Warren et al. (2004) studied the expression of FLCN mRNA in both normal and neoplastic human tissue and found that in normal cells FLCN was expressed in the skin, the distal nephron of the kidney, stromal cells, type 1 pneumocytes of the lung, acinar cells of the pancreas, parotid gland, epithelial ducts of the breast and prostate, areas of the brain and in macrophages and lymphocytes in the tonsils and spleen. Tissues with no FLCN mRNA expression included the heart, muscle and liver (Warren et al., 2004). The fact that FLCN mRNA is not detected in BHD-associated renal tumours provides further evidence that FLCN has tumour suppressor function in the kidney.
The expression patterns of FLCN, FNIP1 and FNIP2 in human tissues were determined by Hasumi et al. (2008) using real-time PCR. The expression patterns of these proteins were generally similar, and consistently high in specific tissues, such as muscle, nasal mucosa, salivary gland and uvula, suggesting that FLCN, FNIP1 and FNIP2 may work together in these organs. However, FNIP2 expression was higher relative to FNIP1 in fat, liver and pancreas, which suggests that FNIP2 may have a specific function in these metabolic tissues (Hasumi et al., 2008).
Hudon et al. (2010) characterised the tissue distribution of murine FLCN expression. It was found to have a similar expression pattern to human FLCN, with high expression in the kidneys, lungs and spleen. Interestingly, no FLCN expression was seen in the mouse epidermis, correlating with the lack of skin lesions in FLCN-null mice.
FLCN/FNIP1 and FLCN/FNIP2 dimers have been shown to co-localise in the cytoplasm in a reticular pattern (Baba et al., 2006; Hasumi et al., 2008; Takagi et al., 2008). Co-expression studies of N-terminal tagged FLCN, FNIP1 and FNIP2 indicate that both FNIPs regulate the cytoplasmic distribution of FLCN (Baba et al., 2006; Hasumi et al., 2008; Takagi et al., 2008). When tagged FNIP2 constructs are expressed alone, FNIP2 is seen to be distributed within the cytoplasm of cells, showing more condensed features around the nucleus. Conversely, when tagged FLCN constructs are expressed alone, they appear to be found mainly in the nucleus (Takagi et al., 2008). However, when FNIP2 and FLCN are co-expressed they co-localise together in the cytoplasm in a reticular pattern, which is similar to the co-localisation of FNIP1 and FLCN (Baba et al., 2006; Hasumi et al., 2008; Takagi et al., 2008).
Three studies have shown that although expressed diffusely under basal conditions, FLCN is rapidly recruited to the cytosolic surface of lysosomes during amino acid depletion in a FNIP1- (Petit et al., 2013) or FNIP2- (Tsun et al., 2013) dependent manner. Upon restimulation with amino acids, FLCN rapidly dissociates from the lysosome (Martina et al., 2014, Petit et al., 2013; Tsun et al., 2013).
Nahorski et al. (2012) also studied the co-localisation of FLCN and PKP4 throughout different phases of the cell cycle. During interphase, FLCN and PKP4 were shown to co-localise most strongly at cell junctions, with a more dispersed co-localisation throughout the cytoplasm, whereas during cytokinesis the proteins co-localised at the midbody. Additionally, Gaur et al. (2013) showed that FLCN co-localises with RPT4 in the nucleolus.
Taken together, these studies suggest that FLCN may be widely expressed, and subsequently recruited to sub-cellular locations by its interacting partners.