Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts 02139, USA.
Institute of Human Genetics, University Hospital Munich, University of Munich, Munich 80336, Germany.
Nat Commun. 2017 Jun 28;8:15866. doi: 10.1038/ncomms15866.
Germline mutations in the Folliculin (FLCN) tumour suppressor gene result in fibrofolliculomas, lung cysts and renal cancers, but the precise mechanisms of tumour suppression by FLCN remain elusive. Here we identify Rab7A, a small GTPase important for endocytic trafficking, as a novel FLCN interacting protein and demonstrate that FLCN acts as a Rab7A GTPase-activating protein. FLCN cells display slower trafficking of epidermal growth factor receptors (EGFR) from early to late endosomes and enhanced activation of EGFR signalling upon ligand stimulation. Reintroduction of wild-type FLCN, but not tumour-associated FLCN mutants, suppresses EGFR signalling in a Rab7A-dependent manner. EGFR signalling is elevated in FLCN tumours and the EGFR inhibitor afatinib suppresses the growth of human FLCN cells as tumour xenografts. The functional interaction between FLCN and Rab7A appears conserved across species. Our work highlights a mechanism explaining, at least in part, the tumour suppressor function of FLCN.
成纤维细胞生长因子受体（FLCN）肿瘤抑制基因的胚系突变导致纤维毛囊瘤、肺囊肿和肾癌，但 FLCN 抑制肿瘤的确切机制仍不清楚。在这里，我们鉴定出 Rab7A 是一种参与内吞作用的小 GTPase，是一种新的 FLCN 相互作用蛋白，并证明 FLCN 作为 Rab7A GTPase 激活蛋白发挥作用。FLCN 细胞显示表皮生长因子受体 (EGFR) 从早期到晚期内体的运输速度较慢，并且在配体刺激下 EGFR 信号的激活增强。野生型 FLCN 的重新导入，但不是肿瘤相关的 FLCN 突变体，以 Rab7A 依赖性方式抑制 EGFR 信号。FLCN 肿瘤中 EGFR 信号升高，表皮生长因子受体抑制剂 afatinib 抑制人 FLCN 细胞作为肿瘤异种移植物的生长。FLCN 和 Rab7A 之间的功能相互作用在物种间似乎是保守的。我们的工作强调了一种解释 FLCN 肿瘤抑制功能的机制，至少在部分程度上是这样。
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