Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 2000 Sep 1;350(Pt 2):589–597.

Fetuin-B, a second member of the fetuin family in mammals.

E Olivier 1, E Soury 1, P Ruminy 1, A Husson 1, F Parmentier 1, M Daveau 1, J P Salier 1
PMCID: PMC1221288  PMID: 10947975

Abstract

A set of orthologous plasma proteins found in human, sheep, pig, cow and rodents, now collectively designated fetuin-A, constitutes the fetuin family. Fetuin-A has been identified as a major protein during fetal life and is also involved in important functions such as inhibition of the insulin receptor tyrosine kinase activity, protease inhibitory activities and development-associated regulation of calcium metabolism and osteogenesis. Furthermore, fetuin-A is a key partner in the recovery phase of an acute inflammatory response. We now describe a second protein of the fetuin family, called fetuin-B, which is found at least in human and rodents. On grounds of domain homology, overall conservation of cysteine residues and chromosomal assignments of the corresponding genes in these species, fetuin-B is unambiguously a paralogue of fetuin-A. Yet, fetuin-A and fetuin-B exhibit significant differences at the amino acid sequence level, notably including variations with respect to the archetypal fetuin-specific signature. Differences and similarities in terms of gene regulation were also observed. Indeed, studies performed during development in rat and mouse showed for the first time high expression of a member of the fetuin family in adulthood, as shown with the fetuin-B mRNA in rat. However, like its fetuin-A counterpart, the fetuin-B mRNA level is down-regulated during the acute phase of experimentally induced inflammation in rat.

Full Text

The Full Text of this article is available as a PDF (265.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akhoundi C., Amiot M., Auberger P., Le Cam A., Rossi B. Insulin and interleukin-1 differentially regulate pp63, an acute phase phosphoprotein in hepatoma cell line. J Biol Chem. 1994 Jun 3;269(22):15925–15930. [PubMed] [Google Scholar]
  2. Auberger P., Falquerho L., Contreres J. O., Pages G., Le Cam G., Rossi B., Le Cam A. Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity. Cell. 1989 Aug 25;58(4):631–640. doi: 10.1016/0092-8674(89)90098-6. [DOI] [PubMed] [Google Scholar]
  3. Binkert C., Demetriou M., Sukhu B., Szweras M., Tenenbaum H. C., Dennis J. W. Regulation of osteogenesis by fetuin. J Biol Chem. 1999 Oct 1;274(40):28514–28520. doi: 10.1074/jbc.274.40.28514. [DOI] [PubMed] [Google Scholar]
  4. Brown W. M., Dziegielewska K. M. Friends and relations of the cystatin superfamily--new members and their evolution. Protein Sci. 1997 Jan;6(1):5–12. doi: 10.1002/pro.5560060102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brown W. M., Dziegielewska K. M., Saunders N. R., Christie D. L., Nawratil P., Müller-Esterl W. The nucleotide and deduced amino acid structures of sheep and pig fetuin. Common structural features of the mammalian fetuin family. Eur J Biochem. 1992 Apr 1;205(1):321–331. doi: 10.1111/j.1432-1033.1992.tb16783.x. [DOI] [PubMed] [Google Scholar]
  6. Brown W. M., Saunders N. R., Møllgård K., Dziegielewska K. M. Fetuin--an old friend revisited. Bioessays. 1992 Nov;14(11):749–755. doi: 10.1002/bies.950141105. [DOI] [PubMed] [Google Scholar]
  7. Broze G. J., Jr, Girard T. J., Novotny W. F. Regulation of coagulation by a multivalent Kunitz-type inhibitor. Biochemistry. 1990 Aug 21;29(33):7539–7546. doi: 10.1021/bi00485a001. [DOI] [PubMed] [Google Scholar]
  8. Chen H., Srinivas P. R., Cong L. N., Li Y., Grunberger G., Quon M. J. Alpha2-Heremans Schmid glycoprotein inhibits insulin-stimulated Elk-1 phosphorylation, but not glucose transport, in rat adipose cells. Endocrinology. 1998 Oct;139(10):4147–4154. doi: 10.1210/endo.139.10.6258. [DOI] [PubMed] [Google Scholar]
  9. Daveau M., Davrinche C., Djelassi N., Lemetayer J., Julen N., Hiron M., Arnaud P., Lebreton J. P. Partial hepatectomy and mediators of inflammation decrease the expression of liver alpha 2-HS glycoprotein gene in rats. FEBS Lett. 1990 Oct 29;273(1-2):79–81. doi: 10.1016/0014-5793(90)81055-s. [DOI] [PubMed] [Google Scholar]
  10. Daveau M., Jean L., Soury E., Olivier E., Masson S., Lyoumi S., Chan P., Hiron M., Lebreton J. P., Husson A. Hepatic and extra-hepatic transcription of inter-alpha-inhibitor family genes under normal or acute inflammatory conditions in rat. Arch Biochem Biophys. 1998 Feb 15;350(2):315–323. doi: 10.1006/abbi.1997.0515. [DOI] [PubMed] [Google Scholar]
  11. Daveau M., Rouet P., Scotte M., Faye L., Hiron M., Lebreton J. P., Salier J. P. Human inter-alpha-inhibitor family in inflammation: simultaneous synthesis of positive and negative acute-phase proteins. Biochem J. 1993 Jun 1;292(Pt 2):485–492. doi: 10.1042/bj2920485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Deloukas P., Schuler G. D., Gyapay G., Beasley E. M., Soderlund C., Rodriguez-Tomé P., Hui L., Matise T. C., McKusick K. B., Beckmann J. S. A physical map of 30,000 human genes. Science. 1998 Oct 23;282(5389):744–746. doi: 10.1126/science.282.5389.744. [DOI] [PubMed] [Google Scholar]
  13. Demetriou M., Binkert C., Sukhu B., Tenenbaum H. C., Dennis J. W. Fetuin/alpha2-HS glycoprotein is a transforming growth factor-beta type II receptor mimic and cytokine antagonist. J Biol Chem. 1996 May 31;271(22):12755–12761. doi: 10.1074/jbc.271.22.12755. [DOI] [PubMed] [Google Scholar]
  14. Dziegielewska K. M., Brown W. M., Gould C. C., Matthews N., Sedgwick J. E., Saunders N. R. Fetuin: an acute phase protein in cattle. J Comp Physiol B. 1992;162(2):168–171. doi: 10.1007/BF00398343. [DOI] [PubMed] [Google Scholar]
  15. Elzanowski A., Barker W. C., Hunt L. T., Seibel-Ross E. Cystatin domains in alpha-2-HS-glycoprotein and fetuin. FEBS Lett. 1988 Jan 25;227(2):167–170. doi: 10.1016/0014-5793(88)80890-1. [DOI] [PubMed] [Google Scholar]
  16. Falquerho L., Patey G., Paquereau L., Rossi V., Lahuna O., Szpirer J., Szpirer C., Levan G., Le Cam A. Primary structure of the rat gene encoding an inhibitor of the insulin receptor tyrosine kinase. Gene. 1991 Feb 15;98(2):209–216. doi: 10.1016/0378-1119(91)90175-b. [DOI] [PubMed] [Google Scholar]
  17. Goto K., Yoshida K., Suzuki Y., Yamamoto K., Sinohara H. Molecular cloning and sequencing of cDNA encoding plasma countertrypin, a member of mammalian fetuin family, from the Mongolian gerbil, Meriones unguiculatus. J Biochem. 1997 Mar;121(3):619–625. doi: 10.1093/oxfordjournals.jbchem.a021630. [DOI] [PubMed] [Google Scholar]
  18. Henikoff J. G., Henikoff S. Blocks database and its applications. Methods Enzymol. 1996;266:88–105. doi: 10.1016/s0076-6879(96)66008-x. [DOI] [PubMed] [Google Scholar]
  19. Henikoff S., Pietrokovski S., Henikoff J. G. Superior performance in protein homology detection with the Blocks Database servers. Nucleic Acids Res. 1998 Jan 1;26(1):309–312. doi: 10.1093/nar/26.1.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hofmann K., Bucher P., Falquet L., Bairoch A. The PROSITE database, its status in 1999. Nucleic Acids Res. 1999 Jan 1;27(1):215–219. doi: 10.1093/nar/27.1.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jahnen-Dechent W., Schinke T., Trindl A., Müller-Esterl W., Sablitzky F., Kaiser S., Blessing M. Cloning and targeted deletion of the mouse fetuin gene. J Biol Chem. 1997 Dec 12;272(50):31496–31503. doi: 10.1074/jbc.272.50.31496. [DOI] [PubMed] [Google Scholar]
  22. Jahnen-Dechent W., Trindl A., Godovac-Zimmermann J., Müller-Esterl W. Posttranslational processing of human alpha 2-HS glycoprotein (human fetuin). Evidence for the production of a phosphorylated single-chain form by hepatoma cells. Eur J Biochem. 1994 Nov 15;226(1):59–69. doi: 10.1111/j.1432-1033.1994.tb20026.x. [DOI] [PubMed] [Google Scholar]
  23. Kazi J. A., Nakamura O., Ohnishi T., Arakaki N., Kajihara T., Nakagawa S., Daikuhara Y. Changes with age of the rat fetuin concentration in serum and its mRNA expression. J Biochem. 1998 Jul;124(1):179–186. doi: 10.1093/oxfordjournals.jbchem.a022077. [DOI] [PubMed] [Google Scholar]
  24. Kellermann J., Haupt H., Auerswald E. A., Müller-Ester W. The arrangement of disulfide loops in human alpha 2-HS glycoprotein. Similarity to the disulfide bridge structures of cystatins and kininogens. J Biol Chem. 1989 Aug 25;264(24):14121–14128. [PubMed] [Google Scholar]
  25. Lundin L. G. Evolution of the vertebrate genome as reflected in paralogous chromosomal regions in man and the house mouse. Genomics. 1993 Apr;16(1):1–19. doi: 10.1006/geno.1993.1133. [DOI] [PubMed] [Google Scholar]
  26. Magnuson V. L., McCombs J. L., Lee C. C., Yang F., Bowman B. H., McGill J. R. Human alpha 2-HS-glycoprotein localized to 3q27----q29 by in situ hybridization. Cytogenet Cell Genet. 1988;47(1-2):72–74. doi: 10.1159/000132509. [DOI] [PubMed] [Google Scholar]
  27. Milland J., Tsykin A., Thomas T., Aldred A. R., Cole T., Schreiber G. Gene expression in regenerating and acute-phase rat liver. Am J Physiol. 1990 Sep;259(3 Pt 1):G340–G347. doi: 10.1152/ajpgi.1990.259.3.G340. [DOI] [PubMed] [Google Scholar]
  28. Nielsen H., Engelbrecht J., Brunak S., von Heijne G. Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Protein Eng. 1997 Jan;10(1):1–6. doi: 10.1093/protein/10.1.1. [DOI] [PubMed] [Google Scholar]
  29. Ohnishi T., Nakamura O., Arakaki N., Daikuhara Y. Effect of phosphorylated rat fetuin on the growth of hepatocytes in primary culture in the presence of human hepatocyte-growth factor. Evidence that phosphorylated fetuin is a natural modulator of hepatocyte-growth factor. Eur J Biochem. 1997 Feb 1;243(3):753–761. doi: 10.1111/j.1432-1033.1997.00753.x. [DOI] [PubMed] [Google Scholar]
  30. Olivier E., Soury E., Risler J. L., Smih F., Schneider K., Lochner K., Jouzeau J. Y., Fey G. H., Salier J. P. A novel set of hepatic mRNAs preferentially expressed during an acute inflammation in rat represents mostly intracellular proteins. Genomics. 1999 May 1;57(3):352–364. doi: 10.1006/geno.1999.5795. [DOI] [PubMed] [Google Scholar]
  31. Osawa M., Umetsu K., Sato M., Ohki T., Yukawa N., Suzuki T., Takeichi S. Structure of the gene encoding human alpha 2-HS glycoprotein (AHSG). Gene. 1997 Sep 1;196(1-2):121–125. doi: 10.1016/s0378-1119(97)00216-3. [DOI] [PubMed] [Google Scholar]
  32. Rauth G., Pöschke O., Fink E., Eulitz M., Tippmer S., Kellerer M., Häring H. U., Nawratil P., Haasemann M., Jahnen-Dechent W. The nucleotide and partial amino acid sequences of rat fetuin. Identity with the natural tyrosine kinase inhibitor of the rat insulin receptor. Eur J Biochem. 1992 Mar 1;204(2):523–529. doi: 10.1111/j.1432-1033.1992.tb16663.x. [DOI] [PubMed] [Google Scholar]
  33. Rawlings N. D., Barrett A. J. Evolution of proteins of the cystatin superfamily. J Mol Evol. 1990 Jan;30(1):60–71. doi: 10.1007/BF02102453. [DOI] [PubMed] [Google Scholar]
  34. Rychlik W., Rhoads R. E. A computer program for choosing optimal oligonucleotides for filter hybridization, sequencing and in vitro amplification of DNA. Nucleic Acids Res. 1989 Nov 11;17(21):8543–8551. doi: 10.1093/nar/17.21.8543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Salier J. P., Chan P., Raguenez G., Zwingman T., Erickson R. P. Developmentally regulated transcription of the four liver-specific genes for inter-alpha-inhibitor family in mouse. Biochem J. 1993 Nov 15;296(Pt 1):85–91. doi: 10.1042/bj2960085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Salier J. P. Inter-alpha-trypsin inhibitor: emergence of a family within the Kunitz-type protease inhibitor superfamily. Trends Biochem Sci. 1990 Nov;15(11):435–439. doi: 10.1016/0968-0004(90)90282-g. [DOI] [PubMed] [Google Scholar]
  37. Schinke T., Amendt C., Trindl A., Pöschke O., Müller-Esterl W., Jahnen-Dechent W. The serum protein alpha2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. A possible role in mineralization and calcium homeostasis. J Biol Chem. 1996 Aug 23;271(34):20789–20796. doi: 10.1074/jbc.271.34.20789. [DOI] [PubMed] [Google Scholar]
  38. Schnittger S., Rao V. V., Abrahamson M., Hansmann I. Cystatin C (CST3), the candidate gene for hereditary cystatin C amyloid angiopathy (HCCAA), and other members of the cystatin gene family are clustered on chromosome 20p11.2. Genomics. 1993 Apr;16(1):50–55. doi: 10.1006/geno.1993.1139. [DOI] [PubMed] [Google Scholar]
  39. Soury E., Olivier E., Daveau M., Hiron M., Claeyssens S., Risler J. L., Salier J. P. The H4P heavy chain of inter-alpha-inhibitor family largely differs in the structure and synthesis of its prolin-rich region from rat to human. Biochem Biophys Res Commun. 1998 Feb 13;243(2):522–530. doi: 10.1006/bbrc.1998.8128. [DOI] [PubMed] [Google Scholar]
  40. Wang H., Zhang M., Bianchi M., Sherry B., Sama A., Tracey K. J. Fetuin (alpha2-HS-glycoprotein) opsonizes cationic macrophagedeactivating molecules. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14429–14434. doi: 10.1073/pnas.95.24.14429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Yamamoto K., Sinohara H. Isolation and characterization of mouse countertrypin, a new trypsin inhibitor belonging to the mammalian fetuin family. J Biol Chem. 1993 Aug 25;268(24):17750–17753. [PubMed] [Google Scholar]
  42. Yang F., Chen Z. L., Bergeron J. M., Cupples R. L., Friedrichs W. E. Human alpha 2-HS-glycoprotein/bovine fetuin homologue in mice: identification and developmental regulation of the gene. Biochim Biophys Acta. 1992 Mar 24;1130(2):149–156. doi: 10.1016/0167-4781(92)90522-2. [DOI] [PubMed] [Google Scholar]
  43. Yang F., Schwartz Z., Swain L. D., Lee C. C., Bowman B. H., Boyan B. D. Alpha 2-HS-glycoprotein: expression in chondrocytes and augmentation of alkaline phosphatase and phospholipase A2 activity. Bone. 1991;12(1):7–15. doi: 10.1016/8756-3282(91)90048-n. [DOI] [PubMed] [Google Scholar]
  44. Yasue M., Serikawa T., Yamada J. Chromosomal assignments of 23 biochemical loci of the rat by using rat x mouse somatic cell hybrids. Cytogenet Cell Genet. 1991;57(2-3):142–148. doi: 10.1159/000133133. [DOI] [PubMed] [Google Scholar]
  45. Yoshida K., Suzuki Y., Yamamoto K., Sinohara H. Cystatin-like domain of mouse countertrypin, a member of mammalian fetuin family, is responsible for the inhibition of trypsin. Evidence from site-directed mutagenesis. Biochem Mol Biol Int. 1996 Aug;39(5):1023–1028. doi: 10.1080/15216549600201182. [DOI] [PubMed] [Google Scholar]
  46. Yoshida K., Suzuki Y., Yamamoto K., Sinohara H. cDNA sequencing of guinea pig alpha 2-HS glycoprotein, its expression in various tissues and acute phase expression. Biol Chem. 1999 Jan;380(1):95–99. doi: 10.1515/BC.1999.013. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES