的中体处共定位。先前已经报道 p0071 在胞质分裂期间调节 RhoA 信号转导，我们发现滤泡素缺乏与 RhoA 的表达和活性增加以及胞质分裂紊乱有关。用 RhoA 信号转导的下游抑制剂（ROCK 抑制剂 Y-27632）处理滤泡素缺陷细胞，逆转了在滤泡素缺陷细胞中观察到的增加的细胞迁移表型。滤泡素和 p0071 的缺乏导致紧密连接缺陷和 E-钙粘蛋白在小鼠内髓集合管-3 肾小管细胞中的错误定位。这些发现表明，滤泡素肿瘤抑制功能的某些方面与 p0071 的相互作用和 RhoA 信号转导的调节有关。
