The S. cerevisiae homologue of FLCN, LST7, is part of the cerevisiae complex required for Golgi to plasma membrane transport (Roberg et al., 1997), which provided early evidence that FLCN functions in membrane trafficking (Nahorski et al., 2011).

The subsequent discovery that the C-terminal portion of FLCN forms a non-canonical DENN domain suggested that FLCN may be a Rab-GEF and have a role in membrane trafficking (Nookala et al., 2012). Subsequent experiments confirmed that FLCN has GEF activity towards the Rab35 GTPase in vitro. Rab35 is involved in early endocytic trafficking, recycling events and cytokinesis, and these results suggest that FLCN may also function in these pathways. FLCN has also been shown to down-regulate the expression of Rab27b (Hong et al., 2010a; Klomp et al., 2010; Reiman et al., 2012), which is also a membrane trafficking protein (Gomi et al., 2007).

FLCN has been shown to sequester β-catenin in cilia (Luijten et al., 2013) and to preclude TFE3 from the nucleus of stem cells (Betschinger et al., 2013), further hinting that FLCN’s role may be to shuttle other proteins within the cell. FLCN has also been reported to contain a WE/WD binding motif for the Kinesin 1 motor protein (Dodding et al., 2011) and to regulate the accumulation of LC3B and LC3C, which are required for autophagosome double membrane formation and cargo uptake (Bastola et al., 2013).

Of further interest, a study by Zhang et al. (2012) used FLCN’s divergent DENN domain as a template to search for other non-canonical DENN domain proteins. Six such proteins were found – C9orf72, SMCR8, NPR2, NPR3 and FNIP1 and FNIP2, suggesting that FNIP1 and FNIP2 may also be membrane trafficking proteins (Zhang et al., 2012).