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Advances in Understanding the Expression and Function of Dipeptidyl Peptidase 8 and 9

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Advances in Understanding the Expression and Function of Dipeptidyl Peptidase 8 and 9 Published OnlineFirst September 13, 2013; DOI: 10.1158/1541-7786.MCR-13-0272 Molecular Cancer Review Research Advances in Understanding the Expression and Function of Dipeptidyl Peptidase 8 and 9 Hui Zhang, Yiqian Chen, Fiona M. Keane, and Mark D. Gorrell Abstract DPP8 and DPP9 are recently identified members of the dipeptidyl peptidase IV (DPPIV) enzyme family, which is characterized by the rare ability to cleave a post-proline bond two residues from the N-terminus of a substrate. DPP8 and DPP9 have unique cellular localization patterns, are ubiquitously expressed in tissues and cell lines, and evidence suggests important contributions to various biological processes including: cell behavior, cancer biology, disease pathogenesis, and immune responses. Importantly, functional differences between these two proteins have emerged, such as DPP8 may be more associated with gut inflammation whereas DPP9 is involved in antigen presentation and intracellular signaling. Similarly, the DPP9 connections with H-Ras and SUMO1, and its role in AKT1 pathway downregulation provide essential insights into the molecular mechanisms of DPP9 action. The recent discovery of novel natural substrates of DPP8 and DPP9 highlights the potential role of these proteases in energy metabolism and homeostasis. This review focuses on the recent progress made with these post-proline dipeptidyl peptidases and underscores their emerging importance. Mol Cancer Res; 11(12); 1487–96. Ó2013 AACR. Introduction metabolic processes of obesity and diabetes, the immune – Proteases are efficient processing molecules involved in the system, and cancer biology (7,12 15). Structurally related to physiological maintenance of all cells. They can no longer DPPIV and with overlapping proteolytic activity, DPP8 and simply be thought of as essential for protein degradation and DPP9 remain less understood but are gaining increasing recycling; they are also vital regulators and signaling mole- research attention to decipher their unique proteolytic roles. cules (1). They control all aspects of cellular life by modifying To identify and characterize DPP8 and DPP9, both their targets to alter location and function. In doing so, they proteases were cloned, sequenced, and discovered to display have crucial roles in both normal and pathological processes considerable sequence homology with DPPIV and thus also and are thus important targets for drug treatment. likely structural similarity (2,3). DPP8 and DPP9, however have a different cellular localization to that of DPPIV, as well One such target is the ubiquitous serine protease, dipep- fi tidyl peptidase IV (DPPIV), with inhibitors of this enzyme as some differences in their expression pro le and are now in clinical use to treat type 2 diabetes. DPPIV and therefore likely to have distinct roles. In the past, treatment with a broad DPP family inhibitor produced functional related enzymes are members of the S9b protease subfamily, fl with a conserved catalytic triad of serine, aspartate, and changes in diabetes, the immune system, the in ammatory histidine (2,3) and a rare ability to cleave a post-proline response, and cancer biology (13,16,17). Although these bond 3 residues from the N-terminus of a substrate (2, 4–7). effects were attributed to DPPIV at the time, it is now DPPIV rapidly cleaves and inactivates insulinotropic hor- thought that inhibition of DPP8 and DPP9 contributed to the above outcomes. With more selective DPP8/9 inhibitors mones (incretins) and thus inhibitors of this enzyme are the – basis for the treatment of type 2 diabetes (8,9). Other being developed (18 20), there is now an opportunity to members of this family include DPP8, DPP9, and fibroblast delineate the roles of these enzymes and further explore the therapeutic potential of their chemical inhibitors. The search activation protein (FAP), which are of interest in cancer fi research. FAP is generally expressed at low levels in normal for DPP8- and DPP9-speci c substrates is ongoing, with the adult tissue but is greatly upregulated in diseased and challenge remaining to determine those that are most phys- iologically relevant. Although DPPIV has been reviewed at remodeling tissue as well as in tumors (10,11). Indeed, both fi FAP and DPPIV are multifunctional and have roles in length, few authors have focused speci cally on DPP8 and DPP9. Here we outline the molecular and biochemical characteristics of DPP8 and DPP9 so as to gain a compre- Authors' Affiliation: Molecular Hepatology, Centenary Institute and hensive understanding of these post-proline dipeptidyl pep- Sydney Medical School, University of Sydney, NSW, Australia tidases (Fig. 1). Corresponding Author: Mark D. Gorrell, Molecular Hepatology, Centenary Institute, Locked Bag No. 6, Newtown, NSW 2042, Australia. Phone: 61-2- 95656156; Fax: 61-2-95656101; E-mail: [email protected] Structural Properties of DPP8 and DPP9 doi: 10.1158/1541-7786.MCR-13-0272 Initial identification and cloning of DPP8 was established Ó2013 American Association for Cancer Research. by Abbott and colleagues (2). DPP9 was then identified by www.aacrjournals.org 1487 Downloaded from mcr.aacrjournals.org on September 30, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst September 13, 2013; DOI: 10.1158/1541-7786.MCR-13-0272 Zhang et al. Proliferation Apoptosis ECM interaction adhesion EGF migration Akt Cell behavior Immune Lung organs Spleen Thymus Immunology Inflammation Figure 1. Overview of organs and Lymphocyte processes in which DPP8 and Colitis DPP9 have potential functions, along with molecules that interact with these proteases. DPP8 DPP9 H-Ras H-Ras Tumor Tumor Alcoholic liver disease Liver biology cell lines Liver fibrosis disease Chronic Biliary cirrhosis Testicular lymphocytic tumors leukemia BLAST search and sequence alignment with DPP8. With Gene Properties growing interest in these novel homologues of DPPIV, DPP8 and DPP9 have been localized by fluorescence in several research groups have cloned DPP8 and DPP9 situ hybridization to human chromosome 15q22 and (3,21–23). Comparisons of the main physical attributes 19p13.3, respectively (2,3). A variety of diseases have of DPPIV, FAP, DPP8, and DPP9 are summarized been mapped to these loci, such as pulmonary fibrosis in Table 1. (27), ovarian adenocarcinomas (28), and Bardet–Biedl Table 1. Comparative overviews of the 4 enzyme members of the DPPIV family Attribute DPPIV FAP DPP8 short DPP8-v3 long DPP9 short DPP9 longa Synonyms CD26 Seprase DPRP1 DPRP2 GenBank accession M74777 U09278 AF221634 AF354202 AY374518 AF542510 References (24) (4,25,26) (2) (21) (3,23) (23) Gene location Human 2q24.3 2q23 15q22.32 19q13.3 Mouse 2:62330073 2:62500945 9:65032458 17:56186682 Number of exons 26 26 20 22 19 22 Gene size (kb) 81.8 72.8 71 ? 47.3 48.6 mRNA (bp) 2924 2814 3127 3030 2592 3006 Number of amino 766 760 882 898 863 971 acids Monomer mobility 110 kDa 95 kDa 100 kDa 103 kDa 95–110 kDa ? Dimer HH HH Transmembrane HH ÂÂ domain Catalytic triad Ser630-Asp708-His740 Ser624-Asp702-His734 Ser739-Asp817-His849 Ser730-Asp808-His840 Enzyme activity Dipeptidyl peptidase Dipeptidyl peptidase Dipeptidyl peptidase Dipeptidyl peptidase and endopeptidase Cellular localization Cell surface and Cell surface and Intracellular Intracellular soluble soluble H, yes; Â, no; ?, not known. aThe long form is a splice variant. 1488 Mol Cancer Res; 11(12) December 2013 Molecular Cancer Research Downloaded from mcr.aacrjournals.org on September 30, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst September 13, 2013; DOI: 10.1158/1541-7786.MCR-13-0272 Dipeptidyl Peptidases 8 and 9 syndrome type 4, which has the clinical manifestation of obesity (29). Thus, DPP8 and DPP9 are potentially associated with the pathogenesis of such diseases, but an underlying mechanism has not been elucidated. Adoles- cent idiopathic scoliosis maps to 19p13.3, but it is not associated with DPP9 (30). The human DPP4 gene spans 81.8 kb and contains 26 exons ranging in size from 45 to 1,386 bp (31). In contrast, the human DPP9 gene spans only 48.6 kb of genomic sequence and comprises 22 exons that are 53 to 1431 bp in length (23). The human DPP8 gene spans 71 kb and consists of 20 exons (2). The sequence around the active-site serine is encoded by a single exon in DPP8 and DPP9, but the homologous region in DPP4 and FAP is encoded by 2 exons (3,31), which suggests that DPP8 and DPP9 are the more ancient genes of the 4. Protein Model Protein structure is crucial for substrate binding and specificity, as well as for interacting with binding partners. The primary structure of human DPP8 contains 882 amino acids with 27% identity and 51% amino acid similarity to human DPPIV (2). Two forms of DPP9 have been cloned. A ubiquitously expressed transcript encoding 863 amino acids (short form) displays 26% identity and 47% similarity to Figure 2. A model of DPP9 protein structure. DPP9 residues 51 to 863 are fi depicted in ribbon representation of the monomer. The a/b-hydrolase human DPPIV (23). The most signi cant homology is domain is in red and the 8-blade b-propeller domain in green. The observed between human DPP8 and DPP9 (61% identity catalytic triad (Ser-Asp-His) is shown as blue spheres and the 2 and 79% similarity at the amino acid level; ref. 23). The glutamates essential for catalysis as yellow spheres. An extended arm amino acid sequences of both proteins are highly homolo- (285VEVIHVPSPALEERKTDSYR304) in the propeller surface of DPP9 that gous between human and mouse, with human DPP9 having is critical in SUMO1–DPP9 interaction is colored pink. 92% identity and 95% similarity to mouse DPP9 and human DPP8 having 95% identity and 98% similarity to single-point mutations in the C-terminal loop, such as mouse DPP8 (3,23). Mouse DPP8 and DPP9 enzymes have F822A, V833A, Y844A, and H859A in DPP8 (34), or not been isolated for comparisons with their human counter- F842A in DPP9 (40) inactivate these proteases without parts in enzyme specificity and kinetics studies.
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