Ectopeptidases pp 141-170 | Cite as

Signal Transduction Via Membrane Peptidases

  • Dagmar Riemann
  • Tanja Blosz
  • Jens Wulfänger
  • Jürgen Langner
  • Alexander Navarrete Santos


Human aminopeptidase N (APN)/CD13 is a type-II transmembrane molecule which belongs to a group of ectoenzymes with a ubiquitous expression and a broad functional repertoire. Other members of this group of membrane enzymes, which often are colocalized and which can cooperate in peptide cleavage are neprilysin/CD10, dipeptidyl peptidase IV (DPIV)/CD26, glutamyl aminopeptidase and angiotensin converting enzyme/CD143. Not only do these membrane peptidases hydrolyse small peptide mediators, resulting in activation or inactivation, but they also function as receptors and as molecules participating in cell motility and in adhesion to extracellular matrix. Membrane peptidases may play a key role in the control of growth and differentiation of various cellular systems by modulating the activity of peptides involved in growth and differentiation of cells and by regulating their access to adjacent cells. As an example, neprilysin can modulate proliferation of bronchial epithelial cells by cleavage of mitogenic bombesins (Ganju et al 1994). Expression of neprilysin is inversely correlated with proliferation in bronchial epithelial cells and lung cancer cells (Shipp et al 1991). It is also well known that the expression of DPIV is up-regulated following mitogenic activation (Schön et al 1985). Last not least, recent observations suggest direct involvement of membrane peptidases in signal transduction processes.


Focal Adhesion Kinase Lipid Raft Dipeptidyl Peptidase Membrane Microdomains Neutral Endopeptidase 
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.


  1. Albiston, A.L., McDowall, S.G., Matsacos, D., Sim, P., Clune, E., Mustafa, T., Lee, J„ Mendelsohn, F.A., Simpson, R.J., Connolly, L.M., Chai, S.Y., 2001, Evidence that the angiotensin IV (AT4) receptor is the enzyme insulin regulated aminopeptidase.J. Biol. Chem.In press.Google Scholar
  2. Anderson, R.G.W., 1993, Caveolae: Where incoming and outgoing messengers meet.Proc. Natl Acad. Sci. USA, 90: 10909–10913.PubMedCrossRefGoogle Scholar
  3. Anderson, R.G.W., 1998, The caveolae membrane system.Ann. Rev. Biochem. 67: 199–225.PubMedCrossRefGoogle Scholar
  4. Angelisova, P., Drbal, K., Horejsi, V., Cerny, J., 1999 Association of CDlO/neutral endopeptidase 24.11 with membrane microdomains rich in glycosylphosphatidylinositol-anchored proteins and lyn kinase.Blood, 93: 1437–1439.PubMedGoogle Scholar
  5. Ardouin, L., Boyer, C., Gillet, A., Trucy, J., Bernard, A.M., Nunes, J., Delon, J., Trautmann, A., He, H.T., Malissen, B., Malissen, M., 1999, Crippling of CD3-zeta ITAMs does not impair T cell receptor signaling.Immunity 10: 409–420.PubMedCrossRefGoogle Scholar
  6. Arienti, G., Carlini, E., Verdicchi, R., Cosmi, E.V., Palmerini, C.A., 1997, Prostasome to sperm transfer of CD13/aminopeptidase N (EC Biophys. Acta 1336: 533–538.PubMedCrossRefGoogle Scholar
  7. Baggiolini, M., 1998, Chemokines and leukocyte traffic.Nature 392: 565–568.PubMedCrossRefGoogle Scholar
  8. Bauvois, B., 1988, A collagen-binding glycoprotein on the surface of mouse fibroblasts is identified as dipeptidyl peptidase IV.Biochem. J. 178: 64–72.Google Scholar
  9. Benting, J.H., Rietveld, A.G., Simons, K., 1999, N-Glycans mediate the apical sorting of a GPI-anchored, raft-associated protein in Madin-Darby canine kidney cells.J. Cell. Biol. 146:313–320.PubMedCrossRefGoogle Scholar
  10. Bermpohl, F., Löster, K., Reutter, W., Baum, O., 1998, Rat dipeptidyl peptidase IV (DPPIV) exhibits endopeptidase activity with specificity for denaturated fibrillar collagens.FEBS Lett. 428: 152–166.PubMedCrossRefGoogle Scholar
  11. Brown, D.A., London, E., 1998, Function of lipid rafts in biological membranes.Ann. Rev. Cell. Dev. Biol. 14:111–136.CrossRefGoogle Scholar
  12. Cheng, H.C., Abdel-Ghany, M., Elble, R.C., Pauli, B.U., 1998, Lung endothelial dipeptidyl peptidase IV promotes adhesion and metastasis of rat breast cancer cells via tumor cell surface-associated fibronectin.J. Biol Chem. 273: 24207–24215.PubMedCrossRefGoogle Scholar
  13. Cuenda, A., Rouse, J., Doza, Y.N., Meier, R., Cohen, P., Gallagher, T.F., Young, P.R., Lee, J.C., 1995, SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1.FEBS Lett. 364: 229–233.PubMedCrossRefGoogle Scholar
  14. Dang, N.H., Torimoto, Y, Shimamura, K., Tanaka, T., Daley, J.F., Schlossman, S.F., Morimoto, C, 1991, 1F7 (CD26): A marker of thymic maturation involved in the differential regulation of the CD3 and CD2 pathways of human thymocyte activation.J. Immunol 147: 2825–2832.PubMedGoogle Scholar
  15. Danielsen, E.M., 1995, Involvement of detergent-insoluble complexes in the intracellular transport of intestinal brush border enzymes.Biochemistry, 34: 1596–1605.PubMedCrossRefGoogle Scholar
  16. Danielsen, E.M., van Deurs, B., 1997, Galectin-4 and small intestinal brush border enzymes form clusters.Mol Biol Cell 8: 2241–2251.PubMedGoogle Scholar
  17. Deans, J.P., Robbins, S.M., Polyak, M.J., Savage, J.A., 1998, Rapid redistribution of CD20 to a low density detergent-insoluble membrane compartment.J. Biol Chem. 273: 344–348.PubMedCrossRefGoogle Scholar
  18. Delmas, B., Gelfi, J., L’ Haridon, R., Vogel, L.K., Sjöström, H., Noren, O., Laude, H., 1992, Aminopeptidase N is a major receptor for the entero-pathogenic coronavirus TGEV.Nature 357: 417–420.PubMedCrossRefGoogle Scholar
  19. De Meester, I., Durinx, C, Bal G., Proost, P., Struyf, S., Goossens, R, Augustyns, K., Scharpe, S., 2000, Natural substrates of dipeptidyl peptidase IV.Adv. Exp. Med. Biol. 471: 67–87.Google Scholar
  20. Dudley, D.T., Pang, L., Decker, S.J., Bridges, A.J., Saltiel, A.R., 1995, A synthetic inhibitor of the mitogen-activated protein kinase cascade.Proc. Natl. Acad. Sci. USA, 92: 7686–7689.PubMedCrossRefGoogle Scholar
  21. Ehrlich, B.E., Kaftan, E., Bezprozvannaya, S., Bezprozvanny, I., 1994, The pharmacology of intracellular Ca(2+)-release channels.Trends Pharmacol Sci. 15: 145–149.PubMedCrossRefGoogle Scholar
  22. Field, K.A., Holowka, D., Baird, B., 1997, Compartmentalized activation of the high affinity immunoglobulin E receptor within membrane domains.J. Biol Chem. 272: 4276–4280.PubMedCrossRefGoogle Scholar
  23. Franco, R., Valenzuela, A., Lluis, C., Blanco, J., 1998, Enzymatic and extraenzymatic role of ecto-adenosine deaminase in lymphocytes.Immunol Rev. 161: 27–42.PubMedCrossRefGoogle Scholar
  24. Gaetaniello, L., Fiore, M., DeFilippo, S., Pozzi, N., Tamasi, S., Piguata, C., 1998, Occupancy of dipeptidyl peptidase IV activates an associated tyrosine kinase and triggers an apoptotic signal in human carcinoma cells.Hepatology, 25: 934–942.CrossRefGoogle Scholar
  25. Ganju, R.K., Shpektor, R.G., Brenner, D.G., Shipp, M.A., 1996, CDlO/neutral endopeptidase 24.11 is phosphorylated by casein kinase II and coassociates with other phosphoproteins including the lyn src-related kinase.Blood, 88: 4159–4165.PubMedGoogle Scholar
  26. Ganju, R.K., Sunday, M., Tsarwhas, D.G., Card, A., Shipp, M.A., 1994, CD10/NEP in non-small cell lung carcinomas. Relationship to cellular proliferation.J. Clin. Inves. 94: 1784–1791.CrossRefGoogle Scholar
  27. Garcia, M., Mitre, C, Quadroni, A., Reggio, H., Le Bivic, A., 1993, GPI-anchored proteins associate to form microdomains during their intracellular transport in Caco-2 cells.J. Cell Sci. 104: 1281–1290.PubMedGoogle Scholar
  28. George, S.G., Kenny, J., 1973, Studies on the enzymology of purified preparations of brush border from rabbit kidney.Biochem. J. 134: 43–57.PubMedGoogle Scholar
  29. Godar, S., Horejsi, V., Weidle, U.H., Binder, B.R., Hansmann, C, Stockinger, H., 1999, M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-ßl.Eur. J. Immunol. 29: 1004–1013.PubMedCrossRefGoogle Scholar
  30. Gonzalez-Gronow, M., Weber, M.R., Shearin, T.V., Gawdi, G., Pirle-Shepherd, S.R., Pizzo, S.V., 1998, Plasmin(ogen) carbohydrate chains mediate binding to dipeptidyl peptidase IV(CD26) in rheumatoid arthritis human synovial fibroblasts.Fibrinolysis Proteol 12: 366–374.CrossRefGoogle Scholar
  31. Gonzalez-Gronow, M., Grenett, H.E., Weber, M.R., Gawdi, G., Pizzo, S.V., 2001, Interaction of plasminogen with dipeptidyl peptidase IV initiates a signal transduction mechanism which regulates expression of matrix metalloproteinase-9 by prostate cancer cells.Biochem. J. 355: 397–407.PubMedCrossRefGoogle Scholar
  32. Gorrell, M.D., Gysbers, V., McCaughan, G.W., 2001, CD26: a multifunctional integral membrane and secreted protein of activated lymphocytes.Scand. J. Immunol. 54: 249–264.Google Scholar
  33. Guerin, S., Mari, B., Fernandez, E., Belacene, N., Toribio, M.L., Auberger, P., 1997, CD10 is expressed on human thymic epithelial cell lines and modulates thymopentin-induced cell proliferation.FASEBJ. 11: 1003–1011.Google Scholar
  34. Guerra, B., Issinger, O.G., 1999, Protein kinase CK2 and its role in cellular proliferation, development and pathology.Electrophoresis 20: 391–408.PubMedCrossRefGoogle Scholar
  35. Haasemann, M., Cartaud, J., Muller-Esterl, W., Dunia, I., 1998, Agonist-induced redistribution of bradykinin B2 receptor in caveolae.J. Cell Sci. 111: 917–928.PubMedGoogle Scholar
  36. Hansen, G.H., Delmas, B., Besnardeau, L., Vogel, L.K., Laude, H., Sjöström, H., Noren, O., 1998, The coronavirus transmissible gastroenteritis virus causes infection after receptormediated endocytosis and acid-dependent fusion with an intracellular compartment.J.Virol 72: 527–534.PubMedGoogle Scholar
  37. Harder, T., Simons, K., 1999, Clusters of glycolipid and glycosylphosphatidylinositol-anchored proteins in lymphoid cells: accumulation of actin regulated by local tyrosine phosphorylation.Eur. J. Immunol 29: 556–562.PubMedCrossRefGoogle Scholar
  38. Hegen, M, Niedobitek, G., Klein, C.E., Stein, H., Fleischer, B., 1990, The T cell triggering molecule Tpl03 is associated with dipeptidyl aminopeptidase IV activity.J. Immunol 144: 2908–2914.PubMedGoogle Scholar
  39. Hegen, M., Kameoka, J., Dong, R.P., Schlossman, S.F., Morimoto, C., 1997, Crosslinking of CD26 by antibody induces tyrosine phosphorylation and activation of mitogen-activated protein kinase.Immunology,90: 257–264.PubMedCrossRefGoogle Scholar
  40. Herrera, C., Morimoto, C., Blanco, J., Mallol, J., Arenzana, F., Lluis, C., Franco, R., 2001, Comodulation of CXCR4 and CD26 in human lymphocytes.J. Biol Chem. 276: 19532– 19539.PubMedCrossRefGoogle Scholar
  41. Hoessli, D.C., Ilangumaran, S., Soltermann, A., Robinson, P.J., Borisch, B., Nasir-Ud-Din., 2000, Signaling through sphingolipid microdomains of the plasma membrane: the concept of signaling platform.Glycoconj. J. 17: 191–197.PubMedCrossRefGoogle Scholar
  42. Hoffmann, T., Faust, J., Neubert, K., Ansorge, S., 1993, Dipeptidyl peptidase IV (CD26) and aminopeptidase N (CD13) catalyzed hydrolysis of cytokines and peptides with N-terminal cytokine sequences.FEBS Lett. 336: 61–64.PubMedCrossRefGoogle Scholar
  43. Hooper, N.M., 1994, Families of zinc metalloproteinases.FEBS Lett. 354: 1–6.PubMedCrossRefGoogle Scholar
  44. Horejsi, V., Drbal, K., Cebecauer, M., Cerny, J., Brdicka, T., Angelisova, P., Stockinger, H., 1999, GPI-microdomains: a role in signalling via immunoreceptors.Immunol. Today 20:356–361.PubMedCrossRefGoogle Scholar
  45. Huhn, J., Ehrlich, S., Fleischer, B., von Bonin, A., 2000, Molecular analysis of CD26-mediated signal transduction in T cells.Immunol Lett. 72: 127–32.PubMedCrossRefGoogle Scholar
  46. Ilangumaran, S., Ami, S., Chicheportiche, Y., Briol, A., Hoessli, D.C., 1996, Evaluation by dot-immunoassay of the differential distribution of cell surface and intracellular proteins in glycosylphosphatidylinositol-rich plasma membrane domains.Anal. Biochem. 235: 49–56.PubMedCrossRefGoogle Scholar
  47. Ilangumaran, S., Hoessli, D.C., 1999, Effects of cholesterol depletion by cyclodextrin on the sphingolipid microdomains of the plasma membrane.Biochem. J. 335: 433–440.Google Scholar
  48. Ilangumaran, S., He, H.T., Hoessli, D.C., 2000, Microdomains in lymphocyte signalling: beyond GPI-anchored proteins.Immunol Today 21: 2–7.PubMedCrossRefGoogle Scholar
  49. Ikushima, H., Munakata, Y., Ishii, T., Iwata, S., Terashima, M., Tanaka, H., Schlossman, S.F., Morimoto, C., 2000, Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation.Proc. Natl. Acad. Sci. USA 97: 8439–8444.PubMedCrossRefGoogle Scholar
  50. Ishii, E., Greaves, A., Grunberger, T., Freedman, M.H., Letarte, M., 1995, Tumor formation by a human pre-B leukemia cell line in scid mice is enhanced by matrigel and is associated with induction of CD10 expression.Leukemia 9: 175–184.PubMedGoogle Scholar
  51. Ishii, T., Ohnuma, K., Murakami, A., Takasawa, N., Kobayashi, S., Dang, N.H., Schlossman, S.F., Morimoto, C., 2001, CD26-mediated signaling for T cell activation occurs in lipid rafts through its association with CD45RO.Proc. Natl. Acad. Sci. USA,98: 12138–12143.PubMedCrossRefGoogle Scholar
  52. Kähne, T., Neubert, K., Faust, J., Ansorge, S., 2000, Early phosphorylation events induced by DPIV/CD26-specific inhibitors.Cell Immunol. 189: 60–66.CrossRefGoogle Scholar
  53. Kähne, T., Lendeckel, U., Wrenger, S., Neubert, K., Ansorge, S., Reinhold, D., 1999, Dipeptidyl peptidase IV: a cell surface peptidase involved in regulating T cell growth (review).Int. J. Mol. Med. 4: 3–15.PubMedGoogle Scholar
  54. Kameoka, J., Tanaka, T., Nojima, Y., Schlossman, S.F., Morimoto, C, 1999, Direct association of adenosine deaminase with a T cell activation antigen, CD26.Science 261: 466–469.CrossRefGoogle Scholar
  55. Keller, P., Simons, K., 1998, Cholesterol is required for surface transport of influenza virus hemagglutinin.J. Cell Biol 140: 1357–1367.PubMedCrossRefGoogle Scholar
  56. Kenny, A.J., Stephenson, .LS., Turner, A.J., 1987, Cell surface peptidases. In: Mammalian Ectoenzymes (Kenny AJ and Turner AJ, eds.); Amsterdam:Elsevier Science Publishers,pp. 169–210.Google Scholar
  57. Kerr, M.A., Kenny, A.J., 1974, The purification and specificity of a neutral endopeptidase from rabbit kidney brush border.Biochem. J. 137: 477–488.PubMedGoogle Scholar
  58. Kertesz, Z., Linton, E.A., Redman, C.W., 2000, Adhesion molecules of syncytiotrophoblast microvillous membranes inhibit proliferation of human umbilical vein endothelial cells.Placenta 21: 150–159.PubMedCrossRefGoogle Scholar
  59. Kohno, H., Kanno, T., 1985, Properties and activities of aminopeptidases in normal and mitogen-stimulated human lymphocytes.Biochem. J. 226: 59–65.PubMedGoogle Scholar
  60. Kokkonen, J.O., Kuoppala, A., Saarinen, J., Lindstedt, K.A., Kovanen, P.T., 1999, Kallidinand bradykinin-degrading pathways in human heart: degradation of kallidin by aminopeptidase M-like activity and bradykinin by neutral endopeptidase.Circulation, 99: 1984–1990.PubMedCrossRefGoogle Scholar
  61. Koziak, K., Kaczmarek, E., Kittel, A, Sevigny, J., Blusztajn, J.K., Schulte Am Esch, J. 2nd, Imai, M., Guckelberger, O., Goepfert, C., Qawi, I., Robson, S.C., 2000, Palmitoylation targets CD39/endothelial ATP diphosphohydrolase to caveolae.J. Biol Chem. 275: 2057–2062.PubMedCrossRefGoogle Scholar
  62. Kumano, N., Sugawara, S., 1992, Ubenimex (Bestatin), an aminopeptidase inhibitor, modulates protein kinase C in K562 cells.J. Biol. Regul Homeost. Agents 6: 116–120.PubMedGoogle Scholar
  63. Larsen, S.L., Pedersen, L.O., Buus, S., Stryhn, A., 1996, T cell responses affected by aminopeptidase N (CD13)-mediated trimming of major histocompatibility complex class Il-bound peptides.J. Exp. Med. 184: 183–189.PubMedCrossRefGoogle Scholar
  64. LeBien, T.W., McCormack, R.T., 1989, The common acute lymphoblastic leukemia antigen (CDlO)--emancipation from a functional enigma.Blood 73: 625–635.PubMedGoogle Scholar
  65. Lee, V.H., 2000, Membrane transporters.Eur. J. Pharm. Sci. 11: S41–50.PubMedCrossRefGoogle Scholar
  66. Lendeckel, U., Kaehne, T., Arndt, M., Frank, K., Ansorge, S., 1998, Inhibition of alanyl aminopeptidase induces MAP-kinase p42/ERK2 in the human T cell line KARPAS-299.Biochem. Biophys. Res. Commun. 252: 5–9.PubMedCrossRefGoogle Scholar
  67. Lendeckel, U., Arndt, M., Frank, K., Wex, T., Ansorge, S., 1999, Role of alanyl aminopeptidase in growth and function of human T cells (review).Int. J. Mol. Med. 4: 17–27.PubMedGoogle Scholar
  68. Liu, P., Ying, Y., Anderson, R.G., 1997, Platelet-derived growth factor activates mitogen- activated protein kinase in isolated caveolae.Proc. Natl. Acad. Sci. USA 94: 13666–13670.PubMedCrossRefGoogle Scholar
  69. Löhn, M., Mueller, C., Thiele, K., Kähne, T., Riemann, D., Langner, J., 1997, Aminopeptidase N-mediated signal transduction and inhibition of proliferation of human myeloid cells.Adv. Exp. Med. Biol.421: 85–91.PubMedGoogle Scholar
  70. Löhn, M., Mueller, C., Langner, J., 2001, Cell cycle retardation induced by aminopeptidase N (CD13). Leukemia Lymphoma in pressGoogle Scholar
  71. Löster, K., Zeilinger, K., Schuppan, D., Reutter, W., 1995, The cysteine-rich region of dipeptidyl peptidase IV/CD26 is the collagen-binding site.Biochem. Biophys. Res. Commun. 217:341–348.PubMedCrossRefGoogle Scholar
  72. Louvard, D., Maroux, S., Baratti, J., Desnuelle, P., 1973, On the distribution of enterokinase in porcine intestine and on ist subcellular localization.Biochim. Biophys. Acta. 309: 127–137.PubMedCrossRefGoogle Scholar
  73. Lu, B., Gerard, N.P., Kolakowski, L.F. Jr, Finco, O., Carroll, M.C., Gerard, C., 1996, Neutral endopeptidase modulates septic shock.Ann. N. Y. Acad. Sci. 780: 156–163.PubMedCrossRefGoogle Scholar
  74. Maclntyre, E.A., Jones, H.M., Roberts, P.J., Tidman, N., Linch, D.C., 1987, Identification of signal transduction molecules on monocytic cells. In: Leucocyte Typing III: White cell differentiation antigens. McMichael AJ, Beverly PCL, Cobbold S and Crumpton MJ. Eds.Oxford University Press, pp. 685–688.Google Scholar
  75. Maclntyre, E.A., Roberts, P.J., Jones, M., Van der Schoot, C.E., Favalaro, E.J., Tidman, N., Linch, D.C., 1989, Activation of human monocytes occurs on crosslinking monocytic antigens to an Fc receptor.J. Immunol. 142: 2377–83.Google Scholar
  76. Madueno, J.A., Munoz, E., Blazquez, V., Conzalez, R., Aparicio, P., Pena, J., 1993, The CD26 Antigen is coupled to protein tyrosine phosphorylation and implicated in CD16-mediated lysis in natural killer cells.Scand. J. Immunol. 37: 425–429.PubMedCrossRefGoogle Scholar
  77. Mak, D.O., McBride, S., Foskett, J.K., 1998, Inositol 1,4,5-trisphosphate activation of inositol trisphosphate [correction of tris-phosphate] receptor Ca2+channel by ligand tuning of Ca2+inhibition.Proc. Natl. Acad. Sci. USA, 95: 15821–15825.PubMedCrossRefGoogle Scholar
  78. Malfroy, B., Kuang W.J., Seeburg, P.H., Mason, A.J., Schofield, P.R., 1988, Molecular cloning and amino acid sequence of human enkephalinase (neutral endopeptidase).FEBS Lett. 229: 206–210.PubMedCrossRefGoogle Scholar
  79. Martin, M., Huguet, J., Centelles, J.J., Franco, R., 1995, Expression of ecto-adenosine deaminase and CD26 in human T cells triggered by the TCR-CD3 complex. Possible role of adenosine deaminase as costimulatory molecule.J. Immunol. 155: 4630–4643.PubMedGoogle Scholar
  80. Matsas, R., Stephenson, S.L., Hryszko, J., Kenny, AJ., Turner, A.J., 1985, The metabolism of neuropeptides. Phase separation of synaptic membrane preparations with Triton X-114 reveals the presence of aminopeptidase N.Biochem. J. 231: 445–449.PubMedGoogle Scholar
  81. Mentlein, R., 1999, Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides.Regulatory Peptides 85: 9–24.PubMedCrossRefGoogle Scholar
  82. Miller, B. C., Ackroyd, A., Hersh, L.B., Cottam, G.L., 1994, Methionine enkephalin metabolism by murine macrophage ectopeptidase(s).Regul. Pept. 50: 87–98.PubMedCrossRefGoogle Scholar
  83. Milligan, G., Parenti, M., Magee, A.I., 1995, The dynamic role of palmitoylation in signal transduction.Trends Biochem. Sci. 20: 181–187.PubMedCrossRefGoogle Scholar
  84. Mineo, C., Anderson, R.G., 2001, Potocytosis.Histochem. Cell Biol. 116: 109–118.Google Scholar
  85. Morimoto, C., Schlossman, S.F., 1998, The structure and function of CD26 in the T-cell immune response.Immunol. Rev. 161: 55–70.PubMedCrossRefGoogle Scholar
  86. Mueller, S.C., Ghersi, G., Akiyama, S.K., Sang, Q.X., Howard, L., Pineiro-Sanchez, M., Nakahara, H., Yeh, Y., Chen, W.T., 1999, A novel protease-docking function of integrin at invadopodia.J. Biol. Chem. 274: 24947–24952.PubMedCrossRefGoogle Scholar
  87. Munoz, E., Blazquez, M.V., Madueno, J.A., Rubio, G, Pena, J., 1992, CD26 induces T-cell proliferation by tyrosine protein phosphorylation.Immunology 77:43–50.PubMedGoogle Scholar
  88. Murata, M., Kubota, Y., Tanaka, T., Iida-Tanaka, K., Takahara, J., Irino, S., 1994, Effect of ubenimex on the proliferation and differentiation of U937 human histiocytic lymphoma cells.Leukemia 8: 2188–2193.PubMedGoogle Scholar
  89. Nakanishi, S., Yano, H., Matsuda, Y., 1995, Novel functions of phosphatidylinositol 3-kinase in terminally differentiated cells.Cell Signal, 7: 545–57.PubMedCrossRefGoogle Scholar
  90. Navarrete Santos, A., Langner, J., Herrmann, M., Riemann, D., 2000a, Aminopeptidase N/CD13 is directly linked to signal transduction pathways in monocytes.Cell. Immunol. 200: 22–32.CrossRefGoogle Scholar
  91. Navarrete Santos, A., Langner, J., Riemann, D., 2000b, Enzymatic activity is not a precondition for the intracellular calcium increase mediated by mAbs specific for aminopeptidase N/CD13.Adv. Exp. Med. Biol. 477: 43–47.PubMedCrossRefGoogle Scholar
  92. Navarrete Santos, A., Röntsch, J., Danielsen, E. M., Langner, J., Riemann, D., 2000c, Aminopeptidase N/CD13 is associated with raft membrane microdomains in monocytes.Biochem. Biophys. Res. Commun. 269: 143–148.PubMedCrossRefGoogle Scholar
  93. Navarrete Santos, A., Danielsen, M., Riemann, D., 2001, CD13-specific mAbs induce calcium signals in fibroblast-like synoviocytes.Signal Transduction 1: 67.Google Scholar
  94. Nykjaer, A., Christensen, E.I., Vorum, H., Hager, H., Petersen, CM., Roigaard, H., Min, H.Y., Vilhardt, F., Moller, L.B., Kornfeld, S., Gliemann, J., 1998, Mannose 6-phosphate/insulin-like growth factor-II receptor targets the urokinase receptor to lysosomes via a novel binding interaction.J. Cell. Biol. 141: 815–828.PubMedCrossRefGoogle Scholar
  95. Oefner, C., D’ Arcy, A., Hennig, M., Winkler, F.K., Dale, G.E., 2000, Structure of human neutral endopeptidase (Neprilysin) complexed with phosphoramidon.J. Mol. Biol. 296: 341–349.PubMedCrossRefGoogle Scholar
  96. Oh, P., Schnitzer, J.E., 2001, Segregation of heterotrimeric G proteins in cell surface microdomains. G(q) binds caveolin to concentrate in caveolae, whereas G(i) and G(s) target lipid rafts by default.Mol. Biol. Cell. 12: 685–698.PubMedGoogle Scholar
  97. Okamoto, T., Schlegel, A., Scherer, P.E., Lisanti, M.P., 2001, Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane.J. Biol. Chem. 273: 5419–5422.CrossRefGoogle Scholar
  98. Oliferenko, S., Paiha, K., Harder, T., Gerke, V., Schwarzler, C., Schwarz, H., Beug, H., Gunthert, U., Huber, L.A., 1999, Analysis of CD44-containing lipid rafts: Recruitment of annexin II and stabilization by the actin cytoskeleton.J. Cell. Biol. 146: 843–854.PubMedCrossRefGoogle Scholar
  99. Olsen, J., Cowell, G.M., Konigshofer, E., Danielsen, E.M., Moller, J., Laustsen, L., Hansen, O.C., Welinder, K.G., Engberg, J., Hunziker, W., Spies, M., Sjöström, H., Noren, O., 1988, Complete amino acid sequence of human intestinal aminopeptidase N as deduced from cloned cDNA.FEBS Lett. 238: 307–314.PubMedCrossRefGoogle Scholar
  100. Palade GE, 1953, The fine structure of blood capillaries.J. Appl. Phys. 24: 1424.Google Scholar
  101. Palmieri, F. E„ Bausback, H.H., Ward, P.E., 1989, Metabolism of vasoactive peptides by vascular endothelium and smooth muscle aminopeptidase M.Biochem. Pharmacol. 38: 173–180.PubMedCrossRefGoogle Scholar
  102. Papandreou, C.N., Usmani, B., Geng, Y., Bogenrieder, T., Freeman, R., Wilk, S., Finstad, C.L., Reuter, V.E., Powell, C.T., Scheinberg, D., Magill, C., Scher, H.I., Albino, A.P., Nanus, D.M., 1998, Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen-independent progression.Nat. Med. 4: 50–57.PubMedCrossRefGoogle Scholar
  103. Parker, I., Ivorra, I., 1991, Caffeine inhibits inositol trisphosphate-mediated liberation of intracellular calcium in Xenopus oocytes.J. Physiol. 433: 229–240.PubMedGoogle Scholar
  104. Pasqualini, R., Koivunen, E., Kain, R., Lahdenranta, J., Sakamoto, M., Stryhn, A., Ashmun, R.A., Shapiro, L.H., Arap, W., Ruoslahti, E., 2000, Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis.Cancer Res. 60: 722–727.PubMedGoogle Scholar
  105. Pawson, T., Scott, J.D., 1997, Signaling through scaffold, anchoring, and adaptor proteins.Science 278: 2075–2080.PubMedCrossRefGoogle Scholar
  106. Pethiyagoda, C.L., Welch, D.R., Fleming, T.P., 2000, Dipeptidyl peptidase IV (DPPIV) inhibits cellular invasion of melanoma cells.Clin. Exp. Metastasis 18: 391–400.PubMedCrossRefGoogle Scholar
  107. Phillips, A.J., Tomasec, P., Wang, E.C., Wilkinson, G.W., Borysiewicz, L.K., 1998, Human cytomegalovirus infection downregulates expression of the cellular aminopeptidases CD10 andCD13.Virology 250: 350–358.PubMedCrossRefGoogle Scholar
  108. Reinhold, D., Bank, U., Bühling, F., Täger, M., Born, I., Faust, J., Neubert, K., Ansorge, S., 1997a, Inhibitors of dipeptidyl peptidase IV (DP IV, CD26) induces secretion of transforming growth factor-beta 1 (TGF-beta 1) in stimulated mouse splenocytes and thymocytes.Immunol. Lett. 58: 29–35.PubMedCrossRefGoogle Scholar
  109. Reinhold, D., Kähne, T., Täger, M., Lendeckel, U., Bühling, F., Bank, U., Wrenger, S., Faust, J., Neubert, K., Ansorge, S., 1997b, The effect of anti-CD26 antibodies on DNA synthesis and cytokine production (IL-2, IL-10 and IFN-gamma) depends on enzymatic activity of DP IV/CD26.Adv. Exp. Med. Biol 421: 149–155.PubMedGoogle Scholar
  110. Renneberg, H., Albrecht, M., Kurek, R., Krause, E., Lottspeich, F., Aumuller, G., Wilhelm, B., 2001, Identification and characterization of neutral endopeptidase (EC 3. 4. 24. 11) from human prostasomes-localization in prostatic tissue and cell lines.Prostate 46: 173–183.PubMedCrossRefGoogle Scholar
  111. Rettig, W.J., Garin-Chesa, P., Healey, J.H., Su, S.L., Ozer, H.L., Schwab, M., Albino, A.P., Old, L.J., 1993, Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin.Cancer Res. 53: 3327–3335.PubMedGoogle Scholar
  112. Riemann, D., Schwachula, A., Hentschel, M., Langner, J., 1993, Demonstration of CD13/aminopeptidase N on synovial fluid T cells from patients with different forms of joint effusions.Immunobiology, 187: 24–35.PubMedCrossRefGoogle Scholar
  113. Riemann, D., Göhring, B., Langner, J., 1994, Expression of aminopeptidase N/CD13 in tumour-infiltrating lymphocytes from human renal cell carcinoma. Immunol.Letters, 42: 19–23.CrossRefGoogle Scholar
  114. Riemann, D., Kehlen, A., Langner, J., 1999, CD13 - not just a marker in leukemia typing.Immunol. Today, 20: 83–88.PubMedCrossRefGoogle Scholar
  115. Riemann, D., Hansen, G.H., Niels-Christiansen, L.-L., Thorsen, E, Immerdal, L., Navarrete Santos, A., Kehlen, A:, Langer, J., Danielsen, M, 2001, Caveolae/lipid rafts in fibroblast-like synoviocytes: Ectopeptidase-rich membrane microdomains.Biochem. J. 354: 47–55PubMedCrossRefGoogle Scholar
  116. Robinson, P.J., 1991, Phosphatidylinositol membrane anchors and T-cell activation.Immunol. Today 12: 35–41.PubMedCrossRefGoogle Scholar
  117. Roettger, B.F., Rentsch, R.U., Pinon, D., Holicky, E., Hadac, E., Larkin, J.M., Miller, L.J., 1995, Dual pathways of internalization of the cholecystokinin receptor.J. Cell. Biol. 128: 1029–1041.PubMedCrossRefGoogle Scholar
  118. Rothberg, K.G., Ying, Y.S., Kamen, B.A., Anderson, R.G., 1990, Cholesterol controls the clustering of the glycophospholipid-anchored membrane receptor for 5-methyltetrahydrofolate. J. Cell. Biol. 111: 2931–2938.PubMedCrossRefGoogle Scholar
  119. Rothberg, K.G., Heuser, J.E., Donzell, W.C., Ying, Y.S., Glenney, J.R., Anderson, R.G.W., 1992, Caveolin, a protein component of caveolae membrane coats.Cell, 68: 673–682.PubMedCrossRefGoogle Scholar
  120. Sanderink, G.J., Artur, Y., Schiele, F., Gueguen, R., Siest, G., 1998, Alanine aminopeptidase in serum: biological variations and reference limits.Clin. Chem. 34: 1422–1426.Google Scholar
  121. Schlegel, A., Lisanti, M.P., 2001, The caveolin triad: caveolae biogenesis, cholesterol trafficking, and signal transduction.Cytokine Growth Factor Rev. 12: 41–51.CrossRefGoogle Scholar
  122. Schön, E., Mansfeld, H.W., Demuth, H.U., Barth, A., Ansorge, S., 1985, The dipeptidyl peptidase IV, a membrane enzyme involved in the proliferation of T lymphocytes.Biomed. Biochim. Acta 44: K9–15.PubMedGoogle Scholar
  123. Schön, E., Eichmann, E., Grunow, R., Jahn, S., Kiessig, S.T., Volk, H., Ansorge, S., 1986, Dipeptidyl peptidase IV in human T lymphocytes. An approach to the role of a membrane peptidase in the immune system.Biomed. Biochem. Acta 45: 1523–1528.Google Scholar
  124. Schrimpf, S.P., Hellman, U., Carlsson, L., Larsson, A., Ronquist, G., Nilsson, B.O., Identification of dipeptidyl peptidase IV as the antigen of a monoclonal anti-prostasome antibody.Prostate 38: 35-39.Google Scholar
  125. Sevinsky, J.R., Rao, L.V.M., Ruf, W., 1996, Ligand-induced protease receptor translocation into caveolae: A mechanism for regulating cell surface proteolysis of the tissue factordependent coagulation pathway.J. Cell. Biol. 133: 293–304.PubMedCrossRefGoogle Scholar
  126. Shipp, M.A., Tarr, G.E., Chen, C.Y., Switzer, S.N., Hersh, L.B., Stein, H., Sunday, M.E., Reinherz, E.L., 1991, CDlO/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung.Proc. Natl Acad. Sci. USA, 88: 10662–10666.PubMedCrossRefGoogle Scholar
  127. Shirotani, K., Tsubuki, S., Iwata, N., Takaki, Y., Harigaya, W., Maruyama, K., Kiryu-Seo, S., Kiyama, H., Iwata, H., Tomita, T., Iwatsubo, T., Saido, T.C., 2001, Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan-and phosphoramidon-sensitive endopeptidases.J. Biol. Chem. 276: 21895–21901.PubMedCrossRefGoogle Scholar
  128. Siegbahn, A., 2000, Cellular consequences upon factor Vila binding to tissue factor.Haemostasis 30 S2: 41–47.PubMedGoogle Scholar
  129. Simons, K., Ikonen, E., 1997, Functional rafts in cell membranes.Nature, 387: 569–572.PubMedCrossRefGoogle Scholar
  130. Simons, K., Toomre, D., 2000, Lipid rafts and signal transduction.Nat. Rev. Mol. Cell. Biol. 1: 31–39.PubMedCrossRefGoogle Scholar
  131. Söderberg, C., Giugni, T.D., Zaia, J.A., Larsson, S., Wahlberg, J.M., Möller, E., 1993, CD13 (human aminopeptidase N) mediates human cytomegalovirus infection.J. Virol. 67: 6576–6585.PubMedGoogle Scholar
  132. Sowa, G., Pypaert, M., Sessa, W.C., Distinction between signaling mechanisms in lipid rafts vs. caveolae.Proc. Natl. Acad. Sci. USA 98: 14072-14077.Google Scholar
  133. Stahl, A., Mueller, B.M., 1995, The urokinase-type plasminogen activator receptor, a GPI-linked protein, is localized in caveolae.J. Cell. Biol. 129: 335–344.PubMedCrossRefGoogle Scholar
  134. Stan, R.V., Roberts, W.G., Predescu, D., Ihida, K., Saucan, L., Ghitescu, L., Palade, G.E., 1997, Immunoisolation and partial characterization of endothelial plasmalemmal vesicles (caveolae).Mol. Biol. Cell 8: 595–605.PubMedGoogle Scholar
  135. Steeg, C., Hartwig, U., Fleischer, B., 1995, Unchanged signaling capacity of mutant CD26/dipeptidylpeptidase IV molecules devoid of enzymatic activity.Cell. Immunol. 164: 311–315.PubMedCrossRefGoogle Scholar
  136. Stefanova, I., Horejsi, V., Ansotegui, I.J., Knapp, W., Stockinger, H., 1991, GPI-anchored cell-surface molecules complexed to protein tyrosine kinases.Science 254: 1016–1019.PubMedCrossRefGoogle Scholar
  137. Strohmeier, G.R., Lencer, W.I., Patapoff, T.W., Thompson, L.F., Carlson, S.L., Moe, S.J., Carnes, D.K., Mrsny, R.J., Madara, J.L., 1997, Surface expression, polarization, and functional significance of CD73 in human intestinal epithelia.J. Clin. Invest. 99: 2588–2601.PubMedCrossRefGoogle Scholar
  138. Subramanyam, M., Gutheil, W.G., Bachovchin, W.W., Huber, B.T., 1993, Mechanism of HIV-1 Tat induced inhibition of antigen-specific T cell responsiveness.J. Immunol. 150: 2544–2553.PubMedGoogle Scholar
  139. Sumitomo, M., Shen, R., Walburg, M., Dai, J., Geng, Y., Navarro, D., Boileau, G., Papandreou, C.N., Giancotti, F.G., Knudsen, B., Nanus, D.M., 2000, Neutral endopeptidase inhibits prostate cancer cell migration by blocking focal adhesion kinase signaling.J. Clin. Invest. 106: 1399–1407.PubMedCrossRefGoogle Scholar
  140. Tanaka, T., Kameoka, J., Yaron, A., Schlossman, S.F., Morimoto, C., 1993, The costimulatory activity of the CD26 antigen requires dipeptidyl peptidase IV enzymatic activity.Proc. Natl. Acad. Sci. USA 90: 4586–4590.PubMedCrossRefGoogle Scholar
  141. Tanaka, T., Duke-Cohan, J.S., Kameoka, J., Yaron, A., Lee, I., Schlossman, S.F., Morimoto, C., 1994, Enhancement of antigen-induced T-cell proliferation by soluble CD26/dipeptidyl peptidase IV.Proc. Natl. Acad Sci. USA 91: 3082–3086.PubMedCrossRefGoogle Scholar
  142. Tani, K., Ogushi, F., Huang, L., Kawano, T., Tada, H., Hariguchi, N., Sone, S., 2000, CD13/aminopeptidase N, a novel chemoattractant for T lymphocytes in pulmonary sarcoidosis.Am. J. Respir. Crit. Care Med. 161: 1636–1642.PubMedGoogle Scholar
  143. Torimoto, Y., Dang, N.H., Vivier, E., Tanaka, T., Schlossman, S.F., Morimoto, C., 1991, Coassociation of CD26 (dipeptidyl peptidase IV) with CD45 on the surface of human T lymphocytes.J. Immunol. 147: 2514–2517.PubMedGoogle Scholar
  144. Turner, A.J., 1998, Membrane alanyl aminopeptidase. InHandbook of proteolytic enzymes(A. J. Barrett, N. D. Rawlings, and J. F. Woessner eds.), Academic Press, London, pp.996–1000.Google Scholar
  145. Turner, A.J., Isaac, R.E., Coates, D., 2001, The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function.Bioessays 23: 261–269.PubMedCrossRefGoogle Scholar
  146. Vlahos, C.J., Matter, W.F., Hui, K.Y., Brown, R.F., 1994, A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).J. Biol. Chem. 269: 5241–5248.PubMedGoogle Scholar
  147. Von Bonin, A., Huhn, J., Fleischer, B., 1998, Dipeptidyl-peptidase IV/CD26 on T cells: analysis of an alternative T-cell activation pathway.Immunol. Rev. 161:43–53.CrossRefGoogle Scholar
  148. Wasano, K., Hirakawa, Y., 1999, Two domains of rat galectin-4 bind to distinct structures of the intercellular borders of colorectal epithelia.J. Histochem. Cytochem. 41: 75–82.CrossRefGoogle Scholar
  149. Weber, M., Uguccioni, M., Baggiolini, M., Clark-Lewis, I., and Dahinden, C.A., 1996, Deletion of the NH2-terminal residue converts monocyte chemotactic protein 1 from an activator of basophil mediator release to an eosinophil chemoattractant.J. Exp. Med. 183: 681–5.PubMedCrossRefGoogle Scholar
  150. Wex, T., Lendeckel, U., Reinhold, D., Kahne, T., Arndt, M., Frank, K., Ansorge, S., 1997, Antisense-mediated inhibition of aminopeptidase N (CD13) markedly decreases growth rates of hematopoietic tumour cells.Adv. Exp. Med. Biol. 421: 67–73.PubMedGoogle Scholar
  151. Wrenger, S., Hoffmann, T., Faust, J., Mrestani-Klaus, C, Brandt, W., Neubert, K., Kraft, M., Olek, S., Frank, R., Ansorge, S., Reinhold, D., 1997, The N-terminal structure of HIV-1 Tat is required for suppression of CD26-dependent T cell growth.J. Biol. Chem. 272: 30283–30288.PubMedCrossRefGoogle Scholar
  152. Wrenger, S., Faust, J., Mrestani-Klaus, C., Fengler, A., Stockel-Maschek, A., Lorey, S., Kähne, T., Brandt, W., Neubert, K., Ansorge, S., Reinhold, D., 2000, Down-regulation of T cell activation following inhibition of dipeptidyl peptidase IV/CD26 by the N-terminal part of the thromboxane A2 receptor.J. Biol. Chem. 275: 22180–22186.PubMedGoogle Scholar
  153. Xavier, R., Brennan, T., Li, Q., McCormack, C, Seed, B., 1998, Membrane compartmentation is required for efficient T cell activation.Immunity 8: 723–732.PubMedCrossRefGoogle Scholar
  154. Xu, Y., Wellner, D., Scheinberg, D.A., 1995, Substance P and bradykinin are natural inhibitors of CD13/aminopeptidase N.Biochem. Biophys. Res. Commun. 208: 664–674.PubMedCrossRefGoogle Scholar
  155. Yeager, C.L., Ashmun, R.A., Williams, R.K., Cardellichio, C.B., Shapiro, L.H., Look, A.T., Holmes, K.V., 1992, Human aminopeptidase N is a receptor for human coronavirus 229E.Nature 357: 420–422.PubMedCrossRefGoogle Scholar
  156. Yurochko, A.D., Huang, E.S., 1999, Human cytomegalovirus binding to human monocytes induces immunoregulatory gene expression.J. Immunol. 162:4806–4816.PubMedGoogle Scholar
  157. Zachary, I., Rozengurt, E., 1992, Focal adhesion kinase (pl25FAK): a point of convergence in the action of neuropeptides, integrins, and oncogenes.Cell 71: 891–894.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Dagmar Riemann
    • 1
  • Tanja Blosz
    • 1
  • Jens Wulfänger
    • 2
  • Jürgen Langner
    • 1
  • Alexander Navarrete Santos
    • 2
  1. 1.Institute of Medical ImmunologyMartin-Luther-University Halle-WittenbergHalle/SaaleGermany
  2. 2.ACGT Pro Genomics AGHalle/SaaleGermany

Personalised recommendations