DPP-4: A moonlighting protein

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DPP-4: A moonlighting protein Rahman Md. Asadur Research Fellow Dept. of Pharmacology Kagawa University

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DPP-4? DPP-4 is a multifunctional type II membrane glycoprotein 110-kDa ectoenzyme Belongs to the serine protease family

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1966 - as glycyl-prolyl-ß-naphthylamidase and later has been named dipeptidyl aminopeptidase IV 1970s - the enzyme served initially as a model protein for the study of the catalytic mechanism of serine peptidases 1980s - the potential of the enzyme to convert bioactive peptides in vitro was discovered, which intensified the search for its function in vivo. 1990s - numerous studies on the role of DPP IV in immune responses , particularly in T cell activation, signal transduction and T cell proliferation. History of DPP-4

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3D Structure of DPP-4 Wang XM et al. 2008, Front. Biosci, 13: 3168-3180

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Domain Structure of DPP-4 COOH NH 2

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Cellular localization of DPP-4

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Widely expressed in endothelial cells, epithelial cells, lymphoid and myeloid cells. Highest levels found in the kidneys Lower levels in: liver, pancreas, placenta, thymus, spleen, Expression of DPP-4

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DPP-4 in PTC of kidney Varona et al. BMC Cancer 2010 10:193

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Holger Fuchs et al,2009 Biopharm. Drug Dispos. 30: 229–240 Expression of DPP-4

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Soluble DPP-4 DPP-4 activity is detectable in serum, urine, seminal plasma and amniotic fluid The origin of soluble dpp-4 is not completely understood Inflammatory and malignant processes in tissues expressing high level in serum probably due to tissue disruption.

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CD 26 Multifunctional type II cell surface glycoprotein Widely expressed on T-cell, B cells and NK cells as well as on epithelial, endothelial and aciner cells of variety of tissues The function of CD 26 is identical with DPP-4

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H.-U. Demuth et al. 2005, Biochimica et Biophysica Acta 1751:33– 44 Physiological processes which are affected by DP IV activity SDF 1

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Catalytic function of DPP-4 H.-U. Demuth et al. 2005, Biochimica et Biophysica Acta 1751:33– 44

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Substartes of DPP-4 Martin Hildebrandt et al. 2000, Clinical Science, 99:93-104

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Potential Substartes of DPP-4 among bioactive peptides Martin Hildebrandt et al. 2000, Clinical Science, 99:93-104

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Substartes of DPP-4 in inflammatory response Martin Hildebrandt et al. 2000, Clinical Science, 99:93-104

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DPP-4 in in disease condition Martin Hildebrandt et al. 2000, Clinical Science, 99:93-104

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DPP-4 on glucose homeostasis

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Bona fide substrates that are hydrolyzed by DPP IV, including the chemokines CXCL12 (stromal cell-derived factor-1), CCL5 (RANTES), or substance P or neuropeptide Y and Inhibitory ligands that are not cleaved by DPP IV, such as the HIV Tat protein and synthetic inhibitors Ligands for CD26/DPP IV

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Role of DPP-4/CD26 on immune response Emil Boonacker,2003, European Journal of Cell Biology 82, 53 ± 73

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Function of DPP-4/CD26 on autoimmuniy Vera Preller ,2007, J Immunol, 178;4632-4640

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DPP-4 modulate fibrinolysis Mark D. GORREL,Clinical Science (2005) 108, 277-292

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Benefits of DPP-4 inhibition?

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Mark D. GORRELL ,2005, Clinical Science 108, 277–292 Metabolic benefits of DPP-4 inhibition

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Therapeutic Concept of CD26/DPP-IV Inhibition in cardioprotective effects Marc-Michael Zaruba et al., 2009, Cell Stem Cell 4, 313–323

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Jitendra Vaghasiya,Regulatory Peptides 166 (2011) 48–54 Effects of DPP-4 inhibitors on renal functions

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DPP-4 inhibitors attenuate kidney injury Wei Jing Liu, 2011, JPET Fast Forward.

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Effect of DPP-4 inhibitors on GBM thickness Wei Jing Liu, 2011, JPET Fast Forward.

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Effect of DPP-4 inhibitors on TGF- β1 Expression in kidney Wei Jing Liu, 2011, JPET Fast Forward.

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Summary DPP-4/CD26 is a multifunctional protein Inhibition of DPP-4 has some beneficial effects

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Future? Physiological role of DPP-4 in kidney?? Precise mechanism of the renoprotective effects of DPP-4 inhibitor in pathological condition?

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THANK YOU

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