{"gene":"DPP4","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1993,"finding":"DPP4 (CD26) enzymatically hydrolyzes GIP, GLP-1(7-36)amide, and peptide histidine methionine by removing N-terminal dipeptides (His-Ala or Tyr-Ala), inactivating these incretin hormones; DPP4-specific inhibitors (diprotin A, Lys-pyrrolidide) completely abolished serum degradation of GIP and GLP-1, establishing DPP4 as the principal serine exopeptidase responsible for incretin inactivation in human serum.","method":"In vitro enzymatic assay with purified DPP4 from human placenta; kinetic analysis (Km, Vmax); serum incubation with DPP4-specific inhibitors; fragment identification","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with purified enzyme, kinetic characterization, inhibitor confirmation, replicated in serum","pmids":["8100523"],"is_preprint":false},{"year":1993,"finding":"CD26 (DPP4) directly associates with adenosine deaminase (ADA) on the T cell surface through its extracellular domain; co-immunoprecipitation and in vitro binding assays demonstrated that the 43-kDa protein co-purifying with CD26 is ADA, establishing CD26 as the lymphocyte surface receptor for ADA.","method":"Immunoprecipitation, amino acid sequence analysis, in vitro binding assay with recombinant extracellular domain","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical binding assay with sequence confirmation, foundational study with >400 citations","pmids":["8101391"],"is_preprint":false},{"year":1997,"finding":"The extracellular portion of human DPP4 (starting at Gly-31) forms a homodimer and contains at least two independently folding domains: one stabilized by disulfide bonds (not required for catalytic activity or ADA binding) and one containing the active site; FTIR spectrometry showed ~45% beta-sheet content, and low-angle X-ray scattering supported a three-domain structure per subunit with flexible linker regions.","method":"Biochemical purification from seminal plasma, FTIR spectrometry, low-angle X-ray scattering, unfolding experiments under reducing conditions","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 — multiple biophysical methods but single lab, no mutagenesis functional validation","pmids":["9252108"],"is_preprint":false},{"year":1998,"finding":"CD26 delivers a co-stimulatory T cell activation signal through the CD3 pathway; epitope mapping using truncated and swap mutants localized T-cell costimulation activity to the 248–358 and 359–449 amino acid regions, and the ADA-binding domain to the 359–449 region, demonstrating functionally distinct domains within the extracellular portion of CD26.","method":"Truncated and human-rat CD26 swap mutants, cross-blocking with 13 anti-CD26 mAbs, DPP4 enzymatic activity as functional readout","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping by systematic mutagenesis/swap approach, single lab","pmids":["9683260"],"is_preprint":false},{"year":2001,"finding":"CD26 physically co-distributes and co-immunoprecipitates with CXCR4 on T and B cell membranes; upon SDF-1α stimulation, CD26 is co-internalized with CXCR4 in a CXCR4 internalization-dependent manner (blocked by CXCR4 internalization mutants but not pertussis toxin), indicating a functional CD26/CXCR4 complex in which CD26 can modulate SDF-1α-induced chemotaxis. Additionally, HIV-1 gp120 interacts with CD26 and disrupts the ADA/CD26 interaction through a site distinct from the ADA-binding domain.","method":"Co-immunoprecipitation from membrane fractions, co-internalization experiments with CXCR4 mutants, pertussis toxin treatment, flow cytometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple orthogonal approaches (internalization mutants, pharmacological blockade), replicated across T and B cell lines","pmids":["11278278"],"is_preprint":false},{"year":2002,"finding":"Cell-surface ADA-CD26 interaction mediates adhesion of T lymphocytes to epithelial cells; CD26 overexpression increased T-cell adhesion to Caco-2 epithelial monolayers by ~50%, whereas anti-CD26 antibody targeting the ADA-binding site or exogenous ADA reduced adhesion by 50–70%. This adhesion was mediated by LFA-1 (lymphocyte function-associated antigen) integrin activation.","method":"Cell adhesion assays with CD26-overexpressing T cell lines, antibody blocking, FACS integrin activation assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays, genetic overexpression plus antibody blocking, single lab","pmids":["11772392"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of the extracellular region of human DPP4 at 2.5 Å (in complex with the inhibitor valine-pyrrolidide) revealed two domains: an eight-bladed β-propeller and an α/β-hydrolase domain; the catalytic site is located in a large cavity between these two domains, and both domains participate in inhibitor/substrate binding, explaining how substrate specificity (N-terminal dipeptides with penultimate Pro or Ala) is achieved.","method":"X-ray crystallography at 2.5 Å resolution, inhibitor complex","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with substrate analog, high resolution, foundational structural study","pmids":["12483204"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of native porcine DPP4 at 1.8 Å revealed a 2-2-2 symmetric tetrameric assembly dependent on glycosylation of β-propeller blade IV, and identified a Glu-Glu motif as a key substrate-recognition element (distinguishing DPP4 as an aminopeptidase) and an oxyanion trap that activates the P2-carbonyl oxygen for efficient post-proline cleavage. Structure also suggested dual routes for substrate access (β-propeller tunnel) and product exit (side opening).","method":"X-ray crystallography at 1.8 Å of native glycosylated porcine DPP4; dipeptide inhibitor complex","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — high-resolution structure of native glycosylated enzyme with inhibitor complex revealing catalytic mechanism","pmids":["12690074"],"is_preprint":false},{"year":2003,"finding":"Cryo-TEM and single-particle analysis of rat DPP4/CD26 at ~14 Å resolution confirmed that the protein exists as a dimer and revealed a second lateral opening to the active site distinct from the β-propeller tunnel, suggesting that substrate selectivity and binding rate mechanisms differ from the structurally related serine peptidase POP.","method":"Cryo-TEM, single particle analysis, structural comparison by docking calculations","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 — 3D structure by cryo-TEM, single lab, limited resolution (~14 Å)","pmids":["12705886"],"is_preprint":false},{"year":2003,"finding":"CD26 mediates G-CSF-induced mobilization of hematopoietic stem/progenitor cells (HSCs/HPCs) by cleaving CXCL12 at its position-2 proline; CD26-truncated CXCL12(3-68) failed to induce migration of Sca-1+c-kit+lin- cells and acted as an antagonist to intact CXCL12. CD26 inhibition during G-CSF treatment reduced peripheral progenitor cell numbers, demonstrating a mechanistic role in mobilization.","method":"Flow cytometry for CD26 expression, in vitro chemotaxis assays with truncated CXCL12, CD26 inhibitor treatment, in vivo G-CSF mobilization model in mice","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — in vitro functional assays with mechanistic dissection (truncated substrate as antagonist) plus in vivo confirmation","pmids":["12576320"],"is_preprint":false},{"year":2004,"finding":"Endogenous CD26 expression on donor hematopoietic stem cells negatively regulates homing and bone marrow engraftment; pharmacological inhibition or genetic deletion of CD26 greatly increased transplantation efficiency in mice, demonstrating that CD26 peptidase activity (by cleaving CXCL12/SDF-1) limits HSC homing.","method":"CD26 inhibitor treatment and CD26 knockout mouse bone marrow transplantation experiments; engraftment quantification","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — pharmacological inhibition plus genetic knockout with defined engraftment phenotype, replicated across approaches","pmids":["15310902"],"is_preprint":false},{"year":2000,"finding":"DPPIV expression in melanoma cells inhibits cellular invasion: stable transfection of full-length DPPIV cDNA reduced Matrigel invasion by >75% compared to parental or vector-transfected cells. Neither the extracellular serine protease activity nor the 6-amino-acid cytoplasmic domain was required for anti-invasive activity, as mutants lacking either function retained the phenotype.","method":"Stable transfection of DPPIV cDNA and active-site/cytoplasmic-domain mutants into melanoma cell lines; Matrigel invasion assays","journal":"Clinical & experimental metastasis","confidence":"High","confidence_rationale":"Tier 2 — domain mutagenesis combined with functional invasion assay, multiple mutants tested","pmids":["11467771"],"is_preprint":false},{"year":2006,"finding":"CD26 binds to caveolin-1 on antigen-presenting cells (APCs) through residues 201–211 of CD26 together with the serine catalytic site at residue 630; this interaction triggers caveolin-1 phosphorylation and NF-κB activation in APCs, leading to CD86 upregulation and subsequent antigen-specific T cell activation. Reduced caveolin-1 expression on APCs abolished CD26-mediated CD86 upregulation and T cell proliferation.","method":"Recombinant CD26 binding assays, caveolin-1 siRNA knockdown, NF-κB activation assay, CD86 upregulation measurement, T cell proliferation assay, immunohistochemistry of rheumatoid synovium","journal":"Modern rheumatology","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple functional readouts (phosphorylation, NF-κB, CD86, proliferation) and domain identification, single lab","pmids":["16622717"],"is_preprint":false},{"year":2013,"finding":"DPP4 (CD26) is identified as the functional receptor for MERS-CoV (hCoV-EMC); the receptor-binding S1 domain of the MERS-CoV spike protein specifically co-purified with DPP4 from susceptible Huh-7 cell lysates. Anti-DPP4 antibodies blocked MERS-CoV infection of primary human bronchial epithelial cells. Expression of human or bat DPP4 in non-susceptible COS-7 cells conferred susceptibility to infection.","method":"Co-purification/affinity pull-down of viral S1 domain with DPP4; antibody inhibition of infection; ectopic DPP4 expression in COS-7 cells enabling infection","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (pull-down, antibody block, gain-of-function expression), foundational receptor identification study","pmids":["23486063"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of both the free MERS-CoV spike receptor-binding domain (RBD) and its complex with human DPP4 were determined; the viral RBD contacts blades IV and V of the CD26 β-propeller through a strand-dominated external receptor-binding motif. Binding was confirmed by surface plasmon resonance (Kd = 16.7 nM). The interface is mediated mainly by hydrophilic residues, distinct from other coronavirus-receptor interactions.","method":"X-ray crystallography of free RBD and RBD-DPP4 complex; surface plasmon resonance binding assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus SPR quantification, replicated in companion paper","pmids":["23831647"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of MERS-CoV RBD bound to the extracellular domain of human DPP4 at 3.0 Å resolution showed that the receptor-binding subdomain of MERS-CoV RBD interacts with the DPP4 β-propeller but not its hydrolase domain. Mutagenesis of key residues in the receptor-binding subdomain abrogated viral binding to DPP4 and cell entry.","method":"X-ray crystallography (3.0 Å); site-directed mutagenesis of receptor-binding subdomain residues; viral entry assays","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis functional validation, replicates findings of companion Nature paper","pmids":["23835475"],"is_preprint":false},{"year":2014,"finding":"CD26 (DPP4) expressed on CML leukemic stem cells (LSCs) disrupts the SDF-1-CXCR4 axis by cleaving SDF-1, facilitating abnormal extramedullary spread of BCR/ABL1+ LSCs. CD26+ LSCs engrafted NSG mice with BCR/ABL1+ cells, whereas CD26- stem cells from the same patients produced multilineage BCR/ABL1- engraftment. Gliptin-mediated CD26 inhibition suppressed BCR/ABL1+ cell expansion.","method":"Functional xenograft engraftment assays (NSG mice), flow cytometry cell sorting, CD26 enzymatic inhibition with gliptins, SDF-1 cleavage assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — in vivo engraftment assay with CD26+ vs CD26- sorted cells, mechanistic substrate cleavage demonstration, pharmacological inhibition","pmids":["24778155"],"is_preprint":false},{"year":2016,"finding":"DPP4 in hepatocytes is regulated by DNA methylation: demethylation of four intronic CpG sites amplifies glucose-induced DPP4 transcription; this epigenetic reprogramming occurs early in life (6 weeks) in obesity-prone mice, preceding hepatic triglyceride accumulation, and correlates with subsequent hepatosteatosis.","method":"Bisulfite sequencing of DPP4 CpG sites, glucose stimulation experiments, longitudinal mouse model comparing obese-prone vs normal mice, human liver biopsy analysis","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic epigenetic mapping with functional glucose induction link, mouse and human correlation","pmids":["27999105"],"is_preprint":false},{"year":2017,"finding":"TP53 (p53) limits ferroptosis by blocking DPP4 activity in a transcription-independent manner: loss of TP53 prevents nuclear accumulation of DPP4, allowing plasma-membrane-associated DPP4-dependent lipid peroxidation that triggers ferroptosis. This establishes a direct molecular link between TP53 and DPP4 in the control of lipid metabolism.","method":"DPP4 activity assays, subcellular fractionation, TP53 loss-of-function experiments, lipid peroxidation assays, erastin-induced ferroptosis model in colorectal cancer cells","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays (enzymatic activity, subcellular localization, lipid peroxidation, cell death), genetic manipulation of TP53","pmids":["28813679"],"is_preprint":false},{"year":2017,"finding":"DPP4 is selectively expressed on the surface of senescent (but not proliferating) human diploid fibroblasts, as identified by mass spectrometry surfaceome analysis. Surface DPP4 preferentially sensitizes senescent cells to NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC), enabling their selective elimination.","method":"Mass spectrometry surface proteome analysis, flow cytometry with anti-DPP4 antibodies for cell sorting, ADCC assays with NK cells","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — unbiased proteomic discovery plus functional ADCC validation, multiple experimental approaches","pmids":["28877934"],"is_preprint":false},{"year":2018,"finding":"In obesity, hepatocytes synthesize and secrete DPP4, which acts together with plasma factor Xa to activate ATM (adipose tissue macrophage) inflammation via PAR2 signaling, promoting visceral adipose tissue inflammation and insulin resistance. Silencing hepatocyte DPP4 or macrophage caveolin-1 or PAR2 suppressed inflammation and insulin resistance; the oral DPP4 inhibitor sitagliptin did not recapitulate this effect, indicating a non-enzymatic or paracrine mechanism.","method":"Hepatocyte-specific DPP4 siRNA silencing in mice; caveolin-1 and PAR2 knockdown in macrophages; measurement of VAT inflammation and insulin sensitivity; sitagliptin comparison","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific genetic silencing with defined molecular pathway (DPP4→Factor Xa→PAR2), multiple knockdown targets, in vivo model","pmids":["29562231"],"is_preprint":false},{"year":2018,"finding":"Adenosine deaminase (ADA) bridges CD26 on T cells and adenosine A2A receptor (A2AR) on dendritic cells to form a trimeric CD26-ADA-A2AR complex spanning two cell surfaces. This was demonstrated by NanoBRET (inter-cellular BRET), site-directed mutagenesis of ADA residues involved in A2AR binding, and functional dynamic mass redistribution assays, suggesting ADA acts as a cell-to-cell connector.","method":"NanoBRET (inter-cellular bioluminescence resonance energy transfer), site-directed mutagenesis, dynamic mass redistribution assay, ligand binding assay","journal":"Frontiers in pharmacology","confidence":"High","confidence_rationale":"Tier 1-2 — novel BRET-based inter-cellular complex detection with mutagenesis validation and functional assays","pmids":["29497379"],"is_preprint":false},{"year":2019,"finding":"DPP4 enzymatic cleavage of CCL11 (eotaxin) regulates eosinophil trafficking into tumors; inhibition of DPP4 by sitagliptin preserved functional CCL11, increased eosinophil tumor infiltration, and enhanced tumor control in hepatocellular carcinoma and breast cancer models. This mechanism was independent of lymphocytes and required IL-33 expression by tumor cells and eosinophil degranulation.","method":"DPP4 inhibitor (sitagliptin) treatment in syngeneic mouse tumor models; eosinophil depletion experiments; lymphocyte-deficient mice; IL-33 manipulation; CCL11 quantification","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with multiple depletion/genetic experiments in vivo, substrate (CCL11) quantification, replication across two cancer models","pmids":["30778250"],"is_preprint":false},{"year":2019,"finding":"Oxidized LDL upregulates DPP4 expression on macrophages through a TLR4/TRIF/CD36 signaling pathway; oxLDL (but not native LDL) increased DPP4 expression preferentially in CD36+ macrophages, and this effect was substantially reduced by TLR4 knockdown, CD36 deficiency, or TRIF (but not MyD88) deficiency.","method":"Flow cytometry, TLR4 knockdown, CD36-deficient macrophages, TRIF/MyD88-deficient cells, DPP4 enzymatic activity assay","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic loss-of-function approaches with mechanistic pathway definition, single lab","pmids":["30738832"],"is_preprint":false},{"year":2020,"finding":"Glucocorticoid receptor (GR) directly induces DPP4 gene transcription in macrophages by binding to two glucocorticoid-responsive elements (GREs) within the DPP4 promoter; glucocorticoid-induced DPP4 expression mediates macrophage migration, as siRNA-mediated knockdown of GR or DPP4 blocked dexamethasone-induced macrophage migration in THP-1 cells and murine peritoneal macrophages.","method":"Transcriptome analysis (RNA-seq), ChIP (GR binding to DPP4 promoter GREs), siRNA knockdown of GR and DPP4, GR antagonist (RU-486), macrophage migration assays, DPP4 enzymatic activity measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP demonstrating direct promoter binding, multiple orthogonal interventions (antagonist, siRNA, inhibitor) with defined migration phenotype","pmids":["31988243"],"is_preprint":false},{"year":2011,"finding":"DPP4 was identified as a novel adipokine secreted from differentiated human adipocytes; DPP4 protein concentration in visceral fat was ~5-fold higher than in subcutaneous fat in obese patients. Direct addition of soluble DPP4 to fat, skeletal muscle, and smooth muscle cells impaired insulin signaling in an autocrine/paracrine manner. DPP4 release from adipose tissue strongly correlated with adipocyte volume.","method":"Proteomic profiling of human adipocyte secretome, depot-specific DPP4 expression measurement, direct addition of recombinant DPP4 to target cells with insulin signaling readout, adipose tissue explant release assays","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — proteomic discovery followed by functional validation with recombinant DPP4 and human adipose tissue, multiple orthogonal methods","pmids":["21593202"],"is_preprint":false},{"year":2016,"finding":"DPP4 knockdown in human preadipocytes using lentiviral shRNA altered gene expression (upregulating metabolic genes PDK4 and PGC1α, downregulating proliferation genes including FGF7), retarded preadipocyte proliferation, and markedly diminished basal and insulin-induced ERK (but not Akt) activation by ~60%, indicating DPP4 modulates growth factor signaling during adipocyte differentiation.","method":"Lentiviral DPP4 knockdown, whole-genome DNA array, quantitative PCR, western blotting for ERK and Akt phosphorylation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide expression profiling plus specific signaling pathway validation, single lab","pmids":["26983599"],"is_preprint":false},{"year":2014,"finding":"DPP4 inhibition combined with dmPGE2 treatment synergistically enhances bone marrow HSC engraftment; pretreatment of donor cells with diprotin A (DPP4 inhibitor) or dmPGE2 and pretreatment of irradiated recipients with sitagliptin each improved engraftment, and the combined approach was significantly superior to either treatment alone in a congenic competitive repopulation model.","method":"Congenic CD45+ mouse bone marrow transplantation, pharmacological DPP4 inhibition (diprotin A, sitagliptin), dmPGE2 treatment, competitive repopulation assay","journal":"Blood cells, molecules & diseases","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo functional engraftment assay with multiple inhibitor approaches and combination testing","pmids":["24602918"],"is_preprint":false},{"year":2021,"finding":"Skin fibrosis driven by Wnt/β-catenin signaling requires DPP4 as a downstream effector: DPP4 is a Wnt/β-catenin-responsive gene, and genetic evidence showed the Wnt/DPP4 axis is required for fibrotic dermal remodeling including ECM expansion and dermal adipocyte shrinkage. DPP4 inhibitors reversed established Wnt-induced fibrosis in mouse skin.","method":"Genetically inducible/reversible Wnt activation mouse model, Dpp4 genetic knockout, DPP4 inhibitor treatment, skin architecture analysis, human skin fibrosis correlation","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (Wnt activation + Dpp4 knockout), pharmacological reversal, in vivo fibrosis model with defined molecular pathway","pmids":["34808238"],"is_preprint":false},{"year":2022,"finding":"CD26 promotes colorectal cancer angiogenesis and metastasis through a CAV1/MMP1 signaling axis: CD26 overexpression upregulated MMP1 expression, and caveolin-1 (CAV1) overexpression abrogated CD26-regulated MMP1 induction. CD26 functionally regulated CRC cell migration and invasion in vitro and angiogenesis and metastasis in vivo.","method":"Genome-wide mRNA expression array, qPCR, wound healing and invasion assays, mouse models of CRC metastasis, CAV1 overexpression rescue experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide screening plus functional validation with rescue experiment defining CAV1/MMP1 pathway, in vivo confirmation","pmids":["35163100"],"is_preprint":false},{"year":2020,"finding":"Purified recombinant human DPP4 (produced in insect cells) does not bind SARS-CoV-2 full-length spike protein or its receptor-binding domain, as measured by surface plasmon resonance and ELISA, demonstrating that unlike MERS-CoV, SARS-CoV-2 does not use DPP4 as a receptor.","method":"Recombinant protein purification, surface plasmon resonance, ELISA binding assay","journal":"Molecules","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro binding assay with purified proteins using two orthogonal methods (SPR + ELISA)","pmids":["33218025"],"is_preprint":false},{"year":2023,"finding":"DPP4 on the surface of senescence-associated extracellular vesicles (S-EVs) renders them refractory to uptake by proliferating cells; surfaceome proteomics of EVs from multiple senescence models consistently showed DPP4 enrichment on S-EVs, and ectopic DPP4 overexpression in HeLa cells produced EVs that were no longer taken up by proliferating cells.","method":"Surface proteomics of EVs from replicative, radiation-induced, and etoposide-induced senescent cells; DPP4 overexpression in HeLa cells; EV uptake assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased proteomic discovery replicated across three senescence models, gain-of-function EV uptake experiment","pmids":["37862381"],"is_preprint":false},{"year":2014,"finding":"Bat coronavirus HKU4-RBD binds human DPP4 (hCD26) and pseudotyped viruses with HKU4 spike infect cells via hCD26, supporting a bat origin for MERS-CoV. Crystal structure of HKU4-RBD/hCD26 complex revealed a binding mode similar to MERS-RBD but with lower affinity, explained by fewer optimized contact residues.","method":"Receptor binding assays, pseudovirus infection assays, X-ray crystallography of HKU4-RBD/hCD26 complex","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus functional infection assay, mechanistic comparison with MERS-RBD","pmids":["25211075"],"is_preprint":false},{"year":2008,"finding":"Loss of DPPIV expression in melanomas occurs at the RNA level and is attributable to promoter hypermethylation: DPPIV gene promoter is methylated in 8 of 10 melanoma cell lines, and demethylating agent 5-aza-2'-deoxycytidine restored DPPIV mRNA, protein, and enzyme activity, correlating with growth inhibition and apoptosis in melanoma cells.","method":"Bisulfite genomic sequencing, 5-aza-2'-deoxycytidine treatment, RT-PCR, western blot, DPPIV enzyme activity assay, growth inhibition assay","journal":"Frontiers in bioscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter methylation sequencing with pharmacological demethylation functional rescue, multiple readouts","pmids":["17981724"],"is_preprint":false},{"year":2011,"finding":"CD26 deficiency in mice leads to enhanced ovalbumin-induced airway inflammation characterized by increased eosinophilic infiltrates, elevated Th2 cytokines (IL-4, IL-5, IL-13) in bronchoalveolar lavage, and increased eotaxin/RANTES and their receptors CCR3/CCR5, suggesting CD26 normally restricts Th2-mediated airway inflammation, likely through chemokine cleavage.","method":"CD26 knockout mice, OVA sensitization/challenge model, cytokine measurement in BAL, immunohistochemistry, qRT-PCR","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout with comprehensive inflammatory phenotyping, single lab","pmids":["22101691"],"is_preprint":false},{"year":2014,"finding":"CD26 signaling promotes human osteoclast (OC) differentiation via the MKK3/6–p38 MAPK–mi/Mitf phosphorylation pathway; M-CSF and sRANKL induced CD26 expression on OC precursors concomitantly with p38 MAPK phosphorylation. Anti-CD26 monoclonal antibody (huCD26mAb) blocked early OC differentiation by inactivating MKK3/6 and p38 MAPK, and p38 MAPK inhibitor phenocopied the effect.","method":"Human OC differentiation assay with M-CSF/sRANKL, anti-CD26 mAb treatment, p38 MAPK inhibitor, western blotting for MKK3/6 and MAPK phosphorylation, TRAP staining, OC functional assays","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 — antibody blockade plus pharmacological pathway inhibition with mechanistic phosphorylation readouts","pmids":["24821427"],"is_preprint":false}],"current_model":"DPP4 (CD26) is a type II transmembrane serine exopeptidase with an eight-bladed β-propeller and α/β-hydrolase domain forming the catalytic cavity; it cleaves N-terminal dipeptides from substrates with penultimate Pro or Ala (including incretin hormones GLP-1 and GIP, chemokines CXCL12/SDF-1 and CCL11, and neuropeptides), inactivating or modifying these ligands; it serves as the functional cell-entry receptor for MERS-CoV (binding the viral RBD on β-propeller blades IV-V); it functions as a signaling scaffold that associates with CXCR4, adenosine deaminase, caveolin-1, CD45, and the adenosine A2A receptor to co-stimulate T cells and regulate lymphocyte trafficking; as a hepatocyte- and adipocyte-secreted adipokine it promotes visceral adipose tissue inflammation (via Factor Xa/PAR2) and impairs insulin signaling; it mediates hematopoietic stem cell homing/engraftment by cleaving CXCL12; it is selectively upregulated on senescent cells and their extracellular vesicles; and in cancer it can suppress invasion (e.g., melanoma) or promote metastasis (e.g., colorectal cancer via CAV1/MMP1), while TP53 restrains its plasma-membrane-associated lipid peroxidation activity to limit ferroptosis."},"narrative":{"teleology":[{"year":1993,"claim":"Identifying DPP4 as the principal serine exopeptidase responsible for incretin inactivation established its central role in glucose homeostasis and provided the mechanistic basis for DPP4 inhibitor (gliptin) drug development.","evidence":"Purified placental DPP4 kinetic assays with GLP-1/GIP substrates and specific inhibitors in human serum","pmids":["8100523"],"confidence":"High","gaps":["Kinetics measured with purified enzyme; in vivo substrate hierarchy not fully resolved","Contribution of soluble vs membrane-bound DPP4 to systemic incretin degradation not distinguished"]},{"year":1993,"claim":"Demonstrating that CD26 is the lymphocyte surface receptor for adenosine deaminase (ADA) revealed a non-enzymatic scaffolding function and linked DPP4 to purine metabolism and immune regulation.","evidence":"Co-immunoprecipitation and in vitro binding with recombinant extracellular domain, amino acid sequence confirmation","pmids":["8101391"],"confidence":"High","gaps":["Functional consequence of ADA binding on local adenosine concentrations not quantified","Whether ADA binding modulates DPP4 catalytic activity was not tested"]},{"year":1998,"claim":"Domain mapping showed that T cell co-stimulation and ADA binding map to distinct but overlapping regions (aa 248–449) of the extracellular domain, establishing DPP4 as a modular signaling scaffold independent of its peptidase activity.","evidence":"Truncated and human–rat CD26 swap mutants with functional readouts and cross-blocking by 13 anti-CD26 mAbs","pmids":["9683260"],"confidence":"Medium","gaps":["Downstream signaling pathways triggered by co-stimulation domain not identified","Results from chimeric constructs may not capture native folding constraints"]},{"year":2001,"claim":"Discovery of a physical CD26/CXCR4 complex that co-internalizes upon SDF-1α stimulation explained how DPP4 coordinates chemokine cleavage with receptor signaling to regulate lymphocyte chemotaxis.","evidence":"Reciprocal co-immunoprecipitation from T/B cell membranes, co-internalization with CXCR4 wild-type and mutants, pertussis toxin treatment","pmids":["11278278"],"confidence":"High","gaps":["Stoichiometry and direct binding interface between CD26 and CXCR4 not determined","Whether complex formation alters DPP4 enzymatic kinetics toward SDF-1 is unknown"]},{"year":2003,"claim":"High-resolution crystal structures of DPP4 revealed the β-propeller/α/β-hydrolase architecture, the Glu-Glu substrate recognition motif, and dual substrate-access routes, providing the structural framework for understanding catalytic specificity and inhibitor design.","evidence":"X-ray crystallography of human DPP4 at 2.5 Å (with valine-pyrrolidide) and porcine DPP4 at 1.8 Å; cryo-TEM at ~14 Å confirming dimeric assembly and lateral opening","pmids":["12483204","12690074","12705886"],"confidence":"High","gaps":["No structure of full-length membrane-anchored DPP4 in lipid bilayer","Dynamics of substrate entry through β-propeller tunnel vs. side opening not resolved"]},{"year":2003,"claim":"Showing that DPP4 cleaves CXCL12/SDF-1 to regulate hematopoietic stem cell mobilization and that CD26-truncated CXCL12 acts as a CXCR4 antagonist established a direct mechanism for DPP4 in HSC trafficking.","evidence":"In vitro chemotaxis with truncated CXCL12, DPP4 inhibitor treatment during G-CSF mobilization in mice","pmids":["12576320"],"confidence":"High","gaps":["Relative contributions of membrane-bound vs. soluble DPP4 in HSC niche not distinguished","Other DPP4 substrates in the marrow microenvironment not surveyed"]},{"year":2004,"claim":"Genetic deletion and pharmacological inhibition of CD26 in donor HSCs dramatically enhanced bone marrow engraftment, validating DPP4 as a therapeutic target for transplantation.","evidence":"CD26 knockout mouse and diprotin A/sitagliptin treatment in bone marrow transplant models with competitive repopulation","pmids":["15310902"],"confidence":"High","gaps":["Long-term engraftment and multilineage reconstitution data limited","Whether DPP4 inhibition affects graft-versus-host disease not addressed"]},{"year":2006,"claim":"Identification of CD26–caveolin-1 binding on APCs that triggers NF-κB activation and CD86 upregulation revealed how DPP4 functions as a co-stimulatory molecule bridging T cells and antigen-presenting cells.","evidence":"Recombinant CD26 binding assays, caveolin-1 siRNA, NF-κB and CD86 readouts, T cell proliferation","pmids":["16622717"],"confidence":"Medium","gaps":["Direct binding interface between CD26 and caveolin-1 not structurally resolved","Single-lab finding; independent replication needed"]},{"year":2008,"claim":"Demonstrating that DPP4 silencing in melanoma occurs through promoter hypermethylation, and that demethylation restores expression and suppresses growth, linked epigenetic regulation to DPP4's tumor-suppressive function.","evidence":"Bisulfite sequencing of melanoma cell lines, 5-aza-2'-deoxycytidine restoration of DPP4 mRNA/protein/activity, growth inhibition assay","pmids":["17981724"],"confidence":"Medium","gaps":["Whether restored DPP4 suppresses invasion through the same enzymatic-independent mechanism shown earlier (PMID:11467771) not tested","Methylation status in primary melanoma specimens not comprehensively surveyed"]},{"year":2011,"claim":"Identification of DPP4 as an adipokine secreted preferentially from visceral adipose tissue that directly impairs insulin signaling revealed an autocrine/paracrine metabolic function beyond incretin degradation.","evidence":"Proteomic profiling of human adipocyte secretome, recombinant DPP4 addition to fat/muscle cells with insulin signaling readout","pmids":["21593202"],"confidence":"High","gaps":["Whether insulin-impairing effect requires DPP4 catalytic activity not determined","Receptor or binding partner on target cells mediating this effect not identified"]},{"year":2013,"claim":"Identification and structural characterization of DPP4 as the functional receptor for MERS-CoV, with the viral RBD contacting β-propeller blades IV–V, established a non-enzymatic viral entry role and explained species tropism.","evidence":"Affinity pull-down, antibody blocking, ectopic expression conferring susceptibility, crystal structures of MERS-RBD/DPP4 complex at 2.9–3.0 Å, SPR (Kd = 16.7 nM)","pmids":["23486063","23831647","23835475"],"confidence":"High","gaps":["Whether DPP4 enzymatic activity is altered upon viral binding not determined","Post-binding entry mechanism (endocytic route, membrane fusion) not fully characterized"]},{"year":2017,"claim":"Demonstrating that TP53 retains DPP4 in the nucleus to prevent plasma-membrane-associated lipid peroxidation and ferroptosis established a transcription-independent TP53–DPP4 axis controlling cell death through lipid metabolism.","evidence":"DPP4 activity assays, subcellular fractionation, TP53 loss-of-function, lipid peroxidation quantification, erastin-induced ferroptosis model","pmids":["28813679"],"confidence":"High","gaps":["Nuclear function of DPP4 (if any) not characterized","Direct physical interaction between TP53 and DPP4 not demonstrated"]},{"year":2017,"claim":"Unbiased surfaceome analysis showing selective DPP4 upregulation on senescent cells opened DPP4 as a senescence biomarker and revealed it sensitizes senescent cells to NK-mediated ADCC clearance.","evidence":"Mass spectrometry surface proteomics of senescent vs. proliferating fibroblasts, flow cytometry, ADCC functional assay","pmids":["28877934"],"confidence":"High","gaps":["Mechanism driving senescence-specific DPP4 upregulation not defined","Whether DPP4 enzymatic activity is required for ADCC sensitization not tested"]},{"year":2018,"claim":"Defining a hepatocyte DPP4–Factor Xa–PAR2 pathway that drives adipose tissue macrophage inflammation in obesity revealed a non-enzymatic or paracrine mechanism distinct from the incretin-degradation function targeted by oral gliptins.","evidence":"Hepatocyte-specific DPP4 silencing, caveolin-1 and PAR2 knockdown in macrophages, sitagliptin comparison in obese mice","pmids":["29562231"],"confidence":"High","gaps":["Whether DPP4 directly activates Factor Xa or serves as a co-factor not resolved","Relevance of this pathway in human obesity requires clinical validation"]},{"year":2018,"claim":"Detection of a trimeric CD26–ADA–A2AR complex spanning two cell surfaces demonstrated how ADA bridges DPP4 on T cells to adenosine receptors on dendritic cells, integrating purine catabolism with immune synapse signaling.","evidence":"Inter-cellular NanoBRET, site-directed ADA mutagenesis, dynamic mass redistribution assay","pmids":["29497379"],"confidence":"High","gaps":["In vivo relevance of the trimeric complex not demonstrated","Stoichiometry and structural basis of the ternary complex not resolved"]},{"year":2019,"claim":"Showing that DPP4 cleavage of CCL11/eotaxin limits eosinophil tumor infiltration provided a mechanism by which DPP4 inhibition can enhance anti-tumor innate immunity independently of lymphocytes.","evidence":"Sitagliptin treatment in syngeneic HCC and breast cancer models, eosinophil depletion, lymphocyte-deficient mice, CCL11 quantification","pmids":["30778250"],"confidence":"High","gaps":["Whether other DPP4 chemokine substrates contribute to eosinophil exclusion not addressed","Human clinical relevance of eosinophil-mediated anti-tumor effect with DPP4 inhibition not established"]},{"year":2021,"claim":"Placing DPP4 downstream of Wnt/β-catenin signaling as a required effector of skin fibrosis expanded DPP4's role to extracellular matrix remodeling and identified it as a druggable node in fibrotic disease.","evidence":"Genetically inducible Wnt activation with Dpp4 knockout epistasis, DPP4 inhibitor reversal of established fibrosis in mouse skin","pmids":["34808238"],"confidence":"High","gaps":["DPP4 substrate(s) mediating fibrotic remodeling downstream of Wnt not identified","Applicability to organ fibrosis beyond skin not tested"]},{"year":2023,"claim":"Discovery that DPP4 on senescence-associated extracellular vesicles renders them refractory to uptake by proliferating cells suggested a mechanism for selective senescent cell communication.","evidence":"Surface proteomics of EVs from three senescence models; DPP4 overexpression in HeLa producing EVs with reduced uptake","pmids":["37862381"],"confidence":"Medium","gaps":["Mechanism by which surface DPP4 blocks EV uptake (receptor masking, repulsion) not defined","In vivo consequences of altered EV uptake not examined","Overexpression system may not recapitulate physiological DPP4 density on S-EVs"]},{"year":null,"claim":"Key unresolved questions include the structural basis of full-length membrane-anchored DPP4 in lipid bilayers, the precise mechanism by which TP53 directs DPP4 nuclear retention, the identity of DPP4 substrates mediating Wnt-driven fibrosis, and whether the hepatocyte DPP4–Factor Xa–PAR2 inflammatory pathway operates through DPP4's catalytic or scaffolding function.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of full-length membrane-embedded DPP4","TP53–DPP4 physical interaction and nuclear DPP4 function uncharacterized","Substrate identity in fibrosis context unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,9,10,16,22]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[13,14,15,32]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,12,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,4,13,19]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[25,20,31]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[31]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,3,4,5,12,21,22,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,12,20,26,29,35]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,17,25]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,6,7,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,14,15,16,29,32]}],"complexes":["CD26-ADA-A2AR trimeric complex","CD26/CXCR4 signaling complex"],"partners":["ADA","CXCR4","CAV1","TP53","F10","F2RL1"],"other_free_text":[]},"mechanistic_narrative":"DPP4 (CD26) is a type II transmembrane serine exopeptidase that cleaves N-terminal dipeptides from substrates bearing a penultimate proline or alanine, thereby inactivating incretin hormones (GLP-1, GIP), chemokines (CXCL12/SDF-1, CCL11/eotaxin), and other bioactive peptides to regulate glucose homeostasis, hematopoietic stem cell homing, and immune cell trafficking [PMID:8100523, PMID:12576320, PMID:30778250]. Structurally, the extracellular region forms a homodimer comprising an eight-bladed β-propeller and an α/β-hydrolase domain that together create the catalytic cavity, and the β-propeller additionally serves as the binding site for the MERS-CoV spike receptor-binding domain, establishing DPP4 as the functional entry receptor for MERS-CoV [PMID:12483204, PMID:23486063, PMID:23831647]. Beyond its peptidase activity, DPP4 functions as a multivalent signaling scaffold on T cells and antigen-presenting cells by directly associating with adenosine deaminase, CXCR4, caveolin-1, and the adenosine A2A receptor to co-stimulate T cell activation, regulate lymphocyte adhesion, and modulate NF-κB-dependent antigen presentation [PMID:8101391, PMID:11278278, PMID:16622717, PMID:29497379]. DPP4 also acts as a hepatocyte- and adipocyte-secreted adipokine that promotes visceral adipose tissue inflammation via a Factor Xa/PAR2 pathway and impairs insulin signaling, and its plasma-membrane localization is regulated by TP53 to control lipid peroxidation and ferroptosis sensitivity [PMID:29562231, PMID:21593202, PMID:28813679]."},"prefetch_data":{"uniprot":{"accession":"P27487","full_name":"Dipeptidyl peptidase 4","aliases":["ADABP","Adenosine deaminase complexing protein 2","ADCP-2","Dipeptidyl peptidase IV","DPP IV","T-cell activation antigen CD26","TP103"],"length_aa":766,"mass_kda":88.3,"function":"Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation (PubMed:10900005, PubMed:10951221, PubMed:11772392, PubMed:17287217). Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC (PubMed:10900005, PubMed:10951221, PubMed:11772392, PubMed:14691230). Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (PubMed:17287217). Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion (PubMed:11772392). In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM (PubMed:10593948, PubMed:16651416). May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation (PubMed:18708048). When overexpressed, enhanced cell proliferation, a process inhibited by GPC3 (PubMed:17549790). Also acts as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones such as brain natriuretic peptide 32 (PubMed:10570924, PubMed:16254193). Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline (PubMed:10593948) (Microbial infection) Acts as a receptor for human coronavirus MERS-CoV-2","subcellular_location":"Cell membrane; Apical cell membrane; Cell projection, invadopodium membrane; Cell projection, lamellipodium membrane; Cell junction; Membrane raft","url":"https://www.uniprot.org/uniprotkb/P27487/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DPP4","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DPP4","total_profiled":1310},"omim":[{"mim_id":"621526","title":"GLUTAMINYL-PEPTIDE CYCLOTRANSFERASE-LIKE PROTEIN; QPCTL","url":"https://www.omim.org/entry/621526"},{"mim_id":"616769","title":"NITRILASE FAMILY MEMBER 2; NIT2","url":"https://www.omim.org/entry/616769"},{"mim_id":"615442","title":"T-CELL RECEPTOR ALPHA CHAIN VARIABLE GENE CLUSTER; TRAV@","url":"https://www.omim.org/entry/615442"},{"mim_id":"613872","title":"COAGULATION FACTOR X; F10","url":"https://www.omim.org/entry/613872"},{"mim_id":"611636","title":"N-ACETYLATED ALPHA-LINKED ACIDIC DIPEPTIDASE 2; NAALAD2","url":"https://www.omim.org/entry/611636"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":130.0},{"tissue":"parathyroid gland","ntpm":146.6},{"tissue":"placenta","ntpm":126.0},{"tissue":"prostate","ntpm":100.7}],"url":"https://www.proteinatlas.org/search/DPP4"},"hgnc":{"alias_symbol":["DPPIV"],"prev_symbol":["CD26","ADCP2"]},"alphafold":{"accession":"P27487","domains":[{"cath_id":"3.40.50.1820","chopping":"502-764","consensus_level":"medium","plddt":98.6624,"start":502,"end":764}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P27487","model_url":"https://alphafold.ebi.ac.uk/files/AF-P27487-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P27487-F1-predicted_aligned_error_v6.png","plddt_mean":96.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DPP4","jax_strain_url":"https://www.jax.org/strain/search?query=DPP4"},"sequence":{"accession":"P27487","fasta_url":"https://rest.uniprot.org/uniprotkb/P27487.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P27487/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P27487"}},"corpus_meta":[{"pmid":"28813679","id":"PMC_28813679","title":"The 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 \"finding\": \"CD26/DPP4 is a type II transmembrane glycoprotein with extracellular dipeptidyl peptidase IV (DPPIV) serine exopeptidase activity that cleaves N-terminal dipeptides from polypeptides with L-proline or L-alanine in the penultimate position; it also binds adenosine deaminase (ADA) on the T-cell surface and associates with CD45 to deliver T-cell co-stimulatory signals.\",\n      \"method\": \"Biochemical characterization, co-immunoprecipitation, functional T-cell activation assays\",\n      \"journal\": \"Immunological reviews\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple labs, foundational characterization paper with >360 citations\",\n      \"pmids\": [\"9553764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD26/DPP4 expressed on hematopoietic stem/progenitor cells cleaves CXCL12/SDF-1α at its position-2 proline, generating a truncated form (CXCL12[3-68]) that cannot induce chemotaxis and acts as an antagonist; inhibition or genetic deletion of CD26 enhanced homing and engraftment efficiency in transplantation models.\",\n      \"method\": \"Flow cytometry, chemotaxis assays with truncated vs. intact CXCL12, CD26 inhibitor treatment, CD26 knockout mice, in vivo transplantation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (enzymatic, functional chemotaxis, KO mice, in vivo engraftment), >400 citations\",\n      \"pmids\": [\"15310902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD26/DPP4 peptidase activity on hematopoietic stem/progenitor cells cleaves CXCL12 to its truncated form, which acts as a CXCR4 antagonist; CD26 inhibition during G-CSF mobilization reduced progenitor cell numbers in the periphery, indicating CD26 activity is a mechanism of G-CSF-induced mobilization.\",\n      \"method\": \"Flow cytometry, chemotaxis assays, CD26 inhibitor in vivo treatment during G-CSF mobilization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays with in vivo confirmation\",\n      \"pmids\": [\"12576320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD26 physically associates with CXCR4 on T and B cell lines, as demonstrated by co-immunoprecipitation and co-internalization upon SDF-1α stimulation; this CD26-CXCR4 complex is proposed to form a functional unit in which CD26 peptidase activity directly modulates SDF-1α-induced chemotaxis.\",\n      \"method\": \"Co-immunoprecipitation, co-internalization assay, flow cytometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal co-IP and functional internalization data, single lab\",\n      \"pmids\": [\"11278278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TP53 limits erastin-induced ferroptosis through a transcription-independent mechanism by blocking DPP4 activity; loss of TP53 promotes nuclear-to-plasma-membrane relocalization of DPP4, enabling DPP4-dependent lipid peroxidation at the plasma membrane that drives ferroptosis.\",\n      \"method\": \"Loss-of-function experiments, DPP4 activity assays, subcellular fractionation/localization imaging, erastin-induced ferroptosis model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking TP53, DPP4 localization, enzymatic activity, and ferroptotic cell death in one study; >770 citations\",\n      \"pmids\": [\"28813679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hepatocyte-secreted DPP4 acts together with plasma factor Xa to activate PAR2 on adipose tissue macrophages (ATMs) via a caveolin-1-dependent mechanism, driving adipose tissue inflammation and insulin resistance in obesity; silencing DPP4 in hepatocytes or caveolin-1/PAR2 in ATMs suppressed inflammation.\",\n      \"method\": \"Hepatocyte-specific DPP4 silencing, ATM-specific caveolin-1/PAR2 silencing, in vivo mouse obesity model, mechanistic pathway dissection\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic silencing of specific pathway components with defined molecular mechanism, published in Nature\",\n      \"pmids\": [\"29562231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD26/DPP4 on CML leukemic stem cells (LSCs) cleaves SDF-1/CXCL12, disrupting the SDF-1–CXCR4 axis and facilitating abnormal extramedullary spread; CD26 was identified as a specific marker of CD34+/CD38− CML LSCs and gliptin treatment suppressed BCR/ABL1+ cell expansion.\",\n      \"method\": \"Flow cytometry, enzymatic substrate cleavage assays, NSG mouse engraftment model, imatinib treatment response\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple assays including in vivo engraftment and functional enzymatic data, >179 citations\",\n      \"pmids\": [\"24778155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD26 on T cells binds caveolin-1 on antigen-presenting cells (APCs) via residues 201-211 together with the serine catalytic site (Ser630); upon CD26-caveolin-1 interaction, caveolin-1 is phosphorylated leading to NF-κB activation and CD86 upregulation, mediating antigen-specific T-cell costimulation.\",\n      \"method\": \"Mutagenesis of CD26 binding residues, co-stimulation assays, phosphorylation assays, NF-κB activation measurement, immunohistochemistry of rheumatoid synovium\",\n      \"journal\": \"Modern rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mutagenesis plus functional signaling assays in single lab\",\n      \"pmids\": [\"16622717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cryo-TEM and single particle analysis of rat DPP4/CD26 at ~14 Å resolution confirmed its homodimeric structure and revealed a lateral opening providing direct access to the catalytic site, distinct from the related serine peptidase POP.\",\n      \"method\": \"Cryo-electron microscopy, single particle analysis, structural docking\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct structural determination, moderate resolution (~14 Å)\",\n      \"pmids\": [\"12705886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Physicochemical and low-angle X-ray scattering analysis of human seminal plasma DPP4 demonstrated a dimeric structure with each subunit composed of three domains linked by flexible regions, with 45% β-sheet secondary structure; disulfide bonds stabilize one domain but are not required for catalytic activity, dimerization, or adenosine deaminase binding.\",\n      \"method\": \"FTIR spectroscopy, low-angle X-ray scattering, unfolding experiments, proteolysis susceptibility assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — multiple biophysical methods on purified protein with functional validation\",\n      \"pmids\": [\"9252108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ADA-CD26 interaction on the cell surface mediates lymphocyte adhesion to epithelial cells via integrin activation (LFA-1); increased CD26 expression enhanced T-cell adhesion to Caco-2 monolayers by ~50%, and blocking with anti-CD26 antibody or exogenous ADA reduced adhesion by 50-70%.\",\n      \"method\": \"Cell adhesion assays, anti-CD26 antibody blocking, integrin activation FACS, CD26 overexpression in lymphocyte cell lines\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple functional assays with antibody and molecular controls, single lab\",\n      \"pmids\": [\"11772392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Anti-CD26 mAb stimulation of T cells induced tyrosine phosphorylation of proteins at 50, 46, 26, 24, and 21 kDa; a tyrosine kinase inhibitor (Tyrphostin) blocked CD26-mediated proliferation and IL-2 mRNA expression, establishing protein tyrosine phosphorylation as a mechanism of CD26-driven T-cell activation.\",\n      \"method\": \"Anti-CD26 mAb stimulation, Western blot for tyrosine phosphorylation, tyrosine kinase inhibitor experiments, IL-2 mRNA expression assay\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional signaling assays with inhibitor confirmation, single lab\",\n      \"pmids\": [\"1356916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"DPPIV/CD26 expression inhibited melanoma cell invasion by >75% in Matrigel assays; neither the extracellular serine protease activity nor the cytoplasmic domain was required for this anti-invasive activity, as shown by stable expression of enzymatic and cytoplasmic domain mutants.\",\n      \"method\": \"Stable transfection of wild-type and mutant DPPIV in melanoma cells, Matrigel invasion assays\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis with functional invasion assay, demonstrates mechanism independent of enzymatic activity\",\n      \"pmids\": [\"11467771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DPP4 is selectively expressed on the surface of senescent (but not proliferating) human diploid fibroblasts, as identified by mass spectrometry; this differential surface expression enables flow cytometry-based isolation of senescent cells and their preferential NK cell-mediated elimination via ADCC.\",\n      \"method\": \"Mass spectrometry surface proteomics, flow cytometry, ADCC assay, anti-DPP4 antibody-mediated cytotoxicity\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased MS discovery with orthogonal functional validation (flow cytometry, ADCC), >200 citations\",\n      \"pmids\": [\"28877934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The lncRNA-OIS1 regulates oncogene-induced senescence (OIS) by activating nearby DPP4 expression; DPP4 knockdown caused senescence bypass and ectopic DPP4 expression in lncRNA-OIS1 knockdown cells restored the senescent phenotype, placing DPP4 downstream of lncRNA-OIS1 in the OIS pathway.\",\n      \"method\": \"RNAi knockdown screen, senescence bypass assay, ectopic expression rescue, CDKN1A and cell-cycle gene expression analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by KD and rescue experiments, single lab\",\n      \"pmids\": [\"29481642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Glucocorticoid receptor (GR) directly induces DPP4 gene transcription in macrophages by binding to two glucocorticoid-responsive elements (GREs) within the DPP4 promoter; glucocorticoid-induced DPP4 expression mediates macrophage migration, as siRNA knockdown of GR or DPP4 blocked dexamethasone-induced migration.\",\n      \"method\": \"Transcriptome analysis, GR ChIP (GRE binding), siRNA knockdown, GR antagonist (RU-486), DPP4 activity assay, macrophage migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct GR binding to DPP4 promoter GREs with multiple orthogonal functional validations\",\n      \"pmids\": [\"31988243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DPP4 knockdown in human preadipocytes reduced basal and insulin-induced ERK activation by ~60% (but not Akt), retarded preadipocyte proliferation, and upregulated metabolic genes (PDK4, PGC1α), indicating DPP4 regulates growth factor-ERK signaling and differentiation onset in adipocytes.\",\n      \"method\": \"Lentiviral DPP4 knockdown, whole-genome DNA microarray, Western blot for ERK/Akt phosphorylation, proliferation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple orthogonal readouts (genome-wide, signaling, proliferation), single lab\",\n      \"pmids\": [\"26983599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DPP4 inhibition by sitagliptin preserves functional CXCL10 and also increases CCL11 concentrations, driving eosinophil migration into tumors; DPP4 cleaves and inactivates both CXCL10 and CCL11 (an eosinophil chemoattractant), and its inhibition enables IL-33-dependent eosinophil-mediated anti-tumor control.\",\n      \"method\": \"DPP4 inhibitor (sitagliptin) in pre-clinical HCC and breast cancer models, eosinophil depletion, lymphocyte-deficient mice, IL-33 manipulation, chemokine level measurement\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacologic interventions with defined pathway (DPP4→CCL11→eosinophils→IL-33→tumor control), >166 citations\",\n      \"pmids\": [\"30778250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD26 signaling in osteoclast precursors activates phosphorylation of MKK3/6 and p38 MAPK, which is required for early osteoclast differentiation and microphthalmia-associated transcription factor (MITF) phosphorylation; anti-CD26 monoclonal antibody inhibited osteoclast formation and bone resorption by blocking this pathway.\",\n      \"method\": \"Anti-CD26 mAb treatment, phosphorylation assays (MKK3/6, p38 MAPK, MITF), TRAP staining, osteoclast functional bone resorption assay, p38 MAPK inhibitor\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple signaling assays with pathway inhibitors confirming mechanism, single lab\",\n      \"pmids\": [\"24821427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Skin fibrosis driven by Wnt/β-catenin activation requires DPP4 as a downstream effector; DPP4 is a Wnt/β-catenin-responsive gene and genetic evidence showed the Wnt/DPP4 axis drives fibrotic dermal remodeling; DPP4 inhibitors accelerated recovery from established Wnt-induced fibrosis.\",\n      \"method\": \"Inducible Wnt activation mouse model, DPP4 genetic knockout, DPP4 inhibitor treatment, human skin fibrosis correlation\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with inducible model and pharmacologic rescue, single lab\",\n      \"pmids\": [\"34808238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Adenosine deaminase (ADA) bridges CD26-expressing T cells and A2A receptor (A2AR)-expressing dendritic cells by forming a trimeric CD26-ADA-A2AR complex spanning two cells, as demonstrated by NanoBRET and site-directed mutagenesis of the ADA-A2AR binding interface.\",\n      \"method\": \"NanoBRET (bioluminescence resonance energy transfer between cells), site-directed mutagenesis, dynamic mass redistribution assays, ligand binding experiments\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — novel structural/interaction finding with direct BRET evidence and mutagenesis, single lab\",\n      \"pmids\": [\"29497379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Oxidized LDL (oxLDL) upregulates DPP4 expression on macrophages via a TLR4/TRIF/CD36 pathway; TLR4 knockdown and CD36 deficiency reduced oxLDL-induced DPP4 upregulation, and TRIF (but not MyD88) deficiency attenuated this effect.\",\n      \"method\": \"Flow cytometry for DPP4 expression, TLR4 siRNA knockdown, CD36 knockout macrophages, TRIF/MyD88 deficient cells, DPP4 enzymatic activity assay\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic loss-of-function approaches defining upstream pathway, single lab\",\n      \"pmids\": [\"30738832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DPP4 on the surface of senescence-associated extracellular vesicles (S-EVs) prevents their uptake by proliferating cells; ectopic overexpression of DPP4 in HeLa cells rendered their EVs refractory to internalization by proliferating cells, identifying DPP4 as an uptake repressor on S-EVs.\",\n      \"method\": \"Surfaceome proteomics (mass spectrometry), EV uptake assays, DPP4 ectopic overexpression in EV-producing cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — MS discovery with ectopic expression functional validation, single lab\",\n      \"pmids\": [\"37862381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD26 promotes colorectal cancer angiogenesis and metastasis through a CAV1/MMP1 signaling axis; CD26 overexpression upregulated MMP1, and overexpression of CAV1 abrogated CD26-regulated MMP1 induction, placing CAV1 between CD26 and MMP1.\",\n      \"method\": \"Wound healing assay, migration/invasion assays, genome-wide mRNA expression array, qPCR validation, CAV1 overexpression epistasis, in vivo mouse models\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — epistasis by overexpression plus genome-wide expression data and in vivo confirmation, single lab\",\n      \"pmids\": [\"35163100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of DPPIV expression in melanoma cells is caused in large part by promoter CpG island hypermethylation; treatment with the demethylating agent 5-aza-2'-deoxycytidine restored DPPIV mRNA, protein, and enzymatic activity and correlated with growth inhibition and apoptosis.\",\n      \"method\": \"Sodium bisulfite genomic sequencing, 5-aza-2'-deoxycytidine demethylation, RT-PCR, Western blot, enzymatic activity assay, growth inhibition assay\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods confirming epigenetic silencing mechanism and functional consequence, single lab\",\n      \"pmids\": [\"17981724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Human serum DPP4 is a homodimer (250 kDa) of two identical 100 kDa subunits; Gly-X dipeptides allosterically enhance both apparent Km (~10-fold) and kcat (~4-fold) of the enzyme, and serum DPP4 binds adenosine deaminase isoforms I and II.\",\n      \"method\": \"Protein purification, enzymatic kinetics, native PAGE, ADA binding assays\",\n      \"journal\": \"Journal of clinical laboratory analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinetic and binding characterization with purified protein\",\n      \"pmids\": [\"8951616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Angiotensin II stimulates DPP4 activity in proximal tubule cells via AT1R signaling, which involves EGFR transactivation and MEK/ERK phosphorylation; DPP4 inhibition with MK0626 or MEK inhibitor U0126 partially restored megalin expression, linking AT1R→DPP4→ERK to regulation of the endocytic receptor megalin.\",\n      \"method\": \"In vivo Ang II infusion in mice, proximal tubule cell treatment, DPP4 activity assay, DPP4 inhibitor, MEK inhibitor, EGFR inhibitor, Western blot for ERK phosphorylation and megalin\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway dissection with multiple pharmacological inhibitors in vitro and in vivo, single lab\",\n      \"pmids\": [\"27213360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD26-deficient mice show enhanced ovalbumin-induced airway inflammation with increased Th2 cytokines (IL-4, IL-5, IL-13), eosinophilia, and elevated eotaxin/RANTES and their receptors (CCR3, CCR5), demonstrating that CD26 normally restricts Th2-driven airway inflammation.\",\n      \"method\": \"CD26 knockout mice, OVA sensitization/challenge model, cytokine ELISA and mRNA, BAL analysis, immunohistochemistry\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined Th2 cytokine and chemokine phenotypic readouts\",\n      \"pmids\": [\"22101691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD26-deficient mice showed delayed allogeneic skin graft rejection with reduced IFN-γ, IL-2, IL-6, IL-4, IL-13 and IL-17, elevated IL-10, higher regulatory T cell frequency, and fewer infiltrating CD8+ T cells and macrophages, demonstrating CD26 promotes immune activation in allograft rejection.\",\n      \"method\": \"CD26 knockout mice, tail-skin allograft transplantation, serum cytokine measurement, FACS for T cell subsets and Tregs, tissue immunohistochemistry\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple immune readouts in defined in vivo model\",\n      \"pmids\": [\"29572550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Purified recombinant soluble human DPP4 showed no specific binding to SARS-CoV-2 full-length spike protein or its receptor-binding domain by surface plasmon resonance or ELISA, demonstrating DPP4 is not a receptor for SARS-CoV-2 (unlike MERS-CoV).\",\n      \"method\": \"Recombinant protein purification, surface plasmon resonance, ELISA\",\n      \"journal\": \"Molecules\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding measurement with purified recombinant proteins using two orthogonal methods\",\n      \"pmids\": [\"33218025\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DPP4/CD26 is a dimeric type II transmembrane serine exopeptidase that cleaves N-terminal dipeptides from substrates with Pro or Ala in the penultimate position (including incretin hormones GLP-1/GIP, chemokines such as CXCL12 and CXCL10/CCL11, and neuropeptides), thereby regulating their bioactivity; it functions as the cell-surface receptor for MERS-CoV (binding the viral spike RBD at blades IV-V of its β-propeller via a hydrophilic interface), co-stimulates T-cell activation through interactions with CD45, adenosine deaminase (ADA), caveolin-1, and CXCR4, mediates hematopoietic stem cell homing by cleaving CXCL12, drives ferroptosis regulation by TP53 through transcription-independent control of DPP4 plasma membrane localization and lipid peroxidation, and is secreted by hepatocytes in obesity to activate adipose tissue macrophage inflammation via a factor Xa/caveolin-1/PAR2 pathway, while its expression is transcriptionally induced by glucocorticoid receptor binding to GRE elements in its promoter and epigenetically silenced by promoter hypermethylation in certain cancers.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"DPP4 (CD26) enzymatically hydrolyzes GIP, GLP-1(7-36)amide, and peptide histidine methionine by removing N-terminal dipeptides (His-Ala or Tyr-Ala), inactivating these incretin hormones; DPP4-specific inhibitors (diprotin A, Lys-pyrrolidide) completely abolished serum degradation of GIP and GLP-1, establishing DPP4 as the principal serine exopeptidase responsible for incretin inactivation in human serum.\",\n      \"method\": \"In vitro enzymatic assay with purified DPP4 from human placenta; kinetic analysis (Km, Vmax); serum incubation with DPP4-specific inhibitors; fragment identification\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with purified enzyme, kinetic characterization, inhibitor confirmation, replicated in serum\",\n      \"pmids\": [\"8100523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD26 (DPP4) directly associates with adenosine deaminase (ADA) on the T cell surface through its extracellular domain; co-immunoprecipitation and in vitro binding assays demonstrated that the 43-kDa protein co-purifying with CD26 is ADA, establishing CD26 as the lymphocyte surface receptor for ADA.\",\n      \"method\": \"Immunoprecipitation, amino acid sequence analysis, in vitro binding assay with recombinant extracellular domain\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical binding assay with sequence confirmation, foundational study with >400 citations\",\n      \"pmids\": [\"8101391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The extracellular portion of human DPP4 (starting at Gly-31) forms a homodimer and contains at least two independently folding domains: one stabilized by disulfide bonds (not required for catalytic activity or ADA binding) and one containing the active site; FTIR spectrometry showed ~45% beta-sheet content, and low-angle X-ray scattering supported a three-domain structure per subunit with flexible linker regions.\",\n      \"method\": \"Biochemical purification from seminal plasma, FTIR spectrometry, low-angle X-ray scattering, unfolding experiments under reducing conditions\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — multiple biophysical methods but single lab, no mutagenesis functional validation\",\n      \"pmids\": [\"9252108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD26 delivers a co-stimulatory T cell activation signal through the CD3 pathway; epitope mapping using truncated and swap mutants localized T-cell costimulation activity to the 248–358 and 359–449 amino acid regions, and the ADA-binding domain to the 359–449 region, demonstrating functionally distinct domains within the extracellular portion of CD26.\",\n      \"method\": \"Truncated and human-rat CD26 swap mutants, cross-blocking with 13 anti-CD26 mAbs, DPP4 enzymatic activity as functional readout\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping by systematic mutagenesis/swap approach, single lab\",\n      \"pmids\": [\"9683260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD26 physically co-distributes and co-immunoprecipitates with CXCR4 on T and B cell membranes; upon SDF-1α stimulation, CD26 is co-internalized with CXCR4 in a CXCR4 internalization-dependent manner (blocked by CXCR4 internalization mutants but not pertussis toxin), indicating a functional CD26/CXCR4 complex in which CD26 can modulate SDF-1α-induced chemotaxis. Additionally, HIV-1 gp120 interacts with CD26 and disrupts the ADA/CD26 interaction through a site distinct from the ADA-binding domain.\",\n      \"method\": \"Co-immunoprecipitation from membrane fractions, co-internalization experiments with CXCR4 mutants, pertussis toxin treatment, flow cytometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple orthogonal approaches (internalization mutants, pharmacological blockade), replicated across T and B cell lines\",\n      \"pmids\": [\"11278278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cell-surface ADA-CD26 interaction mediates adhesion of T lymphocytes to epithelial cells; CD26 overexpression increased T-cell adhesion to Caco-2 epithelial monolayers by ~50%, whereas anti-CD26 antibody targeting the ADA-binding site or exogenous ADA reduced adhesion by 50–70%. This adhesion was mediated by LFA-1 (lymphocyte function-associated antigen) integrin activation.\",\n      \"method\": \"Cell adhesion assays with CD26-overexpressing T cell lines, antibody blocking, FACS integrin activation assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays, genetic overexpression plus antibody blocking, single lab\",\n      \"pmids\": [\"11772392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of the extracellular region of human DPP4 at 2.5 Å (in complex with the inhibitor valine-pyrrolidide) revealed two domains: an eight-bladed β-propeller and an α/β-hydrolase domain; the catalytic site is located in a large cavity between these two domains, and both domains participate in inhibitor/substrate binding, explaining how substrate specificity (N-terminal dipeptides with penultimate Pro or Ala) is achieved.\",\n      \"method\": \"X-ray crystallography at 2.5 Å resolution, inhibitor complex\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with substrate analog, high resolution, foundational structural study\",\n      \"pmids\": [\"12483204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of native porcine DPP4 at 1.8 Å revealed a 2-2-2 symmetric tetrameric assembly dependent on glycosylation of β-propeller blade IV, and identified a Glu-Glu motif as a key substrate-recognition element (distinguishing DPP4 as an aminopeptidase) and an oxyanion trap that activates the P2-carbonyl oxygen for efficient post-proline cleavage. Structure also suggested dual routes for substrate access (β-propeller tunnel) and product exit (side opening).\",\n      \"method\": \"X-ray crystallography at 1.8 Å of native glycosylated porcine DPP4; dipeptide inhibitor complex\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution structure of native glycosylated enzyme with inhibitor complex revealing catalytic mechanism\",\n      \"pmids\": [\"12690074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cryo-TEM and single-particle analysis of rat DPP4/CD26 at ~14 Å resolution confirmed that the protein exists as a dimer and revealed a second lateral opening to the active site distinct from the β-propeller tunnel, suggesting that substrate selectivity and binding rate mechanisms differ from the structurally related serine peptidase POP.\",\n      \"method\": \"Cryo-TEM, single particle analysis, structural comparison by docking calculations\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — 3D structure by cryo-TEM, single lab, limited resolution (~14 Å)\",\n      \"pmids\": [\"12705886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD26 mediates G-CSF-induced mobilization of hematopoietic stem/progenitor cells (HSCs/HPCs) by cleaving CXCL12 at its position-2 proline; CD26-truncated CXCL12(3-68) failed to induce migration of Sca-1+c-kit+lin- cells and acted as an antagonist to intact CXCL12. CD26 inhibition during G-CSF treatment reduced peripheral progenitor cell numbers, demonstrating a mechanistic role in mobilization.\",\n      \"method\": \"Flow cytometry for CD26 expression, in vitro chemotaxis assays with truncated CXCL12, CD26 inhibitor treatment, in vivo G-CSF mobilization model in mice\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional assays with mechanistic dissection (truncated substrate as antagonist) plus in vivo confirmation\",\n      \"pmids\": [\"12576320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Endogenous CD26 expression on donor hematopoietic stem cells negatively regulates homing and bone marrow engraftment; pharmacological inhibition or genetic deletion of CD26 greatly increased transplantation efficiency in mice, demonstrating that CD26 peptidase activity (by cleaving CXCL12/SDF-1) limits HSC homing.\",\n      \"method\": \"CD26 inhibitor treatment and CD26 knockout mouse bone marrow transplantation experiments; engraftment quantification\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition plus genetic knockout with defined engraftment phenotype, replicated across approaches\",\n      \"pmids\": [\"15310902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"DPPIV expression in melanoma cells inhibits cellular invasion: stable transfection of full-length DPPIV cDNA reduced Matrigel invasion by >75% compared to parental or vector-transfected cells. Neither the extracellular serine protease activity nor the 6-amino-acid cytoplasmic domain was required for anti-invasive activity, as mutants lacking either function retained the phenotype.\",\n      \"method\": \"Stable transfection of DPPIV cDNA and active-site/cytoplasmic-domain mutants into melanoma cell lines; Matrigel invasion assays\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis combined with functional invasion assay, multiple mutants tested\",\n      \"pmids\": [\"11467771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD26 binds to caveolin-1 on antigen-presenting cells (APCs) through residues 201–211 of CD26 together with the serine catalytic site at residue 630; this interaction triggers caveolin-1 phosphorylation and NF-κB activation in APCs, leading to CD86 upregulation and subsequent antigen-specific T cell activation. Reduced caveolin-1 expression on APCs abolished CD26-mediated CD86 upregulation and T cell proliferation.\",\n      \"method\": \"Recombinant CD26 binding assays, caveolin-1 siRNA knockdown, NF-κB activation assay, CD86 upregulation measurement, T cell proliferation assay, immunohistochemistry of rheumatoid synovium\",\n      \"journal\": \"Modern rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple functional readouts (phosphorylation, NF-κB, CD86, proliferation) and domain identification, single lab\",\n      \"pmids\": [\"16622717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DPP4 (CD26) is identified as the functional receptor for MERS-CoV (hCoV-EMC); the receptor-binding S1 domain of the MERS-CoV spike protein specifically co-purified with DPP4 from susceptible Huh-7 cell lysates. Anti-DPP4 antibodies blocked MERS-CoV infection of primary human bronchial epithelial cells. Expression of human or bat DPP4 in non-susceptible COS-7 cells conferred susceptibility to infection.\",\n      \"method\": \"Co-purification/affinity pull-down of viral S1 domain with DPP4; antibody inhibition of infection; ectopic DPP4 expression in COS-7 cells enabling infection\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (pull-down, antibody block, gain-of-function expression), foundational receptor identification study\",\n      \"pmids\": [\"23486063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of both the free MERS-CoV spike receptor-binding domain (RBD) and its complex with human DPP4 were determined; the viral RBD contacts blades IV and V of the CD26 β-propeller through a strand-dominated external receptor-binding motif. Binding was confirmed by surface plasmon resonance (Kd = 16.7 nM). The interface is mediated mainly by hydrophilic residues, distinct from other coronavirus-receptor interactions.\",\n      \"method\": \"X-ray crystallography of free RBD and RBD-DPP4 complex; surface plasmon resonance binding assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus SPR quantification, replicated in companion paper\",\n      \"pmids\": [\"23831647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of MERS-CoV RBD bound to the extracellular domain of human DPP4 at 3.0 Å resolution showed that the receptor-binding subdomain of MERS-CoV RBD interacts with the DPP4 β-propeller but not its hydrolase domain. Mutagenesis of key residues in the receptor-binding subdomain abrogated viral binding to DPP4 and cell entry.\",\n      \"method\": \"X-ray crystallography (3.0 Å); site-directed mutagenesis of receptor-binding subdomain residues; viral entry assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis functional validation, replicates findings of companion Nature paper\",\n      \"pmids\": [\"23835475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD26 (DPP4) expressed on CML leukemic stem cells (LSCs) disrupts the SDF-1-CXCR4 axis by cleaving SDF-1, facilitating abnormal extramedullary spread of BCR/ABL1+ LSCs. CD26+ LSCs engrafted NSG mice with BCR/ABL1+ cells, whereas CD26- stem cells from the same patients produced multilineage BCR/ABL1- engraftment. Gliptin-mediated CD26 inhibition suppressed BCR/ABL1+ cell expansion.\",\n      \"method\": \"Functional xenograft engraftment assays (NSG mice), flow cytometry cell sorting, CD26 enzymatic inhibition with gliptins, SDF-1 cleavage assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo engraftment assay with CD26+ vs CD26- sorted cells, mechanistic substrate cleavage demonstration, pharmacological inhibition\",\n      \"pmids\": [\"24778155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DPP4 in hepatocytes is regulated by DNA methylation: demethylation of four intronic CpG sites amplifies glucose-induced DPP4 transcription; this epigenetic reprogramming occurs early in life (6 weeks) in obesity-prone mice, preceding hepatic triglyceride accumulation, and correlates with subsequent hepatosteatosis.\",\n      \"method\": \"Bisulfite sequencing of DPP4 CpG sites, glucose stimulation experiments, longitudinal mouse model comparing obese-prone vs normal mice, human liver biopsy analysis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic epigenetic mapping with functional glucose induction link, mouse and human correlation\",\n      \"pmids\": [\"27999105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TP53 (p53) limits ferroptosis by blocking DPP4 activity in a transcription-independent manner: loss of TP53 prevents nuclear accumulation of DPP4, allowing plasma-membrane-associated DPP4-dependent lipid peroxidation that triggers ferroptosis. This establishes a direct molecular link between TP53 and DPP4 in the control of lipid metabolism.\",\n      \"method\": \"DPP4 activity assays, subcellular fractionation, TP53 loss-of-function experiments, lipid peroxidation assays, erastin-induced ferroptosis model in colorectal cancer cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays (enzymatic activity, subcellular localization, lipid peroxidation, cell death), genetic manipulation of TP53\",\n      \"pmids\": [\"28813679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DPP4 is selectively expressed on the surface of senescent (but not proliferating) human diploid fibroblasts, as identified by mass spectrometry surfaceome analysis. Surface DPP4 preferentially sensitizes senescent cells to NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC), enabling their selective elimination.\",\n      \"method\": \"Mass spectrometry surface proteome analysis, flow cytometry with anti-DPP4 antibodies for cell sorting, ADCC assays with NK cells\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — unbiased proteomic discovery plus functional ADCC validation, multiple experimental approaches\",\n      \"pmids\": [\"28877934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In obesity, hepatocytes synthesize and secrete DPP4, which acts together with plasma factor Xa to activate ATM (adipose tissue macrophage) inflammation via PAR2 signaling, promoting visceral adipose tissue inflammation and insulin resistance. Silencing hepatocyte DPP4 or macrophage caveolin-1 or PAR2 suppressed inflammation and insulin resistance; the oral DPP4 inhibitor sitagliptin did not recapitulate this effect, indicating a non-enzymatic or paracrine mechanism.\",\n      \"method\": \"Hepatocyte-specific DPP4 siRNA silencing in mice; caveolin-1 and PAR2 knockdown in macrophages; measurement of VAT inflammation and insulin sensitivity; sitagliptin comparison\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific genetic silencing with defined molecular pathway (DPP4→Factor Xa→PAR2), multiple knockdown targets, in vivo model\",\n      \"pmids\": [\"29562231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Adenosine deaminase (ADA) bridges CD26 on T cells and adenosine A2A receptor (A2AR) on dendritic cells to form a trimeric CD26-ADA-A2AR complex spanning two cell surfaces. This was demonstrated by NanoBRET (inter-cellular BRET), site-directed mutagenesis of ADA residues involved in A2AR binding, and functional dynamic mass redistribution assays, suggesting ADA acts as a cell-to-cell connector.\",\n      \"method\": \"NanoBRET (inter-cellular bioluminescence resonance energy transfer), site-directed mutagenesis, dynamic mass redistribution assay, ligand binding assay\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — novel BRET-based inter-cellular complex detection with mutagenesis validation and functional assays\",\n      \"pmids\": [\"29497379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DPP4 enzymatic cleavage of CCL11 (eotaxin) regulates eosinophil trafficking into tumors; inhibition of DPP4 by sitagliptin preserved functional CCL11, increased eosinophil tumor infiltration, and enhanced tumor control in hepatocellular carcinoma and breast cancer models. This mechanism was independent of lymphocytes and required IL-33 expression by tumor cells and eosinophil degranulation.\",\n      \"method\": \"DPP4 inhibitor (sitagliptin) treatment in syngeneic mouse tumor models; eosinophil depletion experiments; lymphocyte-deficient mice; IL-33 manipulation; CCL11 quantification\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with multiple depletion/genetic experiments in vivo, substrate (CCL11) quantification, replication across two cancer models\",\n      \"pmids\": [\"30778250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Oxidized LDL upregulates DPP4 expression on macrophages through a TLR4/TRIF/CD36 signaling pathway; oxLDL (but not native LDL) increased DPP4 expression preferentially in CD36+ macrophages, and this effect was substantially reduced by TLR4 knockdown, CD36 deficiency, or TRIF (but not MyD88) deficiency.\",\n      \"method\": \"Flow cytometry, TLR4 knockdown, CD36-deficient macrophages, TRIF/MyD88-deficient cells, DPP4 enzymatic activity assay\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic loss-of-function approaches with mechanistic pathway definition, single lab\",\n      \"pmids\": [\"30738832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Glucocorticoid receptor (GR) directly induces DPP4 gene transcription in macrophages by binding to two glucocorticoid-responsive elements (GREs) within the DPP4 promoter; glucocorticoid-induced DPP4 expression mediates macrophage migration, as siRNA-mediated knockdown of GR or DPP4 blocked dexamethasone-induced macrophage migration in THP-1 cells and murine peritoneal macrophages.\",\n      \"method\": \"Transcriptome analysis (RNA-seq), ChIP (GR binding to DPP4 promoter GREs), siRNA knockdown of GR and DPP4, GR antagonist (RU-486), macrophage migration assays, DPP4 enzymatic activity measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP demonstrating direct promoter binding, multiple orthogonal interventions (antagonist, siRNA, inhibitor) with defined migration phenotype\",\n      \"pmids\": [\"31988243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DPP4 was identified as a novel adipokine secreted from differentiated human adipocytes; DPP4 protein concentration in visceral fat was ~5-fold higher than in subcutaneous fat in obese patients. Direct addition of soluble DPP4 to fat, skeletal muscle, and smooth muscle cells impaired insulin signaling in an autocrine/paracrine manner. DPP4 release from adipose tissue strongly correlated with adipocyte volume.\",\n      \"method\": \"Proteomic profiling of human adipocyte secretome, depot-specific DPP4 expression measurement, direct addition of recombinant DPP4 to target cells with insulin signaling readout, adipose tissue explant release assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomic discovery followed by functional validation with recombinant DPP4 and human adipose tissue, multiple orthogonal methods\",\n      \"pmids\": [\"21593202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DPP4 knockdown in human preadipocytes using lentiviral shRNA altered gene expression (upregulating metabolic genes PDK4 and PGC1α, downregulating proliferation genes including FGF7), retarded preadipocyte proliferation, and markedly diminished basal and insulin-induced ERK (but not Akt) activation by ~60%, indicating DPP4 modulates growth factor signaling during adipocyte differentiation.\",\n      \"method\": \"Lentiviral DPP4 knockdown, whole-genome DNA array, quantitative PCR, western blotting for ERK and Akt phosphorylation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide expression profiling plus specific signaling pathway validation, single lab\",\n      \"pmids\": [\"26983599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DPP4 inhibition combined with dmPGE2 treatment synergistically enhances bone marrow HSC engraftment; pretreatment of donor cells with diprotin A (DPP4 inhibitor) or dmPGE2 and pretreatment of irradiated recipients with sitagliptin each improved engraftment, and the combined approach was significantly superior to either treatment alone in a congenic competitive repopulation model.\",\n      \"method\": \"Congenic CD45+ mouse bone marrow transplantation, pharmacological DPP4 inhibition (diprotin A, sitagliptin), dmPGE2 treatment, competitive repopulation assay\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo functional engraftment assay with multiple inhibitor approaches and combination testing\",\n      \"pmids\": [\"24602918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Skin fibrosis driven by Wnt/β-catenin signaling requires DPP4 as a downstream effector: DPP4 is a Wnt/β-catenin-responsive gene, and genetic evidence showed the Wnt/DPP4 axis is required for fibrotic dermal remodeling including ECM expansion and dermal adipocyte shrinkage. DPP4 inhibitors reversed established Wnt-induced fibrosis in mouse skin.\",\n      \"method\": \"Genetically inducible/reversible Wnt activation mouse model, Dpp4 genetic knockout, DPP4 inhibitor treatment, skin architecture analysis, human skin fibrosis correlation\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (Wnt activation + Dpp4 knockout), pharmacological reversal, in vivo fibrosis model with defined molecular pathway\",\n      \"pmids\": [\"34808238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD26 promotes colorectal cancer angiogenesis and metastasis through a CAV1/MMP1 signaling axis: CD26 overexpression upregulated MMP1 expression, and caveolin-1 (CAV1) overexpression abrogated CD26-regulated MMP1 induction. CD26 functionally regulated CRC cell migration and invasion in vitro and angiogenesis and metastasis in vivo.\",\n      \"method\": \"Genome-wide mRNA expression array, qPCR, wound healing and invasion assays, mouse models of CRC metastasis, CAV1 overexpression rescue experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screening plus functional validation with rescue experiment defining CAV1/MMP1 pathway, in vivo confirmation\",\n      \"pmids\": [\"35163100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Purified recombinant human DPP4 (produced in insect cells) does not bind SARS-CoV-2 full-length spike protein or its receptor-binding domain, as measured by surface plasmon resonance and ELISA, demonstrating that unlike MERS-CoV, SARS-CoV-2 does not use DPP4 as a receptor.\",\n      \"method\": \"Recombinant protein purification, surface plasmon resonance, ELISA binding assay\",\n      \"journal\": \"Molecules\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro binding assay with purified proteins using two orthogonal methods (SPR + ELISA)\",\n      \"pmids\": [\"33218025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DPP4 on the surface of senescence-associated extracellular vesicles (S-EVs) renders them refractory to uptake by proliferating cells; surfaceome proteomics of EVs from multiple senescence models consistently showed DPP4 enrichment on S-EVs, and ectopic DPP4 overexpression in HeLa cells produced EVs that were no longer taken up by proliferating cells.\",\n      \"method\": \"Surface proteomics of EVs from replicative, radiation-induced, and etoposide-induced senescent cells; DPP4 overexpression in HeLa cells; EV uptake assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased proteomic discovery replicated across three senescence models, gain-of-function EV uptake experiment\",\n      \"pmids\": [\"37862381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Bat coronavirus HKU4-RBD binds human DPP4 (hCD26) and pseudotyped viruses with HKU4 spike infect cells via hCD26, supporting a bat origin for MERS-CoV. Crystal structure of HKU4-RBD/hCD26 complex revealed a binding mode similar to MERS-RBD but with lower affinity, explained by fewer optimized contact residues.\",\n      \"method\": \"Receptor binding assays, pseudovirus infection assays, X-ray crystallography of HKU4-RBD/hCD26 complex\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus functional infection assay, mechanistic comparison with MERS-RBD\",\n      \"pmids\": [\"25211075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of DPPIV expression in melanomas occurs at the RNA level and is attributable to promoter hypermethylation: DPPIV gene promoter is methylated in 8 of 10 melanoma cell lines, and demethylating agent 5-aza-2'-deoxycytidine restored DPPIV mRNA, protein, and enzyme activity, correlating with growth inhibition and apoptosis in melanoma cells.\",\n      \"method\": \"Bisulfite genomic sequencing, 5-aza-2'-deoxycytidine treatment, RT-PCR, western blot, DPPIV enzyme activity assay, growth inhibition assay\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter methylation sequencing with pharmacological demethylation functional rescue, multiple readouts\",\n      \"pmids\": [\"17981724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD26 deficiency in mice leads to enhanced ovalbumin-induced airway inflammation characterized by increased eosinophilic infiltrates, elevated Th2 cytokines (IL-4, IL-5, IL-13) in bronchoalveolar lavage, and increased eotaxin/RANTES and their receptors CCR3/CCR5, suggesting CD26 normally restricts Th2-mediated airway inflammation, likely through chemokine cleavage.\",\n      \"method\": \"CD26 knockout mice, OVA sensitization/challenge model, cytokine measurement in BAL, immunohistochemistry, qRT-PCR\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with comprehensive inflammatory phenotyping, single lab\",\n      \"pmids\": [\"22101691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD26 signaling promotes human osteoclast (OC) differentiation via the MKK3/6–p38 MAPK–mi/Mitf phosphorylation pathway; M-CSF and sRANKL induced CD26 expression on OC precursors concomitantly with p38 MAPK phosphorylation. Anti-CD26 monoclonal antibody (huCD26mAb) blocked early OC differentiation by inactivating MKK3/6 and p38 MAPK, and p38 MAPK inhibitor phenocopied the effect.\",\n      \"method\": \"Human OC differentiation assay with M-CSF/sRANKL, anti-CD26 mAb treatment, p38 MAPK inhibitor, western blotting for MKK3/6 and MAPK phosphorylation, TRAP staining, OC functional assays\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody blockade plus pharmacological pathway inhibition with mechanistic phosphorylation readouts\",\n      \"pmids\": [\"24821427\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DPP4 (CD26) is a type II transmembrane serine exopeptidase with an eight-bladed β-propeller and α/β-hydrolase domain forming the catalytic cavity; it cleaves N-terminal dipeptides from substrates with penultimate Pro or Ala (including incretin hormones GLP-1 and GIP, chemokines CXCL12/SDF-1 and CCL11, and neuropeptides), inactivating or modifying these ligands; it serves as the functional cell-entry receptor for MERS-CoV (binding the viral RBD on β-propeller blades IV-V); it functions as a signaling scaffold that associates with CXCR4, adenosine deaminase, caveolin-1, CD45, and the adenosine A2A receptor to co-stimulate T cells and regulate lymphocyte trafficking; as a hepatocyte- and adipocyte-secreted adipokine it promotes visceral adipose tissue inflammation (via Factor Xa/PAR2) and impairs insulin signaling; it mediates hematopoietic stem cell homing/engraftment by cleaving CXCL12; it is selectively upregulated on senescent cells and their extracellular vesicles; and in cancer it can suppress invasion (e.g., melanoma) or promote metastasis (e.g., colorectal cancer via CAV1/MMP1), while TP53 restrains its plasma-membrane-associated lipid peroxidation activity to limit ferroptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DPP4/CD26 is a homodimeric type II transmembrane serine exopeptidase that cleaves N-terminal dipeptides from substrates bearing proline or alanine at position 2, thereby regulating the bioactivity of chemokines, incretins, and other signaling peptides, while also serving as a multifunctional co-stimulatory molecule on T cells and a viral entry receptor [PMID:9553764, PMID:15310902, PMID:23831647]. Its cleavage of CXCL12 truncates the chemokine into a CXCR4 antagonist, controlling hematopoietic stem cell homing and mobilization, and its processing of CXCL10 and CCL11 modulates eosinophil and lymphocyte tumor infiltration [PMID:15310902, PMID:12576320, PMID:30738250]. Beyond peptidase activity, DPP4 delivers T-cell co-stimulatory signals through association with CD45, ADA, caveolin-1, and CXCR4, triggering tyrosine phosphorylation cascades and NF-κB activation, and in non-immune contexts it regulates ferroptosis via TP53-dependent control of its plasma membrane localization and drives adipose tissue macrophage inflammation through a secreted DPP4–factor Xa–caveolin-1–PAR2 axis [PMID:1356916, PMID:16622717, PMID:28813679, PMID:29562231]. Its transcription is directly induced by glucocorticoid receptor binding to GRE elements in the DPP4 promoter and is epigenetically silenced by promoter hypermethylation in melanoma [PMID:31988243, PMID:17981724].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing that CD26 ligation triggers intracellular signaling resolved whether CD26 is merely an ectoenzyme or also a signal-transducing co-stimulatory molecule on T cells.\",\n      \"evidence\": \"Anti-CD26 mAb stimulation induced tyrosine phosphorylation and IL-2 expression in T cells, blocked by tyrosine kinase inhibitor\",\n      \"pmids\": [\"1356916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the tyrosine kinases activated downstream of CD26 was not determined\", \"Single lab observation without independent replication at the time\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Biophysical characterization of purified DPP4 established its homodimeric quaternary structure, domain organization, and ADA-binding capacity independent of catalytic activity.\",\n      \"evidence\": \"Low-angle X-ray scattering, FTIR, and kinetic analysis of purified human serum DPP4 showing 250 kDa dimer with three domains per subunit\",\n      \"pmids\": [\"9252108\", \"8951616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Atomic-resolution structure was not yet available\", \"Allosteric regulation by Gly-X dipeptides not confirmed in cellular context\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"A comprehensive characterization defined the dual identity of CD26 as both a serine exopeptidase cleaving after Pro/Ala and a T-cell co-stimulatory molecule that associates with CD45 and ADA.\",\n      \"evidence\": \"Biochemical characterization, co-IP, and T-cell activation assays across multiple labs\",\n      \"pmids\": [\"9553764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CD45 interaction unresolved\", \"Relative contributions of enzymatic versus non-enzymatic functions in vivo unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery of a physical CD26-CXCR4 complex on lymphocytes suggested a mechanism by which CD26 peptidase activity could locally regulate CXCL12 signaling at its receptor.\",\n      \"evidence\": \"Co-immunoprecipitation and co-internalization of CD26 and CXCR4 upon SDF-1α stimulation in T and B cell lines\",\n      \"pmids\": [\"11278278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab co-IP without reciprocal validation from independent group\", \"Whether complex formation is direct or bridged by CXCL12 was not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Two studies established that DPP4 cleavage of CXCL12 on hematopoietic progenitors generates a CXCR4 antagonist, providing the molecular mechanism for DPP4's role in stem cell mobilization and homing.\",\n      \"evidence\": \"Chemotaxis assays with intact vs truncated CXCL12, CD26 inhibitor in G-CSF mobilization model, cryo-EM confirmation of homodimeric structure with lateral catalytic access\",\n      \"pmids\": [\"12576320\", \"12705886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other DPP4 substrates contributing to mobilization not excluded\", \"Cryo-EM resolution (~14 Å) insufficient for atomic detail\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"In vivo validation using CD26 knockout mice and transplantation demonstrated that DPP4-mediated CXCL12 truncation functionally controls hematopoietic engraftment efficiency.\",\n      \"evidence\": \"CD26 KO mice, DPP4 inhibitor treatment, and in vivo transplantation showing enhanced homing and engraftment\",\n      \"pmids\": [\"15310902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of other DPP4 substrates (e.g., neuropeptides, other chemokines) to engraftment phenotype not dissected\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapping the caveolin-1 binding site on CD26 and demonstrating NF-κB/CD86 induction defined a trans-cellular co-stimulatory pathway between T cells and APCs mediated by CD26-caveolin-1 interaction.\",\n      \"evidence\": \"Mutagenesis of CD26 residues 201-211 and Ser630, caveolin-1 phosphorylation and NF-κB activation assays\",\n      \"pmids\": [\"16622717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CD26-caveolin-1 interface not determined at atomic level\", \"Single lab; independent replication needed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that DPP4 silencing in melanoma occurs through promoter CpG hypermethylation revealed an epigenetic mechanism controlling DPP4 expression in cancer.\",\n      \"evidence\": \"Bisulfite sequencing of DPP4 promoter, 5-aza-2'-deoxycytidine restoration of DPP4 mRNA/protein/activity with growth inhibition\",\n      \"pmids\": [\"17981724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether methylation-mediated silencing is causative or correlative for melanoma progression not established\", \"Mechanism by which restored DPP4 induces apoptosis unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The atomic-resolution crystal structure of MERS-CoV RBD bound to CD26 defined the virus entry mechanism through blades IV-V of the β-propeller domain, separate from the catalytic domain.\",\n      \"evidence\": \"X-ray crystallography of MERS-CoV RBD–DPP4 complex, SPR binding (Kd 16.7 nM)\",\n      \"pmids\": [\"23831647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether enzymatic activity is affected by RBD binding not addressed\", \"Structure from one viral isolate; strain variation in binding not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of CD26 as a leukemic stem cell marker in CML, where its CXCL12 cleavage disrupts marrow retention, provided a disease-specific mechanism for abnormal mobilization.\",\n      \"evidence\": \"Flow cytometry, enzymatic cleavage assays, NSG mouse engraftment, gliptin treatment reducing BCR/ABL1+ expansion\",\n      \"pmids\": [\"24778155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DPP4 inhibitors affect CML LSC engraftment in patients not confirmed clinically\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Multiple studies expanded DPP4's signaling roles: DPP4 knockdown in preadipocytes revealed ERK-dependent proliferative control, DPP4 inhibition preserved chemokine integrity enabling eosinophil anti-tumor immunity, and angiotensin II was shown to stimulate DPP4 via AT1R/EGFR/MEK/ERK signaling in proximal tubules.\",\n      \"evidence\": \"Lentiviral KD with microarray/Western blot in preadipocytes; sitagliptin in HCC/breast cancer models with eosinophil depletion; Ang II infusion with DPP4/MEK inhibitors in proximal tubules\",\n      \"pmids\": [\"26983599\", \"30778250\", \"27213360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DPP4 substrates mediating ERK activation in preadipocytes not identified\", \"Relative contributions of CXCL10 vs CCL11 cleavage to tumor immune evasion not fully dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two discoveries placed DPP4 in cell fate decisions: TP53 controls DPP4 plasma membrane localization to regulate ferroptosis, and DPP4 surface expression marks senescent cells for NK-mediated elimination.\",\n      \"evidence\": \"Subcellular fractionation and erastin-induced ferroptosis in TP53-null cells; surface proteomics and ADCC assays on senescent fibroblasts\",\n      \"pmids\": [\"28813679\", \"28877934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which TP53 retains DPP4 in the nucleus not defined\", \"Whether DPP4 enzymatic activity is required for ferroptosis or senescence clearance is unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Hepatocyte-secreted DPP4 was shown to activate adipose tissue macrophage inflammation through a factor Xa/caveolin-1/PAR2 pathway, establishing a liver-adipose endocrine axis in obesity, while ADA was shown to bridge CD26 on T cells to A2A receptors on dendritic cells via a trimeric complex.\",\n      \"evidence\": \"Hepatocyte-specific DPP4 silencing in obese mice with ATM-specific caveolin-1/PAR2 silencing; NanoBRET and site-directed mutagenesis of ADA-A2AR interface\",\n      \"pmids\": [\"29562231\", \"29497379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether soluble DPP4's enzymatic activity is required for PAR2 activation or serves a scaffolding function unclear\", \"Stoichiometry of the CD26-ADA-A2AR trimeric complex not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"GR-mediated transcriptional induction of DPP4 via direct GRE binding defined a glucocorticoid-responsive regulatory module controlling DPP4 expression and macrophage migration, while DPP4 was excluded as a SARS-CoV-2 receptor.\",\n      \"evidence\": \"GR ChIP at DPP4 promoter GREs with siRNA/antagonist validation; SPR and ELISA showing no binding between DPP4 and SARS-CoV-2 spike\",\n      \"pmids\": [\"31988243\", \"33218025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GR-driven DPP4 induction operates in non-macrophage cell types not tested\", \"Other potential co-receptors for SARS-CoV-2 involving DPP4 not fully excluded\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic and pharmacological evidence placed DPP4 downstream of Wnt/β-catenin in skin fibrosis, extending DPP4's roles beyond immune and metabolic regulation into tissue remodeling.\",\n      \"evidence\": \"Inducible Wnt mouse model, DPP4 knockout, DPP4 inhibitor reversing established fibrosis\",\n      \"pmids\": [\"34808238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DPP4 substrates mediating fibrotic remodeling not identified\", \"Whether DPP4 enzymatic activity or surface expression drives fibrosis unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"DPP4 on senescence-associated extracellular vesicles was found to repress EV uptake by proliferating cells, revealing a non-enzymatic role in intercellular communication.\",\n      \"evidence\": \"Surface proteomics of S-EVs followed by ectopic DPP4 overexpression blocking EV internalization\",\n      \"pmids\": [\"37862381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which surface DPP4 blocks EV uptake is unknown\", \"Whether enzymatic activity contributes to EV uptake repression not tested\", \"In vivo relevance not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: what mechanism underlies TP53-dependent nuclear retention of DPP4, which specific DPP4 substrates drive ferroptosis-associated lipid peroxidation, whether enzymatic versus scaffolding functions can be genetically separated in vivo across disease contexts, and the structural basis of DPP4 interactions with CD45 and CXCR4.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No separation-of-function mutant tested in vivo for enzymatic vs scaffolding roles\", \"Structural basis of DPP4-CD45 and DPP4-CXCR4 interactions lacking\", \"Nuclear function of DPP4 entirely undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3, 7, 18, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 17]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 12, 19]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5, 14, 23]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [6, 10, 26]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 8, 12, 18, 28, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 17, 19, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 7, 24, 25]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 26]}\n    ],\n    \"complexes\": [\n      \"CD26-ADA-A2AR trimeric complex\",\n      \"CD26-CXCR4 complex\"\n    ],\n    \"partners\": [\n      \"ADA\",\n      \"CXCR4\",\n      \"CAV1\",\n      \"CD45\",\n      \"CXCL12\",\n      \"TP53\",\n      \"F2RL1\",\n      \"F10\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"DPP4 (CD26) is a type II transmembrane serine exopeptidase that cleaves N-terminal dipeptides from substrates bearing a penultimate proline or alanine, thereby inactivating incretin hormones (GLP-1, GIP), chemokines (CXCL12/SDF-1, CCL11/eotaxin), and other bioactive peptides to regulate glucose homeostasis, hematopoietic stem cell homing, and immune cell trafficking [PMID:8100523, PMID:12576320, PMID:30778250]. Structurally, the extracellular region forms a homodimer comprising an eight-bladed β-propeller and an α/β-hydrolase domain that together create the catalytic cavity, and the β-propeller additionally serves as the binding site for the MERS-CoV spike receptor-binding domain, establishing DPP4 as the functional entry receptor for MERS-CoV [PMID:12483204, PMID:23486063, PMID:23831647]. Beyond its peptidase activity, DPP4 functions as a multivalent signaling scaffold on T cells and antigen-presenting cells by directly associating with adenosine deaminase, CXCR4, caveolin-1, and the adenosine A2A receptor to co-stimulate T cell activation, regulate lymphocyte adhesion, and modulate NF-κB-dependent antigen presentation [PMID:8101391, PMID:11278278, PMID:16622717, PMID:29497379]. DPP4 also acts as a hepatocyte- and adipocyte-secreted adipokine that promotes visceral adipose tissue inflammation via a Factor Xa/PAR2 pathway and impairs insulin signaling, and its plasma-membrane localization is regulated by TP53 to control lipid peroxidation and ferroptosis sensitivity [PMID:29562231, PMID:21593202, PMID:28813679].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identifying DPP4 as the principal serine exopeptidase responsible for incretin inactivation established its central role in glucose homeostasis and provided the mechanistic basis for DPP4 inhibitor (gliptin) drug development.\",\n      \"evidence\": \"Purified placental DPP4 kinetic assays with GLP-1/GIP substrates and specific inhibitors in human serum\",\n      \"pmids\": [\"8100523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics measured with purified enzyme; in vivo substrate hierarchy not fully resolved\", \"Contribution of soluble vs membrane-bound DPP4 to systemic incretin degradation not distinguished\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrating that CD26 is the lymphocyte surface receptor for adenosine deaminase (ADA) revealed a non-enzymatic scaffolding function and linked DPP4 to purine metabolism and immune regulation.\",\n      \"evidence\": \"Co-immunoprecipitation and in vitro binding with recombinant extracellular domain, amino acid sequence confirmation\",\n      \"pmids\": [\"8101391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of ADA binding on local adenosine concentrations not quantified\", \"Whether ADA binding modulates DPP4 catalytic activity was not tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Domain mapping showed that T cell co-stimulation and ADA binding map to distinct but overlapping regions (aa 248–449) of the extracellular domain, establishing DPP4 as a modular signaling scaffold independent of its peptidase activity.\",\n      \"evidence\": \"Truncated and human–rat CD26 swap mutants with functional readouts and cross-blocking by 13 anti-CD26 mAbs\",\n      \"pmids\": [\"9683260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathways triggered by co-stimulation domain not identified\", \"Results from chimeric constructs may not capture native folding constraints\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery of a physical CD26/CXCR4 complex that co-internalizes upon SDF-1α stimulation explained how DPP4 coordinates chemokine cleavage with receptor signaling to regulate lymphocyte chemotaxis.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation from T/B cell membranes, co-internalization with CXCR4 wild-type and mutants, pertussis toxin treatment\",\n      \"pmids\": [\"11278278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and direct binding interface between CD26 and CXCR4 not determined\", \"Whether complex formation alters DPP4 enzymatic kinetics toward SDF-1 is unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"High-resolution crystal structures of DPP4 revealed the β-propeller/α/β-hydrolase architecture, the Glu-Glu substrate recognition motif, and dual substrate-access routes, providing the structural framework for understanding catalytic specificity and inhibitor design.\",\n      \"evidence\": \"X-ray crystallography of human DPP4 at 2.5 Å (with valine-pyrrolidide) and porcine DPP4 at 1.8 Å; cryo-TEM at ~14 Å confirming dimeric assembly and lateral opening\",\n      \"pmids\": [\"12483204\", \"12690074\", \"12705886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of full-length membrane-anchored DPP4 in lipid bilayer\", \"Dynamics of substrate entry through β-propeller tunnel vs. side opening not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that DPP4 cleaves CXCL12/SDF-1 to regulate hematopoietic stem cell mobilization and that CD26-truncated CXCL12 acts as a CXCR4 antagonist established a direct mechanism for DPP4 in HSC trafficking.\",\n      \"evidence\": \"In vitro chemotaxis with truncated CXCL12, DPP4 inhibitor treatment during G-CSF mobilization in mice\",\n      \"pmids\": [\"12576320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of membrane-bound vs. soluble DPP4 in HSC niche not distinguished\", \"Other DPP4 substrates in the marrow microenvironment not surveyed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic deletion and pharmacological inhibition of CD26 in donor HSCs dramatically enhanced bone marrow engraftment, validating DPP4 as a therapeutic target for transplantation.\",\n      \"evidence\": \"CD26 knockout mouse and diprotin A/sitagliptin treatment in bone marrow transplant models with competitive repopulation\",\n      \"pmids\": [\"15310902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term engraftment and multilineage reconstitution data limited\", \"Whether DPP4 inhibition affects graft-versus-host disease not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of CD26–caveolin-1 binding on APCs that triggers NF-κB activation and CD86 upregulation revealed how DPP4 functions as a co-stimulatory molecule bridging T cells and antigen-presenting cells.\",\n      \"evidence\": \"Recombinant CD26 binding assays, caveolin-1 siRNA, NF-κB and CD86 readouts, T cell proliferation\",\n      \"pmids\": [\"16622717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface between CD26 and caveolin-1 not structurally resolved\", \"Single-lab finding; independent replication needed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that DPP4 silencing in melanoma occurs through promoter hypermethylation, and that demethylation restores expression and suppresses growth, linked epigenetic regulation to DPP4's tumor-suppressive function.\",\n      \"evidence\": \"Bisulfite sequencing of melanoma cell lines, 5-aza-2'-deoxycytidine restoration of DPP4 mRNA/protein/activity, growth inhibition assay\",\n      \"pmids\": [\"17981724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether restored DPP4 suppresses invasion through the same enzymatic-independent mechanism shown earlier (PMID:11467771) not tested\", \"Methylation status in primary melanoma specimens not comprehensively surveyed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of DPP4 as an adipokine secreted preferentially from visceral adipose tissue that directly impairs insulin signaling revealed an autocrine/paracrine metabolic function beyond incretin degradation.\",\n      \"evidence\": \"Proteomic profiling of human adipocyte secretome, recombinant DPP4 addition to fat/muscle cells with insulin signaling readout\",\n      \"pmids\": [\"21593202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether insulin-impairing effect requires DPP4 catalytic activity not determined\", \"Receptor or binding partner on target cells mediating this effect not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification and structural characterization of DPP4 as the functional receptor for MERS-CoV, with the viral RBD contacting β-propeller blades IV–V, established a non-enzymatic viral entry role and explained species tropism.\",\n      \"evidence\": \"Affinity pull-down, antibody blocking, ectopic expression conferring susceptibility, crystal structures of MERS-RBD/DPP4 complex at 2.9–3.0 Å, SPR (Kd = 16.7 nM)\",\n      \"pmids\": [\"23486063\", \"23831647\", \"23835475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DPP4 enzymatic activity is altered upon viral binding not determined\", \"Post-binding entry mechanism (endocytic route, membrane fusion) not fully characterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that TP53 retains DPP4 in the nucleus to prevent plasma-membrane-associated lipid peroxidation and ferroptosis established a transcription-independent TP53–DPP4 axis controlling cell death through lipid metabolism.\",\n      \"evidence\": \"DPP4 activity assays, subcellular fractionation, TP53 loss-of-function, lipid peroxidation quantification, erastin-induced ferroptosis model\",\n      \"pmids\": [\"28813679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear function of DPP4 (if any) not characterized\", \"Direct physical interaction between TP53 and DPP4 not demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Unbiased surfaceome analysis showing selective DPP4 upregulation on senescent cells opened DPP4 as a senescence biomarker and revealed it sensitizes senescent cells to NK-mediated ADCC clearance.\",\n      \"evidence\": \"Mass spectrometry surface proteomics of senescent vs. proliferating fibroblasts, flow cytometry, ADCC functional assay\",\n      \"pmids\": [\"28877934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism driving senescence-specific DPP4 upregulation not defined\", \"Whether DPP4 enzymatic activity is required for ADCC sensitization not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining a hepatocyte DPP4–Factor Xa–PAR2 pathway that drives adipose tissue macrophage inflammation in obesity revealed a non-enzymatic or paracrine mechanism distinct from the incretin-degradation function targeted by oral gliptins.\",\n      \"evidence\": \"Hepatocyte-specific DPP4 silencing, caveolin-1 and PAR2 knockdown in macrophages, sitagliptin comparison in obese mice\",\n      \"pmids\": [\"29562231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DPP4 directly activates Factor Xa or serves as a co-factor not resolved\", \"Relevance of this pathway in human obesity requires clinical validation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Detection of a trimeric CD26–ADA–A2AR complex spanning two cell surfaces demonstrated how ADA bridges DPP4 on T cells to adenosine receptors on dendritic cells, integrating purine catabolism with immune synapse signaling.\",\n      \"evidence\": \"Inter-cellular NanoBRET, site-directed ADA mutagenesis, dynamic mass redistribution assay\",\n      \"pmids\": [\"29497379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the trimeric complex not demonstrated\", \"Stoichiometry and structural basis of the ternary complex not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that DPP4 cleavage of CCL11/eotaxin limits eosinophil tumor infiltration provided a mechanism by which DPP4 inhibition can enhance anti-tumor innate immunity independently of lymphocytes.\",\n      \"evidence\": \"Sitagliptin treatment in syngeneic HCC and breast cancer models, eosinophil depletion, lymphocyte-deficient mice, CCL11 quantification\",\n      \"pmids\": [\"30778250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other DPP4 chemokine substrates contribute to eosinophil exclusion not addressed\", \"Human clinical relevance of eosinophil-mediated anti-tumor effect with DPP4 inhibition not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placing DPP4 downstream of Wnt/β-catenin signaling as a required effector of skin fibrosis expanded DPP4's role to extracellular matrix remodeling and identified it as a druggable node in fibrotic disease.\",\n      \"evidence\": \"Genetically inducible Wnt activation with Dpp4 knockout epistasis, DPP4 inhibitor reversal of established fibrosis in mouse skin\",\n      \"pmids\": [\"34808238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DPP4 substrate(s) mediating fibrotic remodeling downstream of Wnt not identified\", \"Applicability to organ fibrosis beyond skin not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that DPP4 on senescence-associated extracellular vesicles renders them refractory to uptake by proliferating cells suggested a mechanism for selective senescent cell communication.\",\n      \"evidence\": \"Surface proteomics of EVs from three senescence models; DPP4 overexpression in HeLa producing EVs with reduced uptake\",\n      \"pmids\": [\"37862381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which surface DPP4 blocks EV uptake (receptor masking, repulsion) not defined\", \"In vivo consequences of altered EV uptake not examined\", \"Overexpression system may not recapitulate physiological DPP4 density on S-EVs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of full-length membrane-anchored DPP4 in lipid bilayers, the precise mechanism by which TP53 directs DPP4 nuclear retention, the identity of DPP4 substrates mediating Wnt-driven fibrosis, and whether the hepatocyte DPP4–Factor Xa–PAR2 inflammatory pathway operates through DPP4's catalytic or scaffolding function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of full-length membrane-embedded DPP4\", \"TP53–DPP4 physical interaction and nuclear DPP4 function uncharacterized\", \"Substrate identity in fibrosis context unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 9, 10, 16, 22]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [13, 14, 15, 32]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 12, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 4, 13, 19]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [25, 20, 31]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [31]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3, 4, 5, 12, 21, 22, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 12, 20, 26, 29, 35]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 17, 25]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 6, 7, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 14, 15, 16, 29, 32]}\n    ],\n    \"complexes\": [\n      \"CD26-ADA-A2AR trimeric complex\",\n      \"CD26/CXCR4 signaling complex\"\n    ],\n    \"partners\": [\n      \"ADA\",\n      \"CXCR4\",\n      \"CAV1\",\n      \"TP53\",\n      \"F10\",\n      \"F2RL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}