| Written | 2009-01 | Michael Grusch |
| Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Borschkegasse 8a, A-1090 Vienna, Austria | ||
| Updated | 2012-09 | Michael Grusch |
| Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Borschkegasse 8a, A-1090 Vienna, Austria |
| Identity |
| Alias_names | follistatin-like 3 (secreted glycoprotein) |
| Alias_symbol (synonym) | FLRG |
| FSRP | |
| Other alias | |
| HGNC (Hugo) | FSTL3 |
| LocusID (NCBI) | 10272 |
| Atlas_Id | 111 |
| Location | 19p13.3 [Link to chromosome band 19p13] |
| Location_base_pair | Starts at 676389 and ends at 683392 bp from pter ( according to hg19-Feb_2009) [Mapping FSTL3.png] |
| Local_order | RNF126 (ring finger protein 126) - FSTL3 - PRSSL1 (protease, serine-like 1). |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| CCND1 (11q13.3) / FSTL3 (19p13.3) | FSTL3 (19p13.3) / BCL6 (3q27.3) | FSTL3 (19p13.3) / CCND1 (11q13.3) | |
| FSTL3 (19p13.3) / FSTL3 (19p13.3) | FSTL3 (19p13.3) / SCARNA2 (1p13.3) | MKL2 (16p13.12) / FSTL3 (19p13.3) | |
| Note | The term follistatin-related protein has been used to refer to either FSTL3 (FSRP) or FSTL1 (FRP), which may cause some confusion. A search in MEDLINE for FSTL3 will also retrieve several reports not mentioning FSTL3 but dealing with FRP/FSTL1 instead. |
| DNA/RNA |
 | |
| Intron/exon structure of the FSTL3 gene and domain architecture of FSTL3 protein. 1,2,3,4,5: exon number; SP: signal peptide; NTD: N-terminal domain; FSD 1: follistatin domain 1; FSD 2: follistatin domain 2; AT: acidic tail. | |
| Description | The human FSTL3 gene is comprised of five exons spanning 7004 bp on chromosome 19p13 and gives rise to a main transcript of 2525 bp. The first exon encodes the signal peptide plus nine residues of the N-terminal domain, the second exon encodes the remainder of the N-terminal domain, the third and the fourth exon each code for a follistatin module and the fifth exon encodes the C-terminus rich in acidic amino acids (Schneyer et al., 2001; Sidis et al., 2002). |
| Transcription | Transcription of FSTL3 mRNA was shown to be stimulated by TGF beta and activin A via Smad proteins (Bartholin et al., 2001; Bartholin et al., 2002), which seems to be part of a negative feedback loop as FSTL3 can antagonize activin A (see below). In a different study it was found that GDF9 - another TGF beta superfamily cytokine - can suppress both basal and activin A-induced FSTL3 (and follistatin) mRNA and protein levels in cultured human granulosa-lutein (hGL) cells from women undergoing in vitro fertilization (IVF) treatment (Shi et al., 2011). In addition NF-kappaB responsive elements have been identified in the FSTL3 promoter and are involved in the cooperative stimulation of FSTL3 transcription by TNF alpha and TGF beta (Bartholin et al., 2007). Upregulation of FSTL3 mRNA was observed as a response to hypoxia in human trophoblasts and a role for hypoxia inducible factor (HIF1 alpha) was suggested. In another study a combination of 17 beta estradiol and progesterone, but not either factor alone, stimulated FSTL3 expression in cultured human endometrial stromal cells (Wang et al., 2003). An analysis of the murine FSTL3 promoter identified phorbol 12-myristate 13-acetate (PMA) but not cAMP as transcriptional activators. |
| Protein |
| Description | The FSTL3 protein precursor consists of 263 amino acids. Amino acids 1-26 form the signal peptide, which is reponsible for directing the protein to the secretory pathway but not present in the mature secreted protein. FSTL3 has been described to contain 2 follistatin (FS) domains (aa 97-168 and 169-244) (Schneyer et al., 2001) characterized by a conserved arrangement of 10 cysteine residues. The FS domains also have similarity with the Kazal domains found in multiple serine protease inhibitors. The FSTL3 protein contains two potential N-glycosilation sites on asparagines 73 and 215. Peptide N-glycosidase F digestion reduced the size of ectopically expressed FSTL3 from 33 to 27 kDa in Western analysis (Hayette et al., 1998). |
| Expression | FSTL3 is expressed in a wide variety of tissues and organs with the highest expression in placenta and testis and low to absent expression in the hematopoietic system (Hayette et al., 1998; Tortoriello et al., 2001). |
| Localisation | The signal peptide directs the nascent protein to the secretory pathway and FSTL3 has been detected in cell culture supernatants and in human serum (Hayette et al., 1998; Hill et al., 2002; Pryor-Koishi et al., 2007). In addition to its role as a secreted protein FSTL3 has also been found in the cell nucleus in a number of different cell lines, primary cells (Tortoriello et al., 2001) and tissue sections (Torres et al., 2007). Nuclear FSTL3 was glycosylated, albeit to a lower degree than secreted FSTL3, suggesting that it enters the nucleus after partial processing in the ER (Saito et al., 2005). |
| Function | Similar to follistatin, secreted FSTL3 was shown to bind activin A and with lower affinity several other members of the TGF beta family including activin B, myostatin and BMP2, BMP6, and BMP7 (but excluding for instance TGF beta and BMP4) (Tsuchida et al., 2000; Tortoriello et al., 2001; Sidis et al., 2002; Hill et al., 2002; Schneyer et al., 2003). Affinity for BMPs, however, seems to be quite low and has been questioned by other studies (Sidis et al., 2006). FSTL3 bound ligands are unable to activate their cognate receptors and thus FSTL3 blocks signal transduction. Structural and biochemical data have implicated the N-terminal domain and the two FS domains in ligand binding and antagonism (Sidis et al., 2005; Stamler et al., 2008; Cash et al., 2012). In contrast to follistatin, FSTL3 does not contain a heparin binding motif and does not bind cell surface heparan-sulfate proteoglycans (Sidis et al., 2002). In addition to binding TGF beta family ligands, FSTL3 was demonstrated to interact with ADAM12 (a disintegrin and metalloprotease 12), an extracellular protein that has been implicated in insulin-like growth factor (IGF) and epidermal growth factor (EGF) receptor signaling (Bartholin et al., 2005), as well as with fibronectin type 1, which could indicate a role of FSTL3 in cell adhesion (Maguer-Satta et al., 2006). Nuclear FSTL3 was shown to interact with AF10 (ALL-1 fused gene from chromosome 10) enhancing its homo-oligomerization and transcriptional activity (Forissier et al., 2007). FSTL3 knock-out mice had increased pancreatic island number and size, enhanced insulin sensitivity and hepatic steatosis suggesting a role of FSTL3 in glucose and fat homeostasis (Mukherjee et al., 2007). Combined knockout of FSTL3 and follistatin, however, led to increased fat mass and insulin resistance despite elevated insulin production (Brown et al., 2011). |
| Homology | FSTL3 has a similar domain architecture as follistatin, but harbours only two instead of three follistatin modules (Tortoriello et al., 2001). Follistatin modules are found in varying numbers in a wider set of secreted proteins including FSTL1, SPARC/osteonectin, or agrin (Ullman and Perkins, 1997). With respect to activin binding ability, functional homology among follistatin domain-containing proteins has only been demonstrated for FSTL3 and follistatin (Tsuchida et al., 2000). Between different species FSTL3 is clearly conserved (96% amino acid identity between mouse and rat and about 80% for either of these species compared to human), albeit to a lesser degree than follistatin, which has around 97% amino acid identity between human, mouse and rat. |
| Mutations |
| Somatic | A t(11;19)(q13;p13) translocation has been described in a case of B-cell chronic lymphocytic leukemia. The chromosomal breakpoint occurred about 7 kbp upstream of FSTL3 leading to ectopic expression of the complete FSTL3 protein, likely as a consequence of altered upstream cis-regulatory sequences (Hayette et al., 1998). In the same study structural rearrangement of the FSTL3 locus has also been described in a case of non-Hodgkin lymphoma. A deletion of about 1.2 Mb on chromosome 19p13.3 was identified in a patient with cleft palate, hearing impairment, congenital heart malformation, keloid scarring, immune dysregulation, and mild learning difficulties. The deleted area encompasses about 60 genes including FSTL3 (Archer et al., 2005). |
| Implicated in |
| Note | |
| Entity | Malignant blood disorders |
| Disease | Structural rearrangement of the FSTL3 locus has been described in malignant blood disorders (see above) and it has been suggested that deregulated expression of FSTL3 could contribute to leukemogenesis (Hayette et al., 1998). |
| Entity | Breast carcinoma |
| Disease | High expression of FSTL3 was observed in invasive breast carcinoma compared to normal luminal epithelial cells. SiRNA-mediated knock-down of FSTL3 expression in breast cancer cell lines lead to growth inhibition, smad2 phosphorylation and increased transcription of activin target genes (Razanajaona et al., 2007). These observations suggest that FSTL3 may contribute to tumorigenesis by antagonizing growth limiting activin effects. In agreement with this notion another study reported increased FSTL3 mRNA and protein levels in the epithelial compartment in infiltrating ductal carcinoma of the breast when compared to normal breast tissue (Bloise et al., 2009). |
| Entity | Hepatocellular carcinoma |
| Disease | FSTL3 expression levels were increased in hepatocytes in chemical hepatocarcinogenesis models in the rat but decreased in hepatocellular carcinoma (HCC) in humans (Grusch et al., 2006). |
| Entity | Endometrial adenocarcinoma |
| Disease | Downregulation of FSTL3 expression was found in human endometrial adenocarcinoma (Ciarmela et al., 2004). |
| Entity | Endometriosis |
| Disease | Ovarian endometriotic lesions showed a deranged expression of FSTL3 as well as follistatin. While follistatin expression was increased, FSTL3 mRNA and protein expression were lower in ovarian endometriosis than in healthy eutopic endometrium (Torres et al., 2007). |
| Entity | Pre-eclampsia |
| Disease | The mRNA and protein levels of FSTL3 were compared in placentas and maternal sera of women with uncomplicated pregnancy and those with pre-eclampsia. FSTL3 was upregulated in syncytiotrophoblast cells of pre-eclamptic placental tissue and in maternal serum. Its further evaluation as potential addition to existing diagnostic markers of pre-eclampsia was suggested (Pryor-Koishi et al., 2007). |
| Entity | Heart disease |
| Disease | FSTL3 (and FSTL1) were elevated in heart failure. FSTL3 expression correlated with markers of disease severity and returned to normal after recovery. The protein was localized to myocytes and endothelium and the expression profile of FSTL3 on microarrays revealed an association with the nuclear compartment and with genes involved in signal transduction and transcription (Lara-Pezzi et al., 2008). In a mouse model activin A and FSTL3 were upregulated in the herat by ischemic injury. While activin A protected myocytes from cell death, this effect was antagonized by FSTL3 (Oshima et al., 2009). |
| Bibliography |
| Distinct phenotype associated with a cryptic subtelomeric deletion of 19p13.3-pter. |
| Archer HL, Gupta S, Enoch S, Thompson P, Rowbottom A, Chua I, Warren S, Johnson D, Ledbetter DH, Lese-Martin C, Williams P, Pilz DT. |
| Am J Med Genet A. 2005 Jul 1;136(1):38-44. Review |
| PMID 15937949 |
| Identification of NF-kappaB responsive elements in follistatin related gene (FLRG) promoter. |
| Bartholin L, Guindon S, Martel S, Corbo L, Rimokh R. |
| Gene. 2007 May 15;393(1-2):153-62. Epub 2007 Mar 1. |
| PMID 17395406 |
| Differential expression of follistatin and FLRG in human breast proliferative disorders. |
| Bloise E, Couto HL, Massai L, Ciarmela P, Mencarelli M, Borges LE, Muscettola M, Grasso G, Amaral VF, Cassali GD, Petraglia F, Reis FM. |
| BMC Cancer. 2009 Sep 9;9:320. |
| PMID 19740438 |
| Follistatin and follistatin like-3 differentially regulate adiposity and glucose homeostasis. |
| Brown ML, Bonomi L, Ungerleider N, Zina J, Kimura F, Mukherjee A, Sidis Y, Schneyer A. |
| Obesity (Silver Spring). 2011 Oct;19(10):1940-9. doi: 10.1038/oby.2011.97. Epub 2011 May 5. |
| PMID 21546932 |
| Structure of myostatin follistatin-like 3: N-terminal domains of follistatin-type molecules exhibit alternate modes of binding. |
| Cash JN, Angerman EB, Kattamuri C, Nolan K, Zhao H, Sidis Y, Keutmann HT, Thompson TB. |
| J Biol Chem. 2012 Jan 6;287(2):1043-53. Epub 2011 Nov 3. |
| PMID 22052913 |
| 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 Aug;151(2):251-7. |
| PMID 15296481 |
| AF10-dependent transcription is enhanced by its interaction with FLRG. |
| Forissier S, Razanajaona D, Ay AS, Martel S, Bartholin L, Rimokh R. |
| Biol Cell. 2007 Oct;99(10):563-71. |
| PMID 17868029 |
| Deregulation of the activin/follistatin system in hepatocarcinogenesis. |
| Grusch M, Drucker C, Peter-Vorosmarty 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. |
| J Hepatol. 2006 Nov;45(5):673-80. Epub 2006 Jul 28. |
| PMID 16935389 |
| 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 JP, Rimokh R. |
| Oncogene. 1998 Jun 4;16(22):2949-54. |
| PMID 9671416 |
| The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. |
| Hill JJ, Davies MV, Pearson AA, Wang JH, Hewick RM, Wolfman NM, Qiu Y. |
| J Biol Chem. 2002 Oct 25;277(43):40735-41. Epub 2002 Aug 22. |
| PMID 12194980 |
| Expression of follistatin-related genes is altered in heart failure. |
| Lara-Pezzi E, Felkin LE, Birks EJ, Sarathchandra P, Panse KD, George R, Hall JL, Yacoub MH, Rosenthal N, Barton PJ. |
| Endocrinology. 2008 Nov;149(11):5822-7. Epub 2008 Jul 10. |
| PMID 18617621 |
| A novel role for fibronectin type I domain in the regulation of human hematopoietic cell adhesiveness through binding to follistatin domains of FLRG and follistatin. |
| Maguer-Satta V, Forissier S, Bartholin L, Martel S, Jeanpierre S, Bachelard E, Rimokh R. |
| Exp Cell Res. 2006 Feb 15;312(4):434-42. Epub 2005 Dec 5. |
| PMID 16336961 |
| FSTL3 deletion reveals roles for TGF-beta family ligands in glucose and fat homeostasis in adults. |
| Mukherjee A, Sidis Y, Mahan A, Raher MJ, Xia Y, Rosen ED, Bloch KD, Thomas MK, Schneyer AL. |
| Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1348-53. Epub 2007 Jan 17. |
| PMID 17229845 |
| Activin A and follistatin-like 3 determine the susceptibility of heart to ischemic injury. |
| Oshima Y, Ouchi N, Shimano M, Pimentel DR, Papanicolaou KN, Panse KD, Tsuchida K, Lara-Pezzi E, Lee SJ, Walsh K. |
| Circulation. 2009 Oct 20;120(16):1606-15. Epub 2009 Oct 5. |
| PMID 19805648 |
| Overproduction of the follistatin-related gene protein in the placenta and maternal serum of women with pre-eclampsia. |
| Pryor-Koishi K, Nishizawa H, Kato T, Kogo H, Murakami T, Tsuchida K, Kurahashi H, Udagawa Y. |
| BJOG. 2007 Sep;114(9):1128-37. Epub 2007 Jul 6. |
| PMID 17617189 |
| Silencing of FLRG, an antagonist of activin, inhibits human breast tumor cell growth. |
| Razanajaona D, Joguet S, Ay AS, Treilleux I, Goddard-Leon S, Bartholin L, Rimokh R. |
| Cancer Res. 2007 Aug 1;67(15):7223-9. |
| PMID 17671190 |
| Differential biosynthesis and intracellular transport of follistatin isoforms and follistatin-like-3. |
| Saito S, Sidis Y, Mukherjee A, Xia Y, Schneyer A. |
| Endocrinology. 2005 Dec;146(12):5052-62. Epub 2005 Sep 8. |
| PMID 16150905 |
| 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 May;144(5):1671-4. |
| PMID 12697670 |
| Growth differentiation factor 9 (GDF9) suppresses follistatin and follistatin-like 3 production in human granulosa-lutein cells. |
| Shi FT, Cheung AP, Huang HF, Leung PC. |
| PLoS One. 2011;6(8):e22866. Epub 2011 Aug 1. |
| PMID 21829661 |
| 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 Jul;147(7):3586-97. Epub 2006 Apr 20. |
| PMID 16627583 |
| Heparin and activin-binding determinants in follistatin and FSTL3. |
| Sidis Y, Schneyer AL, Keutmann HT. |
| Endocrinology. 2005 Jan;146(1):130-6. Epub 2004 Oct 7. |
| PMID 15471966 |
| Follistatin-related protein and follistatin differentially neutralize endogenous vs. exogenous activin. |
| Sidis Y, Tortoriello DV, Holmes WE, Pan Y, Keutmann HT, Schneyer AL. |
| Endocrinology. 2002 May;143(5):1613-24. |
| PMID 11956142 |
| The structure of FSTL3.activin A complex. Differential binding of N-terminal domains influences follistatin-type antagonist specificity. |
| Stamler R, Keutmann HT, Sidis Y, Kattamuri C, Schneyer A, Thompson TB. |
| J Biol Chem. 2008 Nov 21;283(47):32831-8. Epub 2008 Sep 2. |
| PMID 18768470 |
| Deranged expression of follistatin and follistatin-like protein in women with ovarian endometriosis. |
| Torres PB, Florio P, Ferreira MC, Torricelli M, Reis FM, Petraglia F. |
| Fertil Steril. 2007 Jul;88(1):200-5. Epub 2007 Feb 12. |
| PMID 17296189 |
| Human follistatin-related protein: a structural homologue of follistatin with nuclear localization. |
| Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer AL. |
| Endocrinology. 2001 Aug;142(8):3426-34. |
| PMID 11459787 |
| Identification and characterization of a novel follistatin-like protein as a binding protein for the TGF-beta family. |
| Tsuchida K, Arai KY, Kuramoto Y, Yamakawa N, Hasegawa Y, Sugino H. |
| J Biol Chem. 2000 Dec 29;275(52):40788-96. |
| PMID 11010968 |
| The Factor I and follistatin domain families: the return of a prodigal son. |
| Ullman CG, Perkins SJ. |
| Biochem J. 1997 Sep 15;326 ( Pt 3):939-41. |
| PMID 9334166 |
| Follistatin-related gene (FLRG) expression in human endometrium: sex steroid hormones regulate the expression of FLRG in cultured human endometrial stromal cells. |
| Wang HQ, Takebayashi K, Tsuchida K, Nishimura M, Noda Y. |
| J Clin Endocrinol Metab. 2003 Sep;88(9):4432-9. |
| PMID 12970321 |
| Citation |
| This paper should be referenced as such : |
| Grusch, M |
| FSTL3 (follistatin-like 3 (secreted glycoprotein)) |
| Atlas Genet Cytogenet Oncol Haematol. 2013;17(3):151-154. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/FSTL3ID111ch19p13.html |
| History of this paper: |
| Grusch, M. FSTL3 (follistatin-like 3 (secreted glycoprotein)). Atlas Genet Cytogenet Oncol Haematol. 2009;13(12):935-938. |
| http://documents.irevues.inist.fr/bitstream/handle/2042/44635/01-2009-FSTL3ID111ch19p13.pdf |
| Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ] |
|
t(11;19)(q13;p13) FSTL3/CCND1
|
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ] |
|
t(16;19)(p13;p13) MKL2/FSTL3
|
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Tue Nov 6 12:23:06 CET 2018 |
For comments and suggestions or contributions, please contact us