The molecular functions of FLCN are poorly understood, but it is known that FLCN and AMPK interaction, as mediated by FNIP1 and FNIP2, is involved in mTOR signalling (Baba et al., 2006; Hasumi et al., 2008). The mTOR pathway is a key regulator of cell growth, proliferation and metabolism (Harris and Lawrence, 2003; Hay and Sonenberg, 2004; Wullschleger et al., 2006) and an increasing amount of evidence suggests that its deregulation is associated with human diseases, such as cancer (Sarbassov et al., 2005; Landau et al., 2009).
The functional role of FLCN in mTOR signalling however is undetermined since several recent publications have reported contradictory impacts on an indicator of mTOR activation (known as phosphorylated ribosomal protein S6 / p-S6R) when FLCN expression is reduced. Two studies recently reported that transient downregulation of FLCN by siRNA in human cell lines results in reduction of phosphorylation of p-S6R (Takagi et al., 2008; Hartman et al., 2009). Reduction of p-S6R was also observed in renal cysts developing in mice heterozygous for FLCN (Hartman et al., 2009). In contrast, kidney-specific homozygous knockout of FLCN resulted in an increase in phosphorylated p-S6R, which contributed to the development of polycystic kidneys (Baba et al., 2008; Chen et al., 2008). Additionally, an activation of mTOR signalling in the kidney tumours of another heterozygous FLCN knockout mouse model was noted by Hasumi et al. (2009). This discrepancy between the heterozygous models could be due to differences in sample preparation and/or the gene targeting strategy used by Hartman et al. (2009). However, Hudon et al. (2010) noted that a loss of FLCN expression in their heterozygous FLCN knockout mouse resulted in both elevated and reduced levels of p-S6R, depending on the cellular context- which may account for the differing results observed in the earlier mouse models.
Further studies in fission yeast, Schizosaccharomyces pombe (S. pombe), revealed that the yeast FLCN homologue (LST7) and yeast TSC1/2 homologues regulate common downstream targets but have opposing roles. Specifically, TSC1/2 inhibits the activation of Tor2 and subsequent downstream elements, but LST7 up-regulates the same elements (van Slegtenhorst et al., 2007). Ultimately, all this data suggests a role for FLCN in nutrient/energy-sensing mediated through the mTOR signalling pathway, and if the relationship between yeast FLCN and TSC1/TSC2 is reiterated in mammalian cells, there would be important implications for the development of therapies for BHD syndrome. However, LST7 only corresponds to the N-terminal region of vertebrate FLCN, which may go some way in explaining these results.
Whilst the work discussed above emphasises the part played by FLCN in the mTOR pathway, recent research has also indicated a role for FLCN in other signalling systems and cellular processes.
