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.
Highlights
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
We found several Rab proteins that interact with FLCN, but the small GTPase, Rab7A, had the highest spectral count in the membrane fraction of FLCN WT cells
We interpreted the data as suggesting that the preferential binding of FLCN to Rab7A WT and Rab7A constitutively active (CA) underscores the possibility that FLCN acts as a Rab7A GTPase activating proteins (GAPs)
Summary
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. FLCN was shown to be required for the recruitment and activation of mTORC1 in response to amino acids through its interaction with Rag GTPases at the lysosome[17,18]. DENN domain proteins function as guanine nucleotide exchange factors (GEFs) that activate Rab GTPases by mediating the exchange of GDP for GTP22. FLCN possessed GTPase-activating protein (GAP) activity for Rag C/D18, while another study suggested that FLCN may act as a GEF for RagA17 In these studies, FLCN was required for the recruitment and activation of mTORC1 in response to amino acids. Our data suggest that the interaction between FLCN and Rab7A is important for EGFR cellular trafficking and that misregulation of Rab7A activity due to FLCN loss results in slower EGFR trafficking and increased EGFR signalling
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