SUFU explained

Suppressor of fused homolog is a protein that in humans is encoded by the SUFU gene.^{[1] [2]} In molecular biology, the protein domain suppressor of fused protein (Sufu) has an important role in the cell. The Sufu is important in negatively regulating an important signalling pathway in the cell, the Hedgehog signalling pathway (HH). This particular pathway is crucial in embryonic development. There are several homologues of Sufu, found in a wide variety of organisms.

Function

SUFU encodes a component of the sonic hedgehog (SHH) / patched (PTCH) signaling pathway. Mutations in genes encoding components of this pathway are deleterious for normal development and are associated with cancer-predisposing syndromes (e.g., holoprosencephaly, HPE3, basal cell nevus syndrome, BCNS, and Greig cephalopolysyndactyly syndrome, GCPS).Sufu has also been found to have a crucial role in tumour suppression. To be more specific, it has a tumour-suppressor gene that predisposes, or in other words makes individuals more susceptible to medulloblastoma, because it modulates the SHH signalling pathway.^[3] The N-terminal domain, which this entry refers to contains Gli transcription factors.^[4]

Interactions

SUFU has been shown to interact with GLI1,^{[5] [6] [7]} GLI3^[8] and PEX26.^[9]

Conservation

The human ortholog of Drosophila suppressor of fused, has a conserved sequence, this means that particular amino acids have remained the same throughout evolution. Consequently, they have very similar roles in repressing Hedgehog signalling. It represses the Gli and Ci transcription factors of the Hedgehog pathway,^[10] and functions by binding to these proteins and preventing their translocation to the nucleus. Homologues of Sufu have been found in bacteria. However their function remains to be elucidated.

Structure

Sufu is actually protein that contains two domains.^[4] In eukaryotic Sufu, an additional domain is found at the C terminus of the protein. This protein domain also binds to the C-terminal domain of the Gli/Ci transcription factors, inhibiting their activity.^[1]

Genes

Human gene that encodes SUFU, also named SUFU, is found to be localized on chromosome 10q24–25, and contains 12 exons.^[10]

Further reading

• Kogerman P, Grimm T, Kogerman L, etal . Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1 . Nat. Cell Biol. . 1 . 5 . 312–9 . 1999 . 10559945 . 10.1038/13031 . 6907964 . free .
• Stone DM, Murone M, Luoh S, etal . Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli . J. Cell Sci. . 112 . 23. 4437–48 . 2000 . 10.1242/jcs.112.23.4437 . 10564661 .
• Murone M, Luoh SM, Stone D, etal . Gli regulation by the opposing activities of fused and suppressor of fused . Nat. Cell Biol. . 2 . 5 . 310–2 . 2000 . 10806483 . 10.1038/35010610 . 31424234 .
• Delattre M, Briand S, Paces-Fessy M, Blanchet-Tournier MF . The Suppressor of fused gene, involved in Hedgehog signal transduction in Drosophila, is conserved in mammals . Dev. Genes Evol. . 209 . 5 . 294–300 . 2001 . 11252182 . 10.1007/s004270050255 . 42211231 .
• Cheng SY, Bishop JM . Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex . Proc. Natl. Acad. Sci. U.S.A. . 99 . 8 . 5442–7 . 2002 . 11960000 . 10.1073/pnas.082096999 . 122788 . 2002PNAS...99.5442C . free .
• Taylor MD, Liu L, Raffel C, etal . Mutations in SUFU predispose to medulloblastoma . Nat. Genet. . 31 . 3 . 306–10 . 2002 . 12068298 . 10.1038/ng916 . 6882566 .
• Dunaeva M, Michelson P, Kogerman P, Toftgard R . Characterization of the physical interaction of Gli proteins with SUFU proteins . J. Biol. Chem. . 278 . 7 . 5116–22 . 2003 . 12426310 . 10.1074/jbc.M209492200 . free .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Clark HF, Gurney AL, Abaya E, etal . The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment . Genome Res. . 13 . 10 . 2265–70 . 2003 . 12975309 . 10.1101/gr.1293003 . 403697 .
• Paces-Fessy M, Boucher D, Petit E, etal . The negative regulator of Gli, Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins . Biochem. J. . 378 . Pt 2 . 353–62 . 2004 . 14611647 . 10.1042/BJ20030786 . 1223961 .
• Taylor MD, Zhang X, Liu L, etal . Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling . Oncogene . 23 . 26 . 4577–83 . 2004 . 15077159 . 10.1038/sj.onc.1207605 . free .
• Deloukas P, Earthrowl ME, Grafham DV, etal . The DNA sequence and comparative analysis of human chromosome 10 . Nature . 429 . 6990 . 375–81 . 2004 . 15164054 . 10.1038/nature02462 . 2004Natur.429..375D . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Rual JF, Venkatesan K, Hao T, etal . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Lyle R, Radhakrishna U, Blouin JL, etal . Split-hand/split-foot malformation 3 (SHFM3) at 10q24, development of rapid diagnostic methods and gene expression from the region . Am. J. Med. Genet. A . 140 . 13 . 1384–95 . 2006 . 16691619 . 10.1002/ajmg.a.31247 . 24199907 .

Notes and References

1. Merchant M, Vajdos FF, Ultsch M, Maun HR, Wendt U, Cannon J, Desmarais W, Lazarus RA, de Vos AM, de Sauvage FJ . Suppressor of fused regulates Gli activity through a dual binding mechanism . Mol Cell Biol . 24 . 19 . 8627–41 . Sep 2004 . 15367681 . 516763 . 10.1128/MCB.24.19.8627-8641.2004 .
2. Web site: Entrez Gene: SUFU suppressor of fused homolog (Drosophila).
3. Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D . Mutations in SUFU predispose to medulloblastoma . Nat. Genet. . 31 . 3 . 306–10 . July 2002 . 12068298 . 10.1038/ng916 . 6882566 .
4. Das D, Finn RD, Abdubek P, Astakhova T, Axelrod HL, Bakolitsa C, etal . The crystal structure of a bacterial Sufu-like protein defines a novel group of bacterial proteins that are similar to the N-terminal domain of human Sufu. . Protein Sci . 2010 . 19 . 11 . 2131–40 . 20836087 . 10.1002/pro.497 . 3005784 .
5. Stone DM, Murone M, Luoh S, Ye W, Armanini MP, Gurney A, Phillips H, Brush J, Goddard A, de Sauvage FJ, Rosenthal A . Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli . J. Cell Sci. . 112 . 23. 4437–48 . December 1999 . 10.1242/jcs.112.23.4437 . 10564661 .
6. Kogerman P, Grimm T, Kogerman L, Krause D, Undén AB, Sandstedt B, Toftgård R, Zaphiropoulos PG . Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1 . Nat. Cell Biol. . 1 . 5 . 312–9 . September 1999 . 10559945 . 10.1038/13031 . 6907964 . free .
7. Dunaeva M, Michelson P, Kogerman P, Toftgard R . Characterization of the physical interaction of Gli proteins with SUFU proteins . J. Biol. Chem. . 278 . 7 . 5116–22 . February 2003 . 12426310 . 10.1074/jbc.M209492200 . free .
8. Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R . The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins . Genes Dev. . 24 . 7 . 670–82 . April 2010 . 20360384 . 10.1101/gad.1902910 . 2849124 .
9. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
10. Rubin JB, Rowitch DH . Medulloblastoma: a problem of developmental biology . Cancer Cell . 2 . 1 . 7–8 . July 2002 . 12150819 . 10.1016/S1535-6108(02)00090-9. free .