Advertisement

The Multifunctional Post-proline Dipeptidyl Peptidase, DPP9, in Mice, Cell Biology and Immunity

  • Margaret G. Gall
  • Mark D. Gorrell
Chapter

Abstract

Dipeptidyl peptidase 9 (DPP9) is a ubiquitous intracellular post-proline protease of the DPP4 (S9b) family of atypical serine proteases. Emerging data support roles for DPP9 in intracellular signalling, particularly in the epidermal growth factor receptor pathway, in immune cells, particularly in macrophages and antigen processing, and in energy metabolism. The focus of this review is the roles of DPP9 in regulating physiological and cellular processes. Such data is derived from a genetically modified mouse strain and from manipulations of cell lines. The mouse strain that lacks DPP9 enzyme activity is homozygous lethal. DPP9 alters behaviours, such as cell adhesion, of cancer cell lines. This review points to the functional importance of DPP9 in immunity, metabolism and cancer.

Keywords

Dipeptidyl peptidase Mouse models Neonate development Fibroblast activation protein 

Abbreviations

AMC

Amino methylcoumarin

AMPK

AMP-activated protein kinase

B-CLL

B-cell chronic lymphocytic leukaemia

CAF

Cancer-associated fibroblasts

CXCL

CXC chemokine ligand

DEN

Diethylnitrosamine

DPP

Dipeptidyl peptidase

DSS

Dextran sulphate sodium

DTT

Dithiothreitol

ECM

Extracellular matrix

EGF

Epidermal growth factor

EGFR

Epidermal growth factor receptor

EMT

Epithelial–mesenchymal transition

ESFT

Ewing sarcoma family of tumours

FAP

Fibroblast activation protein

FGF

Fibroblast growth factor

HCC

Hepatocellular carcinoma

HFD

High fat diet

HSC

Hepatic stellate cells

IRS

Insulin receptor substrate

IκBα

Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha

MMP

Matrix metalloproteinase

NEM

N-ethylmaleimide

NPY

Neuropeptide Y

PARP

Poly(ADP-ribose) polymerase

PGC-1α

PPAR coactivator-1α

PBMC

Peripheral blood mononuclear cells

pNA

P-nitroaniline

POP

Prolyl oligopeptidase

PPAR

Peroxisome proliferator-activated receptor

SUMO

Small ubiquitin-like modifier

TAA

Thioacetamide

TAM

Tumour-associated macrophages

TGF

Transforming growth factor

TNF-α

Tumour necrosis factor α

VEGF-A

Vascular endothelial growth factor-A

WT

Wild-type

Notes

Acknowledgements

This work was supported by National Health and Medical Research Council of Australia Project Grants 512282 and 1113842 (MDG), and a Sydney Medical School Foundation/Francis M. Hooper Scholarship for Medical Research through the University of Sydney (MGG).

References

  1. 1.
    Rawlings ND, Barrett AJ, Finn R (2016) Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 44:D343–D350PubMedCrossRefGoogle Scholar
  2. 2.
    Gorrell MD, Yu DMT (2005) Diverse functions in a conserved structure: the dipeptidyl peptidase IV gene family. In: Robinson JW (ed) Trends in protein research. Nova Science Publishers Inc, New York, pp 1–78Google Scholar
  3. 3.
    Abbott CA, Yu DMT, McCaughan GW, Gorrell MD (2000) Post proline peptidases having DP IV like enzyme activity. Adv Exp Med Biol 477:103–109PubMedCrossRefGoogle Scholar
  4. 4.
    Ajami K, Abbott CA, McCaughan GW, Gorrell MD (2004) Dipeptidyl peptidase 9 has two forms, a broad tissue distribution, cytoplasmic localization and DPIV-like peptidase activity. BBA—Gene Struct Expr 1679:18–28CrossRefGoogle Scholar
  5. 5.
    Qi SY, Riviere PJ, Trojnar J, Junien JL, Akinsanya KO (2003) Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases. Biochem J 373:179–189PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Cunningham DF, O’Connor B (1997) Proline specific peptidases. Biochim Biophys Acta 1343:160–186PubMedCrossRefGoogle Scholar
  7. 7.
    Aertgeerts K, Levin I, Shi L, Snell GP, Jennings A, Prasad GS, Zhang Y et al (2005) Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein α. J Biol Chem 280:19441–19444PubMedCrossRefGoogle Scholar
  8. 8.
    Kim J, Nadal MS, Clemens AM, Baron M, Jung S-C, Misumi Y, Rudy B et al (2008) Kv4 accessory protein DPPX (DPP6) is a critical regulator of membrane excitability in hippocampal CA1 pyramidal neurons. J Neurophysiol 100:1835–1847PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Wada K, Yokotani N, Hunter C, Doi K, Wenthold RJ, Shimasaki S (1992) Differential expression of two distinct forms of mRNA encoding members of a dipeptidyl aminopeptidase family. Proc Natl Acad Sci USA 89:197–201CrossRefGoogle Scholar
  10. 10.
    Chen T, Ajami K, McCaughan GW, Gai W-P, Gorrell MD, Abbott CA (2005) Molecular characterization of a novel dipeptidyl peptidase like 2 short form (DPL2-s) that is highly expressed in the brain and lacks dipeptidyl peptidase activity. Biochim Biophys Acta 1764:33–43PubMedCrossRefGoogle Scholar
  11. 11.
    Kirby MS, Yu DMT, O’Connor SP, Gorrell MD (2010) Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. Clin Sci 118:31–41CrossRefGoogle Scholar
  12. 12.
    Durinx C, Lambeir AM, Bosmans E, Falmagne JB, Berghmans R, Haemers A, Scharpé S et al (2000) Molecular characterization of dipeptidyl peptidase activity in serum—Soluble CD26/dipeptidyl peptidase IV is responsible for the release of X-Pro dipeptides. Eur J Biochem 267:5608–5613PubMedCrossRefGoogle Scholar
  13. 13.
    Ogata S, Misumi Y, Tsuji E, Takami N, Oda K, Ikehara Y (1992) Identification of the active site residues in dipeptidyl peptidase IV by affinity labeling and site-directed mutagenesis. Biochemistry 31:2582–2587PubMedCrossRefGoogle Scholar
  14. 14.
    Harstad EB, Rosenblum JS, Gorrell MD, Achanzar WE, Minimo L, Wu J, Rosini-Marthaler L et al (2013) DPP8 and DPP9 expression in cynomolgus monkey and sprague dawley rat tissues. Regul Pept 186:26–35PubMedCrossRefGoogle Scholar
  15. 15.
    Gorrell MD, Gysbers V, McCaughan GW (2001) CD26: a multifunctional integral membrane and secreted protein of activated lymphocytes. Scand J Immunol 54:249–264PubMedCrossRefGoogle Scholar
  16. 16.
    Keane FM, Chowdhury S, Yao T-W, Nadvi NA, Gall MG, Chen Y, Osborne B et al (2012) Targeting dipeptidyl peptidase-4 (DPP-4) and fibroblast activation protein (FAP) for diabetes and cancer therapy. In: Dunn B (ed) Proteinases as drug targets. Royal Society of Chemistry, Cambridge, UK, pp 119–145Google Scholar
  17. 17.
    Gorrell MD, Wickson J, McCaughan GW (1991) Expression of the rat CD26 Antigen (dipeptidyl peptidase IV) on subpopulations of rat lymphocytes. Cell Immunol 134:205–215PubMedCrossRefGoogle Scholar
  18. 18.
    Keane FM, Yao T-W, Seelk S, Gall MG, Chowdhury S, Poplawski SE, Lai JH et al (2014) Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs. FEBS Open Bio 4:43–54CrossRefGoogle Scholar
  19. 19.
    Yu DMT, Yao T-W, Chowdhury S, Nadvi NA, Osborne B, Church WB, McCaughan GW et al (2010) The dipeptidyl peptidase IV family in cancer and cell biology. FEBS J 277:1126–1144PubMedCrossRefGoogle Scholar
  20. 20.
    Gorrell MD (2005) Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci 108:277–292PubMedCrossRefGoogle Scholar
  21. 21.
    Tinoco AD, Tagore DM, Saghatelian A (2010) Expanding the dipeptidyl peptidase 4-regulated peptidome via an optimized peptidomics platform. J Am Chem Soc 132:3819–3830PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Waumans Y, Baerts L, Kehoe K, Lambeir A-M, De Meester I (2015) The dipeptidyl peptidase family, prolyl oligopeptidase and prolyl carboxypeptidase in the immune system and inflammatory disease, including atherosclerosis. Front Immunol 6:387–405PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Mentlein R, Gallwitz B, Schmidt WE (1993) Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 214:829–835PubMedCrossRefGoogle Scholar
  24. 24.
    Bengsch B, Seigel B, Flecken T, Wolanski J, Blum HE, Thimme R (2012) Human Th17 cells express high levels of enzymatically active dipeptidyl peptidase IV (CD26). J Immunol 188:5438–5447PubMedCrossRefGoogle Scholar
  25. 25.
    Garin-Chesa P, Old LJ, Rettig WJ (1990) Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA 87:7235–7239PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kelly T, Huang Y, Simms AE, Mazur A (2012) Fibroblast activation protein-alpha: a key modulator of the microenvironment in multiple pathologies. In: Kwang WJ, (ed) International Review of Cell and Molecular Biology, vol 297. Academic Press, 83–116Google Scholar
  27. 27.
    Niedermeyer J, Garin-Chesa P, Kriz M, Hilberg F, Mueller E, Bamberger U, Rettig WJ et al (2001) Expression of the fibroblast activation protein during mouse embryo development. Int J Dev Biol 45:445–447PubMedGoogle Scholar
  28. 28.
    Levy MT, McCaughan GW, Abbott CA, Park JE, Cunningham AM, Muller E, Rettig WJ et al (1999) Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis. Hepatology 29:1768–1778PubMedCrossRefGoogle Scholar
  29. 29.
    Levy MT, McCaughan GW, Marinos G, Gorrell MD (2002) Intrahepatic expression of the hepatic stellate cell marker fibroblast activation protein correlates with the degree of fibrosis in hepatitis C virus infection. Liver Internat 22:93–101CrossRefGoogle Scholar
  30. 30.
    Wang XM, Yu DMT, McCaughan GW, Gorrell MD (2005) Fibroblast activation protein increases apoptosis, cell adhesion and migration by the LX-2 human stellate cell line. Hepatology 42:935–945PubMedCrossRefGoogle Scholar
  31. 31.
    Lee KN, Jackson KW, Christiansen VJ, Lee CS, Chun JG, McKee PA (2006) Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein. Blood 107:1397–1404PubMedCrossRefGoogle Scholar
  32. 32.
    Collins PJ, McMahon G, O’Brien P, O’Connor B (2004) Purification, identification and characterisation of seprase from bovine serum. Int J Biochem Cell Biol 36:2320–2333PubMedCrossRefGoogle Scholar
  33. 33.
    Keane FM, Nadvi NA, Yao T-W, Gorrell MD (2011) Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α. FEBS J 278:1316–1332PubMedCrossRefGoogle Scholar
  34. 34.
    Wong PF, Gall MG, Bachovchin WW, McCaughan GW, Keane FM, Gorrell MD (2016) Neuropeptide Y is a physiological substrate of fibroblast activation protein: enzyme kinetics in blood plasma and expression of Y2R and Y5R in human liver cirrhosis and hepatocellular carcinoma. Peptides 75:80–95PubMedCrossRefGoogle Scholar
  35. 35.
    Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ (1999) Fibroblast activation protein: a dual-specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem 274:36505–36512PubMedCrossRefGoogle Scholar
  36. 36.
    Sulda ML, Abbott CA, Macardle PJ, Hall RK, Kuss BJ (2010) Expression and prognostic assessment of dipeptidyl peptidase IV and related enzymes in B-cell chronic lymphocytic leukemia. Cancer Biol Ther 10:180–189PubMedCrossRefGoogle Scholar
  37. 37.
    Hamson EJ, Keane FM, Tholen S, Schilling O, Gorrell MD (2014) Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. Proteomics Clin Appl 8:454–463PubMedCrossRefGoogle Scholar
  38. 38.
    Henderson JM, Zhang HE, Polak N, Gorrell MD (2016) Hepatocellular carcinoma: mouse models and the potential roles of proteases. Cancer Lett (In press)Google Scholar
  39. 39.
    Abbott CA, Gorrell MD (2002) The family of CD26/DPIV and related ectopeptidases. In: Langner J, Ansorge S (eds) Ectopeptidases: CD13/aminopeptidase N and CD26/dipeptidyl peptidase IV in medicine and biology. Kluwer/Plenum, NY, pp 171–195CrossRefGoogle Scholar
  40. 40.
    Ren X, Hayashi Y, Yoshimura N, Takimoto K (2005) Transmembrane interaction mediates complex formation between peptidase homologues and Kv4 channels. Mol Cell Neurosci 29:320–332PubMedCrossRefGoogle Scholar
  41. 41.
    Cronin S, Berger S, Ding J, Schymick JC, Washecka N, Hernandez DG, Greenway MJ et al (2008) A genome-wide association study of sporadic ALS in a homogenous Irish population. Hum Mol Genet 17:768–774PubMedCrossRefGoogle Scholar
  42. 42.
    Abbott CA, Yu DMT, Woollatt E, Sutherland GR, McCaughan GW, Gorrell MD (2000) Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8. Eur J Biochem 267:6140–6150PubMedCrossRefGoogle Scholar
  43. 43.
    Olsen C, Wagtmann N (2002) Identification and characterization of human Dpp9, a novel homologue of dipeptidyl peptidase IV. Gene 299:185–193PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang H, Chen Y, Keane FM, Gorrell MD (2013) Advances in understanding the expression and function of dipeptidyl peptidase 8 and 9. Mol Cancer Res 11:1487–1496PubMedCrossRefGoogle Scholar
  45. 45.
    Park J, Knott HM, Nadvi NA, Collyer CA, Wang XM, Church WB, Gorrell MD (2008) Reversible inactivation of human dipeptidyl peptidases 8 and 9 by oxidation. TOEIJ 1:52–61CrossRefGoogle Scholar
  46. 46.
    Rummey C, Metz G (2007) Homology models of dipeptidyl peptidases 8 and 9 with a focus on loop predictions near the active site. Proteins 66:160–171PubMedCrossRefGoogle Scholar
  47. 47.
    Pitman MR, Menz RI, Abbott CA (2010) Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DPP8). Biol Chem 391:959–972PubMedCrossRefGoogle Scholar
  48. 48.
    Tang H-K, Tang H-Y, Hsu SC, Chu JR, Chien CH, Shu CH, Chen X (2009) Biochemical properties and expression profile of human prolyl dipeptidase DPP9. Arch Biochem Biophys 485:120–127PubMedCrossRefGoogle Scholar
  49. 49.
    Zhu H, Zhou ZM, Lu L, Xu M, Wang H, Li JM, Sha JH (2005) Expression of a novel dipeptidyl peptidase 8 (DPP8) transcript variant, DPP8-v3, in human testis. Asian J Androl 7:245–255PubMedCrossRefGoogle Scholar
  50. 50.
    Abbott C, Gorrell M (2013) Dipeptidyl peptidase 8. In: Rawlings NL, Salvesen G (eds) Handbook of proteolytic enzymes, 3rd edn. Elsevier, San Diego, pp 3379–3384CrossRefGoogle Scholar
  51. 51.
    Justa-Schuch D, Möller U, Geiss-Friedlander R (2014) The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus. Cell Mol Life Sci 71:3611–3626PubMedCrossRefGoogle Scholar
  52. 52.
    Gall MG, Chen Y, Ribeiro AJVd, Zhang H, Bailey CG, Spielman D, Yu DM et al (2013) Targeted inactivation of Dipeptidyl peptidase 9 enzyme activity causes mouse neonate lethality. PLoS ONE 8:e0078378Google Scholar
  53. 53.
    Wagner L, Hoffmann T, Rahfeld JU, Demuth HU (2006) Distribution of dipeptidyl peptidase IV-like activity enzymes in canine and porcine tissue sections by RT-PCR. Adv Exp Med Biol 575:109–116PubMedCrossRefGoogle Scholar
  54. 54.
    Ansorge S, Bank U, Heimburg A, Helmuth M, Koch G, Tadje J, Lendeckel U et al (2009) Recent insights into the role of dipeptidyl aminopeptidase IV (DPIV) and aminopeptidase N (APN) families in immune functions. Clin Chem Lab Med 47:253–261PubMedCrossRefGoogle Scholar
  55. 55.
    Dubois V, Ginneken CV, De Cock H, Lambeir A-M, Van der Veken P, Augustyns K, Chen X et al (2009) Enzyme activity and immunohistochemical localization of dipeptidyl peptidase 8 and 9 in male reproductive tissues. J Histochem Cytochem 57:531–541PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Yu DMT, Ajami K, Gall MG, Park J, Lee CS, Evans KA, McLaughlin EA et al (2009) The in vivo expression of dipeptidyl peptidases 8 and 9. J Histochem Cytochem 57:1025–1040PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Dubois V, Lambeir A-M, Vandamme S, Matheeussen V, Guisez Y, Scharpé S, De Meester I (2010) Dipeptidyl peptidase 9 (DPP9) from bovine testes: identification and characterization as the short form by mass spectrometry. BBA Proteins Proteomics 1804:781–788PubMedCrossRefGoogle Scholar
  58. 58.
    Stremenova J, Krepela E, Mares V, Trim J, Dbaly V, Marek J, Vanickova Z et al (2007) Expression and enzymatic activity of dipeptidyl peptidase-IV in human astrocytic tumours are associated with tumour grade. Int J Oncol 31:785–792PubMedGoogle Scholar
  59. 59.
    Schade J, Stephan M, Schmiedl A, Wagner L, Niestroj AJ, Demuth HU, Frerker N et al (2008) Regulation of expression and function of dipeptidyl peptidase 4 (DP4), DP8/9, and DP10 in allergic responses of the lung in rats. J Histochem Cytochem 56:147–155PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Matheeussen V, Baerts L, De Meyer G, De Keulenaer G, Van Der Veken P, Augustyns K, Dubois V et al (2011) Expression and spatial heterogeneity of dipeptidyl peptidases in endothelial cells of conduct vessels and capillaries. Biol Chem 392:189–198PubMedCrossRefGoogle Scholar
  61. 61.
    Stremenova J, Mares V, Lisa V, Hilser M, Krepela E, Vanickova Z, Syrucek M et al (2010) Expression of dipeptidyl peptidase-IV activity and/or structure homologs in human meningiomas. Int J Oncol 36:351–358PubMedGoogle Scholar
  62. 62.
    Yao T-W, Kim W-S, Yu DM, Sharbeen G, McCaughan GW, Choi K-Y, Xia P et al (2011) A novel role of Dipeptidyl peptidase 9 in epidermal growth factor signaling. Mol Cancer Res 9:948–959PubMedCrossRefGoogle Scholar
  63. 63.
    Chowdhury S, Chen Y, Yao T-W, Ajami K, Wang XM, Popov Y, Schuppan D et al (2013) Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver. World J Gastroenterol 19:2883–2893PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Waumans Y, Vliegen G, Maes L, Rombouts M, Declerck K, Veken PVD, Berghe WV et al (2016) The dipeptidyl peptidases 4, 8, and 9 in mouse monocytes and macrophages: DPP8/9 inhibition attenuates M1 macrophage activation in mice. Inflammation 39:413–424PubMedCrossRefGoogle Scholar
  65. 65.
    Maes M-B, Dubois V, Brandt I, Lambeir A-M, Van der Veken P, Augustyns K, Cheng JD et al (2007) Dipeptidyl peptidase 8/9-like activity in human leukocytes. J Leukoc Biol 81:1252–1257PubMedCrossRefGoogle Scholar
  66. 66.
    Wilson C, Abbott C (2012) Expression profiling of dipeptidyl peptidase 8 and 9 in breast and ovarian carcinoma cell lines. Int J Oncol 41:919–932PubMedCrossRefGoogle Scholar
  67. 67.
    Bjelke JR, Christensen J, Nielsen PF, Branner S, Kanstrup AB, Wagtmann N, Rasmussen HB (2006) Dipeptidyl peptidase 8 and 9 specificity and molecular characterization compared to dipeptidyl peptidase IV. Biochem J 396:391–399PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Lee HJ, Chen YS, Chou CY, Chien CH, Lin CH, Chang GG, Chen X (2006) Investigation of the dimer interface and substrate specificity of prolyl dipeptidase DPP8. J Biol Chem 281:38653–38662PubMedCrossRefGoogle Scholar
  69. 69.
    Geiss-Friedlander R, Parmentier N, Moeller U, Urlaub H, Van den Eynde BJ, Melchior F (2009) The cytoplasmic peptidase DPP9 Is rate-limiting for degradation of proline-containing peptides. J Biol Chem 284:27211–27219PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Pilla E, Möller U, Sauer G, Mattiroli F, Melchior F, Geiss-Friedlander R (2012) A novel SUMO1-specific interacting motif in Dipeptidyl peptidase 9 (DPP9) that is important for enzymatic regulation. J Biol Chem 287:44320–44329PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Pilla E, Kilisch M, Lenz C, Urlaub H, Geiss-Friedlander R (2013) The SUMO1-E67 interacting loop peptide is an allosteric inhibitor of the dipeptidyl peptidases 8 and 9. J Biol Chem 288:32787–32796PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Wilson CH, Indarto D, Doucet A, Pogson LD, Pitman MR, Menz RI, McNicholas K et al (2013) Identifying natural substrates for dipeptidyl peptidase 8 (DP8) and DP9 using terminal amine isotopic labelling of substrates, TAILS, reveals in vivo roles in cellular homeostasis and energy metabolism. J Biol Chem 288:13936–13949PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Zhang H, Maqsudi S, Rainczuk A, Duffield N, Lawrence J, Keane FM, Justa-Schuch D et al (2015) Identification of novel dipeptidyl peptidase 9 substrates by two-dimensional differential in-gel electrophoresis. FEBS J 282:3737–3757PubMedCrossRefGoogle Scholar
  74. 74.
    Ajami K, Pitman MR, Wilson CH, Park J, Menz RI, Starr AE, Cox JH et al (2008) Stromal cell-derived factors 1 alpha and 1 beta, inflammatory protein-10 and interferon-inducible T cell chemo-attractant are novel substrates of dipeptidyl peptidase 8. FEBS Lett 582:819–825PubMedCrossRefGoogle Scholar
  75. 75.
    Mentlein R (1999) Dipeptidyl-peptidase IV (CD26): role in the inactivation of regulatory peptides. Regul Pept 85:9–24PubMedCrossRefGoogle Scholar
  76. 76.
    Frerker N, Wagner L, Wolf R, Heiser U, Hoffmann T, Rahfeld J-U, Schade J et al (2007) Neuropeptide Y (NPY) cleaving enzymes: structural and functional homologues of dipeptidyl peptidase 4. Peptides 28:257–268PubMedCrossRefGoogle Scholar
  77. 77.
    Lu C, Tilan JU, Everhart L, Czarnecka M, Soldin SJ, Mendu DR, Jeha D et al (2011) Dipeptidyl peptidases as survival factors in ewing sarcoma family of tumors: implications for tumor biology and therapy. J Biol Chem 286:27494–27505PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Yu DMT, Wang XM, McCaughan GW, Gorrell MD (2006) Extra-enzymatic functions of the dipeptidyl peptidase (DP) IV related proteins DP8 and DP9 in cell adhesion, migration and apoptosis. FEBS J 273:2447–2461PubMedCrossRefGoogle Scholar
  79. 79.
    Zhang H, Chen Y, Wadham C, McCaughan GW, Keane FM, Gorrell MD (2015) Dipeptidyl peptidase 9 subcellular localization and a role in cell adhesion involving focal adhesion kinase and paxillin. BBA Mol Cell Res 1853:470–480Google Scholar
  80. 80.
    Lankas G, Leiting B, Roy R, Eiermann G, Beconi M, Biftu T, Chan C et al (2005) Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes—Potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 54:2988–2994PubMedCrossRefGoogle Scholar
  81. 81.
    Wu J-J, Tang H-K, Yeh T-K, Chen C-M, Shy H-S, Chu Y-R, Chien C-H et al (2009) Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor. Biochem Pharmacol 78:203–210PubMedCrossRefGoogle Scholar
  82. 82.
    Jiaang WT, Chen YS, Hsu T, Wu SH, Chien CH, Chang CN, Chang SP et al (2005) Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8. Bioorg Med Chem Lett 15:687–691PubMedCrossRefGoogle Scholar
  83. 83.
    Van der Veken P, De Meester I, Dubois V, Soroka A, Van Goethem S, Maes MB, Brandt I et al (2008) Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9. part 1: identification of dipeptide derived leads. Bioorg Med Chem Lett 18:4154–4158PubMedCrossRefGoogle Scholar
  84. 84.
    Van Goethem S, Matheeussen V, Joossens J, Lambeir AM, Chen X, De Meester I, Haemers A et al (2011) Structure-activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9): is DPP8-selectivity an attainable goal? J Med Chem 54:5737–5746PubMedCrossRefGoogle Scholar
  85. 85.
    Wu W, Liu Y, Milo LJ Jr, Shu Y, Zhao P, Li Y, Woznica I et al (2012) 4-Substituted boro-proline dipeptides: Synthesis, characterization, and dipeptidyl peptidase IV, 8, and 9 activities. Bioorg Med Chem Lett 22:5536–5540PubMedCrossRefGoogle Scholar
  86. 86.
    Van der Veken P, Soroka A, Brandt I, Chen YS, Maes MB, Lambeir AM, Chen X et al (2007) Irreversible inhibition of dipeptidyl peptidase 8 by dipeptide-derived diaryl phosphonates. J Med Chem 50:5568–5570PubMedCrossRefGoogle Scholar
  87. 87.
    Burkey BF, Hoffmann PK, Hassiepen U, Trappe J, Juedes M, Foley JE (2008) Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited. Diabetes Obes Metab 10:1057–1061PubMedCrossRefGoogle Scholar
  88. 88.
    Ohnuma K, Ishii T, Iwata S, Hosono O, Kawasaki H, Uchiyama M, Tanaka H et al (2002) G1/S cell cycle arrest provoked in human T cells by antibody to CD26. Immunology 107:325–333PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Ho L, Aytac U, Stephens LC, Ohnuma K, Mills GB, McKee KS, Neumann C et al (2001) In vitro and in vivo antitumor effect of the anti-CD26 monoclonal antibody 1F7 on human CD30 + anaplastic large cell T-cell lymphoma Karpas 299. Clin Cancer Res 7:2031–2040PubMedGoogle Scholar
  90. 90.
    Inamoto T, Yamochi T, Ohnuma K, Iwata S, Kina S, Inamoto S, Tachibana M et al (2006) Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear cell carcinoma Caki-2 is associated with retinoblastoma substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27kip1 enhancement, and disruption of binding to the extracellular matrix. Clin Cancer Res 12:3470–3477PubMedCrossRefGoogle Scholar
  91. 91.
    Wrenger S, Hoffmann T, Faust J, Mrestaniklaus C, Brandt W, Neubert K, Kraft M et al (1997) The N-Terminal structure of HIV-1 tat is required for suppression of CD26-dependent T cell growth. J Biol Chem 272:30283–30288PubMedCrossRefGoogle Scholar
  92. 92.
    Bank U, Heimburg A, Wohlfarth A, Koch G, Nordhoff K, Julius H, Helmuth M et al (2011) Outside or inside: role of the subcellular localization of DP4-like enzymes for substrate conversion and inhibitor effects. Biol Chem 392:169–187PubMedCrossRefGoogle Scholar
  93. 93.
    Matheeussen V, Waumans Y, Martinet W, Van Goethem S, Van der Veken P, Scharpe S, Augustyns K et al (2013) Dipeptidyl peptidases in atherosclerosis: expression and role in macrophage differentiation, activation and apoptosis. Basic Res Cardiol 108:350PubMedCrossRefGoogle Scholar
  94. 94.
    Bühling F, Kunz D, Reinhold D, Ulmer AJ, Ernst M, Flad HD, Ansorge S (1994) Expression and functional role of dipeptidyl peptidase IV (CD26) on human natural killer cells. Nat Immun 13:270–279PubMedGoogle Scholar
  95. 95.
    Madueno JA, Munoz E, Blazquez V, Gonzalez 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 37:425–429PubMedCrossRefGoogle Scholar
  96. 96.
    Shingu K, Helfritz A, Zielinska-Skowronek M, Meyer-Olson D, Jacobs R, Schmidt RE, Mentlein R et al (2003) CD26 expression determines lung metastasis in mutant F344 rats: involvement of NK cell function and soluble CD26. Cancer Immunol Immunother 52:546–554PubMedCrossRefGoogle Scholar
  97. 97.
    Reinhold D, Goihl A, Wrenger S, Reinhold A, Kühlmann UC, Faust J, Neubert K et al (2009) Role of dipeptidyl peptidase IV (DPIV)-like enzymes in T lymphocyte activation: investigations in DPIV/CD26 knockout mice. Clin Chem Lab Med 47:268–274PubMedCrossRefGoogle Scholar
  98. 98.
    Milner JM, Kevorkian L, Young DA, Jones D, Wait R, Donell ST, Barksby E et al (2006) Fibroblast activation protein alpha is expressed by chondrocytes following a pro-inflammatory stimulus and is elevated in osteoarthritis. Arthritis Res Ther 8:R23PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Thielitz A, Vetter RW, Schultze B, Wrenger S, Simeoni L, Ansorge S, Neubert K et al (2008) Inhibitors of dipeptidyl peptidase IV-like activity mediate antifibrotic effects in normal and keloid-derived skin fibroblasts. J Invest Dermatol 128:855–866PubMedCrossRefGoogle Scholar
  100. 100.
    Spagnuolo PA, Hurren R, Gronda M, Maclean N, Datti A, Basheer A, Lin FH et al (2013) Inhibition of intracellular dipeptidyl peptidases 8 and 9 enhances parthenolide’s anti-leukemic activity. Leukemia 27:1236–1244PubMedCrossRefGoogle Scholar
  101. 101.
    Baird S, Rigopoulos A, Cao D, Allan L, Renner C, Scott F, Scott A (2015) Integral membrane protease fibroblast activation protein sensitizes fibrosarcoma to chemotherapy and alters cell death mechanisms. Apoptosis 20:1483–1498PubMedCrossRefGoogle Scholar
  102. 102.
    Kurokawa Y, Matoba R, Takemasa I, Nakamori S, Tsujie M, Nagano H, Dono K et al (2003) Molecular features of non-B, non-C hepatocellular carcinoma: a PCR-array gene expression profiling study. J Hepatol 39:1004–1012PubMedCrossRefGoogle Scholar
  103. 103.
    Yazbeck R, Sulda ML, Howarth GS, Bleich A, Raber K, von Hörsten S, Holst JJ et al (2010) Dipeptidyl peptidase expression during experimental colitis in mice. Inflamm Bowel Dis 16:1340–1351PubMedCrossRefGoogle Scholar
  104. 104.
    Milner JM, Patel A, Rowan AD (2008) Emerging role of serine proteinases in tissue turnover in arthritis. Arthritis Rheum 58:3644–3656PubMedCrossRefGoogle Scholar
  105. 105.
    Röhnert P, Schmidt W, Emmerlich P, Goihl A, Wrenger S, Bank U, Nordhoff K et al (2012) Dipeptidyl peptidase IV, aminopeptidase N and DPIV/APN-like proteases in cerebral ischemia. J Neuroinflammation 9:44PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Matsubara J, Sugiyama S, Sugamura K, Nakamura T, Fujiwara Y, Akiyama E, Kurokawa H et al (2012) A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. J Am Coll Cardiol 59:265–276PubMedCrossRefGoogle Scholar
  107. 107.
    Fingerlin TE, Murphy E, Zhang W, Peljto AL, Brown KK, Steele MP, Loyd JE et al (2013) Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet 45:613–620PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Marguet D, Baggio L, Kobayashi T, Bernard AM, Pierres M, Nielsen PF, Ribel U et al (2000) Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci USA 97:6874–6879PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Niedermeyer J, Kriz M, Hilberg F, Garin-Chesa P, Bamberger U, Lenter MC, Park J et al (2000) Targeted disruption of mouse fibroblast activation protein. Mol Cell Biol 20:1089–1094PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Chen Y, Gall MG, Zhang H, Keane FM, McCaughan GW, Yu DM, Gorrell MD (2016) Dipeptidyl peptidase 9 enzymatic activity influences the expression of neonatal metabolic genes. Exp Cell Res 342:72–82PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Centenary Institute and Sydney Medical SchoolUniversity of SydneySydneyAustralia

Personalised recommendations