With the New Year upon us, we thought we would use this week’s blog to revisit those studies we’ve particularly enjoyed reading and writing about in the past 12 months.
In August, a landmark paper by Nookala et al., (2012) described the C-terminal domain structure of FLCN (PDB ID: 3V42). The authors showed FLCN had characteristics of a DENN domain suggesting it is a guanine nucleotide exchange factor (GEF), thus indicating it could be involved in membrane trafficking, as discussed in blog posts here and here. Nookala et al. reported that FLCN had GEF activity towards Rab35 in vitro and FLCN is found to inhibit Rab27b expression in three different studies, as noted by Reiman et al. (2012). Rab35 and Rab27b and their putative functions are described in last week’s blog post.
This summer, a new role for the FLCN interacting protein, FNIP1, in B-cell development, was described in two independent studies and discussed in blog posts here and here. Although both studies noted a block in B-cell development in FNIP1-null mice, the authors attributed the B-cell phenotype to different causes – Park et al., (2012) suggest the phenotype was due to the dysregulation of homestasis, while Baba et al., (2012) attribute it to an increase in apoptotic cells. Building on these studies to elucidate FNIP1’s precise role in haematopoiesis and the immune system is of importance, as it may provide information about FLCN’s function in these processes.
This autumn, two new proteins were reported to interact with FLCN: Rpt4 and PKP4. Gaur et al., 2012 reported that Rpt4 interacts with FLCN to downregulate rRNA synthesis in the nucleolus (discussed in a previous blog post). This is particularly interesting given that VHL, which acts in similar pathways to FLCN and can also cause kidney cancer when mutated, also downregulates rRNA synthesis under hypoxic conditions (Mekhail et al., 2006 and discussed in this blog post). It would be interesting to determine whether FLCN also downregulates rRNA synthesis under hypoxic conditions, as this would correspond with the known functions of FLCN in energy-sensing and HIF-signalling.
Additionally, two independent studies showed that FLCN interacts with PKP4 and leads to a dysregulation of RhoA signalling and cell-cell adhesion (discussed in blog posts here and here). Although both papers convincingly showed that FLCN interacts with PKP4, Nahorski et al., (2012) and Medvetz et al., (2012) reported opposing effects of FLCN loss on RhoA signalling and cell-cell adhesion. The RhoA and cadherin signalling pathways are clearly complicated, and possibly context dependent, which may explain the differing results between these studies. However, as the dysregulation of both pathways has been previously linked to tumour progression (reviewed by Jeanes et al., 2008 and Rathinam et al., 2011) determining FLCN’s role in these pathways would be a significant milestone, as this would most likely shed light on the causes of the hyperplasia associated with BHD Syndrome.
These papers are just a few of many; 2012 has been a demonstrably successful year for FLCN and BHD research, particularly in terms of elucidating potential new functions for FLCN and this knowledge will hopefully lead to new treatments for BHD in the future. We at the BHD Foundation are very much looking forward to seeing how the field develops in 2013 and wish all our readers a Happy New Year.
- Baba M, Keller JR, Sun HW, Resch W, Kuchen S, Suh HC, Hasumi H, Hasumi Y, Kieffer-Kwon KR, Gonzalez CG, Hughes RM, Klein ME, Oh HF, Bible P, Southon E, Tessarollo L, Schmidt LS, Linehan WM, & Casellas R (2012). The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dubé syndrome is required for murine B-cell development. Blood, 120 (6), 1254-61 PMID: 22709692
- Gaur K, Li J, Wang D, Dutta P, Yan SJ, Tsurumi A, Land H, Wu G, & Li WX (2013). The Birt-Hogg-Dube tumor suppressor Folliculin negatively regulates ribosomal RNA synthesis. Human molecular genetics, 22 (2), 284-99 PMID: 23077212
- Jeanes A, Gottardi CJ, & Yap AS (2008). Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene, 27 (55), 6920-9 PMID: 19029934
- Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, & Henske EP (2012). Folliculin, the Product of the Birt-Hogg-Dube Tumor Suppressor Gene, Interacts with the Adherens Junction Protein p0071 to Regulate Cell-Cell Adhesion. PloS one, 7 (11) PMID: 23139756
- Mekhail K, Rivero-Lopez L, Khacho M, & Lee S (2006). Restriction of rRNA synthesis by VHL maintains energy equilibrium under hypoxia. Cell cycle (Georgetown, Tex.), 5 (20), 2401-13 PMID: 17102617
- Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, Klomp JA, Teh BT, Hatzfeld M, Gissen P, & Maher ER (2012). Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Human molecular genetics, 21 (24), 5268-79 PMID: 22965878
- Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montaño B, Donaldson JC, Blaszczyk BK, Chirgadze DY, Barr FA, Bazan JF, & Blundell TL (2012). Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. Open biology, 2 (8) PMID: 22977732
- Park H, Staehling K, Tsang M, Appleby MW, Brunkow ME, Margineantu D, Hockenbery DM, Habib T, Liggitt HD, Carlson G, & Iritani BM (2012). Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development. Immunity, 36 (5), 769-81 PMID: 22608497
- Rathinam R, Berrier A, & Alahari SK (2011). Role of Rho GTPases and their regulators in cancer progression. Frontiers in bioscience : a journal and virtual library, 16, 2561-71 PMID: 21622195
- Reiman A, Lu X, Seabra L, Boora U, Nahorski MS, Wei W, & Maher ER (2012). Gene Expression and Protein Array Studies of Folliculin-regulated Pathways. Anticancer research, 32 (11), 4663-70 PMID: 23155228