Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant condition that is caused by mutations in the folliculin (Flcn) protein that result in epidermal fibrofolliculomas, renal cell carcinoma and pulmonary cysts. Although this disease affects multiple systems, we have shown that the common factor linking these diverse pathologies centres on disrupted epithelial cell polarity and function (Luitjen et al, 2013). Pulmonary cysts develop as air-filled spaces in the lower airways of BHD patients and are lined by a thin layer of squamous epithelium without apparent inflammation or fibrosis. Since airway epithelial growth and integrity requires vascular endothelial growth factor-A (VEGF-A) signalling (eg Kasahara et al. (2000)), we tested the hypothesis that loss of Flcn destabilises epithelial cell growth by disrupting epithelial VEGF receptor 2 (VEGFR2) signalling. Stable shRNA knockdown of Flcn ( >60%) was achieved in 16HBE14o- human bronchial epithelial cells (HBE) which increased cell doubling time from 32±1.2hrs to 44±3.6hrs and was accompanied by an accumulation of cells in Go/G1. Native VEGF-A secretion was unaffected by Flcn knockdown or over-expression, however, the kinetics of VEGFR2 signalling to downstream kinases were dampened with Flcn shRNA. Since matrix metalloprotease (MMP) cleavage of VEGF-A promotes VEGFR2 endosomal trafficking and downstream receptor signalling, surface biotinylation assays were performed to determine the proportion of VEGF-A and VEGFR2 retained in contact with the cell surface during MMP inhibition with Ilomastat (10μM). Cells stably transformed with scrambled shRNA (control) displayed high native abundance of intracellular, endosomal VEGFR2 that was linked with VEGFR2 Y1175 autophosphorylation. Ilomastat induced VEGFR2 accumulation at the cell surface and this was associated with surface-retention of VEGF-A. In Flcn knockdown cells, however, both VEGF-A and VEGFR2 were retained at the cell surface irrespective of Ilomastat treatment and this was associated with absent Y1175 autophosphorylation on VEGFR2. A role for Flcn in controlling VEGFR2 trafficking was explored in primary cultures of ciliated human nasal epithelial cells (cHNE). Cells transfected with wild-type Flcn responded to VEGF-A (10nM) by trafficking GFP-tagged VEGFR2 from cilia into the cytosol whereas GFP-VEGFR2 was retained in cilia in cHNE transfected with the Y463X Flcn truncation that is commonly associated with BHD syndrome. We conclude that the association of Flcn with growth factor signalling and receptor trafficking points to a central role in epithelial phenotypic conservation and polarity.