follistatin related proteins


Summary: Broadly distributed glycoproteins that are homologous to the activin-binding protein, FOLLISTATIN. These follistatin-related proteins are encoded by a number of genes.

Top Publications

  1. Pryor Koishi K, Nishizawa H, Kato T, Kogo H, Murakami T, Tsuchida K, et al. Overproduction of the follistatin-related gene protein in the placenta and maternal serum of women with pre-eclampsia. BJOG. 2007;114:1128-37 pubmed
    ..Our current data show the placental and secretory changes of FLRG protein in pre-eclampsia, and also indicate the potential usefulness of FLRG as an additional diagnostic marker for pre-eclampsia. ..
  2. Torres P, Florio P, Ferreira M, Torricelli M, Reis F, Petraglia F. Deranged expression of follistatin and follistatin-like protein in women with ovarian endometriosis. Fertil Steril. 2007;88:200-5 pubmed
    ..Ovarian endometriotic lesions show a deranged expression of FLRG and follistatin, which are activin A-binding proteins. This may result in an altered effect of activin A on angiogenesis and/or endometrial differentiation. ..
  3. Ciarmela P, Florio P, Sigurdardottir M, Toti P, Maguer Satta V, Rimokh R, et al. Follistatin-related gene expression, but not follistatin expression, is decreased in human endometrial adenocarcinoma. Eur J Endocrinol. 2004;151:251-7 pubmed
  4. Saito S, Sidis Y, Mukherjee A, Xia Y, Schneyer A. Differential biosynthesis and intracellular transport of follistatin isoforms and follistatin-like-3. Endocrinology. 2005;146:5052-62 pubmed
    ..Moreover, the differential biosynthetic and intracellular transport patterns for FST288 and FSTL3 suggest that these two activin-binding proteins may have distinct intracellular roles. ..
  5. Okamoto A, Endo H, Kalionis B, Shinya M, Saito M, Nikaido T, et al. IGFBP1 and Follistatin-like 3 genes are significantly up-regulated in expression profiles of the IUGR placenta. Placenta. 2006;27:317-21 pubmed
    ..IGFBP1 and Follistatin-like 3 are known critical regulators of fetal growth and differentiation. Pathways associated with these genes might be important for the pathogenesis of IUGR. ..
  6. Tortoriello D, Sidis Y, Holtzman D, Holmes W, Schneyer A. Human follistatin-related protein: a structural homologue of follistatin with nuclear localization. Endocrinology. 2001;142:3426-34 pubmed
  7. de Groot E, Feijen A, Eib D, Zwijsen A, Sugino H, Martens G, et al. Expression patterns of follistatin and two follistatin-related proteins during mouse development. Int J Dev Biol. 2000;44:327-30 pubmed
    ..0, while FRP is detected from E7.5 onwards. Although there is some overlap between the expression of these genes in the primitive streak and somites, their overall expression patterns are distinct. ..
  8. Maguer Satta V, Bartholin L, Jeanpierre S, Gadoux M, Bertrand S, Martel S, et al. Expression of FLRG, a novel activin A ligand, is regulated by TGF-beta and during hematopoiesis [corrected]. Exp Hematol. 2001;29:301-8 pubmed
    ..Moreover, FLRG interacts with activin A, suggesting that FLRG, like follistatin, participates in the diverse regulatory functions of activin A, such as those in hematopoiesis. ..
  9. Mukherjee A, Sidis Y, Mahan A, Raher M, Xia Y, Rosen E, et al. FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults. Proc Natl Acad Sci U S A. 2007;104:1348-53 pubmed

More Information


  1. Sidis Y, Mukherjee A, Keutmann H, Delbaere A, Sadatsuki M, Schneyer A. 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. 2006;147:3586-97 pubmed
    ..These results indicate that the differential biological actions among the FST isoforms and FSTL3 are primarily dependent on their relative cell-surface binding ability and ligand specificity. ..
  2. Razanajaona D, Joguet S, Ay A, Treilleux I, Goddard Leon S, Bartholin L, et al. Silencing of FLRG, an antagonist of activin, inhibits human breast tumor cell growth. Cancer Res. 2007;67:7223-9 pubmed
    ..Our data provide strong evidence that endogenous FLRG contributes to tumor cell proliferation through antagonizing endogenous activin effects. ..
  3. Florio P, Ciarmela P, Toti P, Maguer Satta V, Rimokh R, Buonocore G, et al. Human endometrium and decidua express follistatin-related gene (FLRG) mRNA and peptide. Mol Cell Endocrinol. 2004;218:129-35 pubmed
    ..In conclusion, FLRG is expressed by the human endometrium, and the different cellular localization suggests novel putative functions. ..
  4. Hill J, Davies M, Pearson A, Wang J, Hewick R, Wolfman N, et al. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J Biol Chem. 2002;277:40735-41 pubmed
    ..Functional studies show that FLRG inhibits myostatin activity in a reporter gene assay. These experiments suggest that the myostatin propeptide and FLRG are major negative regulators of myostatin in vivo. ..
  5. Ferreira M, Cavallo I, Florio P, Petraglia F, Reis F. Activin betaA subunit, follistatin and follistatin-like 3 are expressed in the endometrium of ovariectomized rats and regulated by estrogen replacement. J Mol Histol. 2008;39:535-41 pubmed publisher
  6. 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;144:1671-4 pubmed
    ..In addition, biological systems that use primarily activin B, but which have been examined in vitro using activin A, may need to be reevaluated to determine the actual physiologic roles of FS or FSTL-3. ..
  7. Kawabata D, Tanaka M, Fujii T, Umehara H, Fujita Y, Yoshifuji H, et al. Ameliorative effects of follistatin-related protein/TSC-36/FSTL1 on joint inflammation in a mouse model of arthritis. Arthritis Rheum. 2004;50:660-8 pubmed
    ..These findings from in vivo experiments suggest that FRP could be one of the key molecules in the treatment of inflammatory joint diseases such as RA. ..
  8. Hayette S, Gadoux M, Martel S, Bertrand S, Tigaud I, Magaud J, et al. FLRG (follistatin-related gene), a new target of chromosomal rearrangement in malignant blood disorders. Oncogene. 1998;16:2949-54 pubmed
    ..Besides the t(11;19)-carrying leukemia described in this work, structural rearrangements of the FLRG locus have been found in a non-Hodgkin lymphoma, suggesting that it may play a role in leukemogenesis. ..
  9. Tanaka M, Ozaki S, Osakada F, Mori K, Okubo M, Nakao K. Cloning of follistatin-related protein as a novel autoantigen in systemic rheumatic diseases. Int Immunol. 1998;10:1305-14 pubmed
    ..Detection of anti-FRP antibodies, possibly having disease-promoting effects as the blocking antibodies, could be one of the markers for clinical evaluation of systemic rheumatic diseases. ..
  10. Tanaka M. [RA-related autoantibodies (anti-calpastatin, anti-gp130-RAPS, and anti-FRP antibodies)]. Nihon Rinsho. 2005;63 Suppl 7:449-52 pubmed
  11. Takahata T, Hashikawa T, Higo N, Tochitani S, Yamamori T. Difference in sensory dependence of occ1/Follistatin-related protein expression between macaques and mice. J Chem Neuroanat. 2008;35:146-57 pubmed
    ..The characteristic feature of the activity dependency of occ1/Frp mRNA expression is discussed, in comparison with that of the expression of the immediate-early genes, c-fos and zif268. ..
  12. Kumar T. Too many follistatins: racing inside and getting out of the cell. Endocrinology. 2005;146:5048-51 pubmed
  13. Patel K, Connolly D, Amthor H, Nose K, Cooke J. Cloning and early dorsal axial expression of Flik, a chick follistatin-related gene: evidence for involvement in dorsalization/neural induction. Dev Biol. 1996;178:327-42 pubmed
    ..The results are discussed in relation to this hypothesis and to other recent findings regarding control of vertebrate dorsoventral patterning. ..
  14. Bloise E, Couto H, Massai L, Ciarmela P, Mencarelli M, Borges L, et al. Differential expression of follistatin and FLRG in human breast proliferative disorders. BMC Cancer. 2009;9:320 pubmed publisher
  15. Oshima Y, Ouchi N, Shimano M, Pimentel D, Papanicolaou K, Panse K, et al. Activin A and follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation. 2009;120:1606-15 pubmed publisher
    ..Activin A protects myocytes from death, and this activity is antagonized by Fstl3. Thus, the relative expression levels of these factors after injury is a determinant of cell survival in the heart. ..
  16. Walsh K. Adipokines, myokines and cardiovascular disease. Circ J. 2009;73:13-8 pubmed
    ..One of these newly discovered factors, referred to as follistatin-like 1, is able to promote revascularization in ischemic limbs and protect the heart from ischemic stress. ..
  17. Wang H, Takebayashi K, Tsuchida K, Nishimura M, Noda Y. Follistatin-related gene (FLRG) expression in human endometrium: sex steroid hormones regulate the expression of FLRG in cultured human endometrial stromal cells. J Clin Endocrinol Metab. 2003;88:4432-9 pubmed
  18. Zwijsen A, Blockx H, van Arnhem W, Willems J, Fransen L, Devos K, et al. Characterization of a rat C6 glioma-secreted follistatin-related protein (FRP). Cloning and sequence of the human homologue. Eur J Biochem. 1994;225:937-46 pubmed
    ..The protein has no effect on the inhibitory action of transforming growth factor-beta 1, on CCl-64 cell growth. ..
  19. Tsuchida K, Nakatani M, Matsuzaki T, Yamakawa N, Liu Z, Bao Y, et al. Novel factors in regulation of activin signaling. Mol Cell Endocrinol. 2004;225:1-8 pubmed
    ..Thus, although structurally and functionally similar, follistatin and FLRG likely play distinct roles as activin/GDF binding proteins in vivo. ..
  20. Liu S, Shen H, Xu M, Liu O, Zhao L, Liu S, et al. FRP inhibits ox-LDL-induced endothelial cell apoptosis through an Akt-NF-{kappa}B-Bcl-2 pathway and inhibits endothelial cell apoptosis in an apoE-knockout mouse model. Am J Physiol Endocrinol Metab. 2010;299:E351-63 pubmed publisher
    ..We conclude that FRP overexpression maintains EC viability by preventing apoptosis via Bcl-2 upregulation. FRP may be a novel therapeutic target for the prevention and treatment of vascular EC injury and of atherosclerosis. ..
  21. Wilson D, Marinov A, Blair H, Bushnell D, Thompson S, Chaly Y, et al. Follistatin-like protein 1 is a mesenchyme-derived inflammatory protein and may represent a biomarker for systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum. 2010;62:2510-6 pubmed publisher
    ..To examine both the source of follistatin-like protein 1 (FSTL-1) and the factors that induce its expression in arthritis, and to determine whether juvenile rheumatoid arthritis (JRA) is characterized by overexpression of FSTL-1...
  22. Sidis Y, Schneyer A, Keutmann H. Heparin and activin-binding determinants in follistatin and FSTL3. Endocrinology. 2005;146:130-6 pubmed
    ..This implies an evolutionary safeguard against surface binding by FSTL3, supporting other evidence for physiological differences between FS and FSTL3. ..
  23. Bartholin L, Maguer Satta V, Hayette S, Martel S, Gadoux M, Corbo L, et al. 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;21:2227-35 pubmed
    ..This observation, in conjunction with the antagonistic effect of FLRG and follistatin on activin signaling, indicates that these two proteins participate in a negative feedback loop which regulates the activin function. ..
  24. Zhang G, Ohsawa Y, Kametaka S, Shibata M, Waguri S, Uchiyama Y. Regulation of FLRG expression in rat primary astroglial cells and injured brain tissue by transforming growth factor-beta 1 (TGF-beta 1). J Neurosci Res. 2003;72:33-45 pubmed
    ..These results suggest that FLRG is synthesized in and secreted from astroglial cells. In particular, FLRG, but not follistatin, may play a role in the regulation of activin A in brain wound healing in response to TGF-beta1. ..
  25. Tochitani S, Hashikawa T, Yamamori T. Expression of occ1 mRNA in the visual cortex during postnatal development in macaques. Neurosci Lett. 2003;337:114-6 pubmed
    ..This suggests the possible importance of experience-dependent developmental regulations of occ1 in the developing primary visual cortex. ..
  26. Takahata T, Komatsu Y, Watakabe A, Hashikawa T, Tochitani S, Yamamori T. Activity-dependent expression of occ1 in excitatory neurons is a characteristic feature of the primate visual cortex. Cereb Cortex. 2006;16:929-40 pubmed
    ..We conclude that activity-dependent occ1 mRNA expression in the excitatory neurons of V1 was caused by a novel mechanism acquired by primates after their separation from other lineages. ..
  27. Umezu T, Yamanouchi H, Iida Y, Miura M, Tomooka Y. Follistatin-like-1, a diffusible mesenchymal factor determines the fate of epithelium. Proc Natl Acad Sci U S A. 2010;107:4601-6 pubmed publisher
    ..We concluded that Fstl1 is one of the mesenchymal factors determining oviductal epithelial cell fate. This is a unique demonstration that the determination of epithelial cell fate is induced by a single diffusible factor. ..
  28. Tanaka M, Murakami K, Ozaki S, Imura Y, Tong X, Watanabe T, et al. DIP2 disco-interacting protein 2 homolog A (Drosophila) is a candidate receptor for follistatin-related protein/follistatin-like 1--analysis of their binding with TGF-? superfamily proteins. FEBS J. 2010;277:4278-89 pubmed publisher
    ..FRP blocked the ligand-receptor binding of activin and BMP-2, but integrated itself with that of BMP-4. This multi-specific binding may reflect the broad physiological activity of FRP. ..
  29. Prasad S, Clerk A, Cullingford T, Chen A, Kemp T, Cannell T, et al. Gene expression profiling of human hibernating myocardium: increased expression of B-type natriuretic peptide and proenkephalin in hypocontractile vs normally-contracting regions of the heart. Eur J Heart Fail. 2008;10:1177-80 pubmed publisher
    ..Changes in expression of these genes, including increased relative expression of natriuretic and other factors, may constitute a molecular signature for hypocontractile and/or hibernating myocardium. ..
  30. Ouchi N, Oshima Y, Ohashi K, Higuchi A, Ikegami C, Izumiya Y, et al. Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism. J Biol Chem. 2008;283:32802-11 pubmed publisher
  31. Stamler R, Keutmann H, Sidis Y, Kattamuri C, Schneyer A, Thompson T. The structure of FSTL3.activin A complex. Differential binding of N-terminal domains influences follistatin-type antagonist specificity. J Biol Chem. 2008;283:32831-8 pubmed publisher
    ..In addition, structural comparisons with bone morphogenetic proteins suggest that the interface where the N-terminal domain binds may be the key site for determining FS-type antagonist specificity. ..
  32. Yang Y, Liu J, Mao H, Hu Y, Yan Y, Zhao C. The expression pattern of Follistatin-like 1 in mouse central nervous system development. Gene Expr Patterns. 2009;9:532-40 pubmed publisher
    ..A high level of expression was also observed in the ventral horn of the spinal cord. These results indicate that Fstl1 may play an important role during CNS development in the mouse. ..
  33. Dixon Fox M, Bruce A. Short- and long-range functions of Goosecoid in zebrafish axis formation are independent of Chordin, Noggin 1 and Follistatin-like 1b. Development. 2009;136:1675-85 pubmed publisher
    ..Our findings suggest that Gsc has dose dependent effects on axis induction and provide new insights into molecularly distinct short- and long-range signaling activities of the organizer. ..
  34. Le Luduec J, Condamine T, Louvet C, Thebault P, Heslan J, Heslan M, et al. An immunomodulatory role for follistatin-like 1 in heart allograft transplantation. Am J Transplant. 2008;8:2297-306 pubmed publisher
    ..Taken together, these results suggest that FSTL1 could be an active component of the mechanisms mediating heart allograft tolerance. ..
  35. Ciarmela P, Florio P, Toti P, Franchini A, Maguer Satta V, Ginanneschi C, et al. Human placenta and fetal membranes express follistatin-related gene mRNA and protein. J Endocrinol Invest. 2003;26:641-5 pubmed
    ..Its different immunolocalization with respect to follistatin and activin A supports a different role for FLRG in modulating activin A actions into gestational tissues. ..
  36. Vertegaal A, Kuiperij H, van Laar T, Scharnhorst V, van der Eb A, Zantema A. cDNA micro array identification of a gene differentially expressed in adenovirus type 5- versus type 12-transformed cells. FEBS Lett. 2000;487:151-5 pubmed
    ..This cellular gene was found to be the gene encoding follistatin-related protein, a TGF-beta inducible gene. Consistently, a constitutive factor binding to Smad binding elements was found in adenovirus type 12-transformed cells. ..
  37. Balemans W, Van Hul W. Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev Biol. 2002;250:231-50 pubmed
    ..Here, we review the insights in the extracellular regulation of members of the BMP subfamily of secreted growth factors with a major emphasis on vertebrate BMP modulation. ..
  38. Liu J, Vänttinen T, Hyden Granskog C, Voutilainen R. Regulation of follistatin-related gene (FLRG) expression by protein kinase C and prostaglandin E(2) in cultured granulosa-luteal cells. Mol Hum Reprod. 2002;8:992-7 pubmed
    ..Taken together, previous and our present data suggest that protein kinase C and A signal transduction pathways differently regulate the expression of FLRG and follistatin genes in human ovarian granulosa-luteal cells...
  39. Walsh J, Andrews P. Expression of Wnt and Notch pathway genes in a pluripotent human embryonal carcinoma cell line and embryonic stem cell. APMIS. 2003;111:197-210; discussion 210-1 pubmed
    ..We present a model in which interactions between and regulation of Wnt and Notch signalling are important in maintaining EC/ES stem cells and also controlling their differentiation...
  40. Ohsawa Y, Zhang G, Kametaka S, Shibata M, Koike M, Waguri S, et al. Purification, cDNA cloning, and secretory properties of FLRG protein from PC12 cells and the distribution of FLRG mRNA and protein in rat tissues. Arch Histol Cytol. 2003;66:367-81 pubmed
  41. Schneyer A, Sidis Y, Xia Y, Saito S, del Re E, Lin H, et al. Differential actions of follistatin and follistatin-like 3. Mol Cell Endocrinol. 2004;225:25-8 pubmed
    ..These studies have identified important structural elements necessary for biological activity of FS and FSTL3 and potential roles for FSTL3 in vivo. ..
  42. Willoughby D. Effects of an alleged myostatin-binding supplement and heavy resistance training on serum myostatin, muscle strength and mass, and body composition. Int J Sport Nutr Exerc Metab. 2004;14:461-72 pubmed
    ..05). Twelve wk of heavy resistance training and 1200 mg/d of cystoseira canariensis supplementation appears ineffective at inhibiting serum myostatin and increasing muscle strength and mass or decreasing fat mass. ..
  43. Zhou J, Liao M, Hatta T, Tanaka M, Xuan X, Fujisaki K. Identification of a follistatin-related protein from the tick Haemaphysalis longicornis and its effect on tick oviposition. Gene. 2006;372:191-8 pubmed
    ..These results showed that the tick FRP might be involved in tick oviposition. This is the first report of a member of follistatin family proteins in Chelicerata, which include ticks, spiders, and scorpions. ..
  44. Hambrock H, Kaufmann B, Muller S, Hanisch F, Nose K, Paulsson M, et al. Structural characterization of TSC-36/Flik: analysis of two charge isoforms. J Biol Chem. 2004;279:11727-35 pubmed
    ..The lack of conservation of important functional features common to several other members of the BM-40 family indicates that TSC-36, despite its sequence homology to BM-40, has evolved clearly distinct properties. ..
  45. Grusch M, Drucker C, Peter Vörösmarty B, Erlach N, Lackner A, Losert A, et al. Deregulation of the activin/follistatin system in hepatocarcinogenesis. J Hepatol. 2006;45:673-80 pubmed
    ..The sensitivity of preneoplastic hepatocytes to activin signals suggests the activin/follistatin system as promising target for therapeutic intervention. ..
  46. Lombardi M, van den Hoff M, Ruijter J, Luijerink M, Buffing A, Markman M, et al. Expression analysis of subtractively enriched libraries (EASEL): a widely applicable approach to the identification of differentially expressed genes. J Biochem Biophys Methods. 2003;57:17-33 pubmed
  47. Tsuchita K. [Regulation of skeletal muscle mass and adipose tissue mass by follistatin and follistatin-related gene (FLRG) and development of novel polypeptides as medical drugs]. Seikagaku. 2005;77:440-3 pubmed
  48. Geske M, Zhang X, Patel K, Ornitz D, Stappenbeck T. Fgf9 signaling regulates small intestinal elongation and mesenchymal development. Development. 2008;135:2959-68 pubmed publisher
    ..Taken together, the interaction of FGF and TGFbeta signaling pathways in the intestinal mesenchyme could represent novel targets for future short bowel syndrome therapies. ..
  49. Wagner K. Muscle regeneration through myostatin inhibition. Curr Opin Rheumatol. 2005;17:720-4 pubmed
    ..Multiple approaches to inhibiting myostatin are suggested by the recent elucidation of its signaling pathway. An inhibitor of myostatin may be the first drug specifically designed to enhance muscle growth and regeneration. ..
  50. Miron P, Lambert J, Marcil A, Cowans N, Stamatopoulou A, Spencer K. Maternal plasma levels of follistatin-related gene protein in the first trimester of pregnancies with Down syndrome. Prenat Diagn. 2010;30:224-8 pubmed publisher
    ..63). FLRG can be successfully detected in maternal plasma in the first trimester of pregnancy. However, its levels are not significantly altered in the presence of Down syndrome fetuses. ..
  51. Morrissey J, Cockayne A, Hammacott J, Bishop K, Denman Johnson A, Hill P, et al. Conservation, surface exposure, and in vivo expression of the Frp family of iron-regulated cell wall proteins in Staphylococcus aureus. Infect Immun. 2002;70:2399-407 pubmed
    ..Binding of S. aureus to microtiter wells was found to be iron regulated, and iron-restricted S. aureus containing antisense frpA or frpAB but not frpB constructs showed reduced binding compared to vector construct controls...
  52. Schneyer A, Tortoriello D, Sidis Y, Keutmann H, Matsuzaki T, Holmes W. Follistatin-related protein (FSRP): a new member of the follistatin gene family. Mol Cell Endocrinol. 2001;180:33-8 pubmed
    ..These results suggest that FSRP is a structural, but not necessarily a functional homologue of FS. ..
  53. Tsuchida K, Matsuzaki T, Yamakawa N, Liu Z, Sugino H. Intracellular and extracellular control of activin function by novel regulatory molecules. Mol Cell Endocrinol. 2001;180:25-31 pubmed
    ..The mode of association of follistatin and FLRG with activins and their expression patterns are different, suggesting the distinct functions of follistatin and FLRG in vivo. ..