Structure and Expression of Aminopeptidase N

  • Jørgen Olsen
  • Klaus Kokholm
  • Ove Norén
  • Hans Sjöström
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 421)

Abstract

Aminopeptidase N (APN) is a very abundant membrane protein in the microvillar membrane of the small intestinal absorptive epithelial cell the enterocyte 1, 2. APN is an ectopeptidase and from its position in the brush border membrane it faces the small intestinal lumen. The enzyme is therefore readily supplied with substrate molecules in the form of oligopeptides derived from nutritional proteins following the actions of gastric and pancreatic proteases. It is generally accepted that the physiological function of APN (and other brush border peptidases) is to convert oligopeptides in the small intestinal lumen into amino acids which can subsequently be absorbed by amino acid carriers. Besides the small intestine APN is also found in a wide variety of other tissues such as the endometrium3, the kidney, the spleen and the brain 2. The physiological role of APN in these alternative locations is unknown but it has been suggested that APN might be involved in the degradation of regulatory peptides2. In the recent years the realisation that APN is expressed in cells of the immune system has lent support to the idea that APN might be involved in the processing of antigens4.

Keywords

Zinc Sugar Hydrolysis Migration Codon 

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References

  1. 1.
    Norén O, Sjöström H, Danielsen EM, et al. Desnuelle P, Sjöström H, Norén O. editors.Molecular and cellular basis of digestion. Elsevier Science Publishers B.V. 1986; 19, The enzymes of the enterocyte plasma membrane. p. 335–65.Google Scholar
  2. 2.
    Kenny AJ, Stephenson LS, Turner AJ.; Kenny AJ, Turner AJ, editors.Mammalian ectoenzymes. Amsterdam: Elsevier Science Publishers B.V. 1987; 7, Cell surface peptidases. p. 169–210.Google Scholar
  3. 3.
    Classen-Linke I, Denker H-W, Winterhager E. Apical plasma membrane-bound enzymes of rabbit uterine epithelium. Pattern changes during the periimplantation phase. Histochemistry 1987; 87: 517–29.PubMedCrossRefGoogle Scholar
  4. 4.
    Larsen SL. Pedersen LO, Buus S, Stryhn A. T cell responses affected by aminopeptidase N (CD131–mediated trimming of major histocompatibility complex class 11–bound peptides. J Exp Med 1996;184–183–9.Google Scholar
  5. 5.
    Danielsen EM, Cowell GM, Norén O, et al. Kenny AJ, Turner AJ, editors.Mammalian ectoenzymes. Amsterdam: Elsevier Science Phulishers B.V. 1987: 3. Biosynthesis. p. 47–85.Google Scholar
  6. 6.
    Danielsen EM, Cowell GM, Norén O. Sjöström H. Biosynthesis of microvillar proteins. Biochem J 1984; 221: 1–14.PubMedGoogle Scholar
  7. 7.
    Hussain MM, Tranum-Jensen J, Norén O, Sjöström H. Christiansen K. Reconstitution of purified amphiphilic pig intestinal microvillus aminopeptidase. Mode of membrane insertion and morphology. Biochem J 1981: 199: 179–86.PubMedGoogle Scholar
  8. 8.
    Olsen J, Cowel GM, K nigsh fer E, Danielsen EM, M lier J, Laustsen L, Hansen OC, Welinder KG. Eng-berg J, Hunziker W, Spies M, Sjöström H, Norén O. Complete amino acid sequence of human intestinal aminopeptidase N as deduced from cloned eDNA. FEBS Lett 1988; 238: 307–14.CrossRefGoogle Scholar
  9. 9.
    Look AT, Ashmun RA, Shapiro LH, Peiper SC. Human myeloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase N. J Clin Invest 1989; 83: 1299–307.CrossRefGoogle Scholar
  10. 10.
    Danielsen EM. Tyrosine sulfation, a post-translational modification of microvillar enzymes in the small intestinal enterocyte. EMBO J 1987; 6: 2891–6.PubMedGoogle Scholar
  11. 11.
    Hooper NM. Families of zinc metalloproteases. [Review]. FEBS Letters 1994; 354: 1–6.PubMedCrossRefGoogle Scholar
  12. 12.
    McCaman MT, Gabe JD. The nucleotide sequence of the pepN gene and its over-expression in Escherichia coli. Gene 1986; 48: 145–53.PubMedCrossRefGoogle Scholar
  13. 13.
    Foglino M, Gharbi S, Lazdunski A. Nucleotide sequence of the pepN gene encoding aminopeptidase N of Escherichia coli. Gene 1986: 49: 303–9.Google Scholar
  14. 14.
    Delmas B, Gelfi J, L’Haridon R, Vogel LK, Sjöström H, Norén O. Laude, H. Aminopeptidase N is a major receptor for the entero-pathogenic coronavirus TGEV. Nature 1992; 357: 417–20.Google Scholar
  15. 15.
    Yeager CL, Ashmun RA, Williams RK, Cardellichio CB, Shapiro LH. Look, AT, Holmes KV. Human aminopeptidase N is a receptor for human coronavirus 229E. Nature 1992; 357: 420–2.PubMedCrossRefGoogle Scholar
  16. 16.
    Gordon JI. Intestinal epithelial differentiation: new insights from chimeric and transgenic mice..1 Cell Biol 1989; 108: 1187–94.Google Scholar
  17. 17.
    Simon TC, Gordon JI. Intestinal epithelial cell differentiation: new insights from mice, flies and nematodes. Curr Opin Genet Develop 1995; 5: 557–86.CrossRefGoogle Scholar
  18. 18.
    Hansen GH, Niels-Christiansen LL, Poulsen MD, Norén O, Sjöström H. Distribution of three microvillar enzymes along the small intestinal crypt-villus axis. J Submicrosc Cytol Pathol 1994; 26: 453–60.PubMedGoogle Scholar
  19. 19.
    Norén O, Dabelsteen E, Heyer PE, Olsen J, Sjöström H, Hansen GH. Onset of transcription of the aminopeptidase N (leukemia antigen CD13) gene at the crypt/villus transition zone during rabbit enterocyte differentiation. FEBS Lett 1989; 259: 107–12.Google Scholar
  20. 20.
    Hansen GH, Sjöström H, Norén O, Dabelsteen E. Immunomiscroscopic localization of aminopeptidase N in pig enterocyte. Implications for the route of intercellular transport. Eur J Cell Biol 1987; 43: 253–9.Google Scholar
  21. 21.
    Wessels HP, Hansen GH, Fuhrer C, Look AT, Sjöström H, Norén O, Spiess M. Aminopeptidase N is directly sorted to the apical domain in MDCK cells. J Cell Biol 1990; 111: 2923–30.Google Scholar
  22. 22.
    Vogel LK, Spiess M, Sjöström H, Norén O. Evidence for an apical sorting signal on the ectodomain of human aminopeptidase N. J Biol Chem 1992; 267: 2794–7.Google Scholar
  23. 23.
    Vogel LK, Norén O, Sjöström H. Transcytosis of aminopeptidase N in Caco-2 cells is mediated by a non-cytoplasmic signal. J Biol Chem 1995; 270: 22933–8.Google Scholar
  24. 24.
    Look AT, Peiper SC, Rebentisch MB, Ashmun RA, Roussel MF, Lemons RS, Le Beau MM. Rubin CM, Sherr CJ. Molecular cloning, expression, and chromosomal localization of the gene encoding a human myeloid membrane antigen (gp150). J Clin Invest 1986; 78: 914–21.PubMedCrossRefGoogle Scholar
  25. 25.
    Olsen J, Sjöström H, Norén O. Cloning of the pig aminopeptidase N gene. Identification of possible regulatory elements and the exon distribution in relation to the membrane-spanning region. FEBS Letters 1989; 251: 275–81.Google Scholar
  26. 26.
    Kruse TA, Bolund L, Grzeschik KH, Ropers HH, Olsen J, Sjöström H, Norén O. Assignment of the human aminopeptidase N (peptidase E) gene to chromosome 15q 13–qter. FEBS Letters 1988: 239: 305–8.Google Scholar
  27. 27.
    Poulsen PH, Thomsen PD, Olsen J. Assignment of the porcine aminopeptidase N (PEPN) gene to chromosome 7ceng2l. Cytogenet Cell Genet 1991;57:44–-6.Google Scholar
  28. 28.
    Lerche C, Vogel LK, Shapiro LH, Norén O. Sjöström H. Human aminopeptidase N is encoded by 20 exons. Mamm Genome 1996;7 In Press.Google Scholar
  29. 29.
    Olsen J, Laustsen L, Kärnström U, Sjöström H, Norén O. Tissue-specific interactions between nuclear proteins and the aminopeptidase N promoter. J Biol Chem 1991; 266: 18089–96.Google Scholar
  30. 30.
    Shapiro LH, Ashmun RA, Roberts WM, Look T. Separate promoters control transcription of the human aminopeptidase N gene in myeloid and intestinal epithelial cells. J Biol Chem 1991; 266: 11999–2007.Google Scholar
  31. 31.
    Olsen J, Classen-Linke I, Sjöström H, Norén O. Pseudopregnancy induces the expression of hepatocyte nuclear factor-1 beta and its target gene aminopeptidase N in rabbit endometrium via the epithelial promoter. Biochem J 1995; 312: 31–7.Google Scholar
  32. 32.
    Olsen J, Kokholm K, Troelsen JT, Laustsen L. An enhancer with cell-type specific activity is located between the myeloid and epithelial aminipeptidase N (CD13) promoters. Manuscript 1996.Google Scholar
  33. 33.
    Olsen J, Laustsen L, Troelsen J. HNFIa activates the aminopeptidase N promoter in intestinal (Caco-2) cells. FEBS Lett 1994; 342: 325–8.CrossRefGoogle Scholar
  34. 34.
    Courey AJ, Tjian R. Analysis of Spl in vivo reveals multiple transcriptional domains. including a novel glutamine-rich activation motif. Cell 1988; 55: 887–98.PubMedCrossRefGoogle Scholar
  35. 35.
    Kadonaga JT, Courey AJ, Ladika J, Tjian R. Distinct regions of Spl modulate DNA binding and transcriptional activation. Science 1988; 242: 1566–70.PubMedCrossRefGoogle Scholar
  36. 36.
    Kadonaga JT, Camer KR, Masiarz FR, Tjian R. Isolation of eDNA encoding transcription factor Spl and functional analysis of the DNA binding domain. Cell 1987;51:1079–-90.Google Scholar
  37. 37.
    Briggs MR, Kadonaga JT. Bell SP, Tjian R. Purification and biochemical characterization of the promoter-specific transcription factor, Spl. Science 1986; 234: 47–52.CrossRefGoogle Scholar
  38. 38.
    Kadonaga JT, Katherine A, Tjian R. Promoter-specific activation of RNA polymerase II transcription by Spl. Trends Biochem Sci 1986: 11: 20–1CrossRefGoogle Scholar
  39. 39.
    Hagen G, Dennig J, Preiss A, Beato M, Suske G. Functional analyses of the transcription factor Sp4 reveal properties distinct from Spl and Spa. J Biol Chem 1995; 270: 24989–94.PubMedCrossRefGoogle Scholar
  40. 40.
    Hagen G, Muller S, Beato M, Suske G. Cloning by recognition site screening of two novel GT box binding proteins: a family of Spl related genes. Nucleic Acids Res 1992; 20: 5519–25.PubMedCrossRefGoogle Scholar
  41. 41.
    Hagen G, Muller S, Beato M, Suske G. SpI-mediated transcriptional activation is repressed by Sp3_ EMBO J 1994; 13: 3843–51.Google Scholar
  42. 42.
    Tronche F, Yaniv M. HNFI, a homeoprotein member of the hepatic transcription regulatory network. BioEssays 1992; 14: 579–87.PubMedCrossRefGoogle Scholar
  43. 43.
    Mendel DB, Crabtree GR. HNF-1, a member of a novel class of climerizing homeodomain proteins. J Biol Chem 1991; 266: 677–80.PubMedGoogle Scholar
  44. 44.
    Lai E, Darnell JEJ. Transcriptional control in hepatocytes: a window on development. Trends Biochem Sci 1991;16:427–9_Google Scholar
  45. 45.
    De Simone V, Cortese R. Transcription factors and liver-specific genes. Biochim Biophys Acta 1992; 1132: 119–26.PubMedCrossRefGoogle Scholar
  46. 46.
    Nicosia A, Monaci P, Tomei L, De Francesco R, Nuzzo M, Stunnenberg H, Cortese R. A myosin-like dimerization helix and an extra-large homeodomain are essential elements of the tripartite DNA binding structure of LFB 1. Cell 1990; 61: 1225–36.PubMedCrossRefGoogle Scholar
  47. 47.
    Mendel DB, Hansen LP, Graves MK, Conley PB, Crabtree GR. HNF-la and HNFI (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro. Genes, and Dev 1991; 5: 1042–56.CrossRefGoogle Scholar
  48. 48.
    Rey-Campos J, Chouard T, Yaniv M, Cereghini S. vHNFI is a homeoprotein that activates transcription and forms heterodimers with HNFI. EMBO J 1991; 10: 1445–57.PubMedGoogle Scholar
  49. 49.
    De Simone V, De Magistris L, Lazzaro D, Gerstner J, Monaci P, Nicossia A, Cortese R. LFB3, a heterodimer-forming homeoprotein of the LFBI family, is expressed in specialized epithelia. EMBO J 1991; 10: 1435–43.PubMedGoogle Scholar
  50. 50.
    Bach I, Yaniv M. More potent transcriptional activators or a transdominant inhibitor of the HNFI homeoprotein family are generated by alternative RNA processing. EMBO J 1993; 12: 4229–42.PubMedGoogle Scholar
  51. 51.
    Cereghini S, Ott M-O, Power S, Maury M. Expression patterns of vHNFI and HNFI homeoproteins in early postimplantation embryos suggest distinct and sequential developmental roles. Development 1992; 116: 783–97.PubMedGoogle Scholar
  52. 52.
    Blumenfeld M, Maury M, Chouard T, Yaniv M, Condamine H. Hepatic nuclear factor 1 (HNFI) shows a wider distribution than products of its known target genes in developing mouse. Development 1991; 113: 589–99.PubMedGoogle Scholar
  53. 53.
    Wang LH, Tsai SY, Cook RG, Beattie WG, Tsai MJ, O’Malley BW. COUP transcription factor is a member of the steroid receptor superfamily. Nature 1989; 340: 163–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Riemann D, Gohring B, Langner J. Expression of aminopeptidase N/CD13 in tumour-infiltrating lymphocytes from human renal cell carcinoma. Immunol Lett 1994; 42: 19–23.PubMedCrossRefGoogle Scholar
  55. 55.
    Wex T, Lendeckel U, Wex H, Frank K, Ansorge S. Quantification of aminopeptidase N mRNA in T cells by competitive PCR. FEBS Lett 1995; 374: 341–4.CrossRefGoogle Scholar
  56. 56.
    Lendeckel U, Wex T, Kahne T. Frank K, Reinhold D, Ansorge S. Expression of the aminopeptidase N (CD I3) gene in the human T cell lines HuT78 and H9. Cell Immunol 1994; 153: 214–26.Google Scholar
  57. 57.
    Shapiro LH. Myb and Ets proteins cooperate to transactivate an early myeloid gene. J Biol Chem 1995; 270: 8763–71.PubMedGoogle Scholar
  58. 58.
    Mucenski ML, McLain K, Kier AB, Swerdlow SH, Schreiner CM, Miller TA, Pietryga DW, Scott WJ. Jr., Potter SS. A functional c-myb gene is required for normal murine fetal hepatic hematopoìesis. Cell 1991; 65: 677–89.PubMedCrossRefGoogle Scholar
  59. 59.
    Metz T, Graf T. v-myb and v-ets transform chicken erythroid cells and cooperate both in trans and in cis to induce distinct differentiation phenotypes. Genes, and Dev 1991; 5: 369–80.CrossRefGoogle Scholar
  60. 60.
    Melotti P, Calabretta B. Ets-2 and c-Myb act independently in regulating expression of the hematopoietic stem cell antigen CD34. J Biol Chem 1994; 269: 25303–9.PubMedGoogle Scholar
  61. 61.
    Dudek H, Tantravahi RV, Rao VN, Reddy ES, Reddy EP. Myb and Ets proteins cooperate in transcriptional activation of the mim-1 promoter. Proc Natl Acad Sci USA 1992; 89: 1291–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Nunn MF, Seeburg PH, Moscovici C. Duesberg PH. Tripartite structure of the avian erythroblastosis virus E26 transforming gene. Nature 1983; 306: 391–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Leprince D, Gegonne A, Coll J, de Taisne C, Schneeberger A, Lagrou C, Stehelin D. A putative second cell-derived oncogene of the avian leukaemia retrovirus E26. Nature 1983; 306: 395–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Wasylyk B, Hahn SL, Giovane A. The Ets family of transcription factors [published erratum appears in Eur J Biochem 1993 Aug 1;215(3):907]. [Review]. EurJ Biochem 1993; 211: 7–18.CrossRefGoogle Scholar
  65. 65.
    Lozzio CB, Lozzio BB. Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood 1975; 45: 321–34.PubMedGoogle Scholar
  66. 66.
    Hay R, Caputo J, Chen TR, et al.American Type Culture Collection. Catalogue of Cell Lines and Hybridomas. 7th ed. Rockville, Maryland: American Type Culture Collection; 1992.Google Scholar
  67. 67.
    Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Develop 1994; 4: 96–101.CrossRefGoogle Scholar
  68. 68.
    Treisman R. The serum response element. Trends Biochem Sci 1992; 17: 423–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Riemann D, Kehlen A, Langner J. Stimulation of the expression and the enzyme activity of aminopeptidase N/CD 13 and dipeptidylpeptidase I V/CD26 on human renal cell carcinoma cells and renal tubular epithelial cells by T cell-derived cytokines, such as IL-4 and IL-13. Clin Exp Immunol 1995; 100: 277–83.PubMedCrossRefGoogle Scholar
  70. 70.
    Foltzer-Jourdainne C, Raul F. Effect of epidermal growth factor on the expression of digestive hydrolases in the Jejunum and colon of newborn rats. Endocrinology 1990; 127: 1763–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Xin JH, Cowie A, Lachance P, Hassell JA. Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is differentially expressed in mouse embryonic cells. Genes, and Dev 1992; 6: 481–96.CrossRefGoogle Scholar
  72. 72.
    Rehfeld N, Peters JE, Giesecke H, Haschen RJ. Untersuchungen über aminosaüre-arylamidasen. I Verteilung and isoenzyme der aryl-amidase im menschlichen Organismus. Acta Biologica et Medica Germanica 1967; 19: 819–30.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Jørgen Olsen
    • 1
  • Klaus Kokholm
    • 1
  • Ove Norén
    • 1
  • Hans Sjöström
    • 1
  1. 1.Department of Medical Biochemistry and Genetics Biochemistry Laboratory C, The Panum InstituteUniversity of CopenhagenCopenhagen NDenmark

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