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Gene Review

DPP4  -  dipeptidyl-peptidase 4

Homo sapiens

Synonyms: ADABP, ADCP-2, ADCP2, Adenosine deaminase complexing protein 2, CD26, ...
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Disease relevance of DPP4


Psychiatry related information on DPP4


High impact information on DPP4

  • Experiments to identify cell determinants involved in HIV-1 tropism revealed a specific decrease in the expression of the T-cell activation antigen CD26 after monocytotropic (M-tropic) but not T-cell line-tropic (T-tropic) virus infection of the PM1 T-cell line [9].
  • ADA was coexpressed with CD26 on the Jurkat T cell lines, and an in vitro binding assay showed that the binding was through the extracellular domain of CD26 [10].
  • Entry of HIV-1 or HIV-2 into T lymphoblastoid and monocytoid cell lines was inhibited by a specific monoclonal antibody against DPP IV or specific peptide inhibitors of this protease [11].
  • Coexpression of human CD4 and CD26 in murine NIH 3T3 cells rendered them permissive to infection by HIV-1 and HIV-2 [11].
  • Highly underexpressed genes include CD26, Stat-4, and the IL-1 receptors [12].

Chemical compound and disease context of DPP4


Biological context of DPP4

  • Recent studies showed a linkage between DPP4 and down-regulation of certain chemokines and mitogenic growth factors, and degradation of denatured collagens (gelatin), suggesting a role of DPP4 in the cell invasive phenotype [18].
  • Importantly, monoclonal antibodies against the gelatin-binding domain of DPP4 blocked the local gelatin degradation by endothelial cells in the presence of the major metallo- and serine protease systems that modified pericellular collagenous matrices and subsequent cell migration and invasion [18].
  • DPP8 and DPP9 share an identical active site with DPP4 (Gly-Trp-Ser-Tyr-Gly) [19].
  • Isolation of a cDNA probe for the human intestinal dipeptidylpeptidase IV and assignment of the gene locus DPP4 to chromosome 2 [20].
  • These results support the view that downregulation of DPPIV is an important early event in the pathogenesis of melanoma [1].

Anatomical context of DPP4


Associations of DPP4 with chemical compounds


Physical interactions of DPP4

  • Human ADA binds to CD26 on the surface 1-LN cells and immobilized CD26 isolated from the same cells with similar affinity [27].
  • CD26/DPP IV-truncated eotaxin(3-74) showed reduced chemotactic activity for eosinophils and impaired binding and signaling properties through the CC chemokine receptor 3 [23].
  • Moreover, we show that CD26 directly binds to the cytoplasmic domain of CD45 [28].
  • In previous studies we demonstrated that the Pg 2 O-linked carbohydrate chain is essential for its binding to CD26 on 1-LN cells [29].
  • Inability of T cells to express CD25 and CD26 in cocultures with H-RS cells or a plate-bound CD30 chimeric protein is in accordance with the results of immunohistochemistry on disease-involved tissues [30].

Enzymatic interactions of DPP4


Co-localisations of DPP4


Regulatory relationships of DPP4

  • Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells [21].
  • CD26 is expressed on the surface of human prostate cancer 1-LN cells acting as a receptor for plasminogen (Pg) [27].
  • Thus, CD26/DPP IV differently regulates the chemotactic and antiviral potencies of eotaxin by the removal of two NH2-terminal residues [23].
  • DPP-IV inactivates the glucagon-like peptide (GLP-1) and several other naturally produced bioactive peptides that contain preferentially a proline or alanine residue in the second amino acid sequence position by cleaving the N-terminal dipeptide [37].
  • Binding by six anti-DPPIV antibodies that inhibited ADA binding was found to require Leu340 to Arg343 and Thr440/Lys441 but not the 214 residues C-terminal to Ser552 [38].

Other interactions of DPP4


Analytical, diagnostic and therapeutic context of DPP4


  1. A role for dipeptidyl peptidase IV in suppressing the malignant phenotype of melanocytic cells. Wesley, U.V., Albino, A.P., Tiwari, S., Houghton, A.N. J. Exp. Med. (1999) [Pubmed]
  2. CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1. Ohnuma, K., Yamochi, T., Uchiyama, M., Nishibashi, K., Yoshikawa, N., Shimizu, N., Iwata, S., Tanaka, H., Dang, N.H., Morimoto, C. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  3. Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties. Proost, P., Schutyser, E., Menten, P., Struyf, S., Wuyts, A., Opdenakker, G., Detheux, M., Parmentier, M., Durinx, C., Lambeir, A.M., Neyts, J., Liekens, S., Maudgal, P.C., Billiau, A., Van Damme, J. Blood (2001) [Pubmed]
  4. Adenosine down-regulates the surface expression of dipeptidyl peptidase IV on HT-29 human colorectal carcinoma cells: implications for cancer cell behavior. Tan, E.Y., Mujoomdar, M., Blay, J. Am. J. Pathol. (2004) [Pubmed]
  5. Lowered serum dipeptidyl peptidase IV activity is associated with depressive symptoms and cytokine production in cancer patients receiving interleukin-2-based immunotherapy. Maes, M., Capuron, L., Ravaud, A., Gualde, N., Bosmans, E., Egyed, B., Dantzer, R., Neveu, P.J. Neuropsychopharmacology (2001) [Pubmed]
  6. Alterations in expression and in serum activity of dipeptidyl peptidase IV (DPP IV, CD26) in patients with hyporectic eating disorders. Hildebrandt, M., Rose, M., Mayr, C., Schüler, C., Reutter, W., Salama, A., Klapp, B.F. Scand. J. Immunol. (1999) [Pubmed]
  7. Therapeutic assessment of glucagon-like peptide-1 agonists compared with dipeptidyl peptidase IV inhibitors as potential antidiabetic drugs. Mentlein, R. Expert opinion on investigational drugs. (2005) [Pubmed]
  8. The prolyl oligopeptidase family. Polgár, L. Cell. Mol. Life Sci. (2002) [Pubmed]
  9. CD26 expression correlates with entry, replication and cytopathicity of monocytotropic HIV-1 strains in a T-cell line. Oravecz, T., Roderiquez, G., Koffi, J., Wang, J., Ditto, M., Bou-Habib, D.C., Lusso, P., Norcross, M.A. Nat. Med. (1995) [Pubmed]
  10. Direct association of adenosine deaminase with a T cell activation antigen, CD26. Kameoka, J., Tanaka, T., Nojima, Y., Schlossman, S.F., Morimoto, C. Science (1993) [Pubmed]
  11. T cell activation antigen, CD26, as a cofactor for entry of HIV in CD4+ cells. Callebaut, C., Krust, B., Jacotot, E., Hovanessian, A.G. Science (1993) [Pubmed]
  12. Classification and prediction of survival in patients with the leukemic phase of cutaneous T cell lymphoma. Kari, L., Loboda, A., Nebozhyn, M., Rook, A.H., Vonderheid, E.C., Nichols, C., Virok, D., Chang, C., Horng, W.H., Johnston, J., Wysocka, M., Showe, M.K., Showe, L.C. J. Exp. Med. (2003) [Pubmed]
  13. Catalytic properties and inhibition of proline-specific dipeptidyl peptidases II, IV and VII. Leiting, B., Pryor, K.D., Wu, J.K., Marsilio, F., Patel, R.A., Craik, C.S., Ellman, J.A., Cummings, R.T., Thornberry, N.A. Biochem. J. (2003) [Pubmed]
  14. Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway. Tan, E.Y., Richard, C.L., Zhang, H., Hoskin, D.W., Blay, J. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  15. Renal tubular damage: an extraintestinal manifestation of chronic inflammatory bowel disease. Kreisel, W., Wolf, L.M., Grotz, W., Grieshaber, M. European journal of gastroenterology & hepatology. (1996) [Pubmed]
  16. Adenosine deaminase binding to human CD26 is inhibited by HIV-1 envelope glycoprotein gp120 and viral particles. Valenzuela, A., Blanco, J., Callebaut, C., Jacotot, E., Lluis, C., Hovanessian, A.G., Franco, R. J. Immunol. (1997) [Pubmed]
  17. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Herman, G.A., Stevens, C., Van Dyck, K., Bergman, A., Yi, B., De Smet, M., Snyder, K., Hilliard, D., Tanen, M., Tanaka, W., Wang, A.Q., Zeng, W., Musson, D., Winchell, G., Davies, M.J., Ramael, S., Gottesdiener, K.M., Wagner, J.A. Clin. Pharmacol. Ther. (2005) [Pubmed]
  18. The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices. Ghersi, G., Zhao, Q., Salamone, M., Yeh, Y., Zucker, S., Chen, W.T. Cancer Res. (2006) [Pubmed]
  19. Cloning and characterization of dipeptidyl peptidase 10, a new member of an emerging subgroup of serine proteases. Qi, S.Y., Riviere, P.J., Trojnar, J., Junien, J.L., Akinsanya, K.O. Biochem. J. (2003) [Pubmed]
  20. Isolation of a cDNA probe for the human intestinal dipeptidylpeptidase IV and assignment of the gene locus DPP4 to chromosome 2. Darmoul, D., Lacasa, M., Chantret, I., Swallow, D.M., Trugnan, G. Ann. Hum. Genet. (1990) [Pubmed]
  21. Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. Christopherson, K.W., Hangoc, G., Broxmeyer, H.E. J. Immunol. (2002) [Pubmed]
  22. The structure and function of CD26 in the T-cell immune response. Morimoto, C., Schlossman, S.F. Immunol. Rev. (1998) [Pubmed]
  23. CD26/dipeptidyl-peptidase IV down-regulates the eosinophil chemotactic potency, but not the anti-HIV activity of human eotaxin by affecting its interaction with CC chemokine receptor 3. Struyf, S., Proost, P., Schols, D., De Clercq, E., Opdenakker, G., Lenaerts, J.P., Detheux, M., Parmentier, M., De Meester, I., Scharpé, S., Van Damme, J. J. Immunol. (1999) [Pubmed]
  24. Identification of the 170-kDa melanoma membrane-bound gelatinase (seprase) as a serine integral membrane protease. Piñeiro-Sánchez, M.L., Goldstein, L.A., Dodt, J., Howard, L., Yeh, Y., Tran, H., Argraves, W.S., Chen, W.T. J. Biol. Chem. (1997) [Pubmed]
  25. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin. Herman, G.A., Stein, P.P., Thornberry, N.A., Wagner, J.A. Clin. Pharmacol. Ther. (2007) [Pubmed]
  26. Treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes. D'Alessio, D.A., Denney, A.M., Hermiller, L.M., Prigeon, R.L., Martin, J.M., Tharp, W.G., Saylan, M.L., He, Y., Dunning, B.E., Foley, J.E., Pratley, R.E. J. Clin. Endocrinol. Metab. (2009) [Pubmed]
  27. Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1-LN human prostate cancer cells. Gonzalez-Gronow, M., Hershfield, M.S., Arredondo-Vega, F.X., Pizzo, S.V. J. Biol. Chem. (2004) [Pubmed]
  28. CD26-mediated signaling for T cell activation occurs in lipid rafts through its association with CD45RO. Ishii, T., Ohnuma, K., Murakami, A., Takasawa, N., Kobayashi, S., Dang, N.H., Schlossman, S.F., Morimoto, C. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  29. Tissue factor is the receptor for plasminogen type 1 on 1-LN human prostate cancer cells. Gonzalez-Gronow, M., Gawdi, G., Pizzo, S.V. Blood (2002) [Pubmed]
  30. CD30 is involved in inhibition of T-cell proliferation by Hodgkin's Reed-Sternberg cells. Su, C.C., Chiu, H.H., Chang, C.C., Chen, J.C., Hsu, S.M. Cancer Res. (2004) [Pubmed]
  31. Structural and kinetic analysis of the substrate specificity of human fibroblast activation protein alpha. Aertgeerts, K., Levin, I., Shi, L., Snell, G.P., Jennings, A., Prasad, G.S., Zhang, Y., Kraus, M.L., Salakian, S., Sridhar, V., Wijnands, R., Tennant, M.G. J. Biol. Chem. (2005) [Pubmed]
  32. Heparan sulfate/heparin oligosaccharides protect stromal cell-derived factor-1 (SDF-1)/CXCL12 against proteolysis induced by CD26/dipeptidyl peptidase IV. Sadir, R., Imberty, A., Baleux, F., Lortat-Jacob, H. J. Biol. Chem. (2004) [Pubmed]
  33. Inhibition of dipeptidylpeptidase IV activity as a therapyof Type 2 diabetes. Green, B.D., Flatt, P.R., Bailey, C.J. Expert opinion on emerging drugs. (2006) [Pubmed]
  34. Inhibition of dipeptidyl peptidase IV (DP IV) by anti-DP IV antibodies and non-substrate X-X-Pro- oligopeptides ascertained by capillary electrophoresis. Hoffmann, T., Reinhold, D., Kähne, T., Faust, J., Neubert, K., Frank, R., Ansorge, S. Journal of chromatography. A. (1995) [Pubmed]
  35. CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse. Pacheco, R., Martinez-Navio, J.M., Lejeune, M., Climent, N., Oliva, H., Gatell, J.M., Gallart, T., Mallol, J., Lluis, C., Franco, R. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  36. Critical role of dipeptidyl peptidase IV in neuropeptide Y-mediated endothelial cell migration in response to wounding. Ghersi, G., Chen, W., Lee, E.W., Zukowska, Z. Peptides (2001) [Pubmed]
  37. Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors. Longenecker, K.L., Stewart, K.D., Madar, D.J., Jakob, C.G., Fry, E.H., Wilk, S., Lin, C.W., Ballaron, S.J., Stashko, M.A., Lubben, T.H., Yong, H., Pireh, D., Pei, Z., Basha, F., Wiedeman, P.E., von Geldern, T.W., Trevillyan, J.M., Stoll, V.S. Biochemistry (2006) [Pubmed]
  38. Binding to human dipeptidyl peptidase IV by adenosine deaminase and antibodies that inhibit ligand binding involves overlapping, discontinuous sites on a predicted beta propeller domain. Abbott, C.A., McCaughan, G.W., Levy, M.T., Church, W.B., Gorrell, M.D. Eur. J. Biochem. (1999) [Pubmed]
  39. Biological significance of aminopeptidase N/CD13 in thyroid carcinomas. Kehlen, A., Lendeckel, U., Dralle, H., Langner, J., Hoang-Vu, C. Cancer Res. (2003) [Pubmed]
  40. Vesicular localization and characterization of a novel post-proline-cleaving aminodipeptidase, quiescent cell proline dipeptidase. Chiravuri, M., Agarraberes, F., Mathieu, S.L., Lee, H., Huber, B.T. J. Immunol. (2000) [Pubmed]
  41. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Lankas, G.R., Leiting, B., Roy, R.S., Eiermann, G.J., Beconi, M.G., Biftu, T., Chan, C.C., Edmondson, S., Feeney, W.P., He, H., Ippolito, D.E., Kim, D., Lyons, K.A., Ok, H.O., Patel, R.A., Petrov, A.N., Pryor, K.A., Qian, X., Reigle, L., Woods, A., Wu, J.K., Zaller, D., Zhang, X., Zhu, L., Weber, A.E., Thornberry, N.A. Diabetes (2005) [Pubmed]
  42. Lung endothelial dipeptidyl peptidase IV promotes adhesion and metastasis of rat breast cancer cells via tumor cell surface-associated fibronectin. Cheng, H.C., Abdel-Ghany, M., Elble, R.C., Pauli, B.U. J. Biol. Chem. (1998) [Pubmed]
  43. Regional localization of DPP4 (alias CD26 and ADCP2) to chromosome 2q24. Darmoul, D., Fox, M., Harvey, C., Jeggo, P., Gum, J.R., Kim, Y.S., Swallow, D.M. Somat. Cell Mol. Genet. (1994) [Pubmed]
  44. Clustered charged amino acids of human adenosine deaminase comprise a functional epitope for binding the adenosine deaminase complexing protein CD26/dipeptidyl peptidase IV. Richard, E., Alam, S.M., Arredondo-Vega, F.X., Patel, D.D., Hershfield, M.S. J. Biol. Chem. (2002) [Pubmed]
  45. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Lambeir, A.M., Durinx, C., Scharpé, S., De Meester, I. Critical reviews in clinical laboratory sciences. (2003) [Pubmed]
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