Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein.
Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein.
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DOI：
10.1038/ncomms15866
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发表时间：
2017-06-28
影响因子：
16.6
通讯作者：
Iliopoulos O
中科院分区：
文献类型：
--
作者：
Laviolette LA;Mermoud J;Calvo IA;Olson N;Boukhali M;Steinlein OK;Roider E;Sattler EC;Huang D;Teh BT;Motamedi M;Haas W;Iliopoulos O
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. Folliculin is a known tumour suppressor but the molecular mechanisms behind this function are unclear. Here the authors show that Folliculin regulates EGFR signalling by modulating its Rab7a-dependent trafficking.
