Molecular Analyses of Human and Rat Dipeptidyl Peptidase IV

  • C. A. Abbott
  • M. D. Gorrell
  • M. T. Levy
  • G. W. Mccaughan
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 421)


Dipeptidyl peptidase IV (DPP IV) is a highly glycosylated 110 kDa multifunctional protease. DPP IV has a broad tissue distribution but is mainly expressed in epithelial cells, endothelial cells and lymphocytes in both rat and human tissues1–3. DPP IV on the human T cell surface binds or coassociates with adenosine deaminase (ADA)4, 5, collagen6–8 and CD459 and has a role in T cell costimulation7, 10. Our group has investigated the role of DPP IV in hepatocyte function. DPP IV levels are altered during liver regeneration11, human cirrhosis12 and liver tumorigenesis13. It is still unclear which DPP IV functions are involved in hepatocyte growth and regulation. DPP IV is a type II protein, its N terminus is anchored to the cell surface through a hydrophobic domain with a short, six amino acid cytoplasmic tail. Thus, most of the protein is extracellular. Recent work in our group has concentrated on understanding the DPP IV glycoprotein at the molecular level.


Adenosine Deaminase Catalytic Triad Dipeptidyl Peptidase Prolyl Endopeptidase Serine Protease Family 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    McCaughan G W. Wickson J E, Creswick P F and Gorrell M D, Identification of the bile canalicular cell surface molecule GPI 10 as the ectopeptidase dipeptidyl peptidase IV: an analysis by tissue distribution. purification and N-terminal amino acid sequence. Hepatology, 1990. 11 (4): 534–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Gorrell M D, Wickson J and McCaughan G W, Expression of the rat CD26 antigen (dipeptidyl peptidase IV) on subpopulations of rat lymphocytes. Cell Immunol, 1991. 134(1): 205-I 5.Google Scholar
  3. 3.
    Hegen M, Niedobitek G, Klein C E, Stein H and Fleischer B, The T cell triggering molecule Tp103 is associated with dipeptidyl aminopeptidase IV activity. J Immunol, 1990. 144 (8). 2908–14.PubMedGoogle Scholar
  4. 4.
    Morrison M E. Vijayasaradhi S, Engelstein D, Albino A P and Houghton A N, A marker for neoplastic progression of human melanocytes is a cell surface ectopeptidase. J Exp Med, 1993. 177 (4): 1135–43.PubMedCrossRefGoogle Scholar
  5. 5.
    Kameoka J, Tanaka T, Nojima Y, Schlossman S F arid Morimoto C, Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science, 1993. 261 (5120): 466–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Bauvois B, A collagen-binding glycoprotein on the surface of mouse fibroblasts is identified as dipeptidyl peptidase IV. Biochem J, 1988. 252 (3): 723–31.PubMedGoogle Scholar
  7. 7.
    Dang N H, Torimoto Y, Schlossman S F and Morimoto C, Human CD4 helper T cell activation: functional involvement of two distinct collagen receptors, 1F7 and VLA integrin family. J Exp Med, 1990. 172 (2): 649–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Hanski C, Huhle T, Gossrau R and Reutter W, Direct evidence for the binding of rat liver DPP IV to collagen in vitro. Exp Cell Res, 1988. 178 (1): 64–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Torimoto Y, Dang N H, Vivier E, Tanaka T, Schlossman S F and Morimoto C, Coassociation of CD26 (dipeptidyl peptidase IV) with CD45 on the surface of human T lymphocytes. J Immunol, 1991. 147 (8): 2514–7.PubMedGoogle Scholar
  10. 10.
    Dang N H, Torimoto Y, Deusch K, Schlossman S F and Morimoto C, Comitogenic effect of solid-phase immobilized anti-1F7 on human CD4 T cell activation via CD3 and CD2 pathways. J Immunol, 1990. 144 (11): 4092–100.PubMedGoogle Scholar
  11. 11.
    Abbott C A, Gorrell M D, Kobayashi Y, Kawasaki T, Liddle C, Bishop G A and McCaughan G W, Increased serum levels of dipeptidyl peptidase IV (CD26) in rats undergoing liver regeneration. Int Hepatology Commun, 1995. 4 (3): 165–74.CrossRefGoogle Scholar
  12. 12.
    Matsumoto Y, Bishop G A and McCaughan G W, Altered zonal expression of the CD26 antigen (dipeptidyl peptidase 1V) in human cirrhotic liver. Hepatology, 1992. 15 (6): 1048–53.PubMedCrossRefGoogle Scholar
  13. 13.
    McCaughan G W, Siah C L, Abbott C, Wickson J, Ballesteros M and Bishop G A, Dipeptidyl peptidase IV is down-regulated in rat hepatoma cells at the mRNA level. J Gastroenterol Hepatol, 1993. 8 (2): 142–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Abbott C, Baker E, Sutherland G R and McCaughan G W, Genomic organisation, exact localization. and tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics, 1994. 40 (5): 331–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Bernard A M, Mattei M G, Pierres M and Marguet D, Structure of the mouse dipeptidyl peptidase IV (CD26) gene. Biochemistry, 1994. 33: 15204–14.PubMedCrossRefGoogle Scholar
  16. 16.
    Mathew S, Morrison M E, Murty V V, Houghton A N and Chaganti R S, Assignment of the DPP4 gene encoding adenosine deaminase binding protein (CD26idipeptidylpeptidase IV) to 2q23. Genomics, 1994. 22 (1): 211–2.PubMedCrossRefGoogle Scholar
  17. 17.
    Tanaka T, Duke-Cohan J S, Kameoka J, Yaron A, Lee I, Schlossman S F and Morimoto C, Enhancement of antigen-induced T-cell proliferation by soluble CD26/dipeptidyl peptidase IV. Proc Natl Acad Sci U S A, 1994. 91 (8): 3082–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Watanabe Y, Kojima T and Fujimoto Y, Deficiency of membrane-bound dipeptidyl aminopeptidase IV in a certain rat strain. Experientia, 1987. 43 (4): 400–1.PubMedCrossRefGoogle Scholar
  19. 19.
    Tiruppathi C, Miyamoto Y, Ganapathy V, Roesel R A, Whitford G M and Leibach F H, Hydrolysis and transport of proline-containing peptides in renal brush-border membrane vesicles from dipeptidyl peptidase 1V-positive and dipeptidyl peptidase IV-negative rat strains. J Biol Chem, 1990. 265 (3): 1476–83.PubMedGoogle Scholar
  20. 20.
    Thompson N L, Hixson D C, Callanan H, Panzica M, Flanagan D, Faris R A, Hong W J. Hartel-Schenk S and Doyle D, A Fischer rat substrain deficient in dipeptidyl peptidase IV activity makes normal steady-state RNA levels and an altered protein. Use as a liver-cell transplantation model. Biochem J. 1991. 273 (Pí 3): 497–502.PubMedGoogle Scholar
  21. 21.
    Tsuji E. Misumi Y. Fujiwara T, Takami N, Ogata S and Ikehara Y, An active-site mutation (Gly633 >Arg) of dipeptidyl peptidase IV causes its retention and rapid degradation in the endoplasmic reticuium. Biochemistry, 1992. 31 (47): 11921–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Brandsch M, Ganapathy V and Leibach F, Chapter 6: Role of Dipeptidyl peptidase IV(DP IV) in intestinal and renal absorption of peptides, in Dipeptidyl peptidase IV(CD26) in metabolism and the immune response. B. Fleischer, Editor. 1995. R.G. Landes: Georgetown, Texas, USA. p. 111–29.Google Scholar
  23. 23.
    Abbott C A, Koorey D and McCaughan G W, An EcoRl polymorphism within the dipeptidyl peptidase IV (DPPIV) gene. Hum Mol Genet, 1993. 2 (9): 1507.PubMedCrossRefGoogle Scholar
  24. 24.
    Barrett A J and Rawlings N D, Oligopeptidases, and the emergence of the prolyl oligopeptidase family. Biol Chem Hoppe Seyler, 1992. 373 (7): 353–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Polgar L and Szabo E. Prolyl endopeptidase and dipeptidyl peptidase IV are distantly related members of the same family of serine proteases. Biol Chem Hoppe Seyler, 1992. 373(7): 361–6Google Scholar
  26. 26.
    Polgar L, Structural relationship between lipases and peptidases of the prolyl oligopeptidase family. FEBS Lett, 1992. 311 (3): 281–4.PubMedCrossRefGoogle Scholar
  27. 27.
    is D L, Cheah E, Cygler M. Dijkstra B, Frolow F, Franken S M, Harel M, Remington S J, Silman I, Schrag J, et al., The alpha/beta hydrolase fold. Protein Eng, 1992. 5(3): 197 211.Google Scholar
  28. 28.
    Goossens F, De Meester I, Vanhoof G, Hendriks D, Vriend G and Scharpe S, The purification, characterization and analysis of primary and secondary-structure of prolyl oligopeptidase from human lymphocytes. Evidence that the enzyme belongs to the alpha/beta hydrolase fold family. Eur J Biochem. 1995. 233 (2): 432–41.PubMedCrossRefGoogle Scholar
  29. 29.
    Lin L W, Lee F J and Smith J A, Structural organization of the rat acyl-peptide hydrolase gene. Nucleic Acids Res, 1989. 17 (11): 4397–400.PubMedCrossRefGoogle Scholar
  30. 30.
    Wilson R, Ainscough R, Anderson K, Baynes C, Berks M, Bonfield J, Burton J, Connell M, Copsey T, Cooper J, et al., 2.2 Mb of contiguous nucleotide sequence from chromosome Ill of C. elegans. Nature, 1994. 368 (6466): 32–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Bell G I, Quinto C, Quiroga M, Valenzuela P, Craik C S and Rutter W J, Isolation and sequence of a rat chymotrypsin B gene. J Biol Chem, 1984. 259 (22): 14265–70.PubMedGoogle Scholar
  32. 32.
    Swift G H, Craik C S, Stary S J, Quinto C, Lahaie R G, Rutter W J and MacDonald R J, Structure of the two related elastase genes expressed in the rat pancreas. J Biol Chem, 1984. 259 (22): 14271–8.PubMedGoogle Scholar
  33. 33.
    Craik C S, Choo Q L, Swift G H, Quinto C, MacDonald R J and Rutter W J, Structure of two related rat pancreatic trypsin genes. J Biol Chem, 1984. 259 (22): 14255–64.PubMedGoogle Scholar
  34. 34.
    Bohm S K, Gum J R, Jr., Erickson R H, Hicks J W and Kim Y S, Human dipeptidyl peptidase IV gene promoter: tissue-specific regulation from a TATA-less GC-rich sequence characteristic of a housekeeping gene promoter. Biochem J, 1995. 311 (Pt 3): 835–43.PubMedGoogle Scholar
  35. 35.
    Liu W J and Hansen P J, Progesterone-induced secretion of dipeptidyl peptidase-IV (cluster differentiation antigen-26) by the uterine endometrium of the ewe and cow that costimulates lymphocyte proliferation. Endocrinology. 1995. 136 (2): 779–87.PubMedCrossRefGoogle Scholar
  36. 36.
    Ohta N. Takahashi T. Mori T, Park M K, Kawashima S, Takahashi K and Kobayashi H, Hormonal modulation of prolyl endopeptidase and dipeptidyl peptidase IV activities in the mouse uterus and ovary. Acta Endocrinol Copenh, 1992. 127 (3), 262–6.PubMedGoogle Scholar
  37. 37.
    Fujiwara H, Fukuoka M, Yasuda K, Ueda M, lmai K, Goto Y, Suginami H, Kanzaki H, Maeda M and Mori T, Cytokines stimulate dipeptidyl peptidase-IV expression on human luteinizing granulosa cells. J Clin Endocrinol Metab, 1994. 79 (4): 1007–11.PubMedCrossRefGoogle Scholar
  38. 38.
    Hong W and Doyle D, cDNA cloning for a bile canaliculus domain-specific membrane glycoprotein of rat hepatocytes. Proc Natl Acad Sei U S A, 1987. 84 (22): 7962–6.CrossRefGoogle Scholar
  39. 39.
    Misumi Y, Hayashi Y, Arakawa F and Ikehara Y, Molecular cloning and sequence analysis of human dipeptidyl peptidase IV, a serine proteinase on the cell surface. Biochim Biophys Acta, 1992. 1131 (3): 333–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Tanaka T, Camerini D, Seed B, Torimoto Y, Dang N H, Kameoka J, Dahlberg H N, Schlossman S F and Morimoto C, Cloning and functional expression of the T cell activation antigen CD26. J Immunol, 1992. 149 (2): 481–6.PubMedGoogle Scholar
  41. 41.
    Davis S J, Ward H A, Puklavec M J, Willis A C, Williams A F and Barclay A N. High level expression in Chinese hamster ovary cells of soluble forms of CD4 T lymphocyte glycoprotein including glycosylation variants. J Biol Chem, 1990. 265 (18): 10410–8.PubMedGoogle Scholar
  42. 42.
    McCall M N, Shotton D M and Barclay A N, Expression of soluble sot of rat CD45. Analysis by elec- tron microscopy and use to epitope mapping of anti-CD45R monoclonal antibodies. Immunology, 1992. 76 (2): 310–7.PubMedGoogle Scholar
  43. 43.
    Van der Merwe P A, McNamee P N. Davies E A, Barclay A N and Davis S J, Topology of the CD2–CD48 cell-adhesion molecule complex: implications for antigen recognition by T cells. Curr Biol. 1995. 5 (1): 74–84.PubMedCrossRefGoogle Scholar
  44. 44.
    Stceg C, Hartwig U and Fleischer B, Unchanged signaling capacity of mutant CD26/dipeptidylpeptidase IV molecules devoid of enzymatic activity. Cell Immunol, 1995. 164 (2): 311–5.CrossRefGoogle Scholar
  45. 45.
    von Hcijne G, Signal sequences. The limits of variation. J Mol Biol, 1985. 184 (1): 99–105.CrossRefGoogle Scholar
  46. 46.
    Weisz O A, Machamer C E and Hubbard A L, Rat liver dipeptidylpeptidase IV contains competing apical and basolateral targeting information. J Biol Chem, 1992. 267 (31): 22282–8.PubMedGoogle Scholar
  47. 47.
    Ho S N, Hunt H D. Horton R M, Pullen J K and Pease L R, Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene, 1989. 77 (1): 51–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Nagatsu T, Hino M and Fuyamada H, New chromogenic substrates for X-prolyl dipeptidyl-amnopeptidase. Anal Biochem, 1976. 74: 466–76Google Scholar
  49. 49.
    Gorrell M D. Levy M T, Abbott C A, Washington E A and McCaughan G W, CD26: ADA binding, immunoblotting and species cross reactivity examined using recombinant proteins, in Leucocyte Typing VI. T. Kishimoto, Editor. 1997. Garland Publishing Inc.: New York.Google Scholar
  50. 50.
    De Meester I, Vanhoof G, Lambeir A and Scharpe S, Use of immobilized adenosine deaminase(EC for the rapid purifaication of native human CD26/dipeptidyl peptidase IV(EC J Immunol Methods, 1996. 189: 99–105.PubMedCrossRefGoogle Scholar
  51. 51.
    De Meester 1, Vanham G, Kestens L, Vanhoof G, Bosmans E, Gigase P and Scharpe S, Binding of adenosine deaminase to the lymphocyte surface via CD26. Eur J Immunol, 1994. 24 (3): 566–70.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • C. A. Abbott
    • 1
  • M. D. Gorrell
    • 1
  • M. T. Levy
    • 1
  • G. W. Mccaughan
    • 1
  1. 1.A.W Morrow Gastroenterology and Liver Centre Centenary Institute for Cancer Medicine and Cell BiologyRoyal Prince Alfred HospitalSydneyAustralia

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