Reversible Inactivation of Human Dipeptidyl Peptidases 8 and 9 by Oxidation

Park, Joohong; Knott, Heather M.; Nadvi, Naveed A.; Collyer, Charles A.; Wang, Xin M.; Church, W. Bret; Gorrell, Mark D.

doi:10.2174/1874940200801010052

Cited by 43 publications

(61 citation statements)

References 43 publications

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“…We have shown that DPP9 enzyme activity is reversibly inactivated by oxidation (31). An oxidative cellular environment created under oxidative stress or production of reactive oxygen species during cellular metabolism, such as growth factor stimulation, inhibits the PI3K/Akt pathway through inactivation of PTEN, a PtdIns(3,4,5)P3 phosphatase that antagonizes PI3K function (34).…”

Section: Discussionmentioning

confidence: 99%

A Novel Role of Dipeptidyl Peptidase 9 in Epidermal Growth Factor Signaling

Yao

Kim

et al. 2011

Molecular Cancer Research

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Dipeptidyl peptidase IV (DPP4), DPP8, DPP9, and fibroblast activation protein (FAP), the four proteases of the DPP4 gene family, have unique peptidase and extra-enzymatic activities that have been implicated in various diseases including cancers. We report here a novel role of DPP9 in regulating cell survival and proliferation through modulating molecular signaling cascades. Akt (protein kinase B) activation was significantly inhibited by human DPP9 overexpression in human hepatoma cells (HepG2 and Huh7) and human embryonic kidney cells (HEK293T), whereas extracellular signal-regulated kinases (ERK1/2) activity was unaffected, revealing a pathwayspecific effect. Interestingly, the inhibitory effect of DPP9 on Akt pathway activation was growth factor dependent. DPP9 overexpression caused apoptosis and significantly less epidermal growth factor (EGF)-mediated Akt activation in HepG2 cells. However, such inhibitory effect was not observed in cells stimulated with other growth factors, including connective tissue growth factor, hepatic growth factor, insulin or platelet-derived growth factor-BB. The effect of DPP9 on Akt did not occur when DPP9 enzyme activity was ablated by either mutagenesis or inhibition. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a major downstream effector of Ras. We found that DPP9 and DPP8, but not DPP4 or FAP, associate with H-Ras, a key signal molecule of the EGF receptor signaling pathway. These findings suggest an important signaling role of DPP9 in the regulation of survival and proliferation pathways. Mol Cancer Res; 9(7); 948-59. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

A Novel Role of Dipeptidyl Peptidase 9 in Epidermal Growth Factor Signaling

Yao

Kim

et al. 2011

Molecular Cancer Research

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“…Extra-enzymatic functions of DPP8/DPP9 include cell adhesion, migration and apoptosis [57]. Interestingly, DPP8 and DPP9 are inactivated reversibly by H 2 O 2 oxidation involving two cysteines in each monomer [58]. To date, there are no crystal structures of DPP8 and DPP9 available.…”

Section: Dpp4 Gene Familymentioning

confidence: 99%

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

Wagner¹,

Klemann²,

Stephan

et al. 2016

Clinical and Experimental Immunology

100

107

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SummaryDipeptidyl peptidase (DPP) 4 (CD26, DPP4) is a multi-functional protein involved in T cell activation by co-stimulation via its association with adenosine deaminase (ADA), caveolin-1, CARMA-1, CD45, mannose-6-phosphate/insulin growth factor-II receptor (M6P/IGFII-R) and C-X-C motif receptor 4 (CXC-R4). The proline-specific dipeptidyl peptidase also modulates the bioactivity of several chemokines. However, a number of enzymes displaying either DPP4-like activities or representing structural homologues have been discovered in the past two decades and are referred to as DPP4 activity and/or structure homologue (DASH) proteins. Apart from DPP4, DASH proteins include fibroblast activation protein alpha (FAP), DPP8, DPP9, DPP4-like protein 1 (DPL1, DPP6, DPPX L, DPPX S), DPP4-like protein 2 (DPL2, DPP10) from the DPP4-gene family S9b and structurally unrelated enzyme DPP2, displaying DPP4-like activity. In contrast, DPP6 and DPP10 lack enzymatic DPP4-like activity. These DASH proteins play important roles in the immune system involving quiescence (DPP2), proliferation (DPP8/DPP9), antigen-presenting (DPP9), costimulation (DPP4), T cell activation (DPP4), signal transduction (DPP4, DPP8 and DPP9), differentiation (DPP4, DPP8) and tissue remodelling (DPP4, FAP). Thus, they are involved in many pathophysiological processes and have therefore been proposed for potential biomarkers or even drug targets in various cancers (DPP4 and FAP) and inflammatory diseases (DPP4, DPP8/DPP9). However, they also pose the challenge of drug selectivity concerning other DASH members for better efficacy and/or avoidance of unwanted side effects. Therefore, this review unravels the complex roles of DASH proteins in immunology.Keywords: antigen presentation/processing, CD26, co-stimulation, DPP4 activity and/or structure homologue proteins (DASH), signal transductionThe dipeptidyl peptidase (DPP)4 family of DPP4 activity and/or structure homologue (DASH) proteins Within the last two decades a number of enzymes have been discovered to also display DPP4-like activity or are structural homologues to DPP4. These enzymes/proteins are referred to as DPP4 activity and/or structure homologue (DASH) proteins, and can be grouped into the DPP4 gene family and non-related DPP4-like enzymes. Except for DPL1 and DPL2, all members display DPP4-like activity with neutral to basic pH optima and similar inhibition profiles [6,7]. DPP4 (CD26). DPP4 (CD26) is the best-known DASH protein and has been described in detail elsewhere [7][8][9].

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“…Mouse DPP8 and DPP9 enzymes have not been isolated for comparisons with their human counterparts in enzyme specificity and kinetics studies. Given that the crystal structures of DPP8 and DPP9 have not yet been solved, protein homology modeling has shown that DPP8 and DPP9 likely share a similar tertiary structure with DPPIV and FAP (32,33). DPP8 (34) and DPP9 (35) are dimeric, with each monomer likely consisting of an a/b-hydrolase domain and an 8 blade b-propeller domain and the active site of the peptidase locates at the interface of these 2 domains (Fig.…”

Section: Protein Modelmentioning

confidence: 99%

“…Therefore, it would be interesting to explore the consequences of SUMO1 interactions with DPP8 and DPP9. Furthermore, the activity of purified DPP9 from bovine testes (45) and recombinant DPP8 and DPP9 produced by insect cells (33) is dependent on the redox state of their cysteines, whereby enzyme activity is reversibly decreased by oxidation and increased by reduction (33).…”

Section: Dpp8 and Dpp9 Activity Regulationmentioning

confidence: 99%

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

Zhang

Chen

Keane

et al. 2013

Molecular Cancer Research

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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.

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Reversible Inactivation of Human Dipeptidyl Peptidases 8 and 9 by Oxidation

Cited by 43 publications

References 43 publications

A Novel Role of Dipeptidyl Peptidase 9 in Epidermal Growth Factor Signaling

A Novel Role of Dipeptidyl Peptidase 9 in Epidermal Growth Factor Signaling

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

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

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