Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein.
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.
Mesh Terms:
Animals, Birt-Hogg-Dube Syndrome, Cell Line, Tumor, Endosomes, ErbB Receptors, Female, Humans, Kidney Neoplasms, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Proto-Oncogene Proteins, Schizosaccharomyces, Signal Transduction, Tumor Suppressor Proteins, Xenograft Model Antitumor Assays, rab GTP-Binding Proteins
Animals, Birt-Hogg-Dube Syndrome, Cell Line, Tumor, Endosomes, ErbB Receptors, Female, Humans, Kidney Neoplasms, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Proto-Oncogene Proteins, Schizosaccharomyces, Signal Transduction, Tumor Suppressor Proteins, Xenograft Model Antitumor Assays, rab GTP-Binding Proteins
Nat Commun
Date: Dec. 28, 2016
PubMed ID: 28656962
View in: Pubmed Google Scholar
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