Birt-Hogg-Dubé: tumour suppressor function and signalling dynamics central to folliculin

The cellular function of folliculin (FLCN) is a mystery that still needs to be solved. It is known that mutation of FLCN can predispose Birt-Hogg-Dubé (BHD) patient's to renal cell carcinoma , renal and lung cysts, as well as skin fibrofolliculomas. FLCN has been classed as a tumour suppressor, but it is probable that cystic and the skin manifestations do not occur as a consequence of FLCN loss of heterozygosity. Discovery that FLCN is a direct substrate of AMP dependent protein kinase (AMPK) placed FLCN on the cell signalling map, downstream of AMPK. This breakthrough suggested that FLCN might be involved in cell energy homeostasis. Over these more recent years, BHD research has become much more complicated and interesting from a cell signalling perspective. Folliculin has been linked to numerous cell pathways that are known to cause cancer, involving cell growth, metabolism, cell adhesion, cell motility, cytokinesis, and cell survival. The collective evidence implies that FLCN may have a broader housekeeping role in the cell. Of particular importance, FLCN was recently been reported to have guanine exchange factor activity towards the small G protein Rab35 and implicates FLCN in vesicular trafficking and/or membrane sorting. This newer discovery will undoubtedly help in the continued challenge of solving the signalling puzzle that shrouds FLCN function.