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folliculin interacting protein 1

Laura S Schmidt, W Marston Linehan
Germline mutations in the novel tumor suppressor gene FLCN are responsible for the autosomal dominant inherited disorder Birt-Hogg-Dubé (BHD) syndrome that predisposes to fibrofolliculomas, lung cysts and spontaneous pneumothorax, and an increased risk for developing kidney tumors. Although the encoded protein, folliculin (FLCN), has no sequence homology to known functional domains, x-ray crystallographic studies have shown that the C-terminus of FLCN has structural similarity to DENN (differentially expressed in normal cells and neoplasia) domain proteins that act as guanine nucleotide exchange factors (GEFs) for small Rab GTPases...
January 15, 2018: Gene
Qicheng Zhou, Yeyun Gu, Hedong Lang, Xiaolan Wang, Ka Chen, Xinhua Gong, Min Zhou, Li Ran, Jundong Zhu, Mantian Mi
Obesity is often accompanied by decreases in the proportion of skeletal muscle slow-twitch fibers and insulin sensitivity. Increased plasma non-esterified fatty acids (NEFA) levels are responsible for obesity-associated insulin resistance. Palmitate, one of the most elevated plasma NEFA in obesity, has been recognized as the principle inducer of insulin resistance. The present study showed that increased plasma NEFA levels were negatively linked to slow-twitch fiber proportion and insulin sensitivity, while slow-twitch fiber proportion was positively correlated to insulin sensitivity in high fat diet (HFD)-fed and ob/ob mice...
March 29, 2017: Biochimica et Biophysica Acta
Katsuyuki Nagashima, Hidefumi Fukushima, Kouhei Shimizu, Aya Yamada, Masumi Hidaka, Hisashi Hasumi, Tetsuro Ikebe, Satoshi Fukumoto, Koji Okabe, Hiroyuki Inuzuka
Folliculin-interacting protein 1 and 2 (FNIP1 and FNIP2) play critical roles in preventing renal malignancy through their association with the tumor suppressor FLCN. Mutations in FLCN are associated with Birt-Hogg-Dubé (BHD) syndrome, a rare disorder with increased risk of renal 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...
February 7, 2017: Oncotarget
Owen M Siggs, Alexander Stockenhuber, Mukta Deobagkar-Lele, Katherine R Bull, Tanya L Crockford, Bethany L Kingston, Greg Crawford, Consuelo Anzilotti, Violetta Steeples, Sahar Ghaffari, Gabor Czibik, Mohamed Bellahcene, Hugh Watkins, Houman Ashrafian, Benjamin Davies, Angela Woods, David Carling, Arash Yavari, Bruce Beutler, Richard J Cornall
Folliculin (FLCN) is a tumor-suppressor protein mutated in the Birt-Hogg-Dubé (BHD) syndrome, which associates with two paralogous proteins, folliculin-interacting protein (FNIP)1 and FNIP2, forming a complex that interacts with the AMP-activated protein kinase (AMPK). Although it is clear that this complex influences AMPK and other metabolic regulators, reports of its effects have been inconsistent. To address this issue, we created a recessive loss-of-function variant of Fnip1 Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells...
June 28, 2016: Proceedings of the National Academy of Sciences of the United States of America
Angela Pacitto, David B Ascher, Louise H Wong, Beata K Blaszczyk, Ravi K Nookala, Nianshu Zhang, Svetlana Dokudovskaya, Tim P Levine, Tom L Blundell
The folliculin/Fnip complex has been demonstrated to play a crucial role in the mechanisms underlying Birt-Hogg-Dubé (BHD) syndrome, a rare inherited cancer syndrome. Lst4 has been previously proposed to be the Fnip1/2 orthologue in yeast and therefore a member of the DENN family. In order to confirm this, we solved the crystal structure of the N-terminal region of Lst4 from Kluyveromyces lactis and show it contains a longin domain, the first domain of the full DENN module. Furthermore, we demonstrate that Lst4 through its DENN domain interacts with Lst7, the yeast folliculin orthologue...
December 2015: Open Biology
Hisashi Hasumi, Masaya Baba, Yukiko Hasumi, Mitsuko Furuya, Masahiro Yao
Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disease that predisposes patients to develop fibrofolliculoma, lung cysts and bilateral multifocal renal tumors, histologically hybrid oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, oncocytoma, papillary renal cell carcinoma and clear cell renal cell carcinoma. The predominant forms of Birt-Hogg-Dubé syndrome-associated renal tumors, hybrid oncocytic/chromophobe tumors and chromophobe renal cell carcinoma are typically less aggressive, and a therapeutic principle for these tumors is a surgical removal with nephron-sparing...
March 2016: International Journal of Urology: Official Journal of the Japanese Urological Association
Hisashi Hasumi, Masaya Baba, Yukiko Hasumi, Martin Lang, Ying Huang, HyoungBin F Oh, Masayuki Matsuo, Maria J Merino, Masahiro Yao, Yusuke Ito, Mitsuko Furuya, Yasuhiro Iribe, Tatsuhiko Kodama, Eileen Southon, Lino Tessarollo, Kunio Nagashima, Diana C Haines, W Marston Linehan, Laura S Schmidt
Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes similar to those seen in Flcn-deficient mice in multiple organs, but not in kidneys...
March 31, 2015: Proceedings of the National Academy of Sciences of the United States of America
Nicholas L Reyes, Glen B Banks, Mark Tsang, Daciana Margineantu, Haiwei Gu, Danijel Djukovic, Jacky Chan, Michelle Torres, H Denny Liggitt, Dinesh K Hirenallur-S, David M Hockenbery, Daniel Raftery, Brian M Iritani
Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I "red" slow twitch and type II "white" fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined...
January 13, 2015: Proceedings of the National Academy of Sciences of the United States of America
Elaine A Dunlop, Sara Seifan, Tijs Claessens, Christian Behrends, Miriam Af Kamps, Ewelina Rozycka, Alain J Kemp, Ravi K Nookala, John Blenis, Barry J Coull, James T Murray, Maurice Am van Steensel, Simon Wilkinson, Andrew R Tee
Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant condition caused by mutations in the FLCN gene and characterized by benign hair follicle tumors, pneumothorax, and renal cancer. Folliculin (FLCN), the protein product of the FLCN gene, is a poorly characterized tumor suppressor protein, currently linked to multiple cellular pathways. Autophagy maintains cellular homeostasis by removing damaged organelles and macromolecules. Although the autophagy kinase ULK1 drives autophagy, the underlying mechanisms are still being unraveled and few ULK1 substrates have been identified to date...
October 1, 2014: Autophagy
Yukiko Hasumi, Masaya Baba, Hisashi Hasumi, Ying Huang, Martin Lang, Rachel Reindorf, Hyoung-bin Oh, Sebastiano Sciarretta, Kunio Nagashima, Diana C Haines, Michael D Schneider, Robert S Adelstein, Laura S Schmidt, Junichi Sadoshima, W Marston Linehan
Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK-mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction...
November 1, 2014: Human Molecular Genetics
Heon Park, Mark Tsang, Brian M Iritani, Michael J Bevan
Folliculin-interacting protein 1 (Fnip1) is an adaptor protein that physically interacts with AMPK, an energy-sensing kinase that stimulates mitochondrial biogenesis and autophagy in response to low ATP, while turning off energy consumption mediated by mammalian target of rapamycin. Previous studies with Fnip1-null mice revealed that Fnip1 is essential for pre-B-cell development. Here we report a critical role of Fnip1 in invariant natural killer T (iNKT) cell development. Thymic iNKT development in Fnip1(-/-) mice was arrested at stage 2 (NK1...
May 13, 2014: Proceedings of the National Academy of Sciences of the United States of America
Constance S Petit, Agnes Roczniak-Ferguson, Shawn M Ferguson
Birt-Hogg-Dubé syndrome, a human disease characterized by fibrofolliculomas (hair follicle tumors) as well as a strong predisposition toward the development of pneumothorax, pulmonary cysts, and renal carcinoma, arises from loss-of-function mutations in the folliculin (FLCN) gene. In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). Our results indicate that FLCN is specifically required for the amino acid-stimulated recruitment of mTORC1 to lysosomes by Rag GTPases...
September 30, 2013: Journal of Cell Biology
Dapeng Zhang, Lakshminarayan M Iyer, Fang He, L Aravind
The tripartite DENN module, comprised of a N-terminal longin domain, followed by DENN, and d-DENN domains, is a GDP-GTP exchange factor (GEFs) for Rab GTPases, which are regulators of practically all membrane trafficking events in eukaryotes. Using sequence and structure analysis we identify multiple novel homologs of the DENN module, many of which can be traced back to the ancestral eukaryote. These findings provide unexpected leads regarding key cellular processes such as autophagy, vesicle-vacuole interactions, chromosome segregation, and human disease...
2012: Frontiers in Genetics
Mitsuko Furuya, Yukio Nakatani
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant inherited disorder characterised by fibrofolliculomas, renal tumours, pulmonary cysts and pneumothorax. The pulmonary cysts and repeated episodes of pneumothorax are the clinical hallmarks for discovering families affected by the syndrome. This disorder is caused by mutations in the gene coding for folliculin (FLCN). FLCN forms a complex with FLCN-interacting protein 1 (FNIP1) and FNIP2 (also known as FNIPL), and the complex cross-talks with signalling molecules such as 5'-AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR)...
March 2013: Journal of Clinical Pathology
Doug A Medvetz, Damir Khabibullin, Venkatesh Hariharan, Pat P Ongusaha, Elena A Goncharova, Tanja Schlechter, Thomas N Darling, Ilse Hofmann, Vera P Krymskaya, James K Liao, Hayden Huang, Elizabeth P Henske
Birt-Hogg-Dube (BHD) is a tumor suppressor gene syndrome associated with fibrofolliculomas, cystic lung disease, and chromophobe renal cell carcinoma. In seeking to elucidate the pathogenesis of BHD, we discovered a physical interaction between folliculin (FLCN), the protein product of the BHD gene, and p0071, an armadillo repeat containing protein that localizes to the cytoplasm and to adherens junctions. Adherens junctions are one of the three cell-cell junctions that are essential to the establishment and maintenance of the cellular architecture of all epithelial tissues...
2012: PloS One
Masaya Baba, Jonathan R Keller, Hong-Wei Sun, Wolfgang Resch, Stefan Kuchen, Hyung Chan Suh, Hisashi Hasumi, Yukiko Hasumi, Kyong-Rim Kieffer-Kwon, Carme Gallego Gonzalez, Robert M Hughes, Mara E Klein, Hyoungbin F Oh, Paul Bible, Eileen Southon, Lino Tessarollo, Laura S Schmidt, W Marston Linehan, Rafael Casellas
Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models...
August 9, 2012: Blood
Heon Park, Karen Staehling, Mark Tsang, Mark W Appleby, Mary E Brunkow, Daciana Margineantu, David M Hockenbery, Tania Habib, H Denny Liggitt, George Carlson, Brian M Iritani
The coordination of nutrient and energy availability with cell growth and division is essential for proper immune cell development and function. By using a chemical mutagenesis strategy in mice, we identified a pedigree that has a complete block in B cell development at the pre-B cell stage resulting from a deletion in the Fnip1 gene. Enforced expression of an immunoglobulin transgene failed to rescue B cell development. Whereas essential pre-B cell signaling molecules were activated normally in Fnip1-null pre-B cells, the metabolic regulators AMPK and mTOR were dysregulated, resulting in excessive cell growth and enhanced sensitivity to apoptosis in response to metabolic stress (pre-B cell receptor crosslinking, oncogene activation)...
May 25, 2012: Immunity
Masaya Baba, Mutsuo Furihata, Seung-Beom Hong, Lino Tessarollo, Diana C Haines, Eileen Southon, Vishal Patel, Peter Igarashi, W Gregory Alvord, Robert Leighty, Masahiro Yao, Marcelino Bernardo, Lilia Ileva, Peter Choyke, Michelle B Warren, Berton Zbar, W Marston Linehan, Laura S Schmidt
BACKGROUND: Patients with Birt-Hogg-Dubé (BHD) syndrome harbor germline mutations in the BHD tumor suppressor gene that are associated with an increased risk for kidney cancer. BHD encodes folliculin, a protein that may interact with the energy- and nutrient-sensing 5'-AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling pathways. METHODS: We used recombineering methods to generate mice with a conditional BHD allele and introduced the cadherin 16 (KSP)-Cre transgene to target BHD inactivation to the kidney...
January 16, 2008: Journal of the National Cancer Institute
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