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Gene Review

FSTL3  -  follistatin-like 3 (secreted glycoprotein)

Homo sapiens

Synonyms: FLRG, FSRP, Follistatin-like protein 3, Follistatin-related gene protein, Follistatin-related protein 3, ...
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Disease relevance of FSTL3


High impact information on FSTL3

  • This combination of phenotypes appears to arise from increased activin and myostatin bioactivity in specific tissues resulting from the absence of the FSTL3 antagonist [2].
  • FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults [2].
  • Functional studies show that FLRG inhibits myostatin activity in a reporter gene assay [6].
  • Northern blotting revealed that mRNAs for FLRG were abundantly expressed in heart, lung, kidney, and testis in mouse [7].
  • The mouse cDNA encodes a 256-residue precursor and most likely a mouse homologue of human FLRG, which was found at the breakpoint of the chromosomal rearrangement in a B-cell line [7].

Biological context of FSTL3

  • These results suggest that FSTL3 is likely to be a local regulator of activin action in gonadal development and gametogenesis and, further, that activin appears to have important actions in gonadal development and function that are critical for normal reproduction [8].
  • Three FST isoforms have been described that differ in tissue distribution and cell-surface binding activity, suggesting that the FST isoforms and FSTL3 may have some nonoverlapping biological actions [9].
  • Activin-binding affinities and kinetics were comparable between the isoforms and FSTL3, whereas cell-surface binding differed markedly (FST288 > FST303 > FST315 > FSTL3) [9].
  • We therefore investigated the expression and effects of FLRG during human hematopoiesis with particular focus on the effect of this soluble glycoprotein in the regulation of erythropoiesis [10].
  • Deletion analysis of the promoter regions indicates that a proximal 550 base pairs are enough for basal FLRG promoter activity in the cell lines [11].

Anatomical context of FSTL3

  • To investigate the role of local FSTL3 as a potential regulator of activin action in gonad development and function, we examined FSTL3 expression in the mouse testis [8].
  • FSTL3 protein was localized to Leydig cells, spermatagonia, and mature spermatids in normal male mice [8].
  • Moreover, when FSTL3, which does not associate with cell membranes, was expressed as a membrane-anchored protein, its endogenous activin inhibitory activity was dramatically increased [9].
  • Our results indicate that despite their high structural homology, follistatin and FLRG do not regulate the same signaling targets, therefore highlighting distinct functions and mechanisms for these two proteins in the human hematopoietic system [10].
  • In this study we showed that FLRG mRNA was expressed in human endometrium across the menstrual cycle and in decidua of early pregnancy [12].

Associations of FSTL3 with chemical compounds


Physical interactions of FSTL3

  • We have now tested the ability of FS288 and FSTL-3 to bind and neutralize activin B relative to activin A [16].
  • By deletion and point-mutation analysis of the FLRG promoter, we identified a Smad-binding element involved in the TGFbeta-inducible expression of the FLRG gene [17].

Regulatory relationships of FSTL3


Other interactions of FSTL3


Analytical, diagnostic and therapeutic context of FSTL3


  1. FLRG (follistatin-related gene), a new target of chromosomal rearrangement in malignant blood disorders. Hayette, S., Gadoux, M., Martel, S., Bertrand, S., Tigaud, I., Magaud, J.P., Rimokh, R. Oncogene (1998) [Pubmed]
  2. FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults. Mukherjee, A., Sidis, Y., Mahan, A., Raher, M.J., Xia, Y., Rosen, E.D., Bloch, K.D., Thomas, M.K., Schneyer, A.L. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  3. Expression of FLRG, a novel activin A ligand, is regulated by TGF-beta and during hematopoiesis [corrected]. Maguer-Satta, V., Bartholin, L., Jeanpierre, S., Gadoux, M., Bertrand, S., Martel, S., Magaud, J.P., Rimokh, R. Exp. Hematol. (2001) [Pubmed]
  4. IGFBP1 and Follistatin-like 3 genes are significantly up-regulated in expression profiles of the IUGR placenta. Okamoto, A., Endo, H., Kalionis, B., Shinya, M., Saito, M., Nikaido, T., Tanaka, T. Placenta (2006) [Pubmed]
  5. Follistatin-related gene expression, but not follistatin expression, is decreased in human endometrial adenocarcinoma. Ciarmela, P., Florio, P., Sigurdardottir, M., Toti, P., Maguer-Satta, V., Rimokh, R., Altomare, A., Tosi, P., Petraglia, F. Eur. J. Endocrinol. (2004) [Pubmed]
  6. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. Hill, J.J., Davies, M.V., Pearson, A.A., Wang, J.H., Hewick, R.M., Wolfman, N.M., Qiu, Y. J. Biol. Chem. (2002) [Pubmed]
  7. Identification and characterization of a novel follistatin-like protein as a binding protein for the TGF-beta family. Tsuchida, K., Arai, K.Y., Kuramoto, Y., Yamakawa, N., Hasegawa, Y., Sugino, H. J. Biol. Chem. (2000) [Pubmed]
  8. Overexpression of follistatin-like 3 in gonads causes defects in gonadal development and function in transgenic mice. Xia, Y., Sidis, Y., Schneyer, A. Mol. Endocrinol. (2004) [Pubmed]
  9. 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. Sidis, Y., Mukherjee, A., Keutmann, H., Delbaere, A., Sadatsuki, M., Schneyer, A. Endocrinology (2006) [Pubmed]
  10. FLRG, member of the follistatin family, a new player in hematopoiesis. Maguer-Satta, V., Rimokh, R. Mol. Cell. Endocrinol. (2004) [Pubmed]
  11. Genomic organization and promoter analysis of mouse follistatin-related gene (FLRG). Nakatani, M., Yamakawa, N., Matsuzaki, T., Shimasaki, S., Sugino, H., Tsuchida, K. Mol. Cell. Endocrinol. (2002) [Pubmed]
  12. Follistatin-related gene (FLRG) expression in human endometrium: sex steroid hormones regulate the expression of FLRG in cultured human endometrial stromal cells. Wang, H.Q., Takebayashi, K., Tsuchida, K., Nishimura, M., Noda, Y. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  13. Heparin and activin-binding determinants in follistatin and FSTL3. Sidis, Y., Schneyer, A.L., Keutmann, H.T. Endocrinology (2005) [Pubmed]
  14. Regulation of follistatin-related gene (FLRG) expression by protein kinase C and prostaglandin E(2) in cultured granulosa-luteal cells. Liu, J., Vänttinen, T., Hydén-Granskog, C., Voutilainen, R. Mol. Hum. Reprod. (2002) [Pubmed]
  15. Silencing of FLRG, an antagonist of activin, inhibits human breast tumor cell growth. Razanajaona, D., Joguet, S., Ay, A.S., Treilleux, I., Goddard-Léon, S., Bartholin, L., Rimokh, R. Cancer Res. (2007) [Pubmed]
  16. Differential binding and neutralization of activins A and B by follistatin and follistatin like-3 (FSTL-3/FSRP/FLRG). Schneyer, A., Schoen, A., Quigg, A., Sidis, Y. Endocrinology (2003) [Pubmed]
  17. FLRG, an activin-binding protein, is a new target of TGFbeta transcription activation through Smad proteins. Bartholin, L., Maguer-Satta, V., Hayette, S., Martel, S., Gadoux, M., Bertrand, S., Corbo, L., Lamadon, C., Morera, A.M., Magaud, J.P., Rimokh, R. Oncogene (2001) [Pubmed]
  18. Differential biosynthesis and intracellular transport of follistatin isoforms and follistatin-like-3. Saito, S., Sidis, Y., Mukherjee, A., Xia, Y., Schneyer, A. Endocrinology (2005) [Pubmed]
  19. Deregulation of the activin/follistatin system in hepatocarcinogenesis. Grusch, M., Drucker, C., Peter-V??r??smarty, B., Erlach, N., Lackner, A., Losert, A., Macheiner, D., Schneider, W.J., Hermann, M., Groome, N.P., Parzefall, W., Berger, W., Grasl-Kraupp, B., Schulte-Hermann, R. J. Hepatol. (2006) [Pubmed]
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