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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review FST (follistatin) Michael Grusch Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Borschkegasse 8a, A-1090 Vienna, Austria (MG) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/FSTID44477ch5q11.html DOI: 10.4267/2042/44914 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology rise to two main transcripts of 1122 bp (transcript variant FST344) and 1386 bp (transcript variant FST317). The first exon encodes the signal peptide, the second exon the N-terminal domain and exons 3-5 each code for a follistatin module. Alternative splicing leads to usage of either exon 6A, which codes for an acidic region in FST344 or exon 6B, which contains two bases of the stop codon of FST317 (Shimasaki et al., 1988). Identity Other names: FS HGNC (Hugo): FST Location: 5q11.2 Local order RPS19P4 (ribosomal protein S19 pseudogene 4) - FST - NDUFS4 (NADH dehydrogenase (ubiquinone) Fe-S protein 4). Transcription DNA/RNA Transcription of FST mRNA was shown to be stimulated by TGF beta and activin A via Smad proteins (Bartholin et al., 2002), which seems to be part of a negative feedback loop as FST can antagonize activin A (see below). Description The human FST gene is comprised of six exons spanning 5329 bp on chromosome 5q11.2 and gives Intron/exon structure of the FST gene and domain architecture of FST proteins. 1, 2, 3, 4, 5, 6A, 6B: exon number; SP: signal peptide; NTD: N-terminal domain; FSD: follistatin domain; AT: acidic tail. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1132 FST (follistatin) Grusch M bound activin is unable to initiate signal transduction and consequently follistatin is a potent antagonist of physiological activin signals. Of the three follistatin domains present in all follistatin isoforms, (Shimasaki et al., 1988) the first two, but not the third, are necessary for activin A binding (Keutmann et al., 2004; Harrington et al., 2006). Aside from activins, follistatin also binds several bone morphogenetic proteins (BMP) including BMP2, BMP4, BMP6 and BMP7 (Iemura et al., 1998; Glister et al., 2004). In 2004 it was shown that follistatin binds myostatin (also known as growth and differentiation factor 8, GDF8) with high affinity and thereby is able to antagonize the inhibitory effect of myostatin on muscle growth (Amthor et al., 2004). The functional significance of the interaction between follistatin and angiogenin, a pro-angiogenic factor unrelated to the TGF beta family, remains to be determined (Gao et al., 2007). The interaction of follistatin with heparin and heparan sulfates is isoform specific. Follistatin 288 binds to heparan sulfates, whereas this binding is blocked by the acidic tail of follistatin 315 (Sugino et al., 1993). Knock-out mice for follistatin die within hours after birth and show multiple abnormalities of muscles, skin and skeleton (Matzuk et al., 1995). Evidence from many organs and tissues shows that counterbalancing of signals from TGF beta family members by follistatin is crucial for normal tissue development, architecture and function (de Kretser et al., 2004; McDowall et al., 2008; Kreidl et al., 2009; Antsiferova et al., 2009). Due to the capability for efficient antagonization of signals from activin and myostatin, the therapeutic application of follistatin has been discussed in several clinical conditions involving elevated activin/myostatin activity. Potential areas of application include blocking increased activin expression in inflammation (Phillips et al., 2009) and fibrotic disorders (Aoki and Kojima, 2007) and inhibition of myostatin in muscle diseases (Rodino-Klapac et al., 2009). Other factors and pathways that have been demonstrated to stimulate follistatin gene transcription are gonadotropin-releasing hormone (GnRH) acting via cAMP and CREB (Winters et al., 2007), GLI2, a transcription factor activated by hedgehog signaling (Eichberger et al., 2008), dexamethasone (Hayashi et al., 2009), androgens and activators of wnt signaling (Willert et al., 2002; Yao et al., 2004; Singh et al., 2009). Repression of the follistatin promoter in response to peroxisome proliferator-activated receptor gamma was mediated via SP1 (Necela et al., 2008). Protein Description Mature secreted follistatin protein exists in three main forms consisting of 288, 303, and 315 amino acids (Sugino et al., 1993). The FST344 transcript gives rise to a protein precursor of 344 amino acids, which results in the mature 315 amino acid form after removal of the signal peptide. A fraction of follistatin 315 is further converted to the 303 amino acid form by proteolytic cleavage at the C-terminus. Signal peptide removal of FST317 leads to the mature 288 amino acid form of follistatin. All forms of follistatin contain three follistatin domains (FSD) characterized by a conserved arrangement of 10 cysteine residues. The N-terminal subdomains of the FSD have similarity with EGF-like modules, whereas the C-terminal regions resemble the Kazal domains found in multiple serine protease inhibitors. The follistatin protein contains two potential N-glycosilation sites on asparagines 124 and 288. Localisation Follistatin is expressed in a wide variety of tissues and organs with the highest expression in the ovaries and testes (Phillips and de Kretser, 1998; Tortoriello et al., 2001). The signal peptide directs the nascent protein to the secretory pathway and follistatin has been detected in human serum and in cell culture supernatants of multiple cell lines (Phillips and de Kretser, 1998). Among the follistatin isoforms FST315 was secreted faster than FST288 (Schneyer et al., 2003) and due to the lack of binding to cell-surface heparin-sulfated proteoglycans, a larger fraction of FST315 enters the circulation (Schneyer et al., 1996). Homology The follistatin module with its characteristic spacing of cysteines represents a conserved protein domain. Follistatin modules are found in varying numbers in a wider set of secreted proteins including FSTL1, SPARC/osteonectin, or agrin (Ullman and Perkins, 1997). Among these, follistatin-like 3 (FSTL3, FLRG) shares a similar overall domain architecture with follistatin, but harbors only two instead of three follistatin modules (Tortoriello et al., 2001). With respect to activin binding ability, functional homology among follistatin domain-containing proteins is only found between follistatin and FSTL3, whereas all other follistatin family proteins have not been demonstrated to bind proteins of the TGF beta family (Tsuchida et al., 2000). Follistatin is also highly conserved between species with around 97% amino acid identity in human, mouse and rat. Function Follistatin binds to several members of the TGF beta family and blocks the interaction of these cytokines with their cognate receptors. Follistatin was first identified as a factor that could inhibit the release of follicle-stimulating hormone from pituitary cells (Ueno et al., 1987). It binds activins A, B and AB with high affinity and was also reported to bind activin E but not activin C (Nakamura et al., 1990; Schneyer et al., 1994; Hashimoto et al., 2002; Wada et al., 2004). Follistatin- Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1133 FST (follistatin) Grusch M Sugino K, Kurosawa N, Nakamura T, Takio K, Shimasaki S, Ling N, Titani K, Sugino H. Molecular heterogeneity of follistatin, an activin-binding protein. Higher affinity of the carboxyl-terminal truncated forms for heparan sulfate proteoglycans on the ovarian granulosa cell. J Biol Chem. 1993 Jul 25;268(21):15579-87 Implicated in Malignancy Note Overexpression of follistatin has been found in rat and mouse models of hepatocellular carcinoma (HCC) (Rossmanith et al., 2002; Fujiwara et al., 2008) as well as in tumor tissue and serum of HCC patients (Yuen et al., 2002; Grusch et al., 2006; Beale et al., 2008). However, follistatin had no benefit as surveillance biomarker for HCC development in patients with alcoholic and non-alcoholic liver disease (ALD and NAFLD) due to the already elevated levels in the underlying liver pathologies (Beale et al., 2008). Follistatin overexpression was also demonstrated in human melanoma cell lines (Stove et al., 2004) and has been suggested as candidate biomarker for lung cancer (Planque et al., 2009). Schneyer AL, Rzucidlo DA, Sluss PM, Crowley WF Jr. Characterization of unique binding kinetics of follistatin and activin or inhibin in serum. Endocrinology. 1994 Aug;135(2):667-74 Matzuk MM, Lu N, Vogel H, Sellheyer K, Roop DR, Bradley A. Multiple defects and perinatal death in mice deficient in follistatin. Nature. 1995 Mar 23;374(6520):360-3 Schneyer AL, Hall HA, Lambert-Messerlian G, Wang QF, Sluss P, Crowley WF Jr. Follistatin-activin complexes in human serum and follicular fluid differ immunologically and biochemically. Endocrinology. 1996 Jan;137(1):240-7 Ullman CG, Perkins SJ. The Factor I and follistatin domain families: the return of a prodigal son. Biochem J. 1997 Sep 15;326 ( Pt 3):939-41 Iemura S, Yamamoto TS, Takagi C, Uchiyama H, Natsume T, Shimasaki S, Sugino H, Ueno N. Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9337-42 Endometriosis Note Follistatin was increased in serum of women with ovarian endometriosis and suggested as biomarker for endometrioma (Florio et al., 2009). Phillips DJ, de Kretser DM. Follistatin: a multifunctional regulatory protein. Front Neuroendocrinol. 1998 Oct;19(4):287322 Polycystic ovary syndrome Urbanek M, et al. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8573-8 Note A genetic linkage analysis found evidence for linkage of follistatin with polycystic ovary syndrome (PCOS) (Urbanek et al., 1999). Another study reported that the follistatin gene is not a susceptibility locus for PCOS but a single nucleotide polymorphism of the gene may be involved in the hyperandrogenaemia of the disease (Jones et al., 2007). Tsuchida K, Arai KY, Kuramoto Y, Yamakawa N, Hasegawa Y, Sugino H. Identification and characterization of a novel follistatin-like protein as a binding protein for the TGF-beta family. J Biol Chem. 2000 Dec 29;275(52):40788-96 Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer AL. Human follistatin-related protein: a structural homologue of follistatin with nuclear localization. Endocrinology. 2001 Aug;142(8):3426-34 Liver failure Note Serum levels of follistatin and activin A were increased in patients with acute liver failure and it was suggested that a decreased follistatin/activin A ratio in the blood may be an indicator for the severity of liver injury in hepatitis-related acute liver disease (Hughes and Evans, 2003; Lin et al., 2006). Bartholin L, Maguer-Satta V, Hayette S, Martel S, Gadoux M, Corbo L, Magaud JP, Rimokh R. Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function. Oncogene. 2002 Mar 28;21(14):2227-35 Hashimoto O, Tsuchida K, Ushiro Y, Hosoi Y, Hoshi N, Sugino H, Hasegawa Y. cDNA cloning and expression of human activin betaE subunit. Mol Cell Endocrinol. 2002 Aug 30;194(12):117-22 References Rossmanith W, et al. Follistatin overexpression in rodent liver tumors: a possible mechanism to overcome activin growth control. Mol Carcinog. 2002 Sep;35(1):1-5 Ueno N, Ling N, Ying SY, Esch F, Shimasaki S, Guillemin R. Isolation and partial characterization of follistatin: a singlechain Mr 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8282-6 Willert J, Epping M, Pollack JR, Brown PO, Nusse R. A transcriptional response to Wnt protein in human embryonic carcinoma cells. BMC Dev Biol. 2002 Jul 2;2:8 Shimasaki S, Koga M, Esch F, Cooksey K, Mercado M, Koba A, Ueno N, Ying SY, Ling N, Guillemin R. Primary Yuen MF, Norris S, Evans LW, Langley PG, Hughes RD. Transforming growth factor-beta 1, activin and follistatin in patients with hepatocellular carcinoma and patients with alcoholic cirrhosis. Scand J Gastroenterol. 2002 Feb;37(2):233-8 structure of the human follistatin precursor and its genomic organization. Proc Natl Acad Sci U S A. 1988 Jun;85(12):421822 Hughes RD, Evans LW. Activin A and follistatin in acute liver failure. Eur J Gastroenterol Hepatol. 2003 Feb;15(2):127-31 Nakamura T, Takio K, Eto Y, Shibai H, Titani K, Sugino H. Activin-binding protein from rat ovary is follistatin. Science. 1990 Feb 16;247(4944):836-8 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1134 FST (follistatin) Grusch M Schneyer A, Schoen A, Quigg A, Sidis Y. Differential binding and neutralization of activins A and B by follistatin and follistatin like-3 (FSTL-3/FSRP/FLRG). Endocrinology. 2003 May;144(5):1671-4 Beale G, Chattopadhyay D, Gray J, Stewart S, Hudson M, Day C, Trerotoli P, Giannelli G, Manas D, Reeves H. AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease. BMC Cancer. 2008 Jul 18;8:200 Amthor H, Nicholas G, McKinnell I, Kemp CF, Sharma M, Kambadur R, Patel K. Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis. Dev Biol. 2004 Jun 1;270(1):19-30 Eichberger T, et al. GLI2-specific transcriptional activation of the bone morphogenetic protein/activin antagonist follistatin in human epidermal cells. J Biol Chem. 2008 May 2;283(18):12426-37 de Kretser DM, et al. The role of activin, follistatin and inhibin in testicular physiology. Mol Cell Endocrinol. 2004 Oct 15;225(12):57-64 Fujiwara M, Marusawa H, Wang HQ, Iwai A, Ikeuchi K, Imai Y, Kataoka A, Nukina N, Takahashi R, Chiba T. Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene. 2008 Oct 9;27(46):6002-11 Glister C, Kemp CF, Knight PG. Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells: actions of BMP-4, -6 and -7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatin. Reproduction. 2004 Feb;127(2):239-54 McDowall M, Edwards NM, Jahoda CA, Hynd PI. The role of activins and follistatins in skin and hair follicle development and function. Cytokine Growth Factor Rev. 2008 Oct-Dec;19(56):415-26 Keutmann HT, Schneyer AL, Sidis Y. The role of follistatin domains in follistatin biological action. Mol Endocrinol. 2004 Jan;18(1):228-40 Necela BM, Su W, Thompson EA. Peroxisome proliferatoractivated receptor gamma down-regulates follistatin in intestinal epithelial cells through SP1. J Biol Chem. 2008 Oct 31;283(44):29784-94 Stove C, Vanrobaeys F, Devreese B, Van Beeumen J, Mareel M, Bracke M. Melanoma cells secrete follistatin, an antagonist of activin-mediated growth inhibition. Oncogene. 2004 Jul 8;23(31):5330-9 Antsiferova M, Klatte JE, Bodó E, Paus R, Jorcano JL, Matzuk MM, Werner S, Kögel H. Keratinocyte-derived follistatin regulates epidermal homeostasis and wound repair. Lab Invest. 2009 Feb;89(2):131-41 Wada W, Maeshima A, Zhang YQ, Hasegawa Y, Kuwano H, Kojima I. Assessment of the function of the betaC-subunit of activin in cultured hepatocytes. Am J Physiol Endocrinol Metab. 2004 Aug;287(2):E247-54 Florio P, et al. High serum follistatin levels in women with ovarian endometriosis. Hum Reprod. 2009 Oct;24(10):2600-6 Yao HH, Matzuk MM, Jorgez CJ, Menke DB, Page DC, Swain A, Capel B. Follistatin operates downstream of Wnt4 in mammalian ovary organogenesis. Dev Dyn. 2004 Jun;230(2):210-5 Hayashi K, Yamaguchi T, Yano S, Kanazawa I, Yamauchi M, Yamamoto M, Sugimoto T. BMP/Wnt antagonists are upregulated by dexamethasone in osteoblasts and reversed by alendronate and PTH: potential therapeutic targets for glucocorticoid-induced osteoporosis. Biochem Biophys Res Commun. 2009 Feb 6;379(2):261-6 Grusch M, Drucker C, Peter-Vörösmarty B, Erlach N, Lackner A, Losert A, Macheiner D, Schneider WJ, Hermann M, Groome NP, Parzefall W, Berger W, Grasl-Kraupp B, Schulte-Hermann R. Deregulation of the activin/follistatin system in hepatocarcinogenesis. J Hepatol. 2006 Nov;45(5):673-80 Kreidl E, et al. Activins and follistatins: Emerging roles in liver physiology and cancer. World J Hepatol Rev 2009 Oct 31; 1(1): 17-27. (REVIEW) Harrington AE, Morris-Triggs SA, Ruotolo BT, Robinson CV, Ohnuma S, Hyvönen M. Structural basis for the inhibition of activin signalling by follistatin. EMBO J. 2006 Mar 8;25(5):1035-45 Phillips DJ, de Kretser DM, Hedger MP. Activin and related proteins in inflammation: not just interested bystanders. Cytokine Growth Factor Rev. 2009 Apr;20(2):153-64 Planque C, Kulasingam V, Smith CR, Reckamp K, Goodglick L, Diamandis EP. Identification of five candidate lung cancer biomarkers by proteomics analysis of conditioned media of four lung cancer cell lines. Mol Cell Proteomics. 2009 Dec;8(12):2746-58 Lin SD, Kawakami T, Ushio A, Sato A, Sato S, Iwai M, Endo R, Takikawa Y, Suzuki K. Ratio of circulating follistatin and activin A reflects the severity of acute liver injury and prognosis in patients with acute liver failure. J Gastroenterol Hepatol. 2006 Feb;21(2):374-80 Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve. 2009 Mar;39(3):283-96 Aoki F, Kojima I. Therapeutic potential of follistatin to promote tissue regeneration and prevent tissue fibrosis. Endocr J. 2007;54(6):849-54 Gao X, Hu H, Zhu J, Xu Z. Identification and characterization of follistatin as a novel angiogenin-binding protein. FEBS Lett. 2007 Nov 27;581(28):5505-10 Singh R, Bhasin S, Braga M, Artaza JN, Pervin S, Taylor WE, Krishnan V, Sinha SK, Rajavashisth TB, Jasuja R. Regulation of myogenic differentiation by androgens: cross talk between androgen receptor/ beta-catenin and follistatin/transforming growth factor-beta signaling pathways. Endocrinology. 2009 Mar;150(3):1259-68 Jones MR, Wilson SG, Mullin BH, Mead R, Watts GF, Stuckey BG. Polymorphism of the follistatin gene in polycystic ovary syndrome. Mol Hum Reprod. 2007 Apr;13(4):237-41 This article should be referenced as such: Winters SJ, Ghooray D, Fujii Y, Moore JP Jr, Nevitt JR, Kakar SS. Transcriptional regulation of follistatin expression by GnRH in mouse gonadotroph cell lines: evidence for a role for cAMP signaling. Mol Cell Endocrinol. 2007 Jun 15;271(1-2):45-54 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Grusch M. FST (follistatin). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1132-1135. 1135