Research in mice has shown that the Ras–Raf–MEK–ERK pathway, which regulates cell proliferation and is dysregulated in many cancers (Roberts and Der, 2007), is activated in FLCN-null kidneys (Baba et al., 2008; Hudon et al., 2010). This suggests that an upstream effector of this pathway may be activated by loss of FLCN, resulting in cell growth and proliferation within the FLCN-null kidney cell. Gaur et al. (2013) found that heterozygous loss of Drosophila DBHD enhanced the lethal phenotype of flies carrying a hyper-active allele of Ras1, indicating that FLCN also inhibits the Ras-Raf-MEK-Erk signalling pathway in Drosophila.
Gaur et al. (2013) also found that FLCN interacts with Rpt4 in the nucleolus to inhibit rRNA synthesis in both Drosophila and human cells and that increased rRNA synthesis is required for Ras-Raf-MEK-Erk stimulated oncogenic growth in Drosophila. Therefore, the hyperplastic growth seen in BHD syndrome may be due, in part, to an increase in Ras-Raf-MEK-Erk signalling caused by the overexpression of rRNA.
Zhang et al. (2013) and (2014), found that when treated with the chemotherapy Paclitaxel or radiotherapy, autophagy was induced via increased MEK-ERK signalling in FLCN-null but not FLCN-expressing cells.
Heterozygous loss of FLCN was also reported to lead to dysregulated MEK-ERK signalling in a high grade oncocytic carcinoma. However, there were additional genomic rearrangements seen in this tumour, suggesting that additional factors may have contributed to this signalling dysregulation (Sirintrapun et al., 2014).