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Nat Commun. 2017 Jun 28;8:15866. doi: 10.1038/ncomms15866.

Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein.

Author information

1
Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts 02139, USA.
2
Institute of Human Genetics, University Hospital Munich, University of Munich, Munich 80336, Germany.
3
Department of Dermatology and Allergology, University Hospital, Ludwig Maximilian University Munich, Munich D-80337, Germany.
4
Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore 169610, Singapore.
5
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169610, Singapore.
6
Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Abstract

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.

PMID:
28656962
PMCID:
PMC5493755
DOI:
10.1038/ncomms15866
[Indexed for MEDLINE]
Free PMC Article

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