Negative Regulation of EGFR Signalling by the Human Folliculin Tumour Suppressor Protein

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Jun 29

PMID 28656962

Citations 30

Authors

Laura A Laviolette

Julien Mermoud

Isabel A Calvo

Nicholas Olson

Myriam Boukhali

Ortrud K Steinlein

Elisabeth Roider

Elke C Sattler

DaChuan Huang

Bin Tean Teh

Mo Motamedi

Wilhelm Haas

Othon Iliopoulos

Affiliations

Soon will be listed here.

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.

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