In 2008, two groups studying BHD independently identified FNIP2: Hasumi et al and Takagi et al. Hasumi et al identified a novel FLCN-interacting protein, FNIP2, with homology to FNIP1. They showed that FNIP2 interacts with the C-terminal half of the FLCN and with AMPK, which is as we know, a negative regulator of mTOR.
Importantly they demonstrated that FNIP1 and FNIP2 can form complexes independent of FLCN expression, suggesting that these may function independently or co-operatively with FLCN and that their differential expression in human tissues may indicate tissue-specific roles for both FNIP1 and FNIP2 in normal cell signaling. Importantly they showed elevated expression levels of FNIP1 and FNIP2 in specific types of renal tumours found most often in BHD patients. They hypothesised that this may suggest a common pathway for the development of BHD-associated renal tumors, sporadic chromophobe RCC and sporadic oncocytoma in humans.
Similarly, Takagi et al, identified a novel protein binding to Flcn, which they named FnipL (Fnip2). They also noted the ability of FNIP1/FNIP2 to form complexes and used siRNA technology to show a decrease in S6K1 phosphorylation in the BHD-suppressed cell, as well as a decrease in S6K1 phosphorylation in FNIP1- and in FNIPL/FNIP2-suppressed cells (although to a lesser extent in the latter). These results suggested that Flcn-Fnip2 and Flcn-Fnip1 complexes positively regulate S6K1 phosphorylation and that the discovery of Fnip2 provided an important clue to elucidating the function of FLCN.
The significance of these two studies is crucial in understanding the molecular pathogenesis of BHD, not only in terms of contributing to what we know intellectually about the mechanism behind the disease, but also in terms of planning further studies. It makes sense that in a field of research as small as BHD, that groups interact with each other with regards to what they are doing and what they will be doing – whilst the wheel doesn’t need to be re-invented, it’s efficacy should be independently judged. This is easier said than done in the world of academic research, publications, impact factors and funding – but when the goal is to translate bench to bedside, I feel targeted and planned research efforts are called for. The results from both these papers are extremely encouraging and are certain to provide a foundation for our understanding of BHD syndrome.