FST (follistatin)

2010-03-01   Michael Grusch 

Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Borschkegasse 8a, A-1090 Vienna, Austria


Atlas Image
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.



The human FST gene is comprised of six exons spanning 5329 bp on chromosome 5q11.2 and gives 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).


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). 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).



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.


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).


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-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).


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.

Implicated in

Entity name
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).
Entity name
Follistatin was increased in serum of women with ovarian endometriosis and suggested as biomarker for endometrioma (Florio et al., 2009).
Entity name
Polycystic ovary syndrome
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).
Entity name
Liver failure
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).


Pubmed IDLast YearTitleAuthors
151361382004Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis.Amthor H et al
190793222009Keratinocyte-derived follistatin regulates epidermal homeostasis and wound repair.Antsiferova M et al
179385042007Therapeutic potential of follistatin to promote tissue regeneration and prevent tissue fibrosis.Aoki F et al
119484052002Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function.Bartholin L et al
186383912008AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease.Beale G et al
183192602008GLI2-specific transcriptional activation of the bone morphogenetic protein/activin antagonist follistatin in human epidermal cells.Eichberger T et al
195497032009High serum follistatin levels in women with ovarian endometriosis.Florio P et al
185744682008Parkin as a tumor suppressor gene for hepatocellular carcinoma.Fujiwara M et al
179914372007Identification and characterization of follistatin as a novel angiogenin-binding protein.Gao X et al
150567902004Bone 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.Glister C et al
169353892006Deregulation of the activin/follistatin system in hepatocarcinogenesis.Grusch M et al
164822172006Structural basis for the inhibition of activin signalling by follistatin.Harrington AE et al
122420342002cDNA cloning and expression of human activin betaE subunit.Hashimoto O et al
191015122009BMP/Wnt antagonists are upregulated by dexamethasone in osteoblasts and reversed by alendronate and PTH: potential therapeutic targets for glucocorticoid-induced osteoporosis.Hayashi K et al
125607552003Activin A and follistatin in acute liver failure.Hughes RD et al
96890811998Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo.Iemura S et al
172845122007Polymorphism of the follistatin gene in polycystic ovary syndrome.Jones MR et al
145639352004The role of follistatin domains in follistatin biological action.Keutmann HT et al
165098612006Ratio of circulating follistatin and activin A reflects the severity of acute liver injury and prognosis in patients with acute liver failure.Lin SD et al
78854751995Multiple defects and perinatal death in mice deficient in follistatin.Matzuk MM et al
189227342008The role of activins and follistatins in skin and hair follicle development and function.McDowall M et al
21061591990Activin-binding protein from rat ovary is follistatin.Nakamura T et al
187684632008Peroxisome proliferator-activated receptor gamma down-regulates follistatin in intestinal epithelial cells through SP1.Necela BM et al
192615382009Activin and related proteins in inflammation: not just interested bystanders.Phillips DJ et al
197764202009Identification of five candidate lung cancer biomarkers by proteomics analysis of conditioned media of four lung cancer cell lines.Planque C et al
192084032009Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease.Rodino-Klapac LR et al
122033612002Follistatin overexpression in rodent liver tumors: a possible mechanism to overcome activin growth control.Rossmanith W et al
126976702003Differential binding and neutralization of activins A and B by follistatin and follistatin like-3 (FSTL-3/FSRP/FLRG).Schneyer A et al
85366191996Follistatin-activin complexes in human serum and follicular fluid differ immunologically and biochemically.Schneyer AL et al
33807881988Primary structure of the human follistatin precursor and its genomic organization.Shimasaki S et al
189484052009Regulation of myogenic differentiation by androgens: cross talk between androgen receptor/ beta-catenin and follistatin/transforming growth factor-beta signaling pathways.Singh R et al
150647262004Melanoma cells secrete follistatin, an antagonist of activin-mediated growth inhibition.Stove C et al
83403841993Molecular heterogeneity of follistatin, an activin-binding protein. Higher affinity of the carboxyl-terminal truncated forms for heparan sulfate proteoglycans on the ovarian granulosa cell.Sugino K et al
114597872001Human follistatin-related protein: a structural homologue of follistatin with nuclear localization.Tortoriello DV et al
110109682000Identification and characterization of a novel follistatin-like protein as a binding protein for the TGF-beta family.Tsuchida K et al
31201881987Isolation and partial characterization of follistatin: a single-chain Mr 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone.Ueno N et al
93341661997The Factor I and follistatin domain families: the return of a prodigal son.Ullman CG et al
104119171999Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin.Urbanek M et al
150391472004Assessment of the function of the betaC-subunit of activin in cultured hepatocytes.Wada W et al
120954192002A transcriptional response to Wnt protein in human embryonic carcinoma cells.Willert J et al
174827562007Transcriptional regulation of follistatin expression by GnRH in mouse gonadotroph cell lines: evidence for a role for cAMP signaling.Winters SJ et al
151625002004Follistatin operates downstream of Wnt4 in mammalian ovary organogenesis.Yao HH et al
118430632002Transforming growth factor-beta 1, activin and follistatin in patients with hepatocellular carcinoma and patients with alcoholic cirrhosis.Yuen MF et al
154515682004The role of activin, follistatin and inhibin in testicular physiology.de Kretser DM et al

Other Information

Locus ID:

NCBI: 10468
MIM: 136470
HGNC: 3971
Ensembl: ENSG00000134363


dbSNP: 10468
ClinVar: 10468
TCGA: ENSG00000134363


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
TGF-beta signaling pathwayKEGGko04350
TGF-beta signaling pathwayKEGGhsa04350
Signal TransductionREACTOMER-HSA-162582
Signaling by ActivinREACTOMER-HSA-1502540
Antagonism of Activin by FollistatinREACTOMER-HSA-2473224

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
166275832006Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins.78
178932492008Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice.68
190112422009Integrin alpha6beta4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin.62
191061052009FoxL2 and Smad3 coordinately regulate follistatin gene transcription.47
219008452012Strength training with blood flow restriction diminishes myostatin gene expression.47
210681582011Exercise induces a marked increase in plasma follistatin: evidence that follistatin is a contraction-induced hepatokine.42
207340642010A large-scale candidate gene association study of age at menarche and age at natural menopause.38
182455252008Follistatin suppresses the production of experimental multiple-organ metastasis by small cell lung cancer cells in natural killer cell-depleted SCID mice.32
206286242010Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".29
145639352004The role of follistatin domains in follistatin biological action.27


Michael Grusch

FST (follistatin)

Atlas Genet Cytogenet Oncol Haematol. 2010-03-01

Online version: http://atlasgeneticsoncology.org/gene/44477/fst-(follistatin)