{"gene":"ADGRE5","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":1996,"finding":"CD97 binds the cellular ligand CD55 (DAF) via its extracellular EGF domains; lymphocytes and erythrocytes specifically adhere to CD97-transfected COS cells, and erythrocytes lacking CD55 (PNH or Inab phenotype) fail to adhere, establishing CD55 as the first cellular ligand for a 7-TM receptor.","method":"Cell adhesion assay with CD97-transfected COS cells, blocking monoclonal antibody to CD55 SCR domain, use of CD55-deficient erythrocytes (PNH/Inab)","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ligand-blocking and genetic (CD55-null cells) controls; independently replicated across multiple subsequent studies","pmids":["9064337"],"is_preprint":false},{"year":1996,"finding":"CD97 is proteolytically processed intracellularly (in ER or early Golgi) from a single proprotein into a non-covalently associated two-subunit heterodimer: a large extracellular alpha subunit and a seven-transmembrane beta subunit expressed on the cell surface.","method":"Biochemical characterization, protein expression studies, pulse-chase/subcellular fractionation in transfected cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — original structural characterization replicated by multiple subsequent studies confirming the heterodimeric GPS-cleaved structure","pmids":["8955192"],"is_preprint":false},{"year":1998,"finding":"The CD55-binding site on CD97 requires at least three tandemly linked EGF domains; deletion of individual EGF domains and anti-EGF1 antibodies or Ca2+ removal block CD55 binding. Larger CD97 isoforms (EGF1,2,3,5 and EGF1,2,3,4,5) have significantly lower affinity for CD55, indicating that alternative splicing regulates ligand specificity.","method":"CD97 EGF-domain deletion mutants expressed in transfectants; adhesion blocking by domain-specific monoclonal antibodies; Ca2+ chelation assays","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis/deletion analysis with multiple orthogonal blocking approaches; replicated by structural study (PMID 33992645)","pmids":["9603477"],"is_preprint":false},{"year":2001,"finding":"The CD97–CD55 interaction is mediated solely by EGF and SCR domains respectively, has low affinity (Kd ~86 µM) and rapid off-rate (≥0.6 s⁻¹), is Ca2+-dependent but unaffected by EGF-domain glycosylation. EMR2, differing by only three amino acids in the EGF domains, binds CD55 with at least 10-fold lower affinity, indicating fine specificity tuning by a small number of residues.","method":"Surface plasmon resonance (SPR), biotinylated multimerized peptide cell-binding assays, domain-swapped mutant proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative biophysical measurement with mutagenesis; clear mechanistic dissection","pmids":["11297558"],"is_preprint":false},{"year":2004,"finding":"CD97 extracellular domain (CD97alpha) promotes angiogenesis in vivo and stimulates migration/invasion of endothelial cells; integrin α5β1 is identified as a high-affinity counterreceptor for CD97 on endothelial cells, with αvβ3 contributing to cell attachment. Co-engagement of α5β1 and chondroitin sulfate proteoglycan by CD97 synergistically initiates endothelial cell invasion.","method":"Directed in vivo angiogenesis assay (DIVAA), HUVEC migration/invasion assays, integrin-blocking antibodies, protein binding assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods; blocking antibody and integrin-knockdown controls","pmids":["15576472"],"is_preprint":false},{"year":2004,"finding":"The fourth EGF domain of CD97 (and EMR2) interacts with the glycosaminoglycan chondroitin sulfate (CS); this ligand is specifically found on B cells in peripheral blood, suggesting a role for CD97 in interactions of activated T cells, DCs, and macrophages with B cells.","method":"Fluorescent bead coating with soluble recombinant CD97/EMR2 isoforms; isoform-specific monoclonal antibodies; cell-binding assays","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific isoform and domain mapped using recombinant proteins and antibody blocking; single lab","pmids":["15498814"],"is_preprint":false},{"year":2004,"finding":"CD97 is required for neutrophil migration in vivo; anti-CD97 mAbs targeting EGF domain 1 or 3 significantly delayed neutrophil homing to the colon in DSS-induced colitis and reduced granulocytic infiltration and survival in S. pneumoniae pneumonia.","method":"Adoptive transfer of mAb-pretreated neutrophils in DSS-colitis model; murine pneumonia model with bacterial quantification and survival analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent in vivo disease models with functional readouts; mechanistic domain-specific antibody blocking","pmids":["14707087"],"is_preprint":false},{"year":2006,"finding":"Costimulation of CD4+ T cells via CD55 is mediated by its natural ligand CD97: co-engagement of CD55 with CD97 and CD3 enhances T cell proliferation, CD69/CD25 expression, and IL-10/GM-CSF secretion without interfering with CD55-mediated complement regulation.","method":"Human peripheral blood CD4+ T cell proliferation assays, activation marker expression, cytokine secretion; blocking with anti-CD97 and anti-CD55 mAbs","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — natural ligand (CD97) and cross-linking mAbs used in parallel; complement regulation assay as orthogonal control","pmids":["16818763"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of EMR2 EGF domains (close CD97 homolog) combined with NMR chemical shift mapping reveals the molecular basis of CD97–CD55 interaction: CD55 binds CD97 EGF domains on a face opposite to the T-cell costimulatory surface, allowing simultaneous complement regulation and T cell regulation.","method":"X-ray crystallography of EMR2; NMR chemical shift mapping of EMR2–CD55 interaction; model building of CD97–CD55 complex; T-cell proliferation and IFN-γ secretion assays with monocyte CD55/T-cell CD97 blocking","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus NMR plus functional validation in the same study","pmids":["17449467"],"is_preprint":false},{"year":2009,"finding":"GPS autoproteolysis of CD97 is regulated by site-specific N-glycosylation; a unique pattern of N-glycosylation within the GPS motif of CD97 was identified, and N-glycosylation inhibitors and glycosylation-site mutants confirm that N-glycosylation determines the extent of GPS cleavage.","method":"N-glycosylation inhibitors (tunicamycin), N-glycosylation site mutagenesis, Western blot analysis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with pharmacological inhibition in the same study; clear mechanistic conclusion","pmids":["19737555"],"is_preprint":false},{"year":2010,"finding":"GPS autoproteolysis is required for CD97 to upregulate N-cadherin expression, which leads to Ca2+-dependent homotypic cell-cell aggregation; GPS-cleavage-deficient CD97 fails to mediate this effect.","method":"GPS cleavage-deficient CD97 mutant expression, N-cadherin Western blot, Ca2+-dependent cell aggregation assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mutagenesis of GPS site with defined functional readout in a single rigorous study","pmids":["21156175"],"is_preprint":false},{"year":2010,"finding":"CD97 overexpression in intestinal epithelial cells strengthens adherens junctions by increasing and stabilizing junctional β-catenin, associated with inactivation of GSK-3β and activation of Akt; CD97 knockout weakens lateral cell contacts. CD97 localizes to E-cadherin-based adherens junctions.","method":"Transgenic and knockout mouse models; ultrastructural analysis; Western blot for β-catenin, phospho-β-catenin, GSK-3β, Akt; transepithelial resistance measurement; DSS colitis model","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic overexpression and knockout both examined with multiple biochemical and ultrastructural readouts","pmids":["20084281"],"is_preprint":false},{"year":2011,"finding":"CD97 signals through Gα12/13 to increase RHO-GTP levels and mediates invasion in prostate cancer cells by heterodimerizing with LPAR1, leading to enhanced LPA-dependent RHO and ERK activation.","method":"Gα12/13 co-immunoprecipitation and knockdown; RHO-GTP pull-down assay; CD97-LPAR1 co-immunoprecipitation; siRNA depletion in PC3 cells; bone metastasis mouse model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP of CD97-LPAR1 heterodimer, G-protein pathway dissection, in vivo validation","pmids":["21978933"],"is_preprint":false},{"year":2011,"finding":"CD97 on polymorphonuclear cells interacts with Thy-1 (CD90) on activated endothelial cells via its stalk domain (not EGF-like domains); this interaction is calcium-independent and mediates firm adhesion of leukocytes to inflamed endothelium.","method":"Adhesion assays with CD97-overexpressing CHO cells on Thy-1+ ECs and immobilized Thy-1 protein; soluble CD97 binding assays; blocking with domain-specific mAbs; soluble CD97 without stalk and EMR2 as negative controls","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal binding and blocking assays; domain specificity established by stalk-deletion and EMR2 controls","pmids":["22210915"],"is_preprint":false},{"year":2012,"finding":"CD97 amplifies LPA receptor signaling to RHOA and promotes thyroid cancer progression; CD97 transgenic mice crossed with ThrbPV thyroid carcinoma model showed increased vascular invasion, lung metastasis, elevated ERK phosphorylation, and increased Ki67+ cells. Depletion of CD97 in human thyroid cancer cell lines reduced RHO-GTP and LPA-stimulated invasion.","method":"Transgenic mouse model (Tg-CD97 x ThrbPV); ERK phosphorylation Western blot; Ki67 immunostaining; siRNA knockdown; RHO-GTP pull-down; invasion assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model plus in vitro mechanistic dissection with multiple readouts","pmids":["22797060"],"is_preprint":false},{"year":2013,"finding":"Leukocyte CD97 surface expression is downregulated within minutes of contact with CD55 in vivo by a process requiring shear stress (intact circulation); both CD97 alpha and beta subunits are downregulated together, correlating with increased soluble CD97 in plasma. De novo CD97 ligation did not activate ERK or Akt signaling in circulating leukocytes.","method":"CD55-deficient mouse leukocyte transfer experiments; flow cytometry for CD97 surface levels; intravital assays; in vitro co-culture under defined shear stress","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo and in vitro complementary experiments; negative signaling result explicitly controlled for","pmids":["23447688"],"is_preprint":false},{"year":2014,"finding":"CD97 inhibits migration and invasion in HT1080 fibrosarcoma cells by enhancing TIMP-2 secretion, which reduces MT1-MMP and MMP-2 activities; this requires both the NTF and CTF (GPS-cleaved) subunits acting in concert. CD97 also upregulates integrins to promote cell adhesion.","method":"TIMP-2 ELISA; MMP-2/MT1-MMP activity assays; NTF/CTF-only mutant expression; cell migration and invasion assays; in vivo lung metastasis model","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway dissection with GPS mutants, enzyme activity assays, and in vivo validation","pmids":["25174588"],"is_preprint":false},{"year":2015,"finding":"CD97 protects tumor cells from apoptosis; GPS cleavage and the TM7 region are required for this anti-apoptotic effect. Wild-type CD97 reduced caspase activation and modulated BCL-2 family members under serum starvation, staurosporine, and TNF/cycloheximide conditions. shRNA knockdown increased caspase-mediated apoptosis.","method":"Stable CD97 overexpression and shRNA knockdown; GPS cleavage-deficient and TM7-truncated mutants; annexin V staining, sub-G0/G1 FACS, caspase activity assays, BCL-2 family Western blots","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis (GPS mutant, TM7 truncation, alternative splicing variants) with multiple apoptosis readouts in one study","pmids":["26071181"],"is_preprint":false},{"year":2018,"finding":"Mechanical forces rapidly induce phosphorylation of CD97 at its intracellular C-terminal PDZ-binding motif (PBM); this phosphorylation disrupts CD97 binding to the PDZ scaffold protein DLG1. Cells expressing CD97 without the PBM are more deformable, lose cell contacts faster under shear stress, and show altered actin cytoskeleton organization. CD97 associates with F-actin-dependent membrane organization.","method":"Shear stress experiments; phospho-CD97 immunodetection; CD97–DLG1 co-immunoprecipitation; PBM-deletion and CD97-KO cell lines; atomic force microscopy; FACS; actin cytoskeleton imaging","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mutant, KO, AFM, shear stress); mechanistic link of phosphorylation to function established","pmids":["30134161"],"is_preprint":false},{"year":2018,"finding":"Tumor cell-associated CD97 directly interacts with platelets to stimulate platelet activation and granule secretion (including ATP release); platelet-derived LPA then acts through CD97–LPAR1 heterodimer signaling to induce tumor invasiveness and vascular permeability, promoting transendothelial migration and metastasis.","method":"Purified CD97 ECD–platelet binding and activation assays; ATP release measurement; LPA-stimulated invasion assays; in vivo vascular permeability and metastasis models with CD97 depletion","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assays plus in vivo loss-of-function with mechanistic pathway dissection","pmids":["29669286"],"is_preprint":false},{"year":2018,"finding":"CD97 interacts with β-catenin through its seven-span transmembrane/intracellular domain(s) in adherens junctions of normal colon; this interaction is lost during colorectal carcinogenesis when both proteins redistribute from the membrane.","method":"Proximity ligation assay, co-immunoprecipitation of endogenous proteins, GST-pulldown with CD97 TM/intracellular domain; quantitative in situ correlation in 111 patient samples","journal":"Frontiers in oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical binding (Co-IP + GST-pulldown) with domain mapping","pmids":["29888202"],"is_preprint":false},{"year":2018,"finding":"CD97 promotes tumor aggressiveness in hepatocellular carcinoma by cooperating with GRK6 to mediate GPCR desensitization and internalization; down-regulation of GRK6 suppresses CD97 internalization, and the CD97–GRK6 axis stimulates downstream MMP-2/9 secretion to promote metastasis.","method":"CD97 overexpression/knockdown, co-immunoprecipitation of CD97–GRK6, CD97 internalization assay, MMP-2/9 activity assay, in vivo lung metastasis mouse model","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex and functional knockdown with defined readouts; single lab","pmids":["29704239"],"is_preprint":false},{"year":2019,"finding":"CD55 stimulation of CD97 in ovarian cancer cells activates NF-κB, which down-regulates miR-503-5p, leading to increased CD97 expression and activation of the JAK2/STAT3 pathway to promote cell migration and invasion; JAK siRNA or NF-κB inhibitor blocked these effects.","method":"Recombinant CD55 stimulation; miR-503-5p mimic transfection; NF-κB inhibitor treatment; JAK2 siRNA knockdown; migration/invasion assays; Western blot for JAK2/STAT3","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway interventions with functional readouts; single lab","pmids":["30622051"],"is_preprint":false},{"year":2019,"finding":"The RGD motif in CD97 is critical for cell adhesion to fibronectin-coated surfaces partly via upregulation of αvβ5 and α2β1 integrins; RGD-dependent cell adhesion mediates CD97's anti-apoptotic effect in extrinsic (but not intrinsic) apoptosis. Intrinsic apoptosis resistance is mediated by RGD-independent N-cadherin-induced homotypic aggregation.","method":"RGD-to-RGE point mutant CD97 expression in HT1080 cells; integrin FACS analysis; cell adhesion, apoptosis, and viability assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct mutagenesis of functional motif with multiple mechanistic readouts; single lab","pmids":["30728423"],"is_preprint":false},{"year":2020,"finding":"CD97 (ADGRE5) couples to G13 most specifically among G proteins tested, and also to Gα12, Gα14, and Gαz in recombinant systems; both CD97 and EMR2 induce pertussis-toxin-insensitive inhibition of cAMP, consistent with Gαz coupling.","method":"Yeast-based GPCR-G protein coupling assay with chimeric G proteins; mammalian cell cAMP assay with pertussis toxin; constitutively-active truncated receptor constructs","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple recombinant coupling assays; pharmacological dissection; single lab","pmids":["31969668"],"is_preprint":false},{"year":2021,"finding":"The Salmonella effector SteD targets CD97 for degradation by promoting ubiquitination specifically at Lys555 on CD97; CD97 localizes to and stabilizes the immunological synapse between dendritic cells and T cells, and its removal by SteD inhibits DC–T cell interactions and reduces T cell activation independently of SteD's effect on MHCII.","method":"Proteomic screen of dendritic cells; ubiquitination assay; K555R CD97 point mutant; immunological synapse imaging; DC–T cell conjugate formation and T cell activation assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific ubiquitination mapped by mutagenesis, functional synapse stabilization confirmed, independent of MHCII effect","pmids":["34314469"],"is_preprint":false},{"year":2021,"finding":"Crystal structure of the CD97 EGF1,2,5–CD55 SCR1-4 complex (chimeric construct) reveals an antiparallel binding mode involving SCR1-3 of CD55 and all three EGF domains of CD97; mutagenesis confirms the importance of EGF5 in the interaction and explains why the shortest CD97 isoform binds CD55 with highest affinity. The geometry of the complex suggests a force-resisting shearing stretch architecture consistent with mechanosensing in circulatory flow.","method":"X-ray crystallography of CD97-CD55 chimeric fusion; site-directed mutagenesis of EGF5; SPR kinetics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation and biophysical kinetics in a single study","pmids":["33992645"],"is_preprint":false},{"year":2022,"finding":"CD97 function in splenic cDC2 positioning requires its autoproteolytic cleavage and Gα13 signaling; CD55 expressed on red blood cells acts as a CD97 ligand under shear stress to extract the regulatory CD97 N-terminal fragment, triggering a migration and gene expression program. Loss of CD55–CD97 signaling causes cDC2 loss from spleen into circulation and defective lymphocyte responses to blood-borne antigens.","method":"Adgre5 and Gna13 conditional KO mice; CD55 KO mice; adoptive transfer; intravital imaging; flow cytometry for splenic DC populations; antigen-specific lymphocyte response assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic knockouts with complementary in vivo functional readouts; autoproteolysis requirement directly tested","pmids":["35143305"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of CD97 in complex with G13, Gq, and Gs reveal the stalk/Stachel peptide recognition mode, a revised 'FXφφφ' activation motif in the ligand-binding pocket, and key determinants of G13 coupling selectivity (deep insertion of αH5 and closer contact with TM helices 6, 5, and 3).","method":"Cryo-electron microscopy structure determination; structure-guided mutagenesis; functional G-protein coupling assays; metadynamics simulations","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus mutagenesis plus functional validation in a single study","pmids":["37673067"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of human CD97 in inactive apo and G13-bound fully active states reveal a compact inactive conformation with a constrained ligand pocket; activation induces significant conformational changes on both extracellular and intracellular sides, creating larger cavities for Stachel sequence binding and G13 engagement.","method":"Cryo-electron microscopy; functional GPCR signaling assays; metadynamics simulations","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — dual-state cryo-EM structures with functional and computational validation","pmids":["38215752"],"is_preprint":false},{"year":2023,"finding":"CD97 negatively regulates antiviral innate immunity by upregulating RNF125 expression, which promotes K48-linked ubiquitination of RIG-I at Lys181, leading to RIG-I degradation and suppression of type-I interferon signaling; CD97-deficient mice are more resistant to RNA virus infection.","method":"CD97 overexpression and knockout in cells and mice; RIG-I ubiquitination assay specifying K48-linkage at K181; RNF125 expression analysis; IFN-I measurement; viral replication assays; in vivo mouse infection model","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific ubiquitination mapped (K181), mechanism through RNF125 confirmed, in vivo KO validation","pmids":["37978243"],"is_preprint":false},{"year":2024,"finding":"CD97 activates mTORC2 in glioblastoma stem cells, leading to AKT S473 phosphorylation and enhanced expression of downstream genes ARHGAP1, BZW1, and BZW2; mTORC2 inhibition suppresses GSC tumorigenicity and these downstream gene targets.","method":"CD97 silencing in patient-derived GSCs; transcriptome analysis; AKT S473 phosphorylation Western blot; mTORC2 inhibitor (JR-AB2-011) treatment; self-renewal and proliferation assays","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus pharmacological pathway inhibition with transcriptomic profiling; single lab","pmids":["39637858"],"is_preprint":false},{"year":2004,"finding":"N-glycosylation within the EGF domains of CD97 is required for epitope accessibility of EGF-domain antibodies and for binding to its ligand CD55; site-directed mutagenesis of N-glycosylation sites within the EGF domains abolishes both EGF-mAb binding and CD55 binding.","method":"Site-directed mutagenesis of N-glycosylation sites; tunicamycin treatment; immunoprecipitation; N-glycosidase F treatment; mAb staining and CD55 binding assays","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mutagenesis of glycosylation sites with two orthogonal functional readouts (mAb binding and CD55 ligand binding)","pmids":["15386373"],"is_preprint":false},{"year":2010,"finding":"Deletion of CD97 in mice ameliorates collagen-induced and K/BxN serum-transfer arthritis, providing genetic evidence that the CD55–CD97 receptor-ligand interaction contributes to synovial inflammation; CD55 deletion also reduced arthritis, indicating the pathogenic importance of this receptor-ligand pair.","method":"CD97 KO and CD55 KO mouse models; two arthritis models (CIA and K/BxN serum transfer); clinical, radiological, and histological assessment","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent KO mouse lines in two independent disease models with multi-modal readouts","pmids":["20131275"],"is_preprint":false},{"year":2013,"finding":"miR-126 directly targets CD97 mRNA in breast cancer cells, reducing CD97 protein levels and thereby inhibiting cell-autonomous and non-cell-autonomous cancer progression including invasion and angiogenesis.","method":"BONCAT and SILAC quantitative proteomics after miR-126 overexpression; direct miR-126 target site validation for CD97","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics confirming direct targeting; single lab","pmids":["24274104"],"is_preprint":false},{"year":2014,"finding":"CD97 is expressed at the sarcoplasmic reticulum (SR) of skeletal muscle, co-localizing with SERCA but not with DHPR or RYR; CD97 knockout mice display a dilated SR (altered SR structure) without impairment of Ca2+ release, force generation, or fatigue, indicating a structural but not functional role in SR organization.","method":"Immunofluorescence co-localization; flow cytometry of isolated myocytes; CD97 KO mouse ultrastructural analysis (electron microscopy); single myofiber Ca2+ release; isolated muscle force/fatigue assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific subcellular co-localization plus KO phenotype with multiple functional readouts showing specific structural (not functional) consequence","pmids":["24949957"],"is_preprint":false},{"year":2016,"finding":"CD97 overexpression in macrophages inhibits LPS-induced NF-κB activation and TNF-α secretion by upregulating PPAR-γ; CD97 knockout THP-1 cells showed decreased PPAR-γ and increased NF-κB activation upon LPS stimulation.","method":"CD97 knockdown and overexpression in macrophages; PPAR-γ and NF-κB (p65) immunofluorescence and Western blot; TNF-α ELISA; CD97 KO THP-1 cells","journal":"Mediators of inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined pathway readout; single lab","pmids":["26997758"],"is_preprint":false},{"year":2019,"finding":"Edited miR-379-5p (ADAR2-catalyzed A-to-I edit in seed region) directly targets CD97 mRNA; this edited miRNA inhibits cell proliferation and promotes apoptosis in tumor cells, in contrast to wild-type miR-379-5p which does not target CD97.","method":"Reporter assay for direct targeting; in vitro proliferation and apoptosis assays; nanoliposomal edited miRNA delivery in vivo; comparison of wild-type vs. edited miRNA effects","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation with reporter assay; in vivo confirmation; single lab","pmids":["31682236"],"is_preprint":false},{"year":2020,"finding":"CD97 promotes human trophoblast invasion via PI3K/Akt/mTOR signaling pathway; CD97 regulates FOXC2 expression, which modulates PI3K/Akt/mTOR signaling similarly to a FOXC2-specific inhibitor.","method":"CD97 siRNA knockdown and overexpression in HTR-8/SVneo trophoblast cells; invasion assay; Western blot for PI3K/Akt/mTOR pathway; FOXC2 expression analysis","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined signaling readouts; single lab","pmids":["32430705"],"is_preprint":false},{"year":2024,"finding":"CD97 suppresses osteoclast differentiation under orthodontic compressive force through the Rap1a/ERK signaling pathway; compression upregulates CD97 on macrophages, and CD97 knockdown partially rescues osteoclast differentiation under compression. Rap1a inhibitor GGTI298 increased osteoclast activity and accelerated tooth movement in vivo.","method":"Single-cell RNA analysis; CD97 knockdown; RNA sequencing; Rap1a inhibitor GGTI298; in vivo orthodontic tooth movement model","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with RNA-seq pathway identification and in vivo pharmacological validation; single lab","pmids":["38311610"],"is_preprint":false}],"current_model":"CD97/ADGRE5 is an adhesion GPCR that undergoes GPS autoproteolysis (regulated by N-glycosylation) to form a non-covalent NTF–CTF heterodimer on the cell surface; the NTF binds multiple cellular ligands (CD55 via EGF domains 1,2,5 in a Ca2+-dependent, mechanosensitive shear-force geometry; chondroitin sulfate via EGF4; integrins α5β1/αvβ3 via an RGD motif; and Thy-1 via the stalk region), while the seven-TM CTF couples preferentially to Gα12/13 to activate RHO/ERK/Akt signaling—amplified by heterodimerization with LPAR1—and also links to the cytoskeleton through a PDZ-binding motif that undergoes mechano-dependent phosphorylation to modulate DLG1 binding and cell detachment; GPS cleavage is required for N-cadherin upregulation, anti-apoptotic signaling, and intestinal cDC2 positioning via mechanosensing of RBC-expressed CD55 under shear stress, while in innate immunity CD97 upregulates RNF125 to drive K48-ubiquitination and degradation of RIG-I at Lys181, suppressing type-I interferon responses."},"narrative":{"mechanistic_narrative":"ADGRE5 (CD97) is an adhesion G protein-coupled receptor that couples cell-surface adhesion to intracellular signaling, governing leukocyte trafficking, epithelial junction integrity, immune cell positioning, and tumor invasion [PMID:9064337, PMID:14707087, PMID:35143305]. The receptor is synthesized as a single proprotein and processed by GPS autoproteolysis into a non-covalent heterodimer of a large extracellular N-terminal fragment and a seven-transmembrane C-terminal fragment displayed at the cell surface [PMID:8955192]; cleavage extent is set by site-specific N-glycosylation within the GPS motif [PMID:19737555]. The N-terminal fragment engages multiple ligands through distinct modules: CD55/DAF via tandem EGF domains in a Ca2+-dependent, low-affinity interaction whose specificity is tuned by alternative splicing and a small set of EGF residues [PMID:9064337, PMID:9603477, PMID:11297558], chondroitin sulfate via EGF domain 4 [PMID:15498814], integrins via an RGD motif and high-affinity counterreceptor binding [PMID:15576472, PMID:30728423], and Thy-1 via the stalk domain in a calcium-independent mode [PMID:22210915]. Crystal and cryo-EM structures resolved the antiparallel EGF1,2,5–CD55 binding mode with a force-resisting shear-stretch geometry and the Stachel-peptide activation mechanism that selectively engages G13 [PMID:33992645, PMID:37673067, PMID:38215752]. The seven-transmembrane fragment couples preferentially to Gα12/13 to drive RHO-GTP, ERK, and Akt signaling, amplified by heterodimerization with LPAR1, promoting cancer cell invasion and metastasis [PMID:21978933, PMID:22797060, PMID:29669286, PMID:31969668]. GPS cleavage is required for downstream outputs including N-cadherin-dependent homotypic aggregation, anti-apoptotic signaling, and CD55-driven dendritic cell positioning under shear stress [PMID:21156175, PMID:26071181, PMID:35143305]. CD97 stabilizes epithelial adherens junctions through β-catenin association and the immunological synapse between dendritic cells and T cells [PMID:20084281, PMID:29888202, PMID:34314469], links to the actin cytoskeleton via a C-terminal PDZ-binding motif whose mechano-dependent phosphorylation modulates DLG1 binding and cell detachment [PMID:30134161], and in innate immunity suppresses type-I interferon responses by upregulating RNF125 to drive K48-ubiquitination and degradation of RIG-I [PMID:37978243].","teleology":[{"year":1996,"claim":"Establishing that a seven-transmembrane receptor could function as an adhesion molecule, this work identified CD55 as the first cellular ligand for CD97 and revealed the receptor's heterodimeric processed architecture.","evidence":"Cell adhesion assays with CD97 transfectants and CD55-null erythrocytes; biochemical processing analysis in transfected cells","pmids":["9064337","8955192"],"confidence":"High","gaps":["Affinity and kinetics of the CD55 interaction not quantified","Functional consequence of adhesion for signaling unknown"]},{"year":1998,"claim":"Mapping the CD55-binding site to tandem EGF domains and showing splice-isoform-dependent affinity defined how ligand specificity is genetically encoded and regulated.","evidence":"EGF-domain deletion mutants, domain-specific blocking antibodies and Ca2+ chelation in transfectants","pmids":["9603477"],"confidence":"High","gaps":["Atomic-resolution binding geometry not resolved","Physiological relevance of isoform switching unclear"]},{"year":2001,"claim":"Quantitative biophysics established the CD97–CD55 interaction as low-affinity with a rapid off-rate and fine specificity tuned by few residues, reframing it as a transient adhesion rather than a stable receptor-ligand lock.","evidence":"Surface plasmon resonance, multimerized peptide binding, domain-swap mutants comparing CD97 and EMR2","pmids":["11297558"],"confidence":"High","gaps":["Functional meaning of transient binding in vivo not addressed","Did not test multivalent or sheared conditions"]},{"year":2004,"claim":"Identification of additional N-terminal ligands (integrin α5β1, αvβ3, chondroitin sulfate) and a role in angiogenesis and neutrophil migration expanded CD97 from a CD55 receptor to a multi-ligand adhesion hub with in vivo immune function.","evidence":"In vivo angiogenesis and colitis/pneumonia models, integrin-blocking antibodies, recombinant CD97 bead-binding, glycosylation-site mutagenesis","pmids":["15576472","15498814","14707087","15386373"],"confidence":"High","gaps":["Whether multiple ligands are engaged simultaneously or competitively unresolved","Signaling pathway downstream of integrin/CS engagement not defined"]},{"year":2007,"claim":"A crystal structure of the EMR2 EGF domains plus NMR mapping provided the first molecular model of CD97–CD55 contact and showed the binding face is distinct from CD55's complement-regulatory and costimulatory surfaces, explaining how adhesion and immune regulation coexist.","evidence":"X-ray crystallography of EMR2, NMR chemical shift mapping, T-cell costimulation assays","pmids":["16818763","17449467"],"confidence":"High","gaps":["Model based on homolog EMR2, not CD97 itself","Mechanosensing geometry not yet appreciated"]},{"year":2010,"claim":"Genetic and mutagenesis work tied GPS autoproteolysis and N-glycosylation to specific cellular outputs—N-cadherin upregulation, adherens junction stabilization via β-catenin/Akt/GSK-3β, and arthritis pathogenesis—linking the processing event to function.","evidence":"GPS cleavage-deficient mutants, transgenic and knockout mice, glycosylation inhibitors, arthritis models, junction and ultrastructural analysis","pmids":["21156175","20084281","20131275","19737555"],"confidence":"High","gaps":["Mechanism by which the CTF transmits the cleavage-dependent signal not defined","Direct intracellular effectors of junction stabilization unmapped"]},{"year":2012,"claim":"Defining Gα12/13–RHO signaling and CD97–LPAR1 heterodimerization established the cytoplasmic signaling output that drives tumor invasion and metastasis.","evidence":"Gα12/13 Co-IP and knockdown, RHO-GTP pulldowns, CD97-LPAR1 reciprocal Co-IP, prostate and thyroid cancer models","pmids":["21978933","22797060"],"confidence":"High","gaps":["Stoichiometry and dynamics of the CD97-LPAR1 heterodimer unknown","Whether ligand binding triggers G-protein coupling not directly shown"]},{"year":2013,"claim":"Demonstrating shear-stress-dependent CD97 downregulation upon CD55 contact in the circulation revealed the receptor as a mechanosensor whose surface levels are mechanically regulated.","evidence":"CD55-deficient mouse leukocyte transfer, flow cytometry, defined shear-stress co-culture","pmids":["23447688"],"confidence":"High","gaps":["Molecular force-transduction mechanism not yet identified","De novo ligation failed to activate ERK/Akt, leaving signaling context unclear"]},{"year":2014,"claim":"Identification of CD97 at the skeletal muscle SR with a structural-but-not-functional KO phenotype, plus context-dependent inhibition of invasion via TIMP-2, showed CD97 outputs are highly cell-type specific.","evidence":"SR co-localization with SERCA, KO ultrastructure and Ca2+/force assays; TIMP-2 ELISA and MMP activity assays with GPS mutants","pmids":["24949957","25174588"],"confidence":"High","gaps":["Reconciling pro- versus anti-invasive roles across tissues unresolved","SR localization mechanism and partner unknown"]},{"year":2018,"claim":"Discovery of mechano-induced phosphorylation of the C-terminal PDZ-binding motif disrupting DLG1 binding directly connected mechanical force to cytoskeletal organization and cell detachment, defining the intracellular arm of mechanosensing.","evidence":"Shear stress, phospho-CD97 detection, CD97-DLG1 Co-IP, PBM-deletion and KO lines, atomic force microscopy","pmids":["30134161","29888202","29669286"],"confidence":"High","gaps":["Kinase responsible for PBM phosphorylation not identified","How extracellular force is relayed to the intracellular PBM unresolved"]},{"year":2021,"claim":"Crystallography of the CD97 EGF1,2,5–CD55 complex and the SteD-targeted Lys555 ubiquitination work jointly established the force-resisting binding geometry underlying mechanosensing and a mechanism for synapse-stabilizing CD97 turnover.","evidence":"X-ray crystallography with EGF5 mutagenesis and SPR; proteomic ubiquitination screen with K555R mutant and synapse imaging","pmids":["33992645","34314469"],"confidence":"High","gaps":["Physiological force range tested only by structural inference","Endogenous E3 ligase for CD97 turnover not identified"]},{"year":2022,"claim":"Conditional knockouts demonstrated that CD55–CD97 mechanosensing of red blood cells under shear stress, via autoproteolysis and Gα13, drives splenic cDC2 positioning and blood-borne antigen responses, providing definitive in vivo physiological context for the receptor's mechanosensor function.","evidence":"Adgre5, Gna13, and CD55 conditional KO mice; intravital imaging; antigen-specific lymphocyte assays","pmids":["35143305"],"confidence":"High","gaps":["Gene-expression program triggered by NTF extraction not fully mapped","Generalization beyond cDC2 to other immune cells unclear"]},{"year":2023,"claim":"Cryo-EM structures of CD97 bound to G13/Gq/Gs and in apo versus active states defined the Stachel-peptide activation motif and the determinants of G13 coupling selectivity, completing the structural logic from autoproteolysis to G-protein engagement; parallel work revealed RNF125-dependent RIG-I degradation as a CD97 innate-immune suppression mechanism.","evidence":"Cryo-EM with structure-guided mutagenesis and coupling assays; RIG-I K48-ubiquitination mapping at K181 and viral infection KO mice","pmids":["37673067","38215752","37978243"],"confidence":"High","gaps":["How endogenous ligand engagement triggers Stachel-mediated activation in cells unresolved","Mechanism linking surface CD97 to RNF125 transcriptional upregulation unknown"]},{"year":2024,"claim":"Identification of CD97-driven mTORC2/AKT signaling in glioblastoma stem cells and Rap1a/ERK control of osteoclast differentiation extended the downstream signaling repertoire to new contexts.","evidence":"GSC knockdown with transcriptomics and mTORC2 inhibitor; single-cell RNA analysis, CD97 knockdown and Rap1a inhibitor in orthodontic models","pmids":["39637858","39637858","38311610"],"confidence":"Medium","gaps":["Direct biochemical link between CD97 and mTORC2/Rap1a not established","Whether these depend on canonical G12/13 coupling untested"]},{"year":null,"claim":"How distinct ligand-engagement events (CD55, integrins, Thy-1, chondroitin sulfate) are selectively converted into specific G-protein versus cytoskeletal versus innate-immune outputs in a given cell remains the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking specific ligands to specific signaling branches","Endogenous agonist conditions that trigger G-protein coupling in vivo undefined","Kinase and E3 ligase machinery acting on CD97 intracellular regions incompletely identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[12,24,28]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4,13]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,9]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[18,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,11,18]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,35]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,24,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,25,27,30]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,11,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,9,30]}],"complexes":["CD97 NTF–CTF heterodimer","CD97–LPAR1 heterodimer"],"partners":["CD55","LPAR1","DLG1","CTNNB1","THY1","GRK6","GNA13","RNF125"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48960","full_name":"Adhesion G protein-coupled receptor E5","aliases":["Leukocyte antigen CD97"],"length_aa":835,"mass_kda":91.9,"function":"Receptor potentially involved in both adhesion and signaling processes early after leukocyte activation. Plays an essential role in leukocyte migration","subcellular_location":"Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/P48960/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADGRE5","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":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ADGRE5","total_profiled":1310},"omim":[{"mim_id":"619856","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 50; ANKRD50","url":"https://www.omim.org/entry/619856"},{"mim_id":"601211","title":"ADHESION G PROTEIN-COUPLED RECEPTOR E5; ADGRE5","url":"https://www.omim.org/entry/601211"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":165.3},{"tissue":"bone marrow","ntpm":200.1}],"url":"https://www.proteinatlas.org/search/ADGRE5"},"hgnc":{"alias_symbol":["TM7LN1"],"prev_symbol":["CD97"]},"alphafold":{"accession":"P48960","domains":[{"cath_id":"2.10.25.10","chopping":"35-65","consensus_level":"medium","plddt":81.5235,"start":35,"end":65},{"cath_id":"-","chopping":"176-210","consensus_level":"medium","plddt":74.45,"start":176,"end":210},{"cath_id":"2.10.25.10","chopping":"225-259","consensus_level":"medium","plddt":79.6351,"start":225,"end":259},{"cath_id":"2.60.220.50","chopping":"274-469_489-542","consensus_level":"medium","plddt":82.7304,"start":274,"end":542},{"cath_id":"1.20.1070.10","chopping":"559-803","consensus_level":"high","plddt":86.9418,"start":559,"end":803}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48960","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48960-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48960-F1-predicted_aligned_error_v6.png","plddt_mean":78.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADGRE5","jax_strain_url":"https://www.jax.org/strain/search?query=ADGRE5"},"sequence":{"accession":"P48960","fasta_url":"https://rest.uniprot.org/uniprotkb/P48960.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48960/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48960"}},"corpus_meta":[{"pmid":"9064337","id":"PMC_9064337","title":"The 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in human oral squamous cell carcinomas.","date":"2005","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15668483","citation_count":22,"is_preprint":false},{"pmid":"38215752","id":"PMC_38215752","title":"Conformational transitions and activation of the adhesion receptor CD97.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38215752","citation_count":21,"is_preprint":false},{"pmid":"26071181","id":"PMC_26071181","title":"The Adhesion GPCR CD97/ADGRE5 inhibits apoptosis.","date":"2015","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26071181","citation_count":21,"is_preprint":false},{"pmid":"18326527","id":"PMC_18326527","title":"Differential role of CD97 in interleukin-8-induced and granulocyte-colony stimulating factor-induced 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Europaische chirurgische Forschung. Recherches chirurgicales europeennes","url":"https://pubmed.ncbi.nlm.nih.gov/16374010","citation_count":14,"is_preprint":false},{"pmid":"20428763","id":"PMC_20428763","title":"Role of CD97 isoforms in gastric carcinoma.","date":"2010","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20428763","citation_count":14,"is_preprint":false},{"pmid":"21169517","id":"PMC_21169517","title":"CD97 antibody depletes granulocytes in mice under conditions of acute inflammation via a Fc receptor-dependent mechanism.","date":"2010","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/21169517","citation_count":14,"is_preprint":false},{"pmid":"39637858","id":"PMC_39637858","title":"CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells.","date":"2024","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39637858","citation_count":13,"is_preprint":false},{"pmid":"37907543","id":"PMC_37907543","title":"IL-8 is a novel prometastatic chemokine in intrahepatic cholangiocarcinoma that induces CXCR2-PI3K/AKT signaling upon CD97 activation.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37907543","citation_count":13,"is_preprint":false},{"pmid":"31594642","id":"PMC_31594642","title":"The role of the RGD motif in CD97/ADGRE5-and EMR2/ADGRE2-modulated tumor angiogenesis.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31594642","citation_count":12,"is_preprint":false},{"pmid":"23676664","id":"PMC_23676664","title":"Mice overexpressing CD97 in intestinal epithelial cells provide a unique model for mammalian postnatal intestinal cylindrical growth.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23676664","citation_count":12,"is_preprint":false},{"pmid":"25434383","id":"PMC_25434383","title":"Wilms tumor 1 gene, CD97, and the emerging biogenetic profile of glioblastoma.","date":"2014","source":"Neurosurgical focus","url":"https://pubmed.ncbi.nlm.nih.gov/25434383","citation_count":11,"is_preprint":false},{"pmid":"37673067","id":"PMC_37673067","title":"Structural basis of CD97 activation and G-protein coupling.","date":"2023","source":"Cell chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/37673067","citation_count":10,"is_preprint":false},{"pmid":"35087132","id":"PMC_35087132","title":"CD97 is associated with mitogenic pathway activation, metabolic reprogramming, and immune microenvironment changes in glioblastoma.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35087132","citation_count":10,"is_preprint":false},{"pmid":"37517698","id":"PMC_37517698","title":"Dual role of the adhesion G-protein coupled receptor ADRGE5/CD97 in glioblastoma invasion and proliferation.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37517698","citation_count":10,"is_preprint":false},{"pmid":"30953469","id":"PMC_30953469","title":"Identification of ADGRE5 as discriminating MYC target between Burkitt lymphoma and diffuse large B-cell lymphoma.","date":"2019","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30953469","citation_count":10,"is_preprint":false},{"pmid":"38155248","id":"PMC_38155248","title":"Identification of CD38, CD97, and CD278 on the HIV surface using a novel flow virometry screening assay.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38155248","citation_count":10,"is_preprint":false},{"pmid":"26997758","id":"PMC_26997758","title":"CD97/ADGRE5 Inhibits LPS Induced NF-κB Activation through PPAR-γ Upregulation in Macrophages.","date":"2016","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/26997758","citation_count":9,"is_preprint":false},{"pmid":"34028660","id":"PMC_34028660","title":"Genetic manipulation of adhesion GPCR CD97/ADGRE5 modulates invasion in patient-derived glioma stem cells.","date":"2021","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34028660","citation_count":9,"is_preprint":false},{"pmid":"38311610","id":"PMC_38311610","title":"CD97 inhibits osteoclast differentiation via Rap1a/ERK pathway under compression.","date":"2024","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/38311610","citation_count":8,"is_preprint":false},{"pmid":"38343549","id":"PMC_38343549","title":"ADGRE5-centered Tsurv model in T cells recognizes responders to neoadjuvant cancer immunotherapy.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38343549","citation_count":8,"is_preprint":false},{"pmid":"27641734","id":"PMC_27641734","title":"Biochemical features of the adhesion G protein-coupled receptor CD97 related to its auto-proteolysis and HeLa cell attachment activities.","date":"2016","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/27641734","citation_count":8,"is_preprint":false},{"pmid":"31397926","id":"PMC_31397926","title":"The role of ADGRE5/CD97 in human retinal pigment epithelial cell growth and survival.","date":"2019","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31397926","citation_count":7,"is_preprint":false},{"pmid":"40425009","id":"PMC_40425009","title":"CD97-directed CAR-T cells with enhanced persistence eradicate acute myeloid leukemia in diverse xenograft models.","date":"2025","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40425009","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50261,"output_tokens":9824,"usd":0.149071,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20272,"output_tokens":5278,"usd":0.116655,"stage2_stop_reason":"end_turn"},"total_usd":0.265726,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"CD97 binds the cellular ligand CD55 (DAF) via its extracellular EGF domains; lymphocytes and erythrocytes specifically adhere to CD97-transfected COS cells, and erythrocytes lacking CD55 (PNH or Inab phenotype) fail to adhere, establishing CD55 as the first cellular ligand for a 7-TM receptor.\",\n      \"method\": \"Cell adhesion assay with CD97-transfected COS cells, blocking monoclonal antibody to CD55 SCR domain, use of CD55-deficient erythrocytes (PNH/Inab)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ligand-blocking and genetic (CD55-null cells) controls; independently replicated across multiple subsequent studies\",\n      \"pmids\": [\"9064337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD97 is proteolytically processed intracellularly (in ER or early Golgi) from a single proprotein into a non-covalently associated two-subunit heterodimer: a large extracellular alpha subunit and a seven-transmembrane beta subunit expressed on the cell surface.\",\n      \"method\": \"Biochemical characterization, protein expression studies, pulse-chase/subcellular fractionation in transfected cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — original structural characterization replicated by multiple subsequent studies confirming the heterodimeric GPS-cleaved structure\",\n      \"pmids\": [\"8955192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The CD55-binding site on CD97 requires at least three tandemly linked EGF domains; deletion of individual EGF domains and anti-EGF1 antibodies or Ca2+ removal block CD55 binding. Larger CD97 isoforms (EGF1,2,3,5 and EGF1,2,3,4,5) have significantly lower affinity for CD55, indicating that alternative splicing regulates ligand specificity.\",\n      \"method\": \"CD97 EGF-domain deletion mutants expressed in transfectants; adhesion blocking by domain-specific monoclonal antibodies; Ca2+ chelation assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis/deletion analysis with multiple orthogonal blocking approaches; replicated by structural study (PMID 33992645)\",\n      \"pmids\": [\"9603477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The CD97–CD55 interaction is mediated solely by EGF and SCR domains respectively, has low affinity (Kd ~86 µM) and rapid off-rate (≥0.6 s⁻¹), is Ca2+-dependent but unaffected by EGF-domain glycosylation. EMR2, differing by only three amino acids in the EGF domains, binds CD55 with at least 10-fold lower affinity, indicating fine specificity tuning by a small number of residues.\",\n      \"method\": \"Surface plasmon resonance (SPR), biotinylated multimerized peptide cell-binding assays, domain-swapped mutant proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative biophysical measurement with mutagenesis; clear mechanistic dissection\",\n      \"pmids\": [\"11297558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD97 extracellular domain (CD97alpha) promotes angiogenesis in vivo and stimulates migration/invasion of endothelial cells; integrin α5β1 is identified as a high-affinity counterreceptor for CD97 on endothelial cells, with αvβ3 contributing to cell attachment. Co-engagement of α5β1 and chondroitin sulfate proteoglycan by CD97 synergistically initiates endothelial cell invasion.\",\n      \"method\": \"Directed in vivo angiogenesis assay (DIVAA), HUVEC migration/invasion assays, integrin-blocking antibodies, protein binding assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods; blocking antibody and integrin-knockdown controls\",\n      \"pmids\": [\"15576472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The fourth EGF domain of CD97 (and EMR2) interacts with the glycosaminoglycan chondroitin sulfate (CS); this ligand is specifically found on B cells in peripheral blood, suggesting a role for CD97 in interactions of activated T cells, DCs, and macrophages with B cells.\",\n      \"method\": \"Fluorescent bead coating with soluble recombinant CD97/EMR2 isoforms; isoform-specific monoclonal antibodies; cell-binding assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific isoform and domain mapped using recombinant proteins and antibody blocking; single lab\",\n      \"pmids\": [\"15498814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD97 is required for neutrophil migration in vivo; anti-CD97 mAbs targeting EGF domain 1 or 3 significantly delayed neutrophil homing to the colon in DSS-induced colitis and reduced granulocytic infiltration and survival in S. pneumoniae pneumonia.\",\n      \"method\": \"Adoptive transfer of mAb-pretreated neutrophils in DSS-colitis model; murine pneumonia model with bacterial quantification and survival analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent in vivo disease models with functional readouts; mechanistic domain-specific antibody blocking\",\n      \"pmids\": [\"14707087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Costimulation of CD4+ T cells via CD55 is mediated by its natural ligand CD97: co-engagement of CD55 with CD97 and CD3 enhances T cell proliferation, CD69/CD25 expression, and IL-10/GM-CSF secretion without interfering with CD55-mediated complement regulation.\",\n      \"method\": \"Human peripheral blood CD4+ T cell proliferation assays, activation marker expression, cytokine secretion; blocking with anti-CD97 and anti-CD55 mAbs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — natural ligand (CD97) and cross-linking mAbs used in parallel; complement regulation assay as orthogonal control\",\n      \"pmids\": [\"16818763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of EMR2 EGF domains (close CD97 homolog) combined with NMR chemical shift mapping reveals the molecular basis of CD97–CD55 interaction: CD55 binds CD97 EGF domains on a face opposite to the T-cell costimulatory surface, allowing simultaneous complement regulation and T cell regulation.\",\n      \"method\": \"X-ray crystallography of EMR2; NMR chemical shift mapping of EMR2–CD55 interaction; model building of CD97–CD55 complex; T-cell proliferation and IFN-γ secretion assays with monocyte CD55/T-cell CD97 blocking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus NMR plus functional validation in the same study\",\n      \"pmids\": [\"17449467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GPS autoproteolysis of CD97 is regulated by site-specific N-glycosylation; a unique pattern of N-glycosylation within the GPS motif of CD97 was identified, and N-glycosylation inhibitors and glycosylation-site mutants confirm that N-glycosylation determines the extent of GPS cleavage.\",\n      \"method\": \"N-glycosylation inhibitors (tunicamycin), N-glycosylation site mutagenesis, Western blot analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with pharmacological inhibition in the same study; clear mechanistic conclusion\",\n      \"pmids\": [\"19737555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GPS autoproteolysis is required for CD97 to upregulate N-cadherin expression, which leads to Ca2+-dependent homotypic cell-cell aggregation; GPS-cleavage-deficient CD97 fails to mediate this effect.\",\n      \"method\": \"GPS cleavage-deficient CD97 mutant expression, N-cadherin Western blot, Ca2+-dependent cell aggregation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mutagenesis of GPS site with defined functional readout in a single rigorous study\",\n      \"pmids\": [\"21156175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD97 overexpression in intestinal epithelial cells strengthens adherens junctions by increasing and stabilizing junctional β-catenin, associated with inactivation of GSK-3β and activation of Akt; CD97 knockout weakens lateral cell contacts. CD97 localizes to E-cadherin-based adherens junctions.\",\n      \"method\": \"Transgenic and knockout mouse models; ultrastructural analysis; Western blot for β-catenin, phospho-β-catenin, GSK-3β, Akt; transepithelial resistance measurement; DSS colitis model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic overexpression and knockout both examined with multiple biochemical and ultrastructural readouts\",\n      \"pmids\": [\"20084281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD97 signals through Gα12/13 to increase RHO-GTP levels and mediates invasion in prostate cancer cells by heterodimerizing with LPAR1, leading to enhanced LPA-dependent RHO and ERK activation.\",\n      \"method\": \"Gα12/13 co-immunoprecipitation and knockdown; RHO-GTP pull-down assay; CD97-LPAR1 co-immunoprecipitation; siRNA depletion in PC3 cells; bone metastasis mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP of CD97-LPAR1 heterodimer, G-protein pathway dissection, in vivo validation\",\n      \"pmids\": [\"21978933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD97 on polymorphonuclear cells interacts with Thy-1 (CD90) on activated endothelial cells via its stalk domain (not EGF-like domains); this interaction is calcium-independent and mediates firm adhesion of leukocytes to inflamed endothelium.\",\n      \"method\": \"Adhesion assays with CD97-overexpressing CHO cells on Thy-1+ ECs and immobilized Thy-1 protein; soluble CD97 binding assays; blocking with domain-specific mAbs; soluble CD97 without stalk and EMR2 as negative controls\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal binding and blocking assays; domain specificity established by stalk-deletion and EMR2 controls\",\n      \"pmids\": [\"22210915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD97 amplifies LPA receptor signaling to RHOA and promotes thyroid cancer progression; CD97 transgenic mice crossed with ThrbPV thyroid carcinoma model showed increased vascular invasion, lung metastasis, elevated ERK phosphorylation, and increased Ki67+ cells. Depletion of CD97 in human thyroid cancer cell lines reduced RHO-GTP and LPA-stimulated invasion.\",\n      \"method\": \"Transgenic mouse model (Tg-CD97 x ThrbPV); ERK phosphorylation Western blot; Ki67 immunostaining; siRNA knockdown; RHO-GTP pull-down; invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model plus in vitro mechanistic dissection with multiple readouts\",\n      \"pmids\": [\"22797060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Leukocyte CD97 surface expression is downregulated within minutes of contact with CD55 in vivo by a process requiring shear stress (intact circulation); both CD97 alpha and beta subunits are downregulated together, correlating with increased soluble CD97 in plasma. De novo CD97 ligation did not activate ERK or Akt signaling in circulating leukocytes.\",\n      \"method\": \"CD55-deficient mouse leukocyte transfer experiments; flow cytometry for CD97 surface levels; intravital assays; in vitro co-culture under defined shear stress\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo and in vitro complementary experiments; negative signaling result explicitly controlled for\",\n      \"pmids\": [\"23447688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD97 inhibits migration and invasion in HT1080 fibrosarcoma cells by enhancing TIMP-2 secretion, which reduces MT1-MMP and MMP-2 activities; this requires both the NTF and CTF (GPS-cleaved) subunits acting in concert. CD97 also upregulates integrins to promote cell adhesion.\",\n      \"method\": \"TIMP-2 ELISA; MMP-2/MT1-MMP activity assays; NTF/CTF-only mutant expression; cell migration and invasion assays; in vivo lung metastasis model\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway dissection with GPS mutants, enzyme activity assays, and in vivo validation\",\n      \"pmids\": [\"25174588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD97 protects tumor cells from apoptosis; GPS cleavage and the TM7 region are required for this anti-apoptotic effect. Wild-type CD97 reduced caspase activation and modulated BCL-2 family members under serum starvation, staurosporine, and TNF/cycloheximide conditions. shRNA knockdown increased caspase-mediated apoptosis.\",\n      \"method\": \"Stable CD97 overexpression and shRNA knockdown; GPS cleavage-deficient and TM7-truncated mutants; annexin V staining, sub-G0/G1 FACS, caspase activity assays, BCL-2 family Western blots\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis (GPS mutant, TM7 truncation, alternative splicing variants) with multiple apoptosis readouts in one study\",\n      \"pmids\": [\"26071181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mechanical forces rapidly induce phosphorylation of CD97 at its intracellular C-terminal PDZ-binding motif (PBM); this phosphorylation disrupts CD97 binding to the PDZ scaffold protein DLG1. Cells expressing CD97 without the PBM are more deformable, lose cell contacts faster under shear stress, and show altered actin cytoskeleton organization. CD97 associates with F-actin-dependent membrane organization.\",\n      \"method\": \"Shear stress experiments; phospho-CD97 immunodetection; CD97–DLG1 co-immunoprecipitation; PBM-deletion and CD97-KO cell lines; atomic force microscopy; FACS; actin cytoskeleton imaging\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mutant, KO, AFM, shear stress); mechanistic link of phosphorylation to function established\",\n      \"pmids\": [\"30134161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tumor cell-associated CD97 directly interacts with platelets to stimulate platelet activation and granule secretion (including ATP release); platelet-derived LPA then acts through CD97–LPAR1 heterodimer signaling to induce tumor invasiveness and vascular permeability, promoting transendothelial migration and metastasis.\",\n      \"method\": \"Purified CD97 ECD–platelet binding and activation assays; ATP release measurement; LPA-stimulated invasion assays; in vivo vascular permeability and metastasis models with CD97 depletion\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assays plus in vivo loss-of-function with mechanistic pathway dissection\",\n      \"pmids\": [\"29669286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD97 interacts with β-catenin through its seven-span transmembrane/intracellular domain(s) in adherens junctions of normal colon; this interaction is lost during colorectal carcinogenesis when both proteins redistribute from the membrane.\",\n      \"method\": \"Proximity ligation assay, co-immunoprecipitation of endogenous proteins, GST-pulldown with CD97 TM/intracellular domain; quantitative in situ correlation in 111 patient samples\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical binding (Co-IP + GST-pulldown) with domain mapping\",\n      \"pmids\": [\"29888202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD97 promotes tumor aggressiveness in hepatocellular carcinoma by cooperating with GRK6 to mediate GPCR desensitization and internalization; down-regulation of GRK6 suppresses CD97 internalization, and the CD97–GRK6 axis stimulates downstream MMP-2/9 secretion to promote metastasis.\",\n      \"method\": \"CD97 overexpression/knockdown, co-immunoprecipitation of CD97–GRK6, CD97 internalization assay, MMP-2/9 activity assay, in vivo lung metastasis mouse model\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex and functional knockdown with defined readouts; single lab\",\n      \"pmids\": [\"29704239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD55 stimulation of CD97 in ovarian cancer cells activates NF-κB, which down-regulates miR-503-5p, leading to increased CD97 expression and activation of the JAK2/STAT3 pathway to promote cell migration and invasion; JAK siRNA or NF-κB inhibitor blocked these effects.\",\n      \"method\": \"Recombinant CD55 stimulation; miR-503-5p mimic transfection; NF-κB inhibitor treatment; JAK2 siRNA knockdown; migration/invasion assays; Western blot for JAK2/STAT3\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway interventions with functional readouts; single lab\",\n      \"pmids\": [\"30622051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The RGD motif in CD97 is critical for cell adhesion to fibronectin-coated surfaces partly via upregulation of αvβ5 and α2β1 integrins; RGD-dependent cell adhesion mediates CD97's anti-apoptotic effect in extrinsic (but not intrinsic) apoptosis. Intrinsic apoptosis resistance is mediated by RGD-independent N-cadherin-induced homotypic aggregation.\",\n      \"method\": \"RGD-to-RGE point mutant CD97 expression in HT1080 cells; integrin FACS analysis; cell adhesion, apoptosis, and viability assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mutagenesis of functional motif with multiple mechanistic readouts; single lab\",\n      \"pmids\": [\"30728423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD97 (ADGRE5) couples to G13 most specifically among G proteins tested, and also to Gα12, Gα14, and Gαz in recombinant systems; both CD97 and EMR2 induce pertussis-toxin-insensitive inhibition of cAMP, consistent with Gαz coupling.\",\n      \"method\": \"Yeast-based GPCR-G protein coupling assay with chimeric G proteins; mammalian cell cAMP assay with pertussis toxin; constitutively-active truncated receptor constructs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple recombinant coupling assays; pharmacological dissection; single lab\",\n      \"pmids\": [\"31969668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Salmonella effector SteD targets CD97 for degradation by promoting ubiquitination specifically at Lys555 on CD97; CD97 localizes to and stabilizes the immunological synapse between dendritic cells and T cells, and its removal by SteD inhibits DC–T cell interactions and reduces T cell activation independently of SteD's effect on MHCII.\",\n      \"method\": \"Proteomic screen of dendritic cells; ubiquitination assay; K555R CD97 point mutant; immunological synapse imaging; DC–T cell conjugate formation and T cell activation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific ubiquitination mapped by mutagenesis, functional synapse stabilization confirmed, independent of MHCII effect\",\n      \"pmids\": [\"34314469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structure of the CD97 EGF1,2,5–CD55 SCR1-4 complex (chimeric construct) reveals an antiparallel binding mode involving SCR1-3 of CD55 and all three EGF domains of CD97; mutagenesis confirms the importance of EGF5 in the interaction and explains why the shortest CD97 isoform binds CD55 with highest affinity. The geometry of the complex suggests a force-resisting shearing stretch architecture consistent with mechanosensing in circulatory flow.\",\n      \"method\": \"X-ray crystallography of CD97-CD55 chimeric fusion; site-directed mutagenesis of EGF5; SPR kinetics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation and biophysical kinetics in a single study\",\n      \"pmids\": [\"33992645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD97 function in splenic cDC2 positioning requires its autoproteolytic cleavage and Gα13 signaling; CD55 expressed on red blood cells acts as a CD97 ligand under shear stress to extract the regulatory CD97 N-terminal fragment, triggering a migration and gene expression program. Loss of CD55–CD97 signaling causes cDC2 loss from spleen into circulation and defective lymphocyte responses to blood-borne antigens.\",\n      \"method\": \"Adgre5 and Gna13 conditional KO mice; CD55 KO mice; adoptive transfer; intravital imaging; flow cytometry for splenic DC populations; antigen-specific lymphocyte response assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic knockouts with complementary in vivo functional readouts; autoproteolysis requirement directly tested\",\n      \"pmids\": [\"35143305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of CD97 in complex with G13, Gq, and Gs reveal the stalk/Stachel peptide recognition mode, a revised 'FXφφφ' activation motif in the ligand-binding pocket, and key determinants of G13 coupling selectivity (deep insertion of αH5 and closer contact with TM helices 6, 5, and 3).\",\n      \"method\": \"Cryo-electron microscopy structure determination; structure-guided mutagenesis; functional G-protein coupling assays; metadynamics simulations\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus mutagenesis plus functional validation in a single study\",\n      \"pmids\": [\"37673067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of human CD97 in inactive apo and G13-bound fully active states reveal a compact inactive conformation with a constrained ligand pocket; activation induces significant conformational changes on both extracellular and intracellular sides, creating larger cavities for Stachel sequence binding and G13 engagement.\",\n      \"method\": \"Cryo-electron microscopy; functional GPCR signaling assays; metadynamics simulations\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — dual-state cryo-EM structures with functional and computational validation\",\n      \"pmids\": [\"38215752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD97 negatively regulates antiviral innate immunity by upregulating RNF125 expression, which promotes K48-linked ubiquitination of RIG-I at Lys181, leading to RIG-I degradation and suppression of type-I interferon signaling; CD97-deficient mice are more resistant to RNA virus infection.\",\n      \"method\": \"CD97 overexpression and knockout in cells and mice; RIG-I ubiquitination assay specifying K48-linkage at K181; RNF125 expression analysis; IFN-I measurement; viral replication assays; in vivo mouse infection model\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific ubiquitination mapped (K181), mechanism through RNF125 confirmed, in vivo KO validation\",\n      \"pmids\": [\"37978243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD97 activates mTORC2 in glioblastoma stem cells, leading to AKT S473 phosphorylation and enhanced expression of downstream genes ARHGAP1, BZW1, and BZW2; mTORC2 inhibition suppresses GSC tumorigenicity and these downstream gene targets.\",\n      \"method\": \"CD97 silencing in patient-derived GSCs; transcriptome analysis; AKT S473 phosphorylation Western blot; mTORC2 inhibitor (JR-AB2-011) treatment; self-renewal and proliferation assays\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus pharmacological pathway inhibition with transcriptomic profiling; single lab\",\n      \"pmids\": [\"39637858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"N-glycosylation within the EGF domains of CD97 is required for epitope accessibility of EGF-domain antibodies and for binding to its ligand CD55; site-directed mutagenesis of N-glycosylation sites within the EGF domains abolishes both EGF-mAb binding and CD55 binding.\",\n      \"method\": \"Site-directed mutagenesis of N-glycosylation sites; tunicamycin treatment; immunoprecipitation; N-glycosidase F treatment; mAb staining and CD55 binding assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mutagenesis of glycosylation sites with two orthogonal functional readouts (mAb binding and CD55 ligand binding)\",\n      \"pmids\": [\"15386373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Deletion of CD97 in mice ameliorates collagen-induced and K/BxN serum-transfer arthritis, providing genetic evidence that the CD55–CD97 receptor-ligand interaction contributes to synovial inflammation; CD55 deletion also reduced arthritis, indicating the pathogenic importance of this receptor-ligand pair.\",\n      \"method\": \"CD97 KO and CD55 KO mouse models; two arthritis models (CIA and K/BxN serum transfer); clinical, radiological, and histological assessment\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent KO mouse lines in two independent disease models with multi-modal readouts\",\n      \"pmids\": [\"20131275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-126 directly targets CD97 mRNA in breast cancer cells, reducing CD97 protein levels and thereby inhibiting cell-autonomous and non-cell-autonomous cancer progression including invasion and angiogenesis.\",\n      \"method\": \"BONCAT and SILAC quantitative proteomics after miR-126 overexpression; direct miR-126 target site validation for CD97\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics confirming direct targeting; single lab\",\n      \"pmids\": [\"24274104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD97 is expressed at the sarcoplasmic reticulum (SR) of skeletal muscle, co-localizing with SERCA but not with DHPR or RYR; CD97 knockout mice display a dilated SR (altered SR structure) without impairment of Ca2+ release, force generation, or fatigue, indicating a structural but not functional role in SR organization.\",\n      \"method\": \"Immunofluorescence co-localization; flow cytometry of isolated myocytes; CD97 KO mouse ultrastructural analysis (electron microscopy); single myofiber Ca2+ release; isolated muscle force/fatigue assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific subcellular co-localization plus KO phenotype with multiple functional readouts showing specific structural (not functional) consequence\",\n      \"pmids\": [\"24949957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD97 overexpression in macrophages inhibits LPS-induced NF-κB activation and TNF-α secretion by upregulating PPAR-γ; CD97 knockout THP-1 cells showed decreased PPAR-γ and increased NF-κB activation upon LPS stimulation.\",\n      \"method\": \"CD97 knockdown and overexpression in macrophages; PPAR-γ and NF-κB (p65) immunofluorescence and Western blot; TNF-α ELISA; CD97 KO THP-1 cells\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined pathway readout; single lab\",\n      \"pmids\": [\"26997758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Edited miR-379-5p (ADAR2-catalyzed A-to-I edit in seed region) directly targets CD97 mRNA; this edited miRNA inhibits cell proliferation and promotes apoptosis in tumor cells, in contrast to wild-type miR-379-5p which does not target CD97.\",\n      \"method\": \"Reporter assay for direct targeting; in vitro proliferation and apoptosis assays; nanoliposomal edited miRNA delivery in vivo; comparison of wild-type vs. edited miRNA effects\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation with reporter assay; in vivo confirmation; single lab\",\n      \"pmids\": [\"31682236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD97 promotes human trophoblast invasion via PI3K/Akt/mTOR signaling pathway; CD97 regulates FOXC2 expression, which modulates PI3K/Akt/mTOR signaling similarly to a FOXC2-specific inhibitor.\",\n      \"method\": \"CD97 siRNA knockdown and overexpression in HTR-8/SVneo trophoblast cells; invasion assay; Western blot for PI3K/Akt/mTOR pathway; FOXC2 expression analysis\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined signaling readouts; single lab\",\n      \"pmids\": [\"32430705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD97 suppresses osteoclast differentiation under orthodontic compressive force through the Rap1a/ERK signaling pathway; compression upregulates CD97 on macrophages, and CD97 knockdown partially rescues osteoclast differentiation under compression. Rap1a inhibitor GGTI298 increased osteoclast activity and accelerated tooth movement in vivo.\",\n      \"method\": \"Single-cell RNA analysis; CD97 knockdown; RNA sequencing; Rap1a inhibitor GGTI298; in vivo orthodontic tooth movement model\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with RNA-seq pathway identification and in vivo pharmacological validation; single lab\",\n      \"pmids\": [\"38311610\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD97/ADGRE5 is an adhesion GPCR that undergoes GPS autoproteolysis (regulated by N-glycosylation) to form a non-covalent NTF–CTF heterodimer on the cell surface; the NTF binds multiple cellular ligands (CD55 via EGF domains 1,2,5 in a Ca2+-dependent, mechanosensitive shear-force geometry; chondroitin sulfate via EGF4; integrins α5β1/αvβ3 via an RGD motif; and Thy-1 via the stalk region), while the seven-TM CTF couples preferentially to Gα12/13 to activate RHO/ERK/Akt signaling—amplified by heterodimerization with LPAR1—and also links to the cytoskeleton through a PDZ-binding motif that undergoes mechano-dependent phosphorylation to modulate DLG1 binding and cell detachment; GPS cleavage is required for N-cadherin upregulation, anti-apoptotic signaling, and intestinal cDC2 positioning via mechanosensing of RBC-expressed CD55 under shear stress, while in innate immunity CD97 upregulates RNF125 to drive K48-ubiquitination and degradation of RIG-I at Lys181, suppressing type-I interferon responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADGRE5 (CD97) is an adhesion G protein-coupled receptor that couples cell-surface adhesion to intracellular signaling, governing leukocyte trafficking, epithelial junction integrity, immune cell positioning, and tumor invasion [#0, #6, #27]. The receptor is synthesized as a single proprotein and processed by GPS autoproteolysis into a non-covalent heterodimer of a large extracellular N-terminal fragment and a seven-transmembrane C-terminal fragment displayed at the cell surface [#1]; cleavage extent is set by site-specific N-glycosylation within the GPS motif [#9]. The N-terminal fragment engages multiple ligands through distinct modules: CD55/DAF via tandem EGF domains in a Ca2+-dependent, low-affinity interaction whose specificity is tuned by alternative splicing and a small set of EGF residues [#0, #2, #3], chondroitin sulfate via EGF domain 4 [#5], integrins via an RGD motif and high-affinity counterreceptor binding [#4, #23], and Thy-1 via the stalk domain in a calcium-independent mode [#13]. Crystal and cryo-EM structures resolved the antiparallel EGF1,2,5–CD55 binding mode with a force-resisting shear-stretch geometry and the Stachel-peptide activation mechanism that selectively engages G13 [#26, #28, #29]. The seven-transmembrane fragment couples preferentially to Gα12/13 to drive RHO-GTP, ERK, and Akt signaling, amplified by heterodimerization with LPAR1, promoting cancer cell invasion and metastasis [#12, #14, #19, #24]. GPS cleavage is required for downstream outputs including N-cadherin-dependent homotypic aggregation, anti-apoptotic signaling, and CD55-driven dendritic cell positioning under shear stress [#10, #17, #27]. CD97 stabilizes epithelial adherens junctions through β-catenin association and the immunological synapse between dendritic cells and T cells [#11, #20, #25], links to the actin cytoskeleton via a C-terminal PDZ-binding motif whose mechano-dependent phosphorylation modulates DLG1 binding and cell detachment [#18], and in innate immunity suppresses type-I interferon responses by upregulating RNF125 to drive K48-ubiquitination and degradation of RIG-I [#30].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that a seven-transmembrane receptor could function as an adhesion molecule, this work identified CD55 as the first cellular ligand for CD97 and revealed the receptor's heterodimeric processed architecture.\",\n      \"evidence\": \"Cell adhesion assays with CD97 transfectants and CD55-null erythrocytes; biochemical processing analysis in transfected cells\",\n      \"pmids\": [\"9064337\", \"8955192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity and kinetics of the CD55 interaction not quantified\", \"Functional consequence of adhesion for signaling unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapping the CD55-binding site to tandem EGF domains and showing splice-isoform-dependent affinity defined how ligand specificity is genetically encoded and regulated.\",\n      \"evidence\": \"EGF-domain deletion mutants, domain-specific blocking antibodies and Ca2+ chelation in transfectants\",\n      \"pmids\": [\"9603477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution binding geometry not resolved\", \"Physiological relevance of isoform switching unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Quantitative biophysics established the CD97–CD55 interaction as low-affinity with a rapid off-rate and fine specificity tuned by few residues, reframing it as a transient adhesion rather than a stable receptor-ligand lock.\",\n      \"evidence\": \"Surface plasmon resonance, multimerized peptide binding, domain-swap mutants comparing CD97 and EMR2\",\n      \"pmids\": [\"11297558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional meaning of transient binding in vivo not addressed\", \"Did not test multivalent or sheared conditions\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of additional N-terminal ligands (integrin α5β1, αvβ3, chondroitin sulfate) and a role in angiogenesis and neutrophil migration expanded CD97 from a CD55 receptor to a multi-ligand adhesion hub with in vivo immune function.\",\n      \"evidence\": \"In vivo angiogenesis and colitis/pneumonia models, integrin-blocking antibodies, recombinant CD97 bead-binding, glycosylation-site mutagenesis\",\n      \"pmids\": [\"15576472\", \"15498814\", \"14707087\", \"15386373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether multiple ligands are engaged simultaneously or competitively unresolved\", \"Signaling pathway downstream of integrin/CS engagement not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A crystal structure of the EMR2 EGF domains plus NMR mapping provided the first molecular model of CD97–CD55 contact and showed the binding face is distinct from CD55's complement-regulatory and costimulatory surfaces, explaining how adhesion and immune regulation coexist.\",\n      \"evidence\": \"X-ray crystallography of EMR2, NMR chemical shift mapping, T-cell costimulation assays\",\n      \"pmids\": [\"16818763\", \"17449467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Model based on homolog EMR2, not CD97 itself\", \"Mechanosensing geometry not yet appreciated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic and mutagenesis work tied GPS autoproteolysis and N-glycosylation to specific cellular outputs—N-cadherin upregulation, adherens junction stabilization via β-catenin/Akt/GSK-3β, and arthritis pathogenesis—linking the processing event to function.\",\n      \"evidence\": \"GPS cleavage-deficient mutants, transgenic and knockout mice, glycosylation inhibitors, arthritis models, junction and ultrastructural analysis\",\n      \"pmids\": [\"21156175\", \"20084281\", \"20131275\", \"19737555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the CTF transmits the cleavage-dependent signal not defined\", \"Direct intracellular effectors of junction stabilization unmapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining Gα12/13–RHO signaling and CD97–LPAR1 heterodimerization established the cytoplasmic signaling output that drives tumor invasion and metastasis.\",\n      \"evidence\": \"Gα12/13 Co-IP and knockdown, RHO-GTP pulldowns, CD97-LPAR1 reciprocal Co-IP, prostate and thyroid cancer models\",\n      \"pmids\": [\"21978933\", \"22797060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of the CD97-LPAR1 heterodimer unknown\", \"Whether ligand binding triggers G-protein coupling not directly shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating shear-stress-dependent CD97 downregulation upon CD55 contact in the circulation revealed the receptor as a mechanosensor whose surface levels are mechanically regulated.\",\n      \"evidence\": \"CD55-deficient mouse leukocyte transfer, flow cytometry, defined shear-stress co-culture\",\n      \"pmids\": [\"23447688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular force-transduction mechanism not yet identified\", \"De novo ligation failed to activate ERK/Akt, leaving signaling context unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of CD97 at the skeletal muscle SR with a structural-but-not-functional KO phenotype, plus context-dependent inhibition of invasion via TIMP-2, showed CD97 outputs are highly cell-type specific.\",\n      \"evidence\": \"SR co-localization with SERCA, KO ultrastructure and Ca2+/force assays; TIMP-2 ELISA and MMP activity assays with GPS mutants\",\n      \"pmids\": [\"24949957\", \"25174588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling pro- versus anti-invasive roles across tissues unresolved\", \"SR localization mechanism and partner unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery of mechano-induced phosphorylation of the C-terminal PDZ-binding motif disrupting DLG1 binding directly connected mechanical force to cytoskeletal organization and cell detachment, defining the intracellular arm of mechanosensing.\",\n      \"evidence\": \"Shear stress, phospho-CD97 detection, CD97-DLG1 Co-IP, PBM-deletion and KO lines, atomic force microscopy\",\n      \"pmids\": [\"30134161\", \"29888202\", \"29669286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for PBM phosphorylation not identified\", \"How extracellular force is relayed to the intracellular PBM unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Crystallography of the CD97 EGF1,2,5–CD55 complex and the SteD-targeted Lys555 ubiquitination work jointly established the force-resisting binding geometry underlying mechanosensing and a mechanism for synapse-stabilizing CD97 turnover.\",\n      \"evidence\": \"X-ray crystallography with EGF5 mutagenesis and SPR; proteomic ubiquitination screen with K555R mutant and synapse imaging\",\n      \"pmids\": [\"33992645\", \"34314469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological force range tested only by structural inference\", \"Endogenous E3 ligase for CD97 turnover not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Conditional knockouts demonstrated that CD55–CD97 mechanosensing of red blood cells under shear stress, via autoproteolysis and Gα13, drives splenic cDC2 positioning and blood-borne antigen responses, providing definitive in vivo physiological context for the receptor's mechanosensor function.\",\n      \"evidence\": \"Adgre5, Gna13, and CD55 conditional KO mice; intravital imaging; antigen-specific lymphocyte assays\",\n      \"pmids\": [\"35143305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Gene-expression program triggered by NTF extraction not fully mapped\", \"Generalization beyond cDC2 to other immune cells unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-EM structures of CD97 bound to G13/Gq/Gs and in apo versus active states defined the Stachel-peptide activation motif and the determinants of G13 coupling selectivity, completing the structural logic from autoproteolysis to G-protein engagement; parallel work revealed RNF125-dependent RIG-I degradation as a CD97 innate-immune suppression mechanism.\",\n      \"evidence\": \"Cryo-EM with structure-guided mutagenesis and coupling assays; RIG-I K48-ubiquitination mapping at K181 and viral infection KO mice\",\n      \"pmids\": [\"37673067\", \"38215752\", \"37978243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How endogenous ligand engagement triggers Stachel-mediated activation in cells unresolved\", \"Mechanism linking surface CD97 to RNF125 transcriptional upregulation unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of CD97-driven mTORC2/AKT signaling in glioblastoma stem cells and Rap1a/ERK control of osteoclast differentiation extended the downstream signaling repertoire to new contexts.\",\n      \"evidence\": \"GSC knockdown with transcriptomics and mTORC2 inhibitor; single-cell RNA analysis, CD97 knockdown and Rap1a inhibitor in orthodontic models\",\n      \"pmids\": [\"39637858\", \"39637858\", \"38311610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between CD97 and mTORC2/Rap1a not established\", \"Whether these depend on canonical G12/13 coupling untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct ligand-engagement events (CD55, integrins, Thy-1, chondroitin sulfate) are selectively converted into specific G-protein versus cytoskeletal versus innate-immune outputs in a given cell remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking specific ligands to specific signaling branches\", \"Endogenous agonist conditions that trigger G-protein coupling in vivo undefined\", \"Kinase and E3 ligase machinery acting on CD97 intracellular regions incompletely identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [12, 24, 28]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4, 13]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [18, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 11, 18]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 24, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 25, 27, 30]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 11, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 9, 30]}\n    ],\n    \"complexes\": [\n      \"CD97 NTF–CTF heterodimer\",\n      \"CD97–LPAR1 heterodimer\"\n    ],\n    \"partners\": [\n      \"CD55\",\n      \"LPAR1\",\n      \"DLG1\",\n      \"CTNNB1\",\n      \"THY1\",\n      \"GRK6\",\n      \"GNA13\",\n      \"RNF125\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}