Structure and Expression of Aminopeptidase N
- 32 Citations
- 309 Downloads
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
Small Intestinal Lumen HEXXH Motif Human Coronavirus 229E Abundant Membrane Protein pepN GeneReferences
- 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.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.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.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.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.Danielsen EM, Cowell GM, Norén O. Sjöström H. Biosynthesis of microvillar proteins. Biochem J 1984; 221: 1–14.PubMedGoogle Scholar
- 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.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.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.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.Hooper NM. Families of zinc metalloproteases. [Review]. FEBS Letters 1994; 354: 1–6.PubMedCrossRefGoogle Scholar
- 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.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.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.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.Gordon JI. Intestinal epithelial differentiation: new insights from chimeric and transgenic mice..1 Cell Biol 1989; 108: 1187–94.Google Scholar
- 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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.Tronche F, Yaniv M. HNFI, a homeoprotein member of the hepatic transcription regulatory network. BioEssays 1992; 14: 579–87.PubMedCrossRefGoogle Scholar
- 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.Lai E, Darnell JEJ. Transcriptional control in hepatocytes: a window on development. Trends Biochem Sci 1991;16:427–9_Google Scholar
- 45.De Simone V, Cortese R. Transcription factors and liver-specific genes. Biochim Biophys Acta 1992; 1132: 119–26.PubMedCrossRefGoogle Scholar
- 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.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.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.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.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.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.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.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.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.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.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.Shapiro LH. Myb and Ets proteins cooperate to transactivate an early myeloid gene. J Biol Chem 1995; 270: 8763–71.PubMedGoogle Scholar
- 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.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.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.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.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.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.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.Lozzio CB, Lozzio BB. Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood 1975; 45: 321–34.PubMedGoogle Scholar
- 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.Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Develop 1994; 4: 96–101.CrossRefGoogle Scholar
- 68.Treisman R. The serum response element. Trends Biochem Sci 1992; 17: 423–6.PubMedCrossRefGoogle Scholar
- 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.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.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.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