Download Gene Section FST (follistatin) Atlas of Genetics and Cytogenetics

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