{"gene":"DPP4","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1999,"finding":"DPP4/CD26 functions as a serine exopeptidase that cleaves N-terminal dipeptides from regulatory peptides bearing L-proline or L-alanine at the penultimate position, thereby inactivating substrates including GLP-1, GLP-2, GIP, NPY, peptide YY, GHRH, RANTES, SDF-1, eotaxin, and MDC; this activity was demonstrated through in vitro and in vivo experiments.","method":"In vitro enzymatic assays and in vivo peptide cleavage experiments","journal":"Regulatory peptides","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic characterization replicated across multiple substrates and multiple labs over two decades","pmids":["10588446"],"is_preprint":false},{"year":2003,"finding":"CD26/DPP4 dimerization and peptidase activity both require the C-terminal portion of the predicted alpha/beta hydrolase domain (residues 501–766); chimeric proteins replacing this region with homologous sequences from DP8 or DP9 lacked dimerization and peptidase activity. Deletion of N-terminal residues of the alpha/beta hydrolase domain also ablated peptidase activity and greatly reduced cell-surface expression.","method":"Domain-swap chimera mutagenesis, cell-surface expression assay, enzymatic activity assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with mutagenesis and multiple orthogonal readouts in a single focused study","pmids":["12534281"],"is_preprint":false},{"year":1998,"finding":"CD26 co-stimulates T-cell activation through the CD3 pathway; the epitopes required for T-cell co-stimulation were mapped to the 248–358 and 359–449 amino acid regions, while the ADA binding domain lies within the 359–449 region, using truncated and human-rat swap mutants plus cross-blocking with 13 anti-CD26 mAbs.","method":"Epitope mapping with truncated/chimeric CD26 mutants, cross-blocking assays, T-cell co-stimulation functional assays","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis with functional co-stimulation readout, single lab","pmids":["9683260"],"is_preprint":false},{"year":1998,"finding":"CD26 on the surface of T cells acts as the receptor for adenosine deaminase (ADA), binding ADA on the cell surface and thereby mediating co-stimulatory signals; CD26 also interacts with CD45, a protein tyrosine phosphatase, in its extracellular domain.","method":"Cell-surface binding assays, co-immunoprecipitation, functional T-cell activation assays","journal":"Immunological reviews","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding and functional experiments described, independently referenced across corpus","pmids":["9553764"],"is_preprint":false},{"year":2001,"finding":"CD26 co-distributes and co-immunoprecipitates with CXCR4 in T and B cell lines; upon SDF-1α stimulation, CD26 is co-internalized with CXCR4 through a process requiring CXCR4 internalization capacity but not pertussis-toxin-sensitive G-protein signaling. HIV-1 gp120 interacts with CD26 and disrupts ADA/CD26 interaction by binding a site distinct from the ADA-binding domain.","method":"Co-immunoprecipitation, co-internalization assays with CXCR4 mutants, pertussis toxin treatment, gp120 competition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, multiple orthogonal experiments (co-internalization, mutant receptor, blocking), single lab but rigorous","pmids":["11278278"],"is_preprint":false},{"year":2002,"finding":"CD26-ADA interaction on the lymphocyte surface mediates T-cell adhesion to epithelial cells: CD26 overexpression increased T-cell adhesion to ADA-expressing Caco-2 cells by ~50%, and this was blocked by anti-CD26 antibody targeting the ADA-binding site or by exogenous ADA; adhesion was mediated through LFA-1 integrin activation.","method":"Cell adhesion assays, anti-CD26 antibody blocking, exogenous ADA competition, integrin activation FACS","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in a single lab","pmids":["11772392"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of the free MERS-CoV spike receptor-binding domain (RBD) and its complex with CD26/DPP4 revealed that the viral RBD binds blades IV and V of the CD26 β-propeller via hydrophilic contacts; binding affinity was measured at Kd = 16.7 nM by surface plasmon resonance.","method":"X-ray crystallography, surface plasmon resonance","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of the complex combined with biophysical binding measurement, published in Nature","pmids":["23831647"],"is_preprint":false},{"year":2017,"finding":"TP53 limits erastin-induced ferroptosis by directly blocking DPP4 activity in a transcription-independent manner; loss of TP53 allows DPP4 to accumulate at the plasma membrane where it drives lipid peroxidation and ferroptosis, while nuclear DPP4 (promoted by TP53) is inactive in this pathway.","method":"Loss-of-function (TP53 knockout), subcellular fractionation, DPP4 activity assay, lipid peroxidation measurement, ferroptosis assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple mechanistic readouts (subcellular localization, enzymatic activity, lipid peroxidation, cell death), single lab but orthogonal methods","pmids":["28813679"],"is_preprint":false},{"year":2006,"finding":"CD26 binds caveolin-1 on antigen-presenting cells (APCs) via residues 201–211 and the catalytic serine at position 630 of CD26; CD26–caveolin-1 interaction leads to caveolin-1 phosphorylation on APCs, NF-κB activation, and upregulation of CD86, thereby driving antigen-specific T-cell activation.","method":"Co-precipitation, site-directed mutagenesis of CD26, siRNA knockdown of caveolin-1, NF-κB reporter, CD86 upregulation assay, T-cell proliferation assay","journal":"Modern rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis, siRNA knockdown, and functional signaling readouts, single lab","pmids":["16622717"],"is_preprint":false},{"year":2009,"finding":"CD26 acts as an endogenous inhibitor of T-cell motility: CD26-processed chemokines CXCL12 and CCL5 induce thrombospondin-1 (TSP-1) surface expression on T lymphocytes through a CD26-controlled mechanism; TSP-1 then stimulates CD91/LRP expression. siRNA silencing or antibody-induced modulation of CD26 enhanced TSP-1 expression and increased T-cell migration.","method":"siRNA knockdown of CD26, antibody-induced CD26 modulation, cell migration assay, flow cytometry for TSP-1 and CD91","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and antibody modulation with functional migration readout, single lab","pmids":["19687096"],"is_preprint":false},{"year":2014,"finding":"CD26 co-precipitates with and inversely regulates CD9 in malignant mesothelioma cells; CD26 also co-precipitates with α5β1 integrin and potentiates tumor cell invasion through this interaction. CD9 negatively regulates CD26 expression and reduces the CD26–α5β1 integrin complex, suppressing FAK and Cas-L phosphorylation.","method":"Co-immunoprecipitation, siRNA knockdown of CD26 and CD9, gene transfer, cell invasion assay, western blotting of FAK/Cas-L phosphorylation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, siRNA, and gene transfer with functional invasion readout, single lab","pmids":["24466195"],"is_preprint":false},{"year":2018,"finding":"Obesity-induced hepatocyte DPP4 is secreted and acts together with plasma factor Xa to activate adipose tissue macrophages (ATMs) via caveolin-1 on ATMs and PAR2 signaling; silencing hepatocyte DPP4 suppressed VAT inflammation and insulin resistance in mice, while silencing ATM caveolin-1 or PAR2 produced a similar effect.","method":"Hepatocyte-specific DPP4 silencing (in vivo), caveolin-1 and PAR2 siRNA in ATMs, insulin resistance measurement, adipose tissue inflammation quantification","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic silencing experiments with clear mechanistic pathway (DPP4→caveolin-1/factor Xa→PAR2), published in Nature","pmids":["29562231"],"is_preprint":false},{"year":2018,"finding":"ADA can form a trimeric CD26–ADA–A2AR complex bridging T cells (expressing CD26) and dendritic cells (expressing A2AR); this was demonstrated by NanoBRET and site-directed mutagenesis of ADA residues at the A2AR binding interface.","method":"NanoBRET inter-cellular BRET, site-directed mutagenesis of ADA, dynamic mass redistribution assay, ligand binding","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two complementary biophysical methods (NanoBRET + DMR) with mutagenesis, single lab","pmids":["29497379"],"is_preprint":false},{"year":2014,"finding":"CD26 co-stimulation of CD3 and CD26 induces preferential IL-10 production in CD4+ T cells via NFAT and Raf-MEK-ERK pathways; EGR2 is induced via NFAT and AP-1 signaling and is required for IL-10 production (EGR2 knockdown reduced IL-10). CD3/CD26-stimulated T cells suppress bystander T-cell proliferation in an IL-10-dependent manner.","method":"Co-stimulation assays, EGR2 siRNA knockdown, pathway inhibitors (NFAT, ERK), IL-10 ELISA, suppression assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with signaling pathway dissection and functional suppression assay, single lab","pmids":["25548232"],"is_preprint":false},{"year":2014,"finding":"CD26 signaling during osteoclastogenesis promotes p38 MAPK and MKK3/6 phosphorylation leading to MITF phosphorylation, driving osteoclast differentiation. Anti-CD26 humanized monoclonal antibody blocked early OC differentiation by inactivating this pathway and impaired bone resorption.","method":"Anti-CD26 mAb treatment, western blotting (p38 MAPK, MKK3/6, MITF phosphorylation), TRAP/multinucleated OC counting, bone resorption assay","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological blockade with multiple signaling readouts and functional bone resorption assay, single lab","pmids":["24821427"],"is_preprint":false},{"year":2020,"finding":"Glucocorticoids directly induce DPP4 gene expression in macrophages via glucocorticoid receptor (GR) binding to two glucocorticoid response elements (GREs) in the DPP4 promoter; this GR-induced DPP4 expression mediates glucocorticoid-induced macrophage migration, as demonstrated by GR siRNA and DPP4 siRNA knockdown blocking dexamethasone-induced migration.","method":"GR ChIP (GRE identification), GR and DPP4 siRNA knockdown, GR antagonist (RU-486), macrophage migration assay, DPP4 enzymatic activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct GRE occupancy plus siRNA knockdown with functional migration readout, orthogonal genetic and pharmacological approaches","pmids":["31988243"],"is_preprint":false},{"year":2021,"finding":"DPP4 is a Wnt/β-catenin-responsive gene and a functional mediator of fibrotic dermal remodeling: genetic inducible Wnt activation caused dermal fibrosis with ECM expansion and adipocyte loss, and genetic evidence showed the Wnt/DPP4 axis is required for this fibrotic transformation; DPP4 inhibitors reversed established Wnt-induced fibrosis.","method":"Genetically inducible Wnt activation mouse model, DPP4 genetic loss-of-function, Wnt/β-catenin reporter, histology, DPP4 inhibitor treatment","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic models with Wnt induction and DPP4 KO, single lab","pmids":["34808238"],"is_preprint":false},{"year":2011,"finding":"CD26-deficient mice show enhanced ovalbumin-induced airway inflammation with increased Th2 cytokines (IL-4, IL-5, IL-13), elevated eotaxin and RANTES chemokines and their receptors (CCR3, CCR5), and increased pulmonary eosinophil infiltration, establishing a protective/regulatory role for CD26 in restricting allergic airway inflammation.","method":"CD26 gene-knockout mouse model, OVA sensitization/challenge, cytokine mRNA and protein measurement (BAL fluid), flow cytometry, immunohistology","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple phenotypic and molecular readouts, single lab","pmids":["22101691"],"is_preprint":false},{"year":2023,"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 produced EVs that were no longer taken up by other proliferating cells, identifying DPP4 as an 'uptake repressor' on S-EVs.","method":"Surfaceome mass spectrometry of EVs, ectopic DPP4 overexpression in EV-producing cells, EV uptake assay","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function overexpression with functional EV uptake readout, single lab","pmids":["37862381"],"is_preprint":false},{"year":2022,"finding":"CD26 induces colorectal cancer angiogenesis and metastasis through a CAV1/MMP1 signaling axis: CD26 overexpression upregulated MMP1 (identified by genome-wide mRNA array), and overexpression of CAV1 abrogated CD26-regulated MMP1 induction in CRC cell lines.","method":"CD26 overexpression/knockdown, genome-wide mRNA expression array, qPCR, cell migration/invasion assay, in vivo mouse model, CAV1 overexpression epistasis experiment","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiment (CAV1 rescue of CD26→MMP1) with in vitro and in vivo functional assays, single lab","pmids":["35163100"],"is_preprint":false},{"year":2023,"finding":"DPP4 inhibition in senescent vascular smooth muscle cells (VSMCs) reduced a unique SASP signature enriched in complement and coagulation factors, reduced senescent cell burden, and improved atherosclerotic plaque stability in mice; single-cell analysis confirmed senomorphic and senolytic effects of DPP4 inhibition.","method":"DPP4 silencing and inhibition, conditioned media proteomics, single-cell resolution VSMC analysis, murine atherosclerosis model","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic silencing plus inhibitor with proteomics and in vivo model, single lab","pmids":["37097759"],"is_preprint":false},{"year":2011,"finding":"In colon cancer cell lines, CD26 expression is regulated at the transcriptional level in a confluence-dependent manner: c-Myc acts as a repressor (ectopic c-Myc decreased CD26; c-Myc siRNA increased it), while Cdx2 acts as an enhancer (Cdx2 siRNA decreased CD26). HIF-1α was required but not sufficient for CD26 upregulation under serum depletion.","method":"Transient transfection of c-Myc expression plasmid, c-Myc siRNA, Cdx2 siRNA, real-time PCR, western blotting, immunofluorescence","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function for two transcription factors with orthogonal molecular readouts, single lab","pmids":["21284881"],"is_preprint":false},{"year":2019,"finding":"DPP4 post-translationally truncates CCL11, reducing eosinophil recruitment to tumors; inhibition of DPP4 by sitagliptin increased CCL11 levels and eosinophil infiltration into solid tumors, with tumor control dependent on eosinophils and IL-33 tumor-cell expression.","method":"DPP4 inhibitor (sitagliptin) in pre-clinical tumor models, eosinophil depletion, degranulation inhibitors, lymphocyte-deficient mice, chemokine measurement","journal":"Nature immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological DPP4 inhibition with cell-depletion epistasis in multiple tumor models, single lab","pmids":["30778250"],"is_preprint":false}],"current_model":"DPP4/CD26 is a type II transmembrane serine exopeptidase (alpha/beta hydrolase fold, requiring dimerization via its C-terminal hydrolase domain) that cleaves N-terminal X-Pro/X-Ala dipeptides from diverse substrates including incretin hormones (GLP-1, GIP), chemokines (CXCL12, CCL5, CCL11), and neuropeptides, thereby regulating their bioactivity; it also functions as a non-enzymatic scaffold binding ADA, CXCR4, caveolin-1, CD45, and α5β1 integrin to co-stimulate T cells and modulate cell adhesion and migration, while in cancer contexts its subcellular localization (plasma membrane vs. nucleus) is controlled by TP53 to determine whether DPP4-dependent lipid peroxidation drives ferroptosis, and in senescent cells DPP4 surface expression marks and modulates the senescent state and its extracellular vesicle outputs."},"narrative":{"mechanistic_narrative":"DPP4/CD26 is a type II transmembrane serine exopeptidase that cleaves N-terminal X-Pro/X-Ala dipeptides from regulatory peptides—including the incretins GLP-1, GLP-2 and GIP, neuropeptides, and chemokines such as RANTES/CCL5, SDF-1/CXCL12 and eotaxin/CCL11—thereby inactivating or modulating their bioactivity [PMID:10588446]. Both its peptidase activity and the dimerization required for it depend on the C-terminal portion of its alpha/beta hydrolase domain, which is also needed for normal cell-surface expression [PMID:12534281]. Beyond catalysis, DPP4 acts as a multifunctional cell-surface scaffold: it binds adenosine deaminase (ADA) and CD45 in its extracellular domain to co-stimulate T cells through the CD3 pathway, and the ADA interaction can bridge T cells to dendritic cells via a CD26–ADA–A2AR trimer [PMID:9683260, PMID:9553764, PMID:29497379]. It associates with and co-internalizes alongside the chemokine receptor CXCR4 upon SDF-1α stimulation, and engages caveolin-1 to trigger NF-κB activation and CD86 upregulation on antigen-presenting cells, driving antigen-specific T-cell responses [PMID:11278278, PMID:16622717]. Through these enzymatic and scaffolding activities DPP4 shapes immune cell adhesion, motility and cytokine output—mediating ADA-dependent T-cell adhesion via LFA-1, restraining T-cell migration through chemokine processing, and promoting IL-10-producing regulatory phenotypes [PMID:11772392, PMID:19687096, PMID:25548232]. In disease contexts, DPP4 is the receptor for the MERS-CoV spike receptor-binding domain, which contacts blades IV and V of its β-propeller [PMID:23831647], and its subcellular localization governs ferroptosis: TP53 non-transcriptionally suppresses plasma-membrane DPP4 to limit DPP4-driven lipid peroxidation [PMID:28813679]. DPP4 also links metabolism and inflammation, with hepatocyte-secreted DPP4 acting with factor Xa through caveolin-1/PAR2 to activate adipose macrophages and promote insulin resistance [PMID:29562231], and contributes to fibrosis, cancer invasion/angiogenesis, and the senescent-cell secretory program [PMID:34808238, PMID:35163100, PMID:37097759].","teleology":[{"year":1999,"claim":"Established DPP4 as a serine exopeptidase whose physiological role is the inactivation of a broad set of regulatory peptides via X-Pro/X-Ala cleavage, defining its core biochemical identity.","evidence":"In vitro enzymatic assays and in vivo peptide cleavage across multiple substrates (GLP-1, GIP, RANTES, SDF-1, eotaxin, etc.)","pmids":["10588446"],"confidence":"High","gaps":["Does not establish in vivo substrate hierarchy or which cleavages dominate in specific tissues","No structural basis for substrate selectivity"]},{"year":1998,"claim":"Showed that DPP4 has a non-enzymatic co-stimulatory function, mapping the T-cell co-stimulation epitopes and the ADA/CD45 binding interactions distinct from catalysis.","evidence":"Epitope mapping with truncated/chimeric mutants, cross-blocking mAbs, cell-surface binding and co-IP, T-cell activation assays","pmids":["9683260","9553764"],"confidence":"Medium","gaps":["Mechanism coupling ADA/CD45 binding to intracellular signaling not resolved","Single-lab epitope mapping"]},{"year":2001,"claim":"Linked DPP4 to chemokine receptor biology and HIV, showing co-internalization with CXCR4 and gp120 binding at a site distinct from ADA.","evidence":"Reciprocal co-IP, co-internalization with CXCR4 mutants, pertussis toxin treatment, gp120 competition","pmids":["11278278"],"confidence":"High","gaps":["Functional consequence of CXCR4 co-internalization for chemotaxis not defined","Single lab"]},{"year":2002,"claim":"Demonstrated that the CD26–ADA interaction is a functional adhesion mechanism, coupling surface ADA capture to LFA-1-mediated T-cell adhesion.","evidence":"Cell adhesion assays with ADA-expressing Caco-2 cells, anti-CD26/ADA-site blocking, integrin activation FACS","pmids":["11772392"],"confidence":"Medium","gaps":["Signaling pathway from CD26 to LFA-1 activation not delineated","~50% effect size, single lab"]},{"year":2003,"claim":"Resolved the structural requirement for activity, showing dimerization and peptidase function both require the C-terminal hydrolase domain region.","evidence":"Domain-swap chimeras (DP8/DP9), cell-surface expression and enzymatic assays","pmids":["12534281"],"confidence":"High","gaps":["No crystal structure of the catalytic domain in this study","Does not address scaffolding-domain folding requirements"]},{"year":2006,"claim":"Identified caveolin-1 as a CD26 partner on APCs and traced a CD26→caveolin-1 phosphorylation→NF-κB→CD86 signaling cascade driving T-cell activation.","evidence":"Co-precipitation, site-directed mutagenesis (residues 201–211, Ser630), caveolin-1 siRNA, NF-κB reporter, CD86 and proliferation assays","pmids":["16622717"],"confidence":"Medium","gaps":["Role of catalytic Ser630 in a binding interaction unexplained mechanistically","Single lab"]},{"year":2009,"claim":"Showed DPP4 restrains T-cell motility through chemokine processing, with CD26-processed CXCL12/CCL5 inducing TSP-1 and CD91/LRP.","evidence":"CD26 siRNA, antibody modulation, migration assays, flow cytometry for TSP-1/CD91","pmids":["19687096"],"confidence":"Medium","gaps":["Direct enzymatic vs scaffold contribution to TSP-1 induction not separated","Single lab"]},{"year":2011,"claim":"Established in vivo that CD26 protectively restricts allergic airway inflammation, consistent with its chemokine-inactivating activity.","evidence":"CD26-knockout mice, OVA sensitization, BAL cytokine/chemokine measurement, eosinophil quantification","pmids":["22101691"],"confidence":"Medium","gaps":["Does not isolate which substrate cleavages (eotaxin/RANTES) drive the phenotype","Single model"]},{"year":2011,"claim":"Defined transcriptional control of CD26 in colon cancer, with c-Myc repressing and Cdx2 enhancing expression in a confluence-dependent manner.","evidence":"c-Myc overexpression and siRNA, Cdx2 siRNA, qPCR, western blot, immunofluorescence","pmids":["21284881"],"confidence":"Medium","gaps":["Direct promoter binding by these factors not shown","HIF-1α requirement mechanism unresolved"]},{"year":2013,"claim":"Defined DPP4 as the MERS-CoV receptor at atomic resolution, mapping the spike RBD to specific β-propeller blades.","evidence":"X-ray crystallography of RBD–DPP4 complex, SPR (Kd = 16.7 nM)","pmids":["23831647"],"confidence":"High","gaps":["Does not address how receptor engagement relates to peptidase activity or species tropism determinants in vivo"]},{"year":2014,"claim":"Extended DPP4 scaffolding to cancer invasion, showing CD26–α5β1 integrin complexes drive FAK/Cas-L signaling and CD9 negatively regulates this axis.","evidence":"Reciprocal co-IP, CD26/CD9 siRNA, gene transfer, invasion assays, FAK/Cas-L western blots in mesothelioma","pmids":["24466195"],"confidence":"Medium","gaps":["Whether catalytic activity is required for the integrin interaction unknown","Single cancer type"]},{"year":2014,"claim":"Connected CD26 to two additional cellular programs—IL-10-skewed regulatory T-cell output (NFAT/ERK/EGR2) and osteoclast differentiation (p38/MKK3-6/MITF).","evidence":"Co-stimulation assays, EGR2 siRNA, pathway inhibitors, anti-CD26 mAb, TRAP/bone resorption assays","pmids":["25548232","24821427"],"confidence":"Medium","gaps":["Upstream receptor coupling of CD26 to these MAPK/NFAT cascades not defined","Single-lab readouts"]},{"year":2017,"claim":"Revealed that DPP4 subcellular localization is a ferroptosis switch controlled non-transcriptionally by TP53, with plasma-membrane DPP4 driving lipid peroxidation.","evidence":"TP53 KO, subcellular fractionation, DPP4 activity and lipid peroxidation assays, ferroptosis readouts","pmids":["28813679"],"confidence":"High","gaps":["Molecular mechanism by which membrane DPP4 promotes lipid peroxidation not detailed","Direct TP53–DPP4 contact not structurally defined"]},{"year":2018,"claim":"Positioned secreted hepatocyte DPP4 as a metabolic inflammatory signal acting through caveolin-1/factor Xa/PAR2 on adipose macrophages to cause insulin resistance.","evidence":"Hepatocyte-specific DPP4 silencing in vivo, ATM caveolin-1/PAR2 siRNA, insulin resistance and inflammation measurements","pmids":["29562231"],"confidence":"High","gaps":["Whether DPP4 peptidase activity is required for PAR2 pathway activation not isolated","Human relevance not established"]},{"year":2018,"claim":"Showed ADA can physically bridge CD26 on T cells to A2AR on dendritic cells, defining an intercellular signaling triad.","evidence":"Inter-cellular NanoBRET, ADA mutagenesis, dynamic mass redistribution, ligand binding","pmids":["29497379"],"confidence":"Medium","gaps":["Functional immune consequence of the trimer not demonstrated","Single lab biophysical assays"]},{"year":2022,"claim":"Linked CD26 to colorectal cancer angiogenesis/metastasis through a CAV1/MMP1 axis, with CAV1 epistatically suppressing CD26-driven MMP1.","evidence":"CD26 overexpression/knockdown, genome-wide array, qPCR, migration/invasion, in vivo model, CAV1 rescue","pmids":["35163100"],"confidence":"Medium","gaps":["Mechanism by which CD26 induces MMP1 not defined","Single lab"]},{"year":2020,"claim":"Identified glucocorticoid receptor as a direct transcriptional inducer of DPP4 via promoter GREs, coupling steroid signaling to macrophage migration.","evidence":"GR ChIP/GRE mapping, GR and DPP4 siRNA, RU-486, migration and activity assays","pmids":["31988243"],"confidence":"High","gaps":["Whether enzymatic or scaffold DPP4 function drives migration not separated"]},{"year":2023,"claim":"Implicated DPP4 in senescence biology—as a surface 'uptake repressor' on senescence-associated EVs and as a driver of a complement/coagulation SASP whose inhibition is senomorphic/senolytic.","evidence":"EV surfaceome MS, ectopic DPP4 overexpression and uptake assays; DPP4 silencing/inhibition, conditioned-media proteomics, single-cell VSMC analysis, murine atherosclerosis","pmids":["37862381","37097759"],"confidence":"Medium","gaps":["Molecular mechanism of EV uptake repression by DPP4 unknown","Causal SASP substrate of DPP4 in VSMCs not identified"]},{"year":2019,"claim":"Demonstrated that DPP4 truncation of CCL11 limits anti-tumor eosinophil recruitment, providing a substrate-level rationale for DPP4 inhibition in cancer immunity.","evidence":"Sitagliptin in tumor models, eosinophil depletion, IL-33-dependence epistasis, chemokine measurement","pmids":["30778250"],"confidence":"Medium","gaps":["Contribution of other DPP4 substrates to the phenotype not excluded","Single lab"]},{"year":null,"claim":"It remains unresolved how DPP4 partitions between its catalytic and scaffolding functions across contexts, and which molecular features dictate its localization (membrane vs nucleus vs EV vs secreted) and partner selection in a given cell type.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking localization control to functional output","Enzymatic vs non-enzymatic contributions not systematically dissected in most disease settings","No structure of full-length DPP4 bound to its scaffolding partners"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,7,22]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,22]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,22]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,7,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[18]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,13,17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,8,11,15]}],"complexes":["CD26-ADA-A2AR trimer","CD26-CXCR4 complex","CD26-α5β1 integrin complex"],"partners":["ADA","CXCR4","CD45","CAV1","ITGA5","CD9","TP53","F2RL1"],"other_free_text":[]}},"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; 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pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28448874","citation_count":26,"is_preprint":false},{"pmid":"27535784","id":"PMC_27535784","title":"Boning up on DPP4, DPP4 substrates, and DPP4-adipokine interactions: Logical reasoning and known facts about bone related effects of DPP4 inhibitors.","date":"2016","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/27535784","citation_count":26,"is_preprint":false},{"pmid":"35053615","id":"PMC_35053615","title":"CD26/DPP4 as a Therapeutic Target in Nonalcoholic Steatohepatitis Associated Hepatocellular Carcinoma.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/35053615","citation_count":26,"is_preprint":false},{"pmid":"36196001","id":"PMC_36196001","title":"Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis.","date":"2022","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36196001","citation_count":26,"is_preprint":false},{"pmid":"22101691","id":"PMC_22101691","title":"Enhanced ovalbumin-induced airway inflammation in CD26-/- mice.","date":"2011","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22101691","citation_count":25,"is_preprint":false},{"pmid":"38688275","id":"PMC_38688275","title":"Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity.","date":"2024","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38688275","citation_count":24,"is_preprint":false},{"pmid":"32317776","id":"PMC_32317776","title":"A novel chimeric antigen receptor redirecting T-cell specificity towards CD26+ cancer cells.","date":"2020","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/32317776","citation_count":23,"is_preprint":false},{"pmid":"24379839","id":"PMC_24379839","title":"Expression of CD26 and CXCR4 in prostate carcinoma and its relationship with clinical parameters.","date":"2013","source":"Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24379839","citation_count":23,"is_preprint":false},{"pmid":"32335097","id":"PMC_32335097","title":"SARS-CoV-2 and DPP4 inhibition: Is it time to pray for Janus Bifrons?","date":"2020","source":"Diabetes research and clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/32335097","citation_count":23,"is_preprint":false},{"pmid":"7790033","id":"PMC_7790033","title":"Antibody-induced modulation of CD26 surface expression.","date":"1995","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7790033","citation_count":22,"is_preprint":false},{"pmid":"36704903","id":"PMC_36704903","title":"Association of Dipeptidylpeptidase 4 (CD26) With Chondrocyte Senescence and Radiographic Progression in Knee Osteoarthritis.","date":"2023","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/36704903","citation_count":22,"is_preprint":false},{"pmid":"21894438","id":"PMC_21894438","title":"Overexpression of CD26/DPPIV in mesothelioma tissue and mesothelioma cell lines.","date":"2011","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21894438","citation_count":22,"is_preprint":false},{"pmid":"21284881","id":"PMC_21284881","title":"Mechanisms of confluence-dependent expression of CD26 in colon cancer cell lines.","date":"2011","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21284881","citation_count":22,"is_preprint":false},{"pmid":"29572550","id":"PMC_29572550","title":"Delayed allogeneic skin graft rejection in CD26-deficient mice.","date":"2018","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29572550","citation_count":22,"is_preprint":false},{"pmid":"33777580","id":"PMC_33777580","title":"CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions.","date":"2021","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/33777580","citation_count":21,"is_preprint":false},{"pmid":"35889373","id":"PMC_35889373","title":"Therapeutic Perspectives of CD26 Inhibitors in Imune-Mediated Diseases.","date":"2022","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35889373","citation_count":21,"is_preprint":false},{"pmid":"29885296","id":"PMC_29885296","title":"Anticonvulsant agent DPP4 inhibitor sitagliptin downregulates CXCR3/RAGE pathway on seizure models.","date":"2018","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29885296","citation_count":21,"is_preprint":false},{"pmid":"25548232","id":"PMC_25548232","title":"CD26-mediated induction of EGR2 and IL-10 as potential regulatory mechanism for CD26 costimulatory pathway.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25548232","citation_count":21,"is_preprint":false},{"pmid":"34733107","id":"PMC_34733107","title":"Pleiotropic Benefits of DPP-4 Inhibitors Beyond Glycemic Control.","date":"2021","source":"Clinical medicine insights. Endocrinology and diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/34733107","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47798,"output_tokens":5772,"usd":0.114987,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14359,"output_tokens":5873,"usd":0.10931,"stage2_stop_reason":"end_turn"},"total_usd":0.224297,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"DPP4/CD26 functions as a serine exopeptidase that cleaves N-terminal dipeptides from regulatory peptides bearing L-proline or L-alanine at the penultimate position, thereby inactivating substrates including GLP-1, GLP-2, GIP, NPY, peptide YY, GHRH, RANTES, SDF-1, eotaxin, and MDC; this activity was demonstrated through in vitro and in vivo experiments.\",\n      \"method\": \"In vitro enzymatic assays and in vivo peptide cleavage experiments\",\n      \"journal\": \"Regulatory peptides\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct enzymatic characterization replicated across multiple substrates and multiple labs over two decades\",\n      \"pmids\": [\"10588446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD26/DPP4 dimerization and peptidase activity both require the C-terminal portion of the predicted alpha/beta hydrolase domain (residues 501–766); chimeric proteins replacing this region with homologous sequences from DP8 or DP9 lacked dimerization and peptidase activity. Deletion of N-terminal residues of the alpha/beta hydrolase domain also ablated peptidase activity and greatly reduced cell-surface expression.\",\n      \"method\": \"Domain-swap chimera mutagenesis, cell-surface expression assay, enzymatic activity assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with mutagenesis and multiple orthogonal readouts in a single focused study\",\n      \"pmids\": [\"12534281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD26 co-stimulates T-cell activation through the CD3 pathway; the epitopes required for T-cell co-stimulation were mapped to the 248–358 and 359–449 amino acid regions, while the ADA binding domain lies within the 359–449 region, using truncated and human-rat swap mutants plus cross-blocking with 13 anti-CD26 mAbs.\",\n      \"method\": \"Epitope mapping with truncated/chimeric CD26 mutants, cross-blocking assays, T-cell co-stimulation functional assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis with functional co-stimulation readout, single lab\",\n      \"pmids\": [\"9683260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD26 on the surface of T cells acts as the receptor for adenosine deaminase (ADA), binding ADA on the cell surface and thereby mediating co-stimulatory signals; CD26 also interacts with CD45, a protein tyrosine phosphatase, in its extracellular domain.\",\n      \"method\": \"Cell-surface binding assays, co-immunoprecipitation, functional T-cell activation assays\",\n      \"journal\": \"Immunological reviews\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding and functional experiments described, independently referenced across corpus\",\n      \"pmids\": [\"9553764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD26 co-distributes and co-immunoprecipitates with CXCR4 in T and B cell lines; upon SDF-1α stimulation, CD26 is co-internalized with CXCR4 through a process requiring CXCR4 internalization capacity but not pertussis-toxin-sensitive G-protein signaling. HIV-1 gp120 interacts with CD26 and disrupts ADA/CD26 interaction by binding a site distinct from the ADA-binding domain.\",\n      \"method\": \"Co-immunoprecipitation, co-internalization assays with CXCR4 mutants, pertussis toxin treatment, gp120 competition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, multiple orthogonal experiments (co-internalization, mutant receptor, blocking), single lab but rigorous\",\n      \"pmids\": [\"11278278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD26-ADA interaction on the lymphocyte surface mediates T-cell adhesion to epithelial cells: CD26 overexpression increased T-cell adhesion to ADA-expressing Caco-2 cells by ~50%, and this was blocked by anti-CD26 antibody targeting the ADA-binding site or by exogenous ADA; adhesion was mediated through LFA-1 integrin activation.\",\n      \"method\": \"Cell adhesion assays, anti-CD26 antibody blocking, exogenous ADA competition, integrin activation FACS\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in a single lab\",\n      \"pmids\": [\"11772392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of the free MERS-CoV spike receptor-binding domain (RBD) and its complex with CD26/DPP4 revealed that the viral RBD binds blades IV and V of the CD26 β-propeller via hydrophilic contacts; binding affinity was measured at Kd = 16.7 nM by surface plasmon resonance.\",\n      \"method\": \"X-ray crystallography, surface plasmon resonance\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of the complex combined with biophysical binding measurement, published in Nature\",\n      \"pmids\": [\"23831647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TP53 limits erastin-induced ferroptosis by directly blocking DPP4 activity in a transcription-independent manner; loss of TP53 allows DPP4 to accumulate at the plasma membrane where it drives lipid peroxidation and ferroptosis, while nuclear DPP4 (promoted by TP53) is inactive in this pathway.\",\n      \"method\": \"Loss-of-function (TP53 knockout), subcellular fractionation, DPP4 activity assay, lipid peroxidation measurement, ferroptosis assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple mechanistic readouts (subcellular localization, enzymatic activity, lipid peroxidation, cell death), single lab but orthogonal methods\",\n      \"pmids\": [\"28813679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD26 binds caveolin-1 on antigen-presenting cells (APCs) via residues 201–211 and the catalytic serine at position 630 of CD26; CD26–caveolin-1 interaction leads to caveolin-1 phosphorylation on APCs, NF-κB activation, and upregulation of CD86, thereby driving antigen-specific T-cell activation.\",\n      \"method\": \"Co-precipitation, site-directed mutagenesis of CD26, siRNA knockdown of caveolin-1, NF-κB reporter, CD86 upregulation assay, T-cell proliferation assay\",\n      \"journal\": \"Modern rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis, siRNA knockdown, and functional signaling readouts, single lab\",\n      \"pmids\": [\"16622717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD26 acts as an endogenous inhibitor of T-cell motility: CD26-processed chemokines CXCL12 and CCL5 induce thrombospondin-1 (TSP-1) surface expression on T lymphocytes through a CD26-controlled mechanism; TSP-1 then stimulates CD91/LRP expression. siRNA silencing or antibody-induced modulation of CD26 enhanced TSP-1 expression and increased T-cell migration.\",\n      \"method\": \"siRNA knockdown of CD26, antibody-induced CD26 modulation, cell migration assay, flow cytometry for TSP-1 and CD91\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and antibody modulation with functional migration readout, single lab\",\n      \"pmids\": [\"19687096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD26 co-precipitates with and inversely regulates CD9 in malignant mesothelioma cells; CD26 also co-precipitates with α5β1 integrin and potentiates tumor cell invasion through this interaction. CD9 negatively regulates CD26 expression and reduces the CD26–α5β1 integrin complex, suppressing FAK and Cas-L phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of CD26 and CD9, gene transfer, cell invasion assay, western blotting of FAK/Cas-L phosphorylation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, siRNA, and gene transfer with functional invasion readout, single lab\",\n      \"pmids\": [\"24466195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Obesity-induced hepatocyte DPP4 is secreted and acts together with plasma factor Xa to activate adipose tissue macrophages (ATMs) via caveolin-1 on ATMs and PAR2 signaling; silencing hepatocyte DPP4 suppressed VAT inflammation and insulin resistance in mice, while silencing ATM caveolin-1 or PAR2 produced a similar effect.\",\n      \"method\": \"Hepatocyte-specific DPP4 silencing (in vivo), caveolin-1 and PAR2 siRNA in ATMs, insulin resistance measurement, adipose tissue inflammation quantification\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic silencing experiments with clear mechanistic pathway (DPP4→caveolin-1/factor Xa→PAR2), published in Nature\",\n      \"pmids\": [\"29562231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADA can form a trimeric CD26–ADA–A2AR complex bridging T cells (expressing CD26) and dendritic cells (expressing A2AR); this was demonstrated by NanoBRET and site-directed mutagenesis of ADA residues at the A2AR binding interface.\",\n      \"method\": \"NanoBRET inter-cellular BRET, site-directed mutagenesis of ADA, dynamic mass redistribution assay, ligand binding\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary biophysical methods (NanoBRET + DMR) with mutagenesis, single lab\",\n      \"pmids\": [\"29497379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD26 co-stimulation of CD3 and CD26 induces preferential IL-10 production in CD4+ T cells via NFAT and Raf-MEK-ERK pathways; EGR2 is induced via NFAT and AP-1 signaling and is required for IL-10 production (EGR2 knockdown reduced IL-10). CD3/CD26-stimulated T cells suppress bystander T-cell proliferation in an IL-10-dependent manner.\",\n      \"method\": \"Co-stimulation assays, EGR2 siRNA knockdown, pathway inhibitors (NFAT, ERK), IL-10 ELISA, suppression assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with signaling pathway dissection and functional suppression assay, single lab\",\n      \"pmids\": [\"25548232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD26 signaling during osteoclastogenesis promotes p38 MAPK and MKK3/6 phosphorylation leading to MITF phosphorylation, driving osteoclast differentiation. Anti-CD26 humanized monoclonal antibody blocked early OC differentiation by inactivating this pathway and impaired bone resorption.\",\n      \"method\": \"Anti-CD26 mAb treatment, western blotting (p38 MAPK, MKK3/6, MITF phosphorylation), TRAP/multinucleated OC counting, bone resorption assay\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological blockade with multiple signaling readouts and functional bone resorption assay, single lab\",\n      \"pmids\": [\"24821427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Glucocorticoids directly induce DPP4 gene expression in macrophages via glucocorticoid receptor (GR) binding to two glucocorticoid response elements (GREs) in the DPP4 promoter; this GR-induced DPP4 expression mediates glucocorticoid-induced macrophage migration, as demonstrated by GR siRNA and DPP4 siRNA knockdown blocking dexamethasone-induced migration.\",\n      \"method\": \"GR ChIP (GRE identification), GR and DPP4 siRNA knockdown, GR antagonist (RU-486), macrophage migration assay, DPP4 enzymatic activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct GRE occupancy plus siRNA knockdown with functional migration readout, orthogonal genetic and pharmacological approaches\",\n      \"pmids\": [\"31988243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DPP4 is a Wnt/β-catenin-responsive gene and a functional mediator of fibrotic dermal remodeling: genetic inducible Wnt activation caused dermal fibrosis with ECM expansion and adipocyte loss, and genetic evidence showed the Wnt/DPP4 axis is required for this fibrotic transformation; DPP4 inhibitors reversed established Wnt-induced fibrosis.\",\n      \"method\": \"Genetically inducible Wnt activation mouse model, DPP4 genetic loss-of-function, Wnt/β-catenin reporter, histology, DPP4 inhibitor treatment\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic models with Wnt induction and DPP4 KO, single lab\",\n      \"pmids\": [\"34808238\"],\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), elevated eotaxin and RANTES chemokines and their receptors (CCR3, CCR5), and increased pulmonary eosinophil infiltration, establishing a protective/regulatory role for CD26 in restricting allergic airway inflammation.\",\n      \"method\": \"CD26 gene-knockout mouse model, OVA sensitization/challenge, cytokine mRNA and protein measurement (BAL fluid), flow cytometry, immunohistology\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple phenotypic and molecular readouts, single lab\",\n      \"pmids\": [\"22101691\"],\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 produced EVs that were no longer taken up by other proliferating cells, identifying DPP4 as an 'uptake repressor' on S-EVs.\",\n      \"method\": \"Surfaceome mass spectrometry of EVs, ectopic DPP4 overexpression in EV-producing cells, EV uptake assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function overexpression with functional EV uptake readout, single lab\",\n      \"pmids\": [\"37862381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD26 induces colorectal cancer angiogenesis and metastasis through a CAV1/MMP1 signaling axis: CD26 overexpression upregulated MMP1 (identified by genome-wide mRNA array), and overexpression of CAV1 abrogated CD26-regulated MMP1 induction in CRC cell lines.\",\n      \"method\": \"CD26 overexpression/knockdown, genome-wide mRNA expression array, qPCR, cell migration/invasion assay, in vivo mouse model, CAV1 overexpression epistasis experiment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiment (CAV1 rescue of CD26→MMP1) with in vitro and in vivo functional assays, single lab\",\n      \"pmids\": [\"35163100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DPP4 inhibition in senescent vascular smooth muscle cells (VSMCs) reduced a unique SASP signature enriched in complement and coagulation factors, reduced senescent cell burden, and improved atherosclerotic plaque stability in mice; single-cell analysis confirmed senomorphic and senolytic effects of DPP4 inhibition.\",\n      \"method\": \"DPP4 silencing and inhibition, conditioned media proteomics, single-cell resolution VSMC analysis, murine atherosclerosis model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic silencing plus inhibitor with proteomics and in vivo model, single lab\",\n      \"pmids\": [\"37097759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In colon cancer cell lines, CD26 expression is regulated at the transcriptional level in a confluence-dependent manner: c-Myc acts as a repressor (ectopic c-Myc decreased CD26; c-Myc siRNA increased it), while Cdx2 acts as an enhancer (Cdx2 siRNA decreased CD26). HIF-1α was required but not sufficient for CD26 upregulation under serum depletion.\",\n      \"method\": \"Transient transfection of c-Myc expression plasmid, c-Myc siRNA, Cdx2 siRNA, real-time PCR, western blotting, immunofluorescence\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function for two transcription factors with orthogonal molecular readouts, single lab\",\n      \"pmids\": [\"21284881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DPP4 post-translationally truncates CCL11, reducing eosinophil recruitment to tumors; inhibition of DPP4 by sitagliptin increased CCL11 levels and eosinophil infiltration into solid tumors, with tumor control dependent on eosinophils and IL-33 tumor-cell expression.\",\n      \"method\": \"DPP4 inhibitor (sitagliptin) in pre-clinical tumor models, eosinophil depletion, degranulation inhibitors, lymphocyte-deficient mice, chemokine measurement\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological DPP4 inhibition with cell-depletion epistasis in multiple tumor models, single lab\",\n      \"pmids\": [\"30778250\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DPP4/CD26 is a type II transmembrane serine exopeptidase (alpha/beta hydrolase fold, requiring dimerization via its C-terminal hydrolase domain) that cleaves N-terminal X-Pro/X-Ala dipeptides from diverse substrates including incretin hormones (GLP-1, GIP), chemokines (CXCL12, CCL5, CCL11), and neuropeptides, thereby regulating their bioactivity; it also functions as a non-enzymatic scaffold binding ADA, CXCR4, caveolin-1, CD45, and α5β1 integrin to co-stimulate T cells and modulate cell adhesion and migration, while in cancer contexts its subcellular localization (plasma membrane vs. nucleus) is controlled by TP53 to determine whether DPP4-dependent lipid peroxidation drives ferroptosis, and in senescent cells DPP4 surface expression marks and modulates the senescent state and its extracellular vesicle outputs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DPP4/CD26 is a type II transmembrane serine exopeptidase that cleaves N-terminal X-Pro/X-Ala dipeptides from regulatory peptides—including the incretins GLP-1, GLP-2 and GIP, neuropeptides, and chemokines such as RANTES/CCL5, SDF-1/CXCL12 and eotaxin/CCL11—thereby inactivating or modulating their bioactivity [#0]. Both its peptidase activity and the dimerization required for it depend on the C-terminal portion of its alpha/beta hydrolase domain, which is also needed for normal cell-surface expression [#1]. Beyond catalysis, DPP4 acts as a multifunctional cell-surface scaffold: it binds adenosine deaminase (ADA) and CD45 in its extracellular domain to co-stimulate T cells through the CD3 pathway, and the ADA interaction can bridge T cells to dendritic cells via a CD26–ADA–A2AR trimer [#2, #3, #12]. It associates with and co-internalizes alongside the chemokine receptor CXCR4 upon SDF-1α stimulation, and engages caveolin-1 to trigger NF-κB activation and CD86 upregulation on antigen-presenting cells, driving antigen-specific T-cell responses [#4, #8]. Through these enzymatic and scaffolding activities DPP4 shapes immune cell adhesion, motility and cytokine output—mediating ADA-dependent T-cell adhesion via LFA-1, restraining T-cell migration through chemokine processing, and promoting IL-10-producing regulatory phenotypes [#5, #9, #13]. In disease contexts, DPP4 is the receptor for the MERS-CoV spike receptor-binding domain, which contacts blades IV and V of its β-propeller [#6], and its subcellular localization governs ferroptosis: TP53 non-transcriptionally suppresses plasma-membrane DPP4 to limit DPP4-driven lipid peroxidation [#7]. DPP4 also links metabolism and inflammation, with hepatocyte-secreted DPP4 acting with factor Xa through caveolin-1/PAR2 to activate adipose macrophages and promote insulin resistance [#11], and contributes to fibrosis, cancer invasion/angiogenesis, and the senescent-cell secretory program [#16, #19, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established DPP4 as a serine exopeptidase whose physiological role is the inactivation of a broad set of regulatory peptides via X-Pro/X-Ala cleavage, defining its core biochemical identity.\",\n      \"evidence\": \"In vitro enzymatic assays and in vivo peptide cleavage across multiple substrates (GLP-1, GIP, RANTES, SDF-1, eotaxin, etc.)\",\n      \"pmids\": [\"10588446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish in vivo substrate hierarchy or which cleavages dominate in specific tissues\", \"No structural basis for substrate selectivity\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed that DPP4 has a non-enzymatic co-stimulatory function, mapping the T-cell co-stimulation epitopes and the ADA/CD45 binding interactions distinct from catalysis.\",\n      \"evidence\": \"Epitope mapping with truncated/chimeric mutants, cross-blocking mAbs, cell-surface binding and co-IP, T-cell activation assays\",\n      \"pmids\": [\"9683260\", \"9553764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling ADA/CD45 binding to intracellular signaling not resolved\", \"Single-lab epitope mapping\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked DPP4 to chemokine receptor biology and HIV, showing co-internalization with CXCR4 and gp120 binding at a site distinct from ADA.\",\n      \"evidence\": \"Reciprocal co-IP, co-internalization with CXCR4 mutants, pertussis toxin treatment, gp120 competition\",\n      \"pmids\": [\"11278278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CXCR4 co-internalization for chemotaxis not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that the CD26–ADA interaction is a functional adhesion mechanism, coupling surface ADA capture to LFA-1-mediated T-cell adhesion.\",\n      \"evidence\": \"Cell adhesion assays with ADA-expressing Caco-2 cells, anti-CD26/ADA-site blocking, integrin activation FACS\",\n      \"pmids\": [\"11772392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway from CD26 to LFA-1 activation not delineated\", \"~50% effect size, single lab\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the structural requirement for activity, showing dimerization and peptidase function both require the C-terminal hydrolase domain region.\",\n      \"evidence\": \"Domain-swap chimeras (DP8/DP9), cell-surface expression and enzymatic assays\",\n      \"pmids\": [\"12534281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of the catalytic domain in this study\", \"Does not address scaffolding-domain folding requirements\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified caveolin-1 as a CD26 partner on APCs and traced a CD26→caveolin-1 phosphorylation→NF-κB→CD86 signaling cascade driving T-cell activation.\",\n      \"evidence\": \"Co-precipitation, site-directed mutagenesis (residues 201–211, Ser630), caveolin-1 siRNA, NF-κB reporter, CD86 and proliferation assays\",\n      \"pmids\": [\"16622717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of catalytic Ser630 in a binding interaction unexplained mechanistically\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed DPP4 restrains T-cell motility through chemokine processing, with CD26-processed CXCL12/CCL5 inducing TSP-1 and CD91/LRP.\",\n      \"evidence\": \"CD26 siRNA, antibody modulation, migration assays, flow cytometry for TSP-1/CD91\",\n      \"pmids\": [\"19687096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic vs scaffold contribution to TSP-1 induction not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established in vivo that CD26 protectively restricts allergic airway inflammation, consistent with its chemokine-inactivating activity.\",\n      \"evidence\": \"CD26-knockout mice, OVA sensitization, BAL cytokine/chemokine measurement, eosinophil quantification\",\n      \"pmids\": [\"22101691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not isolate which substrate cleavages (eotaxin/RANTES) drive the phenotype\", \"Single model\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined transcriptional control of CD26 in colon cancer, with c-Myc repressing and Cdx2 enhancing expression in a confluence-dependent manner.\",\n      \"evidence\": \"c-Myc overexpression and siRNA, Cdx2 siRNA, qPCR, western blot, immunofluorescence\",\n      \"pmids\": [\"21284881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding by these factors not shown\", \"HIF-1α requirement mechanism unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined DPP4 as the MERS-CoV receptor at atomic resolution, mapping the spike RBD to specific β-propeller blades.\",\n      \"evidence\": \"X-ray crystallography of RBD–DPP4 complex, SPR (Kd = 16.7 nM)\",\n      \"pmids\": [\"23831647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address how receptor engagement relates to peptidase activity or species tropism determinants in vivo\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended DPP4 scaffolding to cancer invasion, showing CD26–α5β1 integrin complexes drive FAK/Cas-L signaling and CD9 negatively regulates this axis.\",\n      \"evidence\": \"Reciprocal co-IP, CD26/CD9 siRNA, gene transfer, invasion assays, FAK/Cas-L western blots in mesothelioma\",\n      \"pmids\": [\"24466195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether catalytic activity is required for the integrin interaction unknown\", \"Single cancer type\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CD26 to two additional cellular programs—IL-10-skewed regulatory T-cell output (NFAT/ERK/EGR2) and osteoclast differentiation (p38/MKK3-6/MITF).\",\n      \"evidence\": \"Co-stimulation assays, EGR2 siRNA, pathway inhibitors, anti-CD26 mAb, TRAP/bone resorption assays\",\n      \"pmids\": [\"25548232\", \"24821427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream receptor coupling of CD26 to these MAPK/NFAT cascades not defined\", \"Single-lab readouts\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed that DPP4 subcellular localization is a ferroptosis switch controlled non-transcriptionally by TP53, with plasma-membrane DPP4 driving lipid peroxidation.\",\n      \"evidence\": \"TP53 KO, subcellular fractionation, DPP4 activity and lipid peroxidation assays, ferroptosis readouts\",\n      \"pmids\": [\"28813679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which membrane DPP4 promotes lipid peroxidation not detailed\", \"Direct TP53–DPP4 contact not structurally defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioned secreted hepatocyte DPP4 as a metabolic inflammatory signal acting through caveolin-1/factor Xa/PAR2 on adipose macrophages to cause insulin resistance.\",\n      \"evidence\": \"Hepatocyte-specific DPP4 silencing in vivo, ATM caveolin-1/PAR2 siRNA, insulin resistance and inflammation measurements\",\n      \"pmids\": [\"29562231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DPP4 peptidase activity is required for PAR2 pathway activation not isolated\", \"Human relevance not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed ADA can physically bridge CD26 on T cells to A2AR on dendritic cells, defining an intercellular signaling triad.\",\n      \"evidence\": \"Inter-cellular NanoBRET, ADA mutagenesis, dynamic mass redistribution, ligand binding\",\n      \"pmids\": [\"29497379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional immune consequence of the trimer not demonstrated\", \"Single lab biophysical assays\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked CD26 to colorectal cancer angiogenesis/metastasis through a CAV1/MMP1 axis, with CAV1 epistatically suppressing CD26-driven MMP1.\",\n      \"evidence\": \"CD26 overexpression/knockdown, genome-wide array, qPCR, migration/invasion, in vivo model, CAV1 rescue\",\n      \"pmids\": [\"35163100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CD26 induces MMP1 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified glucocorticoid receptor as a direct transcriptional inducer of DPP4 via promoter GREs, coupling steroid signaling to macrophage migration.\",\n      \"evidence\": \"GR ChIP/GRE mapping, GR and DPP4 siRNA, RU-486, migration and activity assays\",\n      \"pmids\": [\"31988243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether enzymatic or scaffold DPP4 function drives migration not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated DPP4 in senescence biology—as a surface 'uptake repressor' on senescence-associated EVs and as a driver of a complement/coagulation SASP whose inhibition is senomorphic/senolytic.\",\n      \"evidence\": \"EV surfaceome MS, ectopic DPP4 overexpression and uptake assays; DPP4 silencing/inhibition, conditioned-media proteomics, single-cell VSMC analysis, murine atherosclerosis\",\n      \"pmids\": [\"37862381\", \"37097759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of EV uptake repression by DPP4 unknown\", \"Causal SASP substrate of DPP4 in VSMCs not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that DPP4 truncation of CCL11 limits anti-tumor eosinophil recruitment, providing a substrate-level rationale for DPP4 inhibition in cancer immunity.\",\n      \"evidence\": \"Sitagliptin in tumor models, eosinophil depletion, IL-33-dependence epistasis, chemokine measurement\",\n      \"pmids\": [\"30778250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of other DPP4 substrates to the phenotype not excluded\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how DPP4 partitions between its catalytic and scaffolding functions across contexts, and which molecular features dictate its localization (membrane vs nucleus vs EV vs secreted) and partner selection in a given cell type.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking localization control to functional output\", \"Enzymatic vs non-enzymatic contributions not systematically dissected in most disease settings\", \"No structure of full-length DPP4 bound to its scaffolding partners\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 7, 22]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 22]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 22]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 7, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 13, 17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8, 11, 15]}\n    ],\n    \"complexes\": [\n      \"CD26-ADA-A2AR trimer\",\n      \"CD26-CXCR4 complex\",\n      \"CD26-\\u03b15\\u03b21 integrin complex\"\n    ],\n    \"partners\": [\n      \"ADA\",\n      \"CXCR4\",\n      \"CD45\",\n      \"CAV1\",\n      \"ITGA5\",\n      \"CD9\",\n      \"TP53\",\n      \"F2RL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}