Affinage

Showing ADGRE5 — CD97 is a alias.

ADGRE5

Adhesion G protein-coupled receptor E5 · UniProt P48960

Length
835 aa
Mass
91.9 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    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

    PMID:8955192 PMID:9064337

    Open questions at the time
    • Affinity and kinetics of the CD55 interaction not quantified
    • Functional consequence of adhesion for signaling unknown
  2. 1998 High

    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

    PMID:9603477

    Open questions at the time
    • Atomic-resolution binding geometry not resolved
    • Physiological relevance of isoform switching unclear
  3. 2001 High

    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

    PMID:11297558

    Open questions at the time
    • Functional meaning of transient binding in vivo not addressed
    • Did not test multivalent or sheared conditions
  4. 2004 High

    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

    PMID:14707087 PMID:15386373 PMID:15498814 PMID:15576472

    Open questions at the time
    • Whether multiple ligands are engaged simultaneously or competitively unresolved
    • Signaling pathway downstream of integrin/CS engagement not defined
  5. 2007 High

    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

    PMID:16818763 PMID:17449467

    Open questions at the time
    • Model based on homolog EMR2, not CD97 itself
    • Mechanosensing geometry not yet appreciated
  6. 2010 High

    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

    PMID:19737555 PMID:20084281 PMID:20131275 PMID:21156175

    Open questions at the time
    • Mechanism by which the CTF transmits the cleavage-dependent signal not defined
    • Direct intracellular effectors of junction stabilization unmapped
  7. 2012 High

    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

    PMID:21978933 PMID:22797060

    Open questions at the time
    • Stoichiometry and dynamics of the CD97-LPAR1 heterodimer unknown
    • Whether ligand binding triggers G-protein coupling not directly shown
  8. 2013 High

    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

    PMID:23447688

    Open questions at the time
    • Molecular force-transduction mechanism not yet identified
    • De novo ligation failed to activate ERK/Akt, leaving signaling context unclear
  9. 2014 High

    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

    PMID:24949957 PMID:25174588

    Open questions at the time
    • Reconciling pro- versus anti-invasive roles across tissues unresolved
    • SR localization mechanism and partner unknown
  10. 2018 High

    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

    PMID:29669286 PMID:29888202 PMID:30134161

    Open questions at the time
    • Kinase responsible for PBM phosphorylation not identified
    • How extracellular force is relayed to the intracellular PBM unresolved
  11. 2021 High

    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

    PMID:33992645 PMID:34314469

    Open questions at the time
    • Physiological force range tested only by structural inference
    • Endogenous E3 ligase for CD97 turnover not identified
  12. 2022 High

    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

    PMID:35143305

    Open questions at the time
    • Gene-expression program triggered by NTF extraction not fully mapped
    • Generalization beyond cDC2 to other immune cells unclear
  13. 2023 High

    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

    PMID:37673067 PMID:37978243 PMID:38215752

    Open questions at the time
    • How endogenous ligand engagement triggers Stachel-mediated activation in cells unresolved
    • Mechanism linking surface CD97 to RNF125 transcriptional upregulation unknown
  14. 2024 Medium

    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

    PMID:38311610 PMID:39637858

    Open questions at the time
    • Direct biochemical link between CD97 and mTORC2/Rap1a not established
    • Whether these depend on canonical G12/13 coupling untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0016787 hydrolase activity 2 GO:0060090 molecular adaptor activity 2 GO:0048018 receptor ligand activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3
Partners
CD55CTNNB1DLG1GNA13GRK6LPAR1RNF125THY1
Complex memberships
CD97 NTF–CTF heterodimerCD97–LPAR1 heterodimer

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Cell adhesion assay with CD97-transfected COS cells, blocking monoclonal antibody to CD55 SCR domain, use of CD55-deficient erythrocytes (PNH/Inab) The Journal of experimental medicine High 9064337
1996 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. Biochemical characterization, protein expression studies, pulse-chase/subcellular fractionation in transfected cells Journal of immunology High 8955192
1998 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. CD97 EGF-domain deletion mutants expressed in transfectants; adhesion blocking by domain-specific monoclonal antibodies; Ca2+ chelation assays European journal of immunology High 9603477
2001 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. Surface plasmon resonance (SPR), biotinylated multimerized peptide cell-binding assays, domain-swapped mutant proteins The Journal of biological chemistry High 11297558
2004 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. Directed in vivo angiogenesis assay (DIVAA), HUVEC migration/invasion assays, integrin-blocking antibodies, protein binding assays Blood High 15576472
2004 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. Fluorescent bead coating with soluble recombinant CD97/EMR2 isoforms; isoform-specific monoclonal antibodies; cell-binding assays Journal of leukocyte biology Medium 15498814
2004 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. Adoptive transfer of mAb-pretreated neutrophils in DSS-colitis model; murine pneumonia model with bacterial quantification and survival analysis Journal of immunology High 14707087
2006 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. Human peripheral blood CD4+ T cell proliferation assays, activation marker expression, cytokine secretion; blocking with anti-CD97 and anti-CD55 mAbs Journal of immunology High 16818763
2007 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. 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 The Journal of biological chemistry High 17449467
2009 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-glycosylation inhibitors (tunicamycin), N-glycosylation site mutagenesis, Western blot analysis FEBS letters High 19737555
2010 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. GPS cleavage-deficient CD97 mutant expression, N-cadherin Western blot, Ca2+-dependent cell aggregation assay FEBS letters High 21156175
2010 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. Transgenic and knockout mouse models; ultrastructural analysis; Western blot for β-catenin, phospho-β-catenin, GSK-3β, Akt; transepithelial resistance measurement; DSS colitis model PloS one High 20084281
2011 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. Gα12/13 co-immunoprecipitation and knockdown; RHO-GTP pull-down assay; CD97-LPAR1 co-immunoprecipitation; siRNA depletion in PC3 cells; bone metastasis mouse model Cancer research High 21978933
2011 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. 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 of immunology High 22210915
2012 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. Transgenic mouse model (Tg-CD97 x ThrbPV); ERK phosphorylation Western blot; Ki67 immunostaining; siRNA knockdown; RHO-GTP pull-down; invasion assay Oncogene High 22797060
2013 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. CD55-deficient mouse leukocyte transfer experiments; flow cytometry for CD97 surface levels; intravital assays; in vitro co-culture under defined shear stress Journal of immunology High 23447688
2014 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. TIMP-2 ELISA; MMP-2/MT1-MMP activity assays; NTF/CTF-only mutant expression; cell migration and invasion assays; in vivo lung metastasis model The FEBS journal High 25174588
2015 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. 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 The international journal of biochemistry & cell biology High 26071181
2018 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. Shear stress experiments; phospho-CD97 immunodetection; CD97–DLG1 co-immunoprecipitation; PBM-deletion and CD97-KO cell lines; atomic force microscopy; FACS; actin cytoskeleton imaging Cell reports High 30134161
2018 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. 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 Cell reports High 29669286
2018 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. Proximity ligation assay, co-immunoprecipitation of endogenous proteins, GST-pulldown with CD97 TM/intracellular domain; quantitative in situ correlation in 111 patient samples Frontiers in oncology High 29888202
2018 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. CD97 overexpression/knockdown, co-immunoprecipitation of CD97–GRK6, CD97 internalization assay, MMP-2/9 activity assay, in vivo lung metastasis mouse model Hepatology Medium 29704239
2019 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. Recombinant CD55 stimulation; miR-503-5p mimic transfection; NF-κB inhibitor treatment; JAK2 siRNA knockdown; migration/invasion assays; Western blot for JAK2/STAT3 Neoplasia Medium 30622051
2019 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. RGD-to-RGE point mutant CD97 expression in HT1080 cells; integrin FACS analysis; cell adhesion, apoptosis, and viability assays Scientific reports Medium 30728423
2020 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. Yeast-based GPCR-G protein coupling assay with chimeric G proteins; mammalian cell cAMP assay with pertussis toxin; constitutively-active truncated receptor constructs Scientific reports Medium 31969668
2021 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. Proteomic screen of dendritic cells; ubiquitination assay; K555R CD97 point mutant; immunological synapse imaging; DC–T cell conjugate formation and T cell activation assays PLoS pathogens High 34314469
2021 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. X-ray crystallography of CD97-CD55 chimeric fusion; site-directed mutagenesis of EGF5; SPR kinetics The Journal of biological chemistry High 33992645
2022 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. Adgre5 and Gna13 conditional KO mice; CD55 KO mice; adoptive transfer; intravital imaging; flow cytometry for splenic DC populations; antigen-specific lymphocyte response assays Science High 35143305
2023 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). Cryo-electron microscopy structure determination; structure-guided mutagenesis; functional G-protein coupling assays; metadynamics simulations Cell chemical biology High 37673067
2024 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. Cryo-electron microscopy; functional GPCR signaling assays; metadynamics simulations Molecular cell High 38215752
2023 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. 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 Cellular & molecular immunology High 37978243
2024 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. CD97 silencing in patient-derived GSCs; transcriptome analysis; AKT S473 phosphorylation Western blot; mTORC2 inhibitor (JR-AB2-011) treatment; self-renewal and proliferation assays Cell reports. Medicine Medium 39637858
2004 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. Site-directed mutagenesis of N-glycosylation sites; tunicamycin treatment; immunoprecipitation; N-glycosidase F treatment; mAb staining and CD55 binding assays International journal of cancer High 15386373
2010 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. CD97 KO and CD55 KO mouse models; two arthritis models (CIA and K/BxN serum transfer); clinical, radiological, and histological assessment Arthritis and rheumatism High 20131275
2013 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. BONCAT and SILAC quantitative proteomics after miR-126 overexpression; direct miR-126 target site validation for CD97 ACS chemical biology Medium 24274104
2014 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. Immunofluorescence co-localization; flow cytometry of isolated myocytes; CD97 KO mouse ultrastructural analysis (electron microscopy); single myofiber Ca2+ release; isolated muscle force/fatigue assays PloS one High 24949957
2016 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. CD97 knockdown and overexpression in macrophages; PPAR-γ and NF-κB (p65) immunofluorescence and Western blot; TNF-α ELISA; CD97 KO THP-1 cells Mediators of inflammation Medium 26997758
2019 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. 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 The Journal of clinical investigation Medium 31682236
2020 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. CD97 siRNA knockdown and overexpression in HTR-8/SVneo trophoblast cells; invasion assay; Western blot for PI3K/Akt/mTOR pathway; FOXC2 expression analysis Reproductive sciences Medium 32430705
2024 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. Single-cell RNA analysis; CD97 knockdown; RNA sequencing; Rap1a inhibitor GGTI298; in vivo orthodontic tooth movement model International journal of oral science Medium 38311610

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF). The Journal of experimental medicine 285 9064337
2004 CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells. Blood 161 15576472
1996 CD97 is a processed, seven-transmembrane, heterodimeric receptor associated with inflammation. Journal of immunology (Baltimore, Md. : 1950) 154 8955192
2011 LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells. Cancer research 144 21978933
2018 Platelets Promote Metastasis via Binding Tumor CD97 Leading to Bidirectional Signaling that Coordinates Transendothelial Migration. Cell reports 128 29669286
1995 Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, a new seven-span transmembrane molecule of the secretion receptor superfamily with an unusual extracellular domain. Journal of immunology (Baltimore, Md. : 1950) 128 7636245
1999 Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue. Arthritis and rheumatism 113 10211878
1997 CD97: a dedifferentiation marker in human thyroid carcinomas. Cancer research 111 9135025
2004 The epidermal growth factor-seven transmembrane (EGF-TM7) receptor CD97 is required for neutrophil migration and host defense. Journal of immunology (Baltimore, Md. : 1950) 110 14707087
2002 Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues. The American journal of pathology 109 12414513
1998 Characterization of the CD55 (DAF)-binding site on the seven-span transmembrane receptor CD97. European journal of immunology 100 9603477
2015 CD97 promotes gastric cancer cell proliferation and invasion through exosome-mediated MAPK signaling pathway. World journal of gastroenterology 98 26034356
2001 Molecular analysis of the epidermal growth factor-like short consensus repeat domain-mediated protein-protein interactions: dissection of the CD97-CD55 complex. The Journal of biological chemistry 98 11297558
2006 Costimulation via CD55 on human CD4+ T cells mediated by CD97. Journal of immunology (Baltimore, Md. : 1950) 95 16818763
2011 Thy-1 (CD90) is an interacting partner for CD97 on activated endothelial cells. Journal of immunology (Baltimore, Md. : 1950) 85 22210915
2000 Human EMR2, a novel EGF-TM7 molecule on chromosome 19p13.1, is closely related to CD97. Genomics 85 10903844
2004 Expression of the largest CD97 and EMR2 isoforms on leukocytes facilitates a specific interaction with chondroitin sulfate on B cells. Journal of leukocyte biology 73 15498814
2002 CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic, and esophageal carcinomas. American journal of clinical pathology 73 12428789
2001 Tissue distribution of the human CD97 EGF-TM7 receptor. Tissue antigens 73 11380941
2013 Shear stress-dependent downregulation of the adhesion-G protein-coupled receptor CD97 on circulating leukocytes upon contact with its ligand CD55. Journal of immunology (Baltimore, Md. : 1950) 70 23447688
2022 CD97 promotes spleen dendritic cell homeostasis through the mechanosensing of red blood cells. Science (New York, N.Y.) 64 35143305
2012 CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model. Oncogene 64 22797060
2015 CD97 promotion of gastric carcinoma lymphatic metastasis is exosome dependent. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 63 26233326
2006 Individual cell-based models of tumor-environment interactions: Multiple effects of CD97 on tumor invasion. The American journal of pathology 63 17071601
1999 Structural characterization of mouse CD97 and study of its specific interaction with the murine decay-accelerating factor (DAF, CD55). Immunology 63 10540231
2019 MicroRNA-503-5p Inhibits the CD97-Mediated JAK2/STAT3 Pathway in Metastatic or Paclitaxel-Resistant Ovarian Cancer Cells. Neoplasia (New York, N.Y.) 61 30622051
2019 A-to-I-edited miRNA-379-5p inhibits cancer cell proliferation through CD97-induced apoptosis. The Journal of clinical investigation 61 31682236
2008 Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration. Journal of immunology (Baltimore, Md. : 1950) 61 18941248
2007 Structural and functional characterization of a novel T cell receptor co-regulatory protein complex, CD97-CD55. The Journal of biological chemistry 59 17449467
1999 Regulation of CD97 protein in thyroid carcinoma. The Journal of clinical endocrinology and metabolism 55 10084602
2018 CD97 Promotes Tumor Aggressiveness Through the Traditional G Protein-Coupled Receptor-Mediated Signaling in Hepatocellular Carcinoma. Hepatology (Baltimore, Md.) 52 29704239
2000 Molecular cloning and characterization of mouse CD97. International immunology 50 10744645
2013 Lysophosphatidylethanolamine utilizes LPA(1) and CD97 in MDA-MB-231 breast cancer cells. Cellular signalling 49 23838008
2002 Expression of the EGF-TM7 receptor CD97 and its ligand CD55 (DAF) in multiple sclerosis. Journal of neuroimmunology 49 12417446
1997 Expression characteristics of the human CD97 antigen. Tissue antigens 49 9389316
2010 Deletion of either CD55 or CD97 ameliorates arthritis in mouse models. Arthritis and rheumatism 48 20131275
2013 Overexpression of CD97 confers an invasive phenotype in glioblastoma cells and is associated with decreased survival of glioblastoma patients. PloS one 44 23658650
2004 N-glycosylation of CD97 within the EGF domains is crucial for epitope accessibility in normal and malignant cells as well as CD55 ligand binding. International journal of cancer 42 15386373
2006 CD97 neutralisation increases resistance to collagen-induced arthritis in mice. Arthritis research & therapy 40 17007638
2018 Mechano-Dependent Phosphorylation of the PDZ-Binding Motif of CD97/ADGRE5 Modulates Cellular Detachment. Cell reports 39 30134161
2012 The invasion and metastasis promotion role of CD97 small isoform in gastric carcinoma. PloS one 38 22768192
2013 CD97 is a multifunctional leukocyte receptor with distinct roles in human cancers (Review). International journal of oncology 37 23969601
2009 Site-specific N-glycosylation regulates the GPS auto-proteolysis of CD97. FEBS letters 37 19737555
2009 Therapeutic antibody targeting of CD97 in experimental arthritis: the role of antigen expression, shedding, and internalization on the pharmacokinetics of anti-CD97 monoclonal antibody 1B2. Journal of immunology (Baltimore, Md. : 1950) 34 19717518
2019 CD97 is a critical regulator of acute myeloid leukemia stem cell function. The Journal of experimental medicine 33 31371381
2006 Improved antibacterial host defense and altered peripheral granulocyte homeostasis in mice lacking the adhesion class G protein receptor CD97. Infection and immunity 32 17158902
1996 Structure of the human CD97 gene: exon shuffling has generated a new type of seven-span transmembrane molecule related to the secretin receptor superfamily. Genomics 32 8786105
2010 Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions. PloS one 31 20084281
2012 Novel report of expression and function of CD97 in malignant gliomas: correlation with Wilms tumor 1 expression and glioma cell invasiveness. Journal of neurosurgery 30 22313360
2004 Expression of CD97 and CD55 in human medullary thyroid carcinomas. International journal of oncology 29 14719104
2020 CD36 and CD97 in Pancreatic Cancer versus Other Malignancies. International journal of molecular sciences 28 32781778
2021 CD97 stabilises the immunological synapse between dendritic cells and T cells and is targeted for degradation by the Salmonella effector SteD. PLoS pathogens 27 34314469
2020 G Protein-Coupling of Adhesion GPCRs ADGRE2/EMR2 and ADGRE5/CD97, and Activation of G Protein Signalling by an Anti-EMR2 Antibody. Scientific reports 27 31969668
2018 Cell-surface phenotyping identifies CD36 and CD97 as novel markers of fibroblast quiescence in lung fibrosis. American journal of physiology. Lung cellular and molecular physiology 27 29952218
2010 GPS autoproteolysis is required for CD97 to up-regulate the expression of N-cadherin that promotes homotypic cell-cell aggregation. FEBS letters 27 21156175
2022 To Detach, Migrate, Adhere, and Metastasize: CD97/ADGRE5 in Cancer. Cells 26 35563846
2013 Prometastatic GPCR CD97 is a direct target of tumor suppressor microRNA-126. ACS chemical biology 26 24274104
2000 CD97 isoform expression in leukocytes. Journal of leukocyte biology 25 11037979
2023 CD97 negatively regulates the innate immune response against RNA viruses by promoting RNF125-mediated RIG-I degradation. Cellular & molecular immunology 24 37978243
2021 Structural basis for CD97 recognition of the decay-accelerating factor CD55 suggests mechanosensitive activation of adhesion GPCRs. The Journal of biological chemistry 24 33992645
2019 The RGD motif is involved in CD97/ADGRE5-promoted cell adhesion and viability of HT1080 cells. Scientific reports 24 30728423
2015 Proportional upregulation of CD97 isoforms in glioblastoma and glioblastoma-derived brain tumor initiating cells. PloS one 23 25714433
2005 Expression of the epidermal growth factor seven-transmembrane member CD97 correlates with grading and staging in human oral squamous cell carcinomas. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 22 15668483
2024 Conformational transitions and activation of the adhesion receptor CD97. Molecular cell 21 38215752
2015 The Adhesion GPCR CD97/ADGRE5 inhibits apoptosis. The international journal of biochemistry & cell biology 21 26071181
2008 Differential role of CD97 in interleukin-8-induced and granulocyte-colony stimulating factor-induced hematopoietic stem and progenitor cell mobilization. Haematologica 21 18326527
2006 Diversity of CD97 in smooth muscle cells. Cell and tissue research 20 16408199
2002 CD97, CD95 and Fas-L clearly discriminate between chronic pancreatitis and pancreatic ductal adenocarcinoma in perioperative evaluation of cryocut sections. Pathology international 19 11940212
2018 The Interaction of CD97/ADGRE5 With β-Catenin in Adherens Junctions Is Lost During Colorectal Carcinogenesis. Frontiers in oncology 18 29888202
2014 CD97 inhibits cell migration in human fibrosarcoma cells by modulating TIMP-2/MT1- MMP/MMP-2 activity--role of GPS autoproteolysis and functional cooperation between the N- and C-terminal fragments. The FEBS journal 18 25174588
2010 The role of CD97 in regulating adaptive T-cell responses. Advances in experimental medicine and biology 18 21618833
2006 CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway. Molecular carcinogenesis 18 16929497
2014 Skeletal muscle expression of the adhesion-GPCR CD97: CD97 deletion induces an abnormal structure of the sarcoplasmatic reticulum but does not impair skeletal muscle function. PloS one 17 24949957
2010 Differential expression of the EGF-TM7 family members CD97 and EMR2 in lipid-laden macrophages in atherosclerosis, multiple sclerosis and Gaucher disease. Immunology letters 17 20167235
2009 Differential expression of CD97 on human lymphocyte subsets and limited effect of CD97 antibodies on allogeneic T-cell stimulation. Immunology letters 16 19428565
2010 CD97 in leukocyte trafficking. Advances in experimental medicine and biology 15 21618832
2008 CD97 is differentially expressed on murine hematopoietic stem-and progenitor-cells. Haematologica 15 18603564
2020 CD97 Is Decreased in Preeclamptic Placentas and Promotes Human Trophoblast Invasion Through PI3K/Akt/mTOR Signaling Pathway. Reproductive sciences (Thousand Oaks, Calif.) 14 32430705
2016 Contradictory Role of CD97 in Basal and Tumor Necrosis Factor-Induced Osteoclastogenesis In Vivo. Arthritis & rheumatology (Hoboken, N.J.) 14 26663852
2015 Association of the EGF-TM7 receptor CD97 expression with FLT3-ITD in acute myeloid leukemia. Oncotarget 14 26462154
2010 Role of CD97 isoforms in gastric carcinoma. International journal of oncology 14 20428763
2010 CD97 antibody depletes granulocytes in mice under conditions of acute inflammation via a Fc receptor-dependent mechanism. Journal of leukocyte biology 14 21169517
2005 Expression of CD97 and adhesion molecules on circulating leukocytes in patients undergoing coronary artery bypass surgery. European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes 14 16374010
2024 CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells. Cell reports. Medicine 13 39637858
2023 IL-8 is a novel prometastatic chemokine in intrahepatic cholangiocarcinoma that induces CXCR2-PI3K/AKT signaling upon CD97 activation. Scientific reports 13 37907543
2019 The role of the RGD motif in CD97/ADGRE5-and EMR2/ADGRE2-modulated tumor angiogenesis. Biochemical and biophysical research communications 12 31594642
2013 Mice overexpressing CD97 in intestinal epithelial cells provide a unique model for mammalian postnatal intestinal cylindrical growth. Molecular biology of the cell 12 23676664
2014 Wilms tumor 1 gene, CD97, and the emerging biogenetic profile of glioblastoma. Neurosurgical focus 11 25434383
2023 Dual role of the adhesion G-protein coupled receptor ADRGE5/CD97 in glioblastoma invasion and proliferation. The Journal of biological chemistry 10 37517698
2023 Structural basis of CD97 activation and G-protein coupling. Cell chemical biology 10 37673067
2023 Identification of CD38, CD97, and CD278 on the HIV surface using a novel flow virometry screening assay. Scientific reports 10 38155248
2022 CD97 is associated with mitogenic pathway activation, metabolic reprogramming, and immune microenvironment changes in glioblastoma. Scientific reports 10 35087132
2019 Identification of ADGRE5 as discriminating MYC target between Burkitt lymphoma and diffuse large B-cell lymphoma. BMC cancer 10 30953469
2021 Genetic manipulation of adhesion GPCR CD97/ADGRE5 modulates invasion in patient-derived glioma stem cells. Journal of neuro-oncology 9 34028660
2016 CD97/ADGRE5 Inhibits LPS Induced NF-κB Activation through PPAR-γ Upregulation in Macrophages. Mediators of inflammation 9 26997758
2024 CD97 inhibits osteoclast differentiation via Rap1a/ERK pathway under compression. International journal of oral science 8 38311610
2024 ADGRE5-centered Tsurv model in T cells recognizes responders to neoadjuvant cancer immunotherapy. Frontiers in immunology 8 38343549
2016 Biochemical features of the adhesion G protein-coupled receptor CD97 related to its auto-proteolysis and HeLa cell attachment activities. Acta pharmacologica Sinica 8 27641734
2019 The role of ADGRE5/CD97 in human retinal pigment epithelial cell growth and survival. Annals of the New York Academy of Sciences 7 31397926
2025 CD97-directed CAR-T cells with enhanced persistence eradicate acute myeloid leukemia in diverse xenograft models. Cell reports. Medicine 5 40425009

Missed literature

Know a paper Affinage missed for ADGRE5? Flag it for the maintainers and the community.

No submissions yet.