Skip to main content

Relaxin, the Relaxin-Like Factor and Their Receptors

  • Chapter
Relaxin and Related Peptides

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 612))

Abstract

In 1926 Frederick Hisaw discovered a blood-borne factor in pregnant guinea pigs that would cause relaxation of the pubic symphysis in virgin females of the species.1 The relaxin-like factor gene (RLF), also known as insulin-like 3 (INSL3), was recovered from a library of testicular cDNA.2 The function of RLF as the mediator of testicular positioning in mice was discovered by gene deletion experiments.3,4 The report that deletion of a G-protein-coupled receptor in a mouse mutant caused cryptorchidism5 and that relaxin and RLF and their receptors6,7 were structurally and functionally similar may well have inspired Drs. Hsueh and Sherwood to put LGR7 and relaxin together and thus, after many agonizing years of uncertainty, the relaxin receptor had yielded its identity.8 LGR8 was recognized as the human version of the RLF receptor and together LGR7 and LGR8, with their respective ligands, opened to detailed investigation the large and important field of G-protein activated leucine-rich repeat receptors. In the process RLF and LGR8 have yielded some general information that might contribute to our knowledge of receptor/ligand interaction, in particular the enigmatic signal initiation process.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Hisaw FL. Experimental relaxation of the pubic ligament of the guinea pig. Proc Soc Exp Biol Med 1926; 23:661–663.

    Google Scholar 

  2. Adham IM, Burkhardt E, Benahmed M et al. Cloning of a cDNA for a novel insulin-like peptide of the testicular Leydig cells. J Biol Chem 1993; 268:26668–26672.

    PubMed  CAS  Google Scholar 

  3. Zimmermann S, Steding G, Emmen JM et al. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 1999; 13:681–691.

    Article  PubMed  CAS  Google Scholar 

  4. Nef S, Parada LF. Cryptorchidism in mice mutant for Insl.3 Nat Genet 1999; 22:295–299.

    Article  PubMed  CAS  Google Scholar 

  5. Overbeek PA, Gorlov IP, Sutherland RW et al. A transgenic insertion causing cryptorchidism in mice. Genesis 2001; 30:26–35.

    Article  PubMed  CAS  Google Scholar 

  6. Büllesbach EE, Schwabe C. A novel Leydig cell cDNA-derived protein is a relaxin-like factor (RLF). J Biol Chem 1995; 270:16011–16015.

    Article  PubMed  Google Scholar 

  7. Büllesbach EE, Schwabe C. Specific, high-affinity relaxin-like factor receptors. J Biol Chem 1999; 274:22354–22358.

    Article  PubMed  Google Scholar 

  8. Hsu SY, Nakabayashi K, Nishi S et al. Activation of orphan receptors by the hormone relaxin. Science 2002; 295:671–674.

    Article  PubMed  CAS  Google Scholar 

  9. Sherwood OD, O’Byrne EM. Purification and characterization of porcine relaxin. Arch Biochem Biophys 1974; 160:185–196.

    Article  PubMed  CAS  Google Scholar 

  10. Büllesbach EE, Schwabe C. Naturally occurring porcine relaxins and large-scale preparation of the B29 hormone. Biochemistry 1985; 24:7717–7722.

    Article  PubMed  Google Scholar 

  11. Canova-Davis E, Kessler TJ, Lee PJ et al. Use of recombinant DNA derived human relaxin to probe the structure of the native protein. Biochem 1991; 30:6006–6013.

    Article  CAS  Google Scholar 

  12. Büllesbach EE, Schwabe C. Total synthesis of human relaxin and human relaxin derivatives by solid phase peptide synthesis and site-directed chain combination. J Biol Chem 1991; 266:10754–10761.

    PubMed  Google Scholar 

  13. Schwabe C, Büllesbach E. Relaxin and the fine structure of proteins: R.G. Landers Co.; 1998.

    Google Scholar 

  14. Eigenbrot C, Randal M, Quan C et al. X-ray structure of human relaxin at 1.5 Å: Comparison to insulin and implications for receptor binding determinants. J Mol Biol 1991; 221:15–21.

    PubMed  CAS  Google Scholar 

  15. Reinig JW, Daniel LN, Schwabe C et al. Isolation and characterization of relaxin from the sand tiger shark (odontaspis taurus). Endocrinology 1981; 109:537–543.

    PubMed  CAS  Google Scholar 

  16. Büllesbach EE, Schwabe C. On the receptor binding site of relaxin. Int. J Peptide Protein Res 1988; 32:361–367.

    Google Scholar 

  17. Büllesbach EE, Schwabe C. The functional importance of the A chain loop in relaxin and insulin. J Biol Chem 1994; 269:13124–13128.

    PubMed  Google Scholar 

  18. Büllesbach EE, Schwabc C. The relaxin receptor binding site geometry suggests a novel gripping mode of interaction. J Biol Chem 2000; 275:35276–35280.

    Article  PubMed  Google Scholar 

  19. Kobe B, Deisenhofer J. Crystal structure of porcine ribonuclease inhibitor, a protein with leucine-rich repeats. Nature 1993; 366:751–756.

    Article  PubMed  CAS  Google Scholar 

  20. Kobe B, Deisenhofer J. A structural basis of interactions between leucine-rich repeats and protein ligands. Nature 1995; 374:183–186.

    Article  PubMed  CAS  Google Scholar 

  21. Scott DJ, Layfield S, Yan Y et al. Characterization of novel splice variants of LGR7 and LGR8 reveals that receptor signaling is mediated by their unique LDLa modules. J Biol Chem 2006.

    Google Scholar 

  22. Büllesbach EE, Schwabe C. The trap-like relaxin-binding site of the leucine-rich G-protein-coupled receptor 7. J Biol Chem 2005; 280(14):14051–14056.

    Article  PubMed  CAS  Google Scholar 

  23. Brennand JE, Calder AA, Leitch CR et al. Recombinant human relaxin as a cervical ripening agent. Brit J Obst Gynaecol 1997; 104(7):775–780.

    CAS  Google Scholar 

  24. Dschietzig T, Stangl K. Relaxin: a pregnancy hormone as central player of body fluid and circular homeostasis. Cell Mol Life Sci 2003; 60:688–700.

    Article  PubMed  CAS  Google Scholar 

  25. Samuel CS, Unemori EN, Mookerjee I et al. Relaxin modulates cardiac fibroblast proliferation, differentiation and collagen production and reverses cardiac fibrosis in vivo. Endocrinology 2004; 145:4125–4133.

    Article  PubMed  CAS  Google Scholar 

  26. Seibold JR. Relaxin: lessons and limitations. Curr Rheumatol Rep 2002; 4:275–276.

    Article  PubMed  Google Scholar 

  27. Samuel CS, Zhao C, Bathgate RAD et al. Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis. FASEB J 2003; 17:121.

    Google Scholar 

  28. Møller H, Prener H, Skakkebaek NE. Testicular cancer, cryptorchidism, inguinal hernia, testicular atrophy and genital malformations: Case control studies in Denmark. Cancer Causes Control 1996; 7:264–274.

    Article  PubMed  Google Scholar 

  29. John Radcliffe Hospital Cryptorchidism Study Group. Cryptorchidism: an apparent substantial increase since 1960. Br Med J 1986; 293:1401–1404.

    Article  Google Scholar 

  30. Adham IM, Steding G, Thamm T et al. The overexpression of the INSL3 in female mice causes descent of the ovaries. Mol Endocrinology 2002; 16:244–252.

    Article  CAS  Google Scholar 

  31. Boockfor FR, Fullbright G, Büllesbach EE et al. Relaxin-like factor (RLF) serum concentrations and gubernaculum RLF receptor-display in relation to pre-and neonatal development of rats. Reproduction 2001; 122:899–906.

    Article  PubMed  CAS  Google Scholar 

  32. Spiess AN, Balvert M, Tena-Sempere M et al. Structure and expression of the rat relaxin-like factor (RLF) gene. Mol Reprod Devel 1999; 54:319–325.

    Article  PubMed  CAS  Google Scholar 

  33. Büllesbach EE, Schwabe C. The primary structure and the disulfide links of the bovine relaxin-like factor (RLF). Biochemistry 2002; 41:274–281.

    Article  PubMed  CAS  Google Scholar 

  34. Burkhardt E, Adham IM, Hobohm U et al. A human cDNA coding for the Leydig insulin-like peptide (Ley I-L). Hum Genet 1994; 94:91–94.

    Article  PubMed  CAS  Google Scholar 

  35. Bathgate R, Balvers M, Hunt N et al. Relaxin-like factor gene is highly expressed in the bovine ovary of the cycle and pregnancy—Sequence and messenger ribonucleic acid analysis. Biol Reprod 1996; 55(6):1452–1457.

    Article  PubMed  CAS  Google Scholar 

  36. Pusch W, Balvers M, Ivell R. Molecular cloning and expression of the relaxin-like factor from the mouse testis. Endocrinology 1996; 137(7):3009–3013.

    Article  PubMed  CAS  Google Scholar 

  37. Roche PJ, Butkus A, Wintour EM et al. Structure and expression of Leydig insulin-like peptide mRNA in the sheep. Mol Cell Endocrinology 1996; 121(2):171–177.

    Article  CAS  Google Scholar 

  38. Koskimies P, Spiess AN, Lahti P et al. The mouse relaxin-like factor gene and its promoter are located within the 3’region of the JAC3 genomic sequence. FEBS Lett 1997; 419:186–190.

    Article  PubMed  CAS  Google Scholar 

  39. Zimmermann S, Schottler P, Engel W et al. Mouse Leydig insulin-like (Ley I-L) gene—Structure and expression during testis and ovary development. Mol Reprod Develop 1997; 47(1):30–38.

    Article  CAS  Google Scholar 

  40. Hombach-Klonisch S, Tetens F, Kauffold J et al. Molecular cloning and localization of caprine relaxin-like factor (RLF) mRNA within the goat testis. Mol Reprod Develop 1999; 53:135–141.

    Article  CAS  Google Scholar 

  41. Hombach-Klonisch S, Kauffold J, Rautenberg T et al. Relaxin-like factor (RLF) mRNA expression in the fallow deer. Mol Cell Endocrinology 2000; 159:147–158.

    Article  CAS  Google Scholar 

  42. Truong A, Bogatcheva NV, Schelling C et al. Isolation and expression analysis of the canine insulin-like factor 3 gene. Biol Reprod 2003; 69:1658–1664.

    Article  PubMed  CAS  Google Scholar 

  43. Büllesbach EE, Schwabe C. Tryptophan B27 in the relaxin-like factor (RLF) is crucial for RLF receptor binding. Biochemistry 1999; 38:3073–3078.

    Article  PubMed  Google Scholar 

  44. Büllesbach EE, Schwabe C. Synthetic cross-links arrest the C-terminal region of the relaxin-like factor (RLF) in an active conformation. Biochemistry 2004; 43:8021–8028.

    Article  PubMed  CAS  Google Scholar 

  45. Büllesbach EE, Schwabe C. The mode of interaction of the relaxin-like factor (RLF) with the leucine-rich repeat G protein-activated receptor 8. J Biol Chem 2006; 26136–26143.

    Google Scholar 

  46. Rosengren KJ, Zhang S, Lin F et al. Solution structure and characterization of the receptor binding surface of insulin-like peptide 3. J Biol Chem 2006; 28287–28295.

    Google Scholar 

  47. Del Borgo MP, Hughes RA, Bathgate RA et al. Analogs of insulin-like peptide 3 (INSL3) B-chain are LGR8 antagonists in vitro and in vivo. J Biol Chem 2006; 281(19):13068–13074.

    Article  PubMed  CAS  Google Scholar 

  48. Halls ML, Bond CP, Sudo S et al. Multiple binding sites revealed by interaction of relaxin family peptides with native and chimeric relaxin family peptide receptors 1 and 2 (LGR7 and LGR8). J Pharmacol Exp Trier 2005; 313(2):677–687.

    Article  CAS  Google Scholar 

  49. Dawson NF, Tan YY, Macris M et al. Solid phase synthesis of ovine Leydig cell insulin-like peptide—a putative ovine relaxin? J Peptide Res 1999; 53:542–547.

    Article  CAS  Google Scholar 

  50. Bullesbach EE, Schwabe C. LGR8 signal activation by the relaxin-like factor. J Biol Chem 2005; 280(15):14586–14590.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christian Schwabe .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Schwabe, C., Büllesbach, E.E. (2007). Relaxin, the Relaxin-Like Factor and Their Receptors. In: Agoulnik, A.I. (eds) Relaxin and Related Peptides. Advances in Experimental Medicine and Biology, vol 612. Springer, New York, NY. https://doi.org/10.1007/978-0-387-74672-2_2

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-74672-2_2

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-0-387-74670-8

  • Online ISBN: 978-0-387-74672-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics