Birt-Hogg-Dubé syndrome is a hereditary hamartoma syndrome, which is triggered by metabolic alterations under a functional loss of FLCN/FNIP1/FNIP2 complex, a critical regulator of kidney cell proliferation rate; a mechanistic insight into the FLCN/FNIP1/FNIP2 pathway could provide us a basis for developing new therapeutics for kidney cancer.
Recent studies indicated that FNIP1/FNIP2 double knockout mice display enlarged polycystic kidneys and renal carcinoma, which phenocopies FLCN knockout mice, suggesting that these two proteins function together to suppress renal cancer.
The identification of novel FLCN interacting proteins FNIP1 and FNIP2/L and their interaction with 5'-AMP activated protein kinase (AMPK) has provided a link between FLCN and the AMPK-mTOR axis and suggested molecular targets for therapeutic intervention to treat BHD kidney cancer and fibrofolliculomas.