Follistatin

FST
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3HH2, 2B0U, 2P6A
Identifiers
Aliases	FST , FS, follistatin
External IDs	OMIM: 136470; MGI: 95586; HomoloGene: 7324; GeneCards: FST; OMA:FST - orthologs
Gene location (Human) Chr. Chromosome 5 (human) [1] Band 5q11.2 Start 53,480,626 bp [1] End 53,487,134 bp [1]
Gene location (Mouse) Chr. Chromosome 13 (mouse) [2] Band 13|13 D2.2 Start 114,588,826 bp [2] End 114,595,487 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium buccal mucosa cell right lobe of liver oocyte secondary oocyte mucosa of urinary bladder Achilles tendon pericardium subcutaneous adipose tissue gastric mucosa Top expressed in cumulus cell gastrula primitive streak endothelial cell of lymphatic vessel stroma of bone marrow calvaria ovary decidua epiblast lumbar spinal ganglion More reference expression data BioGPS n/a
Gene ontology Molecular function heparan sulfate proteoglycan binding protein binding signal transducer activity activin binding activin receptor antagonist activity Cellular component extracellular region Biological process positive regulation of hair follicle development negative regulation of activin receptor signaling pathway negative regulation of transcription by RNA polymerase II hematopoietic progenitor cell differentiation signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10468 14313 Ensembl ENSG00000134363 ENSMUSG00000021765 UniProt P19883 P47931 RefSeq (mRNA) NM_006350 NM_013409 NM_008046 NM_001301373 NM_001301375 RefSeq (protein) NP_006341 NP_037541 NP_001288302 NP_001288304 NP_032072 Location (UCSC) Chr 5: 53.48 – 53.49 Mb Chr 13: 114.59 – 114.6 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Follistatin, also known as activin-bindings protein, is a protein that in humans is encoded by the FST gene. ^{[5] [6]} Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals. ^[6]

Its primary function is the binding and bioneutralization of members of the TGF-β superfamily, with a particular focus on activin, a paracrine hormone.

An earlier name for the same protein was FSH-suppressing protein (FSP). At the time of its initial isolation from follicular fluid, it was found to inhibit the anterior pituitary's secretion of follicle-stimulating hormone (FSH).

Biochemistry

Follistatin is part of the inhibin-activin-follistatin axis.

Three isoforms, FS-288, FS-300, and FS-315 have been reported. Two, FS-288 and FS-315, are created by alternative splicing of the primary mRNA transcript. FS-300 (porcine follistatin) is thought to be the product of posttranslational modification via truncation of the C-terminal domain from the primary amino-acid chain.

Although FS is ubiquitous, its highest concentration is in the female ovary, followed by the skin.

Follistatin is produced by folliculostellate (FS) cells of the anterior pituitary. FS cells make numerous contacts with the classical endocrine cells of the anterior pituitary including gonadotrophs.

Function

In tissues, activin plays a significant role in cellular proliferation, while follistatin acts as safeguard against uncontrolled cellular proliferation and an instrument of cellular differentiation. These roles are vital for rebuilding and repairing tissue, and may account for the high prevalence of follistatin in the skin.

In the blood, activin and follistatin are involved in the inflammatory response following tissue injury or pathogenic incursion. The source of follistatin in circulating blood plasma has yet to be determined; however, endothelial cells (lining blood vessels), or macrophages and monocytes (circulating within the blood) have been proposed as likely origins, given its autocrine nature.

Follistatin acts as an inhibitor for bone morphogenic proteins (BMPs) involved in embryo development. Since BMPs facilitate the ectoderm becoming the epidermal ectoderm, their inhibition allows the ectoderm to become the neuroectoderm - eventually forming the neural plate. Other inhibitors involved in this process are noggin and chordin.

Follistatin and BMPs also participate in folliculogenesis within the ovary. The main role of follistatin is for progression of the follicle from early antral to antral/dominant in the oestrus/menstrus ovary. Follistatin is also involved in the promotion of cellular differentiation of estrogen - by converting granulosa cells (GC) to progesterone in the dominant follicle - and production of large lutein cells (LLC) in the corpus luteum.

Clinical significance

Follistatin is studied for its role in regulation of muscle growth in mice, as an antagonist to myostatin (also known as GDF-8, a TGF superfamily member) which inhibits excessive muscle growth. Lee and McPherron demonstrated that inhibition of GDF-8, either by genetic elimination (knockout mice) or by increasing the amount of follistatin, resulted in increased muscle mass. ^{[7] [8]} In 2009, research with macaque monkeys demonstrated that regulating follistatin via gene therapy also resulted in muscle growth and increases in strength. ^[9]

Increased levels of follistatin, by leading to increased muscle mass of certain core muscular groups, can increase life expectancy in cases of spinal muscular atrophy (SMA) in animal models. ^[10]

Elevated circulating follistatin levels are also associated with increased risk of type 2 diabetes, early death, heart failure, stroke and chronic kidney disease. It has been demonstrated that follistatin contributes to insulin resistance in type 2 diabetes development and nonalcoholic fatty liver disease (NAFLD). The genetic regulation of follistatin secretion from the liver is via Glucokinase regulatory protein (GCKR) identified by large GWAS studies. ^{[11] [12]}

It is also investigated for its involvement in polycystic ovary syndrome (PCOS), in part to resolve debate as to its direct role in this disease. ^[13]

Sporadic inclusion body myositis, a variant of inflammatory myopathy, involves muscle weakness. In one clinical trial, rAAV1.CMV.huFS344, 6 × 1011 vg/kg, walk test results significantly improved versus untreated controls, along with decreased fibrosis and improved regeneration.

ACE-083, a follistatin-based fusion protein, was investigated for treatment focal or asymmetric myopathies. Intramuscular ACE-083 increased growth and force production in injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy, without systemic effects or endocrine disruption. ^[14]

AAV-mediated FST reduced obesity-induced inflammatory adipokines and cytokines systemically and in synovial fluid. Mice receiving FST therapy were protected from post-traumatic osteoarthritis and bone remodeling from joint injury. ^[15]

In another mouse study, high dose animals showed significant quadriceps growth.

References

1. GRCh38: Ensembl release 89: ENSG00000134363 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021765 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Ueno N, Ling N, Ying SY, Esch F, Shimasaki S, Guillemin R (December 1987). "Isolation and partial characterization of follistatin: a single-chain Mr 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone". Proceedings of the National Academy of Sciences of the United States of America. 84 (23): 8282–8286. Bibcode:1987PNAS...84.8282U. doi: 10.1073/pnas.84.23.8282 . PMC   299526 . PMID   3120188.
6. Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer AL (August 2001). "Human follistatin-related protein: a structural homologue of follistatin with nuclear localization". Endocrinology. 142 (8): 3426–3434. doi: 10.1210/endo.142.8.8319 . PMID   11459787.
7. Lee SJ, McPherron AC (July 2001). "Regulation of myostatin activity and muscle growth". Proceedings of the National Academy of Sciences of the United States of America. 98 (16): 9306–9311. Bibcode:2001PNAS...98.9306L. doi: 10.1073/pnas.151270098 . PMC   55416 . PMID   11459935.
8. "'Mighty mice' made mightier" . Retrieved 2008-02-26.
9. "Success Boosting Monkey Muscle Could Help Humans". NPR. 11 Nov 2009. Retrieved 2009-11-12.
10. Rose FF, Mattis VB, Rindt H, Lorson CL (March 2009). "Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy". Human Molecular Genetics. 18 (6): 997–1005. doi:10.1093/hmg/ddn426. PMC   2649020 . PMID   19074460.
11. Wu C, Borné Y, Gao R, López Rodriguez M, Roell WC, Wilson JM, et al. (November 2021). "Elevated circulating follistatin associates with an increased risk of type 2 diabetes". Nature Communications. 12 (1): 6486. Bibcode:2021NatCo..12.6486W. doi:10.1038/s41467-021-26536-w. PMC   8580990 . PMID   34759311.
12. Pan J, Nilsson J, Engström G, De Marinis Y (2024). "Elevated circulating follistatin associates with increased risk of mortality and cardiometabolic disorders". Nutr Metab Cardiovasc Dis. 34 (2): 418–425. doi: 10.1016/j.numecd.2023.09.012 . PMID   38000997.
13. Asteria C (October 2000). "Identification of follistatin as a possible trait-causing gene in polycystic ovary syndrome". European Journal of Endocrinology. 143 (4): 467–9. doi: 10.1530/eje.0.1430467 . PMID   11022191.
14. Pearsall RS, Davies MV, Cannell M, Li J, Widrick J, Mulivor AW, et al. (August 2019). "Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease". Scientific Reports. 9 (1): 11392. Bibcode:2019NatSR...911392P. doi:10.1038/s41598-019-47818-w. PMC   6684588 . PMID   31388039.
15. Tang R, Harasymowicz NS, Wu CL, Collins KH, Choi YR, Oswald SJ, et al. (May 2020). "Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet-induced obesity". Science Advances. 6 (19): eaaz7492. Bibcode:2020SciA....6.7492T. doi:10.1126/sciadv.aaz7492. PMC   7209997 . PMID   32426485.

Further reading

• Thompson TB, Lerch TF, Cook RW, Woodruff TK, Jardetzky TS (October 2005). "The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding". Developmental Cell. 9 (4): 535–543. doi: 10.1016/j.devcel.2005.09.008 . PMID   16198295.
• Nakatani M, Takehara Y, Sugino H, Matsumoto M, Hashimoto O, Hasegawa Y, et al. (February 2008). "Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice". FASEB Journal. 22 (2): 477–487. doi: 10.1096/fj.07-8673com . PMID   17893249. S2CID   10405000.
• Lambert-Messerlian G, Eklund E, Pinar H, Tantravahi U, Schneyer AL (2007). "Activin subunit and receptor expression in normal and cleft human fetal palate tissues". Pediatric and Developmental Pathology. 10 (6): 436–445. doi:10.2350/06-05-0087.1. PMID   18001154. S2CID   13268973.
• Walsh S, Metter EJ, Ferrucci L, Roth SM (June 2007). "Activin-type II receptor B (ACVR2B) and follistatin haplotype associations with muscle mass and strength in humans". Journal of Applied Physiology. 102 (6): 2142–2148. doi:10.1152/japplphysiol.01322.2006. PMC   2646094 . PMID   17347381.
• Ogino H, Yano S, Kakiuchi S, Muguruma H, Ikuta K, Hanibuchi M, et al. (February 2008). "Follistatin suppresses the production of experimental multiple-organ metastasis by small cell lung cancer cells in natural killer cell-depleted SCID mice". Clinical Cancer Research. 14 (3): 660–667. doi: 10.1158/1078-0432.CCR-07-1221 . hdl: 2297/18056 . PMID   18245525.
• Reis FM, Nascimento LL, Tsigkou A, Ferreira MC, Luisi S, Petraglia F (May 2007). "Activin A and follistatin in menstrual blood: low concentrations in women with dysfunctional uterine bleeding". Reproductive Sciences. 14 (4): 383–389. doi:10.1177/1933719107303985. PMID   17644811. S2CID   28945135.
• Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, et al. (December 2009). "High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men". Journal of Bone and Mineral Research. 24 (12): 2039–2049. doi:10.1359/jbmr.090524. PMC   2791518 . PMID   19453261.
• Blount AL, Vaughan JM, Vale WW, Bilezikjian LM (March 2008). "A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene". The Journal of Biological Chemistry. 283 (11): 7016–7026. doi: 10.1074/jbc.M709502200 . PMID   18184649.
• Eichberger T, Kaser A, Pixner C, Schmid C, Klingler S, Winklmayr M, et al. (May 2008). "GLI2-specific transcriptional activation of the bone morphogenetic protein/activin antagonist follistatin in human epidermal cells". The Journal of Biological Chemistry. 283 (18): 12426–12437. doi: 10.1074/jbc.M707117200 . PMC   2430996 . PMID   18319260.
• Jones MR, Wilson SG, Mullin BH, Mead R, Watts GF, Stuckey BG (April 2007). "Polymorphism of the follistatin gene in polycystic ovary syndrome". Molecular Human Reproduction. 13 (4): 237–241. doi: 10.1093/molehr/gal120 . PMID   17284512.
• Torres PB, Florio P, Ferreira MC, Torricelli M, Reis FM, Petraglia F (July 2007). "Deranged expression of follistatin and follistatin-like protein in women with ovarian endometriosis". Fertility and Sterility. 88 (1): 200–205. doi: 10.1016/j.fertnstert.2006.11.105 . PMID   17296189.
• Sidis Y, Mukherjee A, Keutmann H, Delbaere A, Sadatsuki M, Schneyer A (July 2006). "Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins". Endocrinology. 147 (7): 3586–3597. doi: 10.1210/en.2006-0089 . PMID   16627583.
• Grusch M, Drucker C, Peter-Vörösmarty B, Erlach N, Lackner A, Losert A, et al. (November 2006). "Deregulation of the activin/follistatin system in hepatocarcinogenesis". Journal of Hepatology. 45 (5): 673–680. doi:10.1016/j.jhep.2006.06.014. PMID   16935389.
• Chen M, Sinha M, Luxon BA, Bresnick AR, O'Connor KL (January 2009). "Integrin alpha6beta4 controls the expression of genes associated with cell motility, invasion, and metastasis, including S100A4/metastasin". The Journal of Biological Chemistry. 284 (3): 1484–1494. doi: 10.1074/jbc.M803997200 . PMC   2615501 . PMID   19011242.
• Blount AL, Schmidt K, Justice NJ, Vale WW, Fischer WH, Bilezikjian LM (March 2009). "FoxL2 and Smad3 coordinately regulate follistatin gene transcription". The Journal of Biological Chemistry. 284 (12): 7631–7645. doi: 10.1074/jbc.M806676200 . PMC   2658057 . PMID   19106105.
• Phillips DJ, de Kretser DM (October 1998). "Follistatin: a multifunctional regulatory protein". Frontiers in Neuroendocrinology. 19 (4): 287–322. doi:10.1006/frne.1998.0169. PMID   9799587. S2CID   3023421.
• Chang SY, Kang HY, Lan KC, Hseh CY, Huang FJ, Huang KE (2006). "Expression of inhibin-activin subunits, follistatin and smads in granulosa-luteal cells collected at oocyte retrieval". Journal of Assisted Reproduction and Genetics. 23 (9–10): 385–392. doi:10.1007/s10815-006-9068-7. PMC   3455100 . PMID   17053951.
• Kostek MA, Angelopoulos TJ, Clarkson PM, Gordon PM, Moyna NM, Visich PS, et al. (May 2009). "Myostatin and follistatin polymorphisms interact with muscle phenotypes and ethnicity". Medicine and Science in Sports and Exercise. 41 (5): 1063–1071. doi:10.1249/MSS.0b013e3181930337. PMC   4147954 . PMID   19346981.
• Flanagan JN, Linder K, Mejhert N, Dungner E, Wahlen K, Decaunes P, et al. (August 2009). "Role of follistatin in promoting adipogenesis in women". The Journal of Clinical Endocrinology and Metabolism. 94 (8): 3003–3009. doi:10.1210/jc.2008-2005. PMC   3214594 . PMID   19470636.
• Peng C, Ohno T, Khorasheh S, Leung PC (1996). "Activin and follistatin as local regulators in the human ovary". Biological Signals. 5 (2): 81–89. doi:10.1159/000109177. PMID   8836491.

External links

• Follistatin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt : P19883 (Follistatin) at the PDBe-KB .