{"gene":"CEACAM1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2014,"finding":"CEACAM1 forms a cis heterodimer with TIM-3 via their membrane-distal IgV-like N-terminal domains, facilitating TIM-3 maturation and cell surface expression; CEACAM1 also binds TIM-3 in trans through the same domains. Both cis and trans interactions are required for TIM-3-mediated T cell inhibition. X-ray crystallography and biochemical/biophysical studies established the structural basis of this interaction.","method":"X-ray crystallography, biochemical co-immunoprecipitation, biophysical binding assays, mouse adoptive transfer colitis model, CEACAM1-deficient T cell reconstitution experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus multiple orthogonal biochemical and in vivo methods in a single rigorous study, widely replicated in follow-up work","pmids":["25363763"],"is_preprint":false},{"year":2006,"finding":"CEACAM1 isoforms containing the long cytoplasmic domain inhibit T cell functions (proliferation, allogeneic reactivity, cytokine production) via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic domain and recruitment of the phosphatase SHP-1. Conditional deletion of CEACAM1 in T cells increased TCR-CD3 complex signaling, confirming inhibitory function.","method":"CEACAM1 overexpression and conditional T cell-specific deletion in mice, in vitro proliferation and cytokine assays, in vivo delayed-type hypersensitivity and IBD models, ITIM mutant analysis, SHP-1 dependency assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic approaches (OE and conditional KO), multiple orthogonal functional readouts, mechanistic ITIM/SHP-1 link established","pmids":["17081782"],"is_preprint":false},{"year":2001,"finding":"The cytoplasmic domain tyrosine motif of CEACAM1 (BGPa) functions as an ITIM: substitution of Y459 with phenylalanine abolished inhibitory signaling. CEACAM1-mediated inhibition of calcium influx required both SHP-1 and SHP-2, shown using SHP-1/SHP-2-deficient DT40 B cells and a FcγRIIB-BGPa chimeric receptor.","method":"FcγRIIB-BGPa chimeric receptor expression in DT40 B cells, tyrosine-to-phenylalanine mutagenesis, calcium influx assay, SHP-1/SHP-2 mutant cell lines","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro functional assay with site-directed mutagenesis and genetic null cell lines, single lab","pmids":["11493628"],"is_preprint":false},{"year":2008,"finding":"Bacterial engagement of CEACAM1 by M. catarrhalis UspA1 or N. meningitidis Opa proteins triggers ITIM tyrosine phosphorylation and SHP-1 recruitment, which negatively regulates TLR2-dependent PI3K-Akt activation and NF-κB-dependent inflammatory responses in primary pulmonary epithelial cells.","method":"Infection of primary pulmonary epithelial cells with bacterial pathogens, phosphorylation assays, SHP-1 recruitment assays, PI3K/Akt and NF-κB pathway readouts","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with multiple readouts in primary cells, single lab but orthogonal approaches","pmids":["18836450"],"is_preprint":false},{"year":2009,"finding":"Trans-homophilic CEACAM1 binding induces cis-dimerization of CEACAM1-L via an allosteric mechanism transmitted through the N-terminal Ig domain. The monomer/dimer equilibrium of CEACAM1-L determines the balance of SHP-2 versus c-Src binding; CEACAM1-S coexpression reduces CEACAM1-L homodimerization. SHP-1 does not bind under physiological conditions.","method":"CFP/YFP-tagged CEACAM1 isoform expression, FRET, cross-linking, co-clustering, co-immunoprecipitation, phosphotyrosine-induced recruitment assays in epithelial cell monolayers","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (FRET, co-IP, crosslinking) in single rigorous study establishing transmembrane signaling mechanism","pmids":["19948503"],"is_preprint":false},{"year":2013,"finding":"CEACAM1 on IL-2-activated NK cells inhibits NKG2D-mediated cytolysis through trans-homophilic CEACAM1 interactions with tumor cells. Co-engagement of NKG2D and CEACAM1 leads to biochemical association between these receptors, recruitment of SHP-1, dephosphorylation of the guanine nucleotide exchange factor Vav1, and blockade of downstream cytolytic signaling.","method":"NK cell activation assays, cytolysis assays, co-immunoprecipitation of NKG2D and CEACAM1, SHP-1 recruitment assays, Vav1 phosphorylation western blotting","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, multiple orthogonal biochemical readouts, functional cytolysis assay with defined molecular mechanism","pmids":["23696226"],"is_preprint":false},{"year":2011,"finding":"Tumor cell-associated CEACAM1 causes intracellular retention of NKG2D ligands (MICA, ULBP2 and others) in mouse and human tumor cells, reducing their cell surface expression and decreasing NK cell-mediated cytolysis. CEACAM1 silencing restored surface NKG2D ligand levels and increased NK-mediated rejection in vitro and in vivo.","method":"CEACAM1 silencing in tumor cells, flow cytometry for NKG2D ligand surface expression, NK cell cytolysis assays in vitro, tumor rejection assays in vivo","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype confirmed in vitro and in vivo, multiple cell lines and mouse model","pmids":["22143889"],"is_preprint":false},{"year":2002,"finding":"CEACAM1 is a substrate of the insulin receptor in liver; CEACAM1 phosphorylation promotes receptor-mediated insulin endocytosis and degradation to regulate insulin clearance. A phosphorylation-defective S503A CEACAM1 mutant expressed as a dominant negative in liver (L-SACC1 transgenic mice) impaired insulin clearance and caused insulin resistance.","method":"Transgenic mouse model (L-SACC1) expressing dominant-negative S503A CEACAM1 mutant, insulin clearance assays, metabolic phenotyping","journal":"Trends in endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic dominant-negative approach, but primarily a review summarizing prior transfection experiments; single lab","pmids":["12128284"],"is_preprint":false},{"year":2004,"finding":"CEACAM1 is a substrate of the EGF receptor (EGFR). Upon EGFR-mediated phosphorylation, CEACAM1 binds and sequesters Shc, uncoupling EGFR signaling from the Ras/MAPK pathway and reducing EGF-dependent cell proliferation.","method":"Transfected COS-7 and MCF-7 cells, EGF stimulation assays, co-immunoprecipitation of CEACAM1 with Shc, L-SACC1 transgenic mouse model, EGFR signaling pathway analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP binding partner identification, in vitro cell assays, and in vivo transgenic model, multiple orthogonal approaches in single study","pmids":["15467833"],"is_preprint":false},{"year":2000,"finding":"CEACAM1 cell surface expression on primary endothelial cells is transcriptionally induced by Neisseria gonorrhoeae infection via NF-κB (p50/p65 heterodimer) activation. LPS from bacteria triggers TLR4-dependent NF-κB activation, upregulating CEACAM1 splice variants (CEACAM1-3L and CEACAM1-4L), which in turn increases Opa52-dependent neisserial binding.","method":"Gonococcal infection of HUVECs, NF-κB activation and nuclear translocation assays, NF-κB inhibitor experiments, RT-PCR for CEACAM1 splice variant expression, bacterial binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibitor approaches, multiple readouts, single lab","pmids":["11306560"],"is_preprint":false},{"year":2008,"finding":"CEACAM1 is expressed on platelet surfaces and in intracellular pools, and negatively regulates platelet signaling through the GPVI/FcR-γ-chain collagen receptor. CEACAM1-null platelets show enhanced collagen-induced aggregation, adhesion, and granule secretion. CEACAM1's inhibitory function depends on its ITIM motifs that recruit SHP-1.","method":"Ceacam1-/- mouse platelets, platelet aggregation assays, collagen adhesion assays, granule secretion assays, intravital microscopy of mesenteric arterioles, pulmonary thromboembolism model, GPVI depletion experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — ceacam1 KO mice with multiple orthogonal platelet function assays and in vivo thrombosis model, GPVI epistasis experiment","pmids":["19008452"],"is_preprint":false},{"year":2006,"finding":"CEACAM1-long isoform engagement activates a PI3K-dependent Akt pathway in human monocytes, upregulating Bcl-2 and preventing caspase-3 activation. This confers survival signals to primary monocytes, distinct from ERK pathway signaling. PI3K inhibitor LY294002 blocked CEACAM1-dependent survival.","method":"CEACAM1-specific antibody and soluble CEACAM1 treatment of peripheral blood mononuclear cells/monocytes, apoptosis assays (annexin V, caspase-3), PI3K inhibitor experiments, Bcl-2 western blotting, ERK and Akt phosphorylation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical readouts with pharmacological inhibition, primary cell system, single lab","pmids":["17071610"],"is_preprint":false},{"year":2005,"finding":"CEACAM1 engagement on granulocytes delays spontaneous and Fas ligand-induced apoptosis. This anti-apoptotic effect requires CEACAM1-L tyrosine phosphorylation, SHP-1 association, and involves ERK1/2 and caspase-3 activation pathways.","method":"CEACAM1-specific antibody, Fab fragments, and soluble CEACAM1-Fc treatment of rat granulocytes; DNA fragmentation assays, annexin V staining, SHP-1 co-immunoprecipitation, ERK1/2 and caspase-3 activation assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal apoptosis assays with biochemical mechanism, single lab","pmids":["15909305"],"is_preprint":false},{"year":2003,"finding":"CEACAM1-4S (short cytoplasmic isoform) directly associates with annexin II via its cytoplasmic domain (KD ~30 nM), confirmed by GST pull-down, reciprocal co-immunoprecipitation, surface plasmon resonance with oriented peptides, and co-localization in mammary epithelial cells in Matrigel. CEACAM1 also co-localizes with annexin II/p11 at plasma membrane and in secretory vesicles.","method":"GST pull-down assay, reciprocal co-immunoprecipitation, surface plasmon resonance with oriented CEACAM1-4S cytoplasmic domain peptides, confocal laser microscopy in 3D Matrigel culture","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with SPR KD measurement plus reciprocal co-IP plus confocal co-localization, multiple orthogonal methods single lab","pmids":["14522961"],"is_preprint":false},{"year":2003,"finding":"CEACAM1-4S expression in MCF7 mammary carcinoma cells restores lumen formation in 3D Matrigel culture via apoptosis of central cells. Apoptosis involves Bax translocation to mitochondria and cytochrome c release into cytoplasm (intrinsic pathway), and is partially inhibited by caspase inhibitors. CEACAM1-4S localizes initially between cells and later exclusively apically in mature acini.","method":"3D Matrigel culture of MCF7 cells stably transfected with CEACAM1-4S, apoptosis assays (nuclear condensation, membrane blebbing, caspase activation, DNA laddering), Bax translocation and cytochrome c release assays, caspase inhibitor treatment, immunofluorescence localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined cellular reconstitution with multiple orthogonal mechanistic readouts, 3D morphogenesis model","pmids":["12522268"],"is_preprint":false},{"year":2002,"finding":"Homotypic CD66a (CEACAM1) interactions between melanoma cells and NK cells inhibit NK cell cytotoxicity via a class I MHC-independent mechanism. 721.221 cells expressing CD66a were protected from lysis by YTS cells and NK cells expressing CD66a; the inhibitory effect correlated with CD66a expression levels.","method":"NK cell cytotoxicity assays, redirected lysis experiments, transfection of 721.221 cells with CD66a, expression level correlation analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cytotoxicity assays with transfection controls and dose-response, single lab","pmids":["11884449"],"is_preprint":false},{"year":2004,"finding":"CEACAM1 enhances melanoma cell invasion and migration, dependent on Tyr-488 within the full-length cytoplasmic CEACAM1 domain. CEACAM1 co-localizes and interacts with integrin β3 via the cytoplasmic domain. RGD peptides blocking integrin αvβ3 abolished CEACAM1-enhanced invasion, and integrin β3 expression induces CEACAM1 upregulation.","method":"Stable CEACAM1 transfection of melanocytic/melanoma cells, in vitro invasion and migration assays (Matrigel), anti-CEACAM1 antibody inhibition, RGD peptide blocking, Tyr-488 mutant analysis, co-immunoprecipitation of CEACAM1 with integrin β3","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis, co-IP, and functional invasion assays, multiple approaches, single lab","pmids":["15509546"],"is_preprint":false},{"year":1999,"finding":"CD66a (CEACAM1) and CD66b are the major galectin-3 receptors on human neutrophils, stored in intracellular gelatinase and specific granules. Galectin-3-Sepharose affinity chromatography from neutrophil granules isolated CD66a (160 kDa) and CD66b (100 kDa) as the primary binding proteins.","method":"Galectin-3-Sepharose affinity chromatography from neutrophil granule preparations, SDS-PAGE, immunoblotting, HL-60 cell differentiation model, subcellular fractionation","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct affinity purification identifying binding partners plus subcellular fractionation, single lab","pmids":["10553088"],"is_preprint":false},{"year":2000,"finding":"CEACAM1 cytoplasmic domain associates with paxillin in a tyrosine phosphorylation-dependent manner (requiring Tyr-488). CEACAM1-paxillin complexes co-immunoprecipitated from granulocytes, HT29 colon cells, and HUVECs, with co-localization at the plasma membrane, linking CEACAM1 to the actin cytoskeleton.","method":"Phosphorylated cytoplasmic domain pull-down from granulocyte extracts, co-immunoprecipitation from multiple cell types, confocal microscopy co-localization, Tyr-488 mutant analysis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down binding partner identification confirmed by co-IP across multiple cell types, site-directed mutagenesis, single lab","pmids":["11035932"],"is_preprint":false},{"year":2018,"finding":"CEACAM1 is induced by HCMV and influenza virus via their respective innate DNA/RNA sensors (IFI16 and RIG-I), mediated by IRF3 binding to an ISRE element in the human CEACAM1 promoter. Upon induction, CEACAM1 suppresses viral replication through an SHP-2-dependent process that inhibits mTOR-mediated protein biosynthesis.","method":"Virus infection assays (HCMV, influenza), innate sensor knockdown, IRF3 chromatin immunoprecipitation at CEACAM1 ISRE, SHP-2-dependent assays, mTOR activity assays, ex vivo human decidua organ culture","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing IRF3-ISRE interaction, SHP-2 functional link, multiple orthogonal approaches, single lab","pmids":["27264178"],"is_preprint":false},{"year":2018,"finding":"CEACAM1 or CEACAM5 expression in AZ-521 cells is necessary and sufficient to restore H. pylori type IV secretion system (T4SS)-dependent CagA translocation and phosphorylation. This defines an integrin-β1- and CEACAM1- or CEACAM5-dependent T4SS delivery pathway for CagA, independent of VacA.","method":"Transfection of CEACAM1 or CEACAM5 into AZ-521 cells, H. pylori infection, CagA translocation and phosphorylation assays, vinculin and cortactin dephosphorylation as functional readouts","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic reconstitution experiment with specific functional readouts, single lab","pmids":["30321907"],"is_preprint":false},{"year":2008,"finding":"CEA induces CEACAM1-mediated apoptosis in HT29 colon cancer cells dependent on CEACAM1 cell surface abundance. Apoptosis triggers dual cleavage of CEACAM1-4L (at intracellular and extracellular sites) and activates caspases including caspase-1 and -3, as well as non-caspase proteases.","method":"CEA treatment of HT29/Jurkat/HEK293 cells, caspase activity assays, CEACAM1 cleavage detection, cell death assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined ligand (CEA), specific cleavage and caspase readouts, multiple cell lines, single lab","pmids":["18278069"],"is_preprint":false},{"year":2015,"finding":"CEACAM1 intrinsic signaling promotes B cell survival via the BTK/Syk/NF-κB axis. CEACAM1 deficiency in Ceacam1-/- mice limits survival of proliferating B cells and prevents generation of protective antiviral neutralizing antibody responses during VSV infection.","method":"Ceacam1-/- mice, VSV infection model, B cell survival assays, BTK/Syk/NF-κB pathway analysis, antibody neutralization assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ceacam1 KO mouse with in vivo viral infection, mechanistic BTK/Syk/NF-κB pathway dissection, multiple readouts","pmids":["25692415"],"is_preprint":false},{"year":2018,"finding":"CEACAM1 is essential for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. Absence of CEACAM1 on virus-specific CD8+ T cells limits antiviral CD8+ T cell responses; anti-CEACAM1 antibody stabilizes Lck in the immunological synapse and prevents CD8+ T cell exhaustion in LCMV infection.","method":"LCMV infection of Ceacam1-/- mice, immunological synapse analysis, Lck recruitment assays, anti-CEACAM1 antibody treatment, CD8+ T cell proliferation and exhaustion assays in mouse and human cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ceacam1 KO mouse, defined molecular mechanism (Lck recruitment), multiple readouts, antibody validation in human cells, single lab with orthogonal methods","pmids":["29967450"],"is_preprint":false},{"year":2010,"finding":"CEACAM1 is tyrosine-phosphorylated in endothelial cells upon VEGF treatment in a SHP-1- and Src-dependent manner. The long cytoplasmic domain of CEACAM1 is required for this phosphorylation and for VEGF-dependent nitric oxide (NO) production. CEACAM1 deficiency causes increased basal Akt and eNOS activation and defective VEGF-mediated vascular permeability.","method":"Ceacam1-/- mice, primary murine lung endothelial cells, VEGF stimulation, CEACAM1 phosphorylation assays, SHP-1/Src inhibitor experiments, eNOS/Akt phosphorylation assays, in vivo vascular permeability assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple biochemical pathway readouts in primary endothelial cells, single lab","pmids":["21081647"],"is_preprint":false},{"year":2002,"finding":"CEACAM1 clustering in PC12 cells induces rapid transient CEACAM1 tyrosine dephosphorylation, reduced SHP-2 association, binding to the actin cytoskeleton, and activation of ERK1/2 (but not JNK or p38) MAPK signaling downstream.","method":"Antibody-induced CEACAM1 clustering on PC12 cell surface, tyrosine phosphorylation assays, SHP-2 co-immunoprecipitation, detergent fractionation for cytoskeletal association, ERK1/2/JNK/p38 activation assays","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical readouts with functional clustering stimulus, single lab","pmids":["12108545"],"is_preprint":false},{"year":2023,"finding":"HIF-1α directly binds the polypyrimidine tract binding protein 1 (Ptbp1) promoter to transcriptionally regulate Ptbp1, which promotes alternative splicing of Ceacam1 toward the short cytoplasmic isoform (Ceacam1-S) during hypoxia/IRI. Ceacam1-S protects hepatocytes by repressing the ASK1/p-p38 cell death pathway. Established by ChIP and luciferase assays.","method":"Chromatin immunoprecipitation (ChIP) of HIF-1α at Ptbp1 promoter, luciferase reporter assays, adenoviral Ceacam1-S transfection into Ceacam1-deficient hepatocytes, morpholino-mediated isoform switching, warm IRI mouse model, human liver biopsy correlations","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP establishing direct HIF-1α/Ptbp1 binding, genetic reconstitution, morpholino isoform switching, in vitro and in vivo validation, single lab with multiple orthogonal methods","pmids":["37531413"],"is_preprint":false},{"year":2023,"finding":"Neutrophil CEACAM1-long (CC1-L) isoform determines susceptibility to NET formation by regulating the S1P-S1PR2/S1PR3 signaling axis and autophagy signaling. Ablation of CC1-L in recipient neutrophils aggravated hepatic ischemia-reperfusion injury in mouse OLT by promoting NETosis.","method":"Mouse OLT model with isoform-specific CC1-L ablation, S1PR2/S1PR3 pathway analysis, autophagy signaling assays, NET formation assays, human OLT patient cohort analysis","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific KO in mouse OLT model with defined pathway, translational human cohort, single lab","pmids":["36719377"],"is_preprint":false},{"year":2021,"finding":"F. nucleatum CbpF (trimeric autotransporter adhesin) binds and activates CEACAM1 to inhibit CD4+ T cell function. Other fusobacterial trimeric autotransporter adhesins (fvcB, fvcC, fvcD) are not involved. Anti-CEACAM1 antibodies directed against the N-terminal domain block CbpF-CEACAM1 interaction.","method":"F. nucleatum deletion mutants lacking fvcA (CbpF)/fvcB/fvcC/fvcD, CEACAM1 binding assays, T cell functional inhibition assays, antibody blocking experiments","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined bacterial mutants with functional T cell assay, antibody blocking, single lab","pmids":["34336716"],"is_preprint":false},{"year":2023,"finding":"S. pyogenes R28 protein specifically targets human CEACAM1 via an IgI3-like fold domain that binds the N-terminal domain of CEACAM1. This interaction mediates bacterial adhesion to cervical cells, suppresses epithelial wound repair, and subverts innate immune responses. High-resolution structural analysis established the binding interface.","method":"High-resolution structural analysis of R28-CEACAM1 N-terminal domain interaction, bacterial adhesion assays to cervical cells, epithelial wound repair assays, innate immune response functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural determination of binding interface plus multiple functional assays, single lab","pmids":["37080973"],"is_preprint":false},{"year":2020,"finding":"In liver transplantation (OLT), CEACAM1 deficiency in donor liver augments ischemia-reperfusion injury by enhancing ROS expression and HMGB1 translocation during cold storage via ASK1/p-p38 pathway upregulation. Adjunctive ASK1 inhibition alleviates IRI in CC1-KO livers by suppressing p-p38, ROS, and HMGB1.","method":"CC1-KO→WT mouse OLT model, ASK1/p38 pathway analysis, ROS and HMGB1 measurement, bone marrow-derived macrophage activation assays from hepatic flush, ASK1 siRNA in hepatocyte cultures, human donor liver biopsy correlations","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ceacam1 KO OLT model with defined ASK1/p38 pathway, siRNA knockdown, translational human data, single lab","pmids":["32027621"],"is_preprint":false},{"year":2015,"finding":"Forced liver-specific CEACAM1 overexpression in mice prevents diet-induced hyperinsulinemia and insulin resistance by protecting hepatic insulin clearance. This is partly mediated by increased hepatic β-fatty acid oxidation and energy expenditure.","method":"Liver-specific inducible CEACAM1 transgenic mice on high-fat diet, insulin clearance assays, metabolic phenotyping, β-fatty acid oxidation measurements","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — liver-specific transgenic gain-of-function with mechanistic metabolic readouts, single lab","pmids":["25972571"],"is_preprint":false},{"year":2014,"finding":"CEACAM1-Long (but not CEACAM1-Short or truncation mutants) intracellularly promotes Sox-2 expression in melanoma cells to enhance cell proliferation. This effect is not blocked by anti-CEACAM1 antibodies, indicating it is not mediated by homophilic intercellular interactions but by intracellular CEACAM1-L signaling.","method":"CEACAM1 knockdown and selective isoform/truncation mutant overexpression in melanoma cells, Sox-2 expression analysis, proliferation assays in vitro and xenograft in vivo, anti-CEACAM1 antibody blocking experiments, CEACAM1 promoter SNP analysis","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific genetic dissection with KD and OE, antibody blocking to define mechanism, in vivo xenograft confirmation, single lab","pmids":["24931667"],"is_preprint":false},{"year":2020,"finding":"TIM-3 and CEACAM1 do not interact in cis or in trans, as shown by extensive binding studies and a T cell reporter platform. CEACAM1-mediated inhibition is confirmed but functions independently of TIM-3; TIM-3 cytoplasmic sequences can independently promote inhibitory signaling.","method":"T cell reporter platform, extensive cell-based and soluble protein binding assays for TIM-3/CEACAM1 interaction, flow cytometric co-expression analysis","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative result from multiple binding assays using reporter system; contradicts PMID 25363763; single lab, lower confidence due to direct contradiction with structural study","pmids":["32222966"],"is_preprint":false},{"year":2004,"finding":"CEACAM1-4S directly associates with and downregulates β1-integrin expression in mammary epithelial cells during 3D morphogenesis. Immuno-electron microscopy reveals CEACAM1-coated vesicles within lumena, and CEACAM1 is detected in breast milk lipid fractions.","method":"3D Matrigel culture, co-immunoprecipitation of CEACAM1 with β1-integrin, immuno-electron microscopy, breast milk lipid fractionation, immunohistochemistry","journal":"Journal of molecular histology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP identifying interaction with functional downstream consequence, immuno-EM, single lab","pmids":["15339048"],"is_preprint":false}],"current_model":"CEACAM1 is a multifunctional transmembrane cell adhesion molecule whose inhibitory signaling is mediated by ITIM phosphorylation and recruitment of SHP-1/SHP-2 phosphatases; it forms cis and trans heterodimers with TIM-3 (established by crystallography) to regulate T cell tolerance, inhibits NK cell NKG2D-mediated cytolysis via SHP-1-dependent Vav1 dephosphorylation, suppresses T cell activation through ITIM/SHP-1-mediated dampening of TCR signaling, recruits Lck to the TCR immunological synapse to sustain CD8+ T cell responses, regulates platelet collagen-GPVI signaling, promotes hepatic insulin clearance as an insulin receptor substrate whose phosphorylation controls Shc binding and Ras/MAPK uncoupling, undergoes HIF-1α/Ptbp1-controlled alternative splicing to generate isoforms with distinct cytoprotective functions in ischemia-reperfusion injury, and is exploited by multiple bacterial pathogens (Neisseria, Helicobacter pylori, Fusobacterium, Streptococcus pyogenes) via direct binding to its N-terminal Ig domain to evade immunity."},"narrative":{"mechanistic_narrative":"CEACAM1 is a transmembrane cell adhesion molecule that functions principally as an inhibitory immunoreceptor, regulating immune cell signaling, hepatic insulin metabolism, epithelial morphogenesis, and host responses to pathogens [PMID:17081782, PMID:12128284]. Its inhibitory output is encoded by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the long cytoplasmic-domain isoform; phosphorylation of the ITIM tyrosine (Y459/Y488) recruits the phosphatases SHP-1 and SHP-2, and mutation of this tyrosine abolishes inhibitory signaling [PMID:11493628, PMID:17081782]. Through this ITIM/SHP-1 module CEACAM1 dampens TCR-CD3 signaling and T cell proliferation and cytokine production [PMID:17081782], inhibits NK cell NKG2D-mediated cytolysis via SHP-1-dependent dephosphorylation of Vav1 [PMID:23696226], and negatively regulates platelet collagen responses through the GPVI/FcR-γ receptor [PMID:19008452]. Trans-homophilic engagement of CEACAM1 induces cis-dimerization transmitted allosterically through the N-terminal Ig domain, and the monomer/dimer equilibrium of CEACAM1-L sets the balance of SHP-2 versus c-Src recruitment, with the short isoform CEACAM1-S antagonizing long-isoform homodimerization [PMID:19948503]. Beyond inhibition, CEACAM1 provides positive and pro-survival signals: it recruits Lck into the TCR immunological synapse to sustain antiviral CD8+ T cell responses [PMID:29967450], promotes B cell survival via the BTK/Syk/NF-κB axis [PMID:25692415], and supports monocyte and granulocyte survival through PI3K/Akt and SHP-1-dependent pathways [PMID:17071610, PMID:15909305]. In the liver CEACAM1 is a substrate of the insulin receptor whose phosphorylation drives receptor-mediated insulin endocytosis and clearance; loss of this function causes insulin resistance, and hepatic overexpression protects against diet-induced hyperinsulinemia [PMID:12128284, PMID:25972571]. As an EGFR substrate, phosphorylated CEACAM1 sequesters Shc to uncouple EGFR from Ras/MAPK signaling [PMID:15467833]. The short isoform CEACAM1-4S binds annexin II and downregulates β1-integrin to drive lumen formation and central-cell apoptosis during epithelial morphogenesis [PMID:14522961, PMID:12522268, PMID:15339048], while HIF-1α/Ptbp1-controlled alternative splicing toward CEACAM1-S protects hepatocytes by repressing the ASK1/p-p38 death pathway in ischemia-reperfusion injury [PMID:37531413, PMID:32027621]. CEACAM1 is exploited as a receptor by multiple pathogens, including Neisseria, Helicobacter pylori, Fusobacterium nucleatum, and Streptococcus pyogenes, all binding its N-terminal Ig domain to subvert epithelial integrity and immune responses [PMID:18836450, PMID:30321907, PMID:34336716, PMID:37080973]. A structurally defined cis/trans heterodimer with TIM-3 has been reported as required for TIM-3-mediated T cell inhibition [PMID:25363763], although a subsequent study found no detectable CEACAM1-TIM-3 interaction and concluded CEACAM1 inhibition operates independently of TIM-3 [PMID:32222966].","teleology":[{"year":1999,"claim":"Establishing CEACAM1's binding partners on innate immune cells, the protein was identified as a major granule-stored galectin-3 receptor on neutrophils, an early clue to its extracellular ligand repertoire.","evidence":"galectin-3-Sepharose affinity chromatography from neutrophil granules with immunoblotting","pmids":["10553088"],"confidence":"Medium","gaps":["functional consequence of galectin-3 binding not defined","single lab affinity capture without binding kinetics"]},{"year":2001,"claim":"To define the molecular basis of CEACAM1 inhibitory signaling, the cytoplasmic Y459 motif was shown to be a functional ITIM requiring both SHP-1 and SHP-2 to suppress calcium influx.","evidence":"FcγRIIB-BGPa chimera in SHP-1/SHP-2-null DT40 B cells with Y-to-F mutagenesis and calcium assays","pmids":["11493628"],"confidence":"High","gaps":["studied in a chimeric receptor context, not native CEACAM1","relative contributions of SHP-1 vs SHP-2 in physiological cells unresolved"]},{"year":2002,"claim":"Defining a metabolic role, CEACAM1 was identified as an insulin receptor substrate whose phosphorylation drives hepatic insulin clearance, linking the receptor to systemic insulin sensitivity.","evidence":"L-SACC1 dominant-negative S503A transgenic mice with insulin clearance and metabolic phenotyping","pmids":["12128284"],"confidence":"Medium","gaps":["primarily a review summarizing prior transfection data","structural basis of insulin receptor docking not resolved"]},{"year":2003,"claim":"To explain epithelial morphogenetic functions, CEACAM1-4S was shown to bind annexin II directly and to restore lumen formation through intrinsic-pathway apoptosis of central acinar cells.","evidence":"GST pull-down, reciprocal co-IP, SPR (KD ~30 nM), and 3D Matrigel culture with Bax/cytochrome c readouts","pmids":["14522961","12522268"],"confidence":"High","gaps":["how cytoplasmic annexin II binding triggers apoptosis mechanistically unclear","isoform-specific signaling downstream of CEACAM1-4S not fully mapped"]},{"year":2004,"claim":"Broadening the substrate concept, CEACAM1 was identified as an EGFR substrate that sequesters Shc to dampen Ras/MAPK proliferation, and as a Tyr-488-dependent promoter of melanoma invasion via integrin β3.","evidence":"co-IP with Shc and integrin β3, EGF stimulation, invasion assays, Tyr-488 mutagenesis, transgenic mice","pmids":["15467833","15509546","15339048"],"confidence":"High","gaps":["context-dependence of growth-suppressive vs invasion-promoting roles unresolved","structural detail of Shc/integrin docking unknown"]},{"year":2006,"claim":"Reciprocal genetic approaches established CEACAM1 as a bona fide negative regulator of T cells, acting through long-isoform ITIMs and SHP-1 to restrain TCR-CD3 signaling, and as a PI3K/Akt-dependent survival factor in monocytes.","evidence":"CEACAM1 overexpression and conditional T cell deletion in mice; antibody/soluble-CEACAM1 treatment of monocytes with apoptosis and inhibitor assays","pmids":["17081782","17071610"],"confidence":"High","gaps":["how the same receptor switches between inhibitory and survival outputs unresolved","monocyte survival mechanism is Medium-confidence and from a single lab"]},{"year":2008,"claim":"Linking CEACAM1 to host defense and hemostasis, the receptor was shown to negatively regulate TLR2-driven inflammation upon bacterial engagement and to inhibit platelet GPVI/collagen signaling, both via ITIM/SHP-1.","evidence":"bacterial infection of primary epithelial cells with pathway readouts; Ceacam1-/- platelet aggregation, adhesion, and in vivo thrombosis assays","pmids":["18836450","19008452"],"confidence":"High","gaps":["how pathogen binding couples to ITIM phosphorylation mechanistically unclear","platelet ITIM kinase upstream of phosphorylation not identified"]},{"year":2009,"claim":"Resolving how trans engagement signals across the membrane, trans-homophilic binding was shown to induce cis-dimerization of CEACAM1-L allosterically, with the monomer/dimer equilibrium setting the SHP-2 vs c-Src balance.","evidence":"FRET, cross-linking, co-clustering and co-IP with CFP/YFP-tagged isoforms in epithelial monolayers","pmids":["19948503"],"confidence":"High","gaps":["physiological triggers shifting the equilibrium in vivo not defined","SHP-1 binding not observed, leaving its in vivo role open"]},{"year":2013,"claim":"Defining a tumor-immune evasion mechanism, NK-cell CEACAM1 was shown to inhibit NKG2D cytolysis via trans-homophilic interaction, NKG2D association, SHP-1 recruitment, and Vav1 dephosphorylation, complementing earlier evidence that tumor CEACAM1 retains NKG2D ligands intracellularly.","evidence":"NK cytolysis assays, reciprocal NKG2D-CEACAM1 co-IP, SHP-1 recruitment, Vav1 phosphorylation blotting; CEACAM1 silencing with surface-ligand flow cytometry","pmids":["23696226","22143889"],"confidence":"High","gaps":["mechanism of NKG2D ligand intracellular retention unresolved","relative importance of homophilic vs receptor-cis mechanisms in vivo unclear"]},{"year":2014,"claim":"A structurally defined CEACAM1-TIM-3 cis/trans heterodimer was reported as required for TIM-3-mediated T cell inhibition, proposing a co-receptor model for T cell tolerance.","evidence":"X-ray crystallography, co-IP, biophysical binding, and adoptive-transfer colitis with CEACAM1-deficient T cell reconstitution","pmids":["25363763"],"confidence":"High","gaps":["the interaction was later not reproduced (see 2020 entry)","structural interface conditions vs cellular physiology not reconciled"]},{"year":2015,"claim":"Extending CEACAM1's survival role to humoral immunity and metabolism, intrinsic CEACAM1 signaling was shown to sustain B cell survival via BTK/Syk/NF-κB for antiviral antibody responses, and hepatic overexpression to protect insulin clearance.","evidence":"Ceacam1-/- mice with VSV infection and B cell survival assays; liver-specific CEACAM1 transgenic mice on high-fat diet","pmids":["25692415","25972571"],"confidence":"High","gaps":["how CEACAM1 couples to BTK/Syk activation mechanistically unclear","link between hepatic insulin clearance and fatty-acid oxidation incompletely defined"]},{"year":2018,"claim":"Defining antiviral and pathogen-cooperative roles, CEACAM1 was shown to be induced via IRF3 at an ISRE to suppress viral replication through SHP-2/mTOR, while also being required for H. pylori T4SS-dependent CagA delivery.","evidence":"IRF3 ChIP at CEACAM1 ISRE, SHP-2/mTOR functional assays, decidua organ culture; CEACAM1/CEACAM5 reconstitution in AZ-521 cells with CagA translocation assays","pmids":["27264178","30321907"],"confidence":"Medium","gaps":["how SHP-2 connects to mTOR inhibition mechanistically unresolved","both single-lab studies awaiting independent confirmation"]},{"year":2018,"claim":"Revising the inhibitory paradigm, CEACAM1 was found to act positively in CD8+ T cells by recruiting Lck into the immunological synapse to sustain antiviral responses and prevent exhaustion.","evidence":"LCMV infection of Ceacam1-/- mice, synapse imaging, Lck recruitment assays, anti-CEACAM1 antibody validation in human cells","pmids":["29967450"],"confidence":"High","gaps":["molecular determinants of Lck recruitment by CEACAM1 not defined","reconciliation of positive CD8 role with ITIM-based inhibition unresolved"]},{"year":2020,"claim":"Directly challenging the 2014 model, a binding and reporter study found no detectable cis or trans CEACAM1-TIM-3 interaction and concluded CEACAM1 inhibition functions independently of TIM-3.","evidence":"T cell reporter platform with extensive cell-based and soluble-protein binding assays and co-expression analysis","pmids":["32222966"],"confidence":"Medium","gaps":["negative result directly contradicts the structural study","single lab; conditions distinguishing the two outcomes not established"]},{"year":2023,"claim":"Defining isoform-selective cytoprotection, HIF-1α/Ptbp1-driven splicing toward CEACAM1-S was shown to repress ASK1/p-p38-mediated hepatocyte death, while neutrophil CEACAM1-L modulates NETosis via S1PR2/S1PR3 in liver ischemia-reperfusion injury.","evidence":"HIF-1α ChIP, luciferase, adenoviral CEACAM1-S reconstitution and morpholino isoform switching in IRI models; isoform-specific CC1-L ablation in mouse OLT with S1PR pathway and NET assays; CC1-KO OLT ASK1/p38 analysis","pmids":["37531413","36719377","32027621"],"confidence":"High","gaps":["how distinct cytoplasmic domains specify opposing cell-fate outcomes unresolved","translation of isoform-switching strategy to human therapy untested"]},{"year":2023,"claim":"Cementing CEACAM1 as a convergent bacterial target, S. pyogenes R28 and F. nucleatum CbpF were shown to bind its N-terminal Ig domain to subvert epithelial repair and T cell function.","evidence":"high-resolution structural analysis of R28-CEACAM1 interface with adhesion/wound-repair/immune assays; defined F. nucleatum adhesin mutants with T cell inhibition and antibody blocking","pmids":["37080973","34336716"],"confidence":"High","gaps":["whether diverse pathogens engage overlapping or distinct N-domain epitopes unresolved","downstream signaling triggered by bacterial vs homophilic binding not compared"]},{"year":null,"claim":"How CEACAM1 switches between inhibitory (ITIM/SHP) and activating/pro-survival (Lck, BTK/Syk, PI3K/Akt) outputs in the same cell, and whether the disputed TIM-3 partnership operates physiologically, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unifying model reconciling inhibitory and activating signaling","CEACAM1-TIM-3 interaction unresolved between contradicting studies","upstream kinases controlling ITIM phosphorylation in each cell type not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[4,5,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,5,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,23,4]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[3,20,28,29]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,8,23]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,10,13,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,4,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[13,17,34]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,5,22,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7,8,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,20,28,29]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,14,21,30]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[10]}],"complexes":[],"partners":["SHP-1","SHP-2","TIM-3","NKG2D","SHC","ANNEXIN II","INTEGRIN BETA3","PAXILLIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P13688","full_name":"Cell adhesion molecule CEACAM1","aliases":["Biliary glycoprotein 1","BGP-1","Carcinoembryonic antigen-related cell adhesion molecule 1","CEA cell adhesion molecule 1"],"length_aa":526,"mass_kda":57.6,"function":"Cell adhesion protein that mediates homophilic cell adhesion in a calcium-independent manner (By similarity). Plays a role as coinhibitory receptor in immune response, insulin action and also functions as an activator during angiogenesis (PubMed:18424730, PubMed:23696226, PubMed:25363763). Its coinhibitory receptor function is phosphorylation- and PTPN6 -dependent, which in turn, suppress signal transduction of associated receptors by dephosphorylation of their downstream effectors. Plays a role in immune response, of T cells, natural killer (NK) and neutrophils (PubMed:18424730, PubMed:23696226). Upon TCR/CD3 complex stimulation, inhibits TCR-mediated cytotoxicity by blocking granule exocytosis by mediating homophilic binding to adjacent cells, allowing interaction with and phosphorylation by LCK and interaction with the TCR/CD3 complex which recruits PTPN6 resulting in dephosphorylation of CD247 and ZAP70 (PubMed:18424730). Also inhibits T cell proliferation and cytokine production through inhibition of JNK cascade and plays a crucial role in regulating autoimmunity and anti-tumor immunity by inhibiting T cell through its interaction with HAVCR2 (PubMed:25363763). Upon natural killer (NK) cells activation, inhibit KLRK1-mediated cytolysis of CEACAM1-bearing tumor cells by trans-homophilic interactions with CEACAM1 on the target cell and lead to cis-interaction between CEACAM1 and KLRK1, allowing PTPN6 recruitment and then VAV1 dephosphorylation (PubMed:23696226). Upon neutrophils activation negatively regulates IL1B production by recruiting PTPN6 to a SYK-TLR4-CEACAM1 complex, that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome. Down-regulates neutrophil production by acting as a coinhibitory receptor for CSF3R by down-regulating the CSF3R-STAT3 pathway through recruitment of PTPN6 that dephosphorylates CSF3R (By similarity). Also regulates insulin action by promoting INS clearance and regulating lipogenesis in liver through regulating insulin signaling (By similarity). Upon INS stimulation, undergoes phosphorylation by INSR leading to INS clearance by increasing receptor-mediated insulin endocytosis. This inernalization promotes interaction with FASN leading to receptor-mediated insulin degradation and to reduction of FASN activity leading to negative regulation of fatty acid synthesis. INSR-mediated phosphorylation also provokes a down-regulation of cell proliferation through SHC1 interaction resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 and phosphatidylinositol 3-kinase pathways (By similarity). Functions as activator in angiogenesis by promoting blood vessel remodeling through endothelial cell differentiation and migration and in arteriogenesis by increasing the number of collateral arteries and collateral vessel calibers after ischemia. Also regulates vascular permeability through the VEGFR2 signaling pathway resulting in control of nitric oxide production (By similarity). Down-regulates cell growth in response to EGF through its interaction with SHC1 that mediates interaction with EGFR resulting in decrease coupling of SHC1 to the MAPK3/ERK1-MAPK1/ERK2 pathway (By similarity). Negatively regulates platelet aggregation by decreasing platelet adhesion on type I collagen through the GPVI-FcRgamma complex (By similarity). Inhibits cell migration and cell scattering through interaction with FLNA; interferes with the interaction of FLNA with RALA (PubMed:16291724). Mediates bile acid transport activity in a phosphorylation dependent manner (By similarity). Negatively regulates osteoclastogenesis (By similarity) Cell adhesion protein that mediates homophilic cell adhesion in a calcium-independent manner (By similarity). Promotes populations of T cells regulating IgA production and secretion associated with control of the commensal microbiota and resistance to enteropathogens (By similarity)","subcellular_location":"Cell projection, microvillus membrane; Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/P13688/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEACAM1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CEACAM1","total_profiled":1310},"omim":[{"mim_id":"619160","title":"CEA CELL ADHESION MOLECULE 7; CEACAM7","url":"https://www.omim.org/entry/619160"},{"mim_id":"615747","title":"CEA CELL ADHESION MOLECULE 8; CEACAM8","url":"https://www.omim.org/entry/615747"},{"mim_id":"611519","title":"POLYMERASE DELTA-INTERACTING PROTEIN 2; POLDIP2","url":"https://www.omim.org/entry/611519"},{"mim_id":"609142","title":"CEA CELL ADHESION MOLECULE 3; CEACAM3","url":"https://www.omim.org/entry/609142"},{"mim_id":"608160","title":"SRY-BOX 9; SOX9","url":"https://www.omim.org/entry/608160"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":230.9}],"url":"https://www.proteinatlas.org/search/CEACAM1"},"hgnc":{"alias_symbol":["BGP1","CD66a"],"prev_symbol":["BGP"]},"alphafold":{"accession":"P13688","domains":[{"cath_id":"2.60.40.10","chopping":"38-142","consensus_level":"high","plddt":95.7179,"start":38,"end":142},{"cath_id":"2.60.40.10","chopping":"149-232","consensus_level":"high","plddt":94.0095,"start":149,"end":232},{"cath_id":"2.60.40.10","chopping":"242-319","consensus_level":"high","plddt":95.4794,"start":242,"end":319},{"cath_id":"2.60.40.10","chopping":"330-416","consensus_level":"high","plddt":91.1815,"start":330,"end":416}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13688","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13688-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13688-F1-predicted_aligned_error_v6.png","plddt_mean":81.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEACAM1","jax_strain_url":"https://www.jax.org/strain/search?query=CEACAM1"},"sequence":{"accession":"P13688","fasta_url":"https://rest.uniprot.org/uniprotkb/P13688.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13688/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13688"}},"corpus_meta":[{"pmid":"25363763","id":"PMC_25363763","title":"CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25363763","citation_count":586,"is_preprint":false},{"pmid":"16724098","id":"PMC_16724098","title":"CEACAM1: contact-dependent control of immunity.","date":"2006","source":"Nature reviews. 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Both cis and trans interactions are required for TIM-3-mediated T cell inhibition. X-ray crystallography and biochemical/biophysical studies established the structural basis of this interaction.\",\n      \"method\": \"X-ray crystallography, biochemical co-immunoprecipitation, biophysical binding assays, mouse adoptive transfer colitis model, CEACAM1-deficient T cell reconstitution experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus multiple orthogonal biochemical and in vivo methods in a single rigorous study, widely replicated in follow-up work\",\n      \"pmids\": [\"25363763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CEACAM1 isoforms containing the long cytoplasmic domain inhibit T cell functions (proliferation, allogeneic reactivity, cytokine production) via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic domain and recruitment of the phosphatase SHP-1. Conditional deletion of CEACAM1 in T cells increased TCR-CD3 complex signaling, confirming inhibitory function.\",\n      \"method\": \"CEACAM1 overexpression and conditional T cell-specific deletion in mice, in vitro proliferation and cytokine assays, in vivo delayed-type hypersensitivity and IBD models, ITIM mutant analysis, SHP-1 dependency assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic approaches (OE and conditional KO), multiple orthogonal functional readouts, mechanistic ITIM/SHP-1 link established\",\n      \"pmids\": [\"17081782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The cytoplasmic domain tyrosine motif of CEACAM1 (BGPa) functions as an ITIM: substitution of Y459 with phenylalanine abolished inhibitory signaling. CEACAM1-mediated inhibition of calcium influx required both SHP-1 and SHP-2, shown using SHP-1/SHP-2-deficient DT40 B cells and a FcγRIIB-BGPa chimeric receptor.\",\n      \"method\": \"FcγRIIB-BGPa chimeric receptor expression in DT40 B cells, tyrosine-to-phenylalanine mutagenesis, calcium influx assay, SHP-1/SHP-2 mutant cell lines\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro functional assay with site-directed mutagenesis and genetic null cell lines, single lab\",\n      \"pmids\": [\"11493628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Bacterial engagement of CEACAM1 by M. catarrhalis UspA1 or N. meningitidis Opa proteins triggers ITIM tyrosine phosphorylation and SHP-1 recruitment, which negatively regulates TLR2-dependent PI3K-Akt activation and NF-κB-dependent inflammatory responses in primary pulmonary epithelial cells.\",\n      \"method\": \"Infection of primary pulmonary epithelial cells with bacterial pathogens, phosphorylation assays, SHP-1 recruitment assays, PI3K/Akt and NF-κB pathway readouts\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with multiple readouts in primary cells, single lab but orthogonal approaches\",\n      \"pmids\": [\"18836450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Trans-homophilic CEACAM1 binding induces cis-dimerization of CEACAM1-L via an allosteric mechanism transmitted through the N-terminal Ig domain. The monomer/dimer equilibrium of CEACAM1-L determines the balance of SHP-2 versus c-Src binding; CEACAM1-S coexpression reduces CEACAM1-L homodimerization. SHP-1 does not bind under physiological conditions.\",\n      \"method\": \"CFP/YFP-tagged CEACAM1 isoform expression, FRET, cross-linking, co-clustering, co-immunoprecipitation, phosphotyrosine-induced recruitment assays in epithelial cell monolayers\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (FRET, co-IP, crosslinking) in single rigorous study establishing transmembrane signaling mechanism\",\n      \"pmids\": [\"19948503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CEACAM1 on IL-2-activated NK cells inhibits NKG2D-mediated cytolysis through trans-homophilic CEACAM1 interactions with tumor cells. Co-engagement of NKG2D and CEACAM1 leads to biochemical association between these receptors, recruitment of SHP-1, dephosphorylation of the guanine nucleotide exchange factor Vav1, and blockade of downstream cytolytic signaling.\",\n      \"method\": \"NK cell activation assays, cytolysis assays, co-immunoprecipitation of NKG2D and CEACAM1, SHP-1 recruitment assays, Vav1 phosphorylation western blotting\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, multiple orthogonal biochemical readouts, functional cytolysis assay with defined molecular mechanism\",\n      \"pmids\": [\"23696226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Tumor cell-associated CEACAM1 causes intracellular retention of NKG2D ligands (MICA, ULBP2 and others) in mouse and human tumor cells, reducing their cell surface expression and decreasing NK cell-mediated cytolysis. CEACAM1 silencing restored surface NKG2D ligand levels and increased NK-mediated rejection in vitro and in vivo.\",\n      \"method\": \"CEACAM1 silencing in tumor cells, flow cytometry for NKG2D ligand surface expression, NK cell cytolysis assays in vitro, tumor rejection assays in vivo\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype confirmed in vitro and in vivo, multiple cell lines and mouse model\",\n      \"pmids\": [\"22143889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CEACAM1 is a substrate of the insulin receptor in liver; CEACAM1 phosphorylation promotes receptor-mediated insulin endocytosis and degradation to regulate insulin clearance. A phosphorylation-defective S503A CEACAM1 mutant expressed as a dominant negative in liver (L-SACC1 transgenic mice) impaired insulin clearance and caused insulin resistance.\",\n      \"method\": \"Transgenic mouse model (L-SACC1) expressing dominant-negative S503A CEACAM1 mutant, insulin clearance assays, metabolic phenotyping\",\n      \"journal\": \"Trends in endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic dominant-negative approach, but primarily a review summarizing prior transfection experiments; single lab\",\n      \"pmids\": [\"12128284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM1 is a substrate of the EGF receptor (EGFR). Upon EGFR-mediated phosphorylation, CEACAM1 binds and sequesters Shc, uncoupling EGFR signaling from the Ras/MAPK pathway and reducing EGF-dependent cell proliferation.\",\n      \"method\": \"Transfected COS-7 and MCF-7 cells, EGF stimulation assays, co-immunoprecipitation of CEACAM1 with Shc, L-SACC1 transgenic mouse model, EGFR signaling pathway analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP binding partner identification, in vitro cell assays, and in vivo transgenic model, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"15467833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CEACAM1 cell surface expression on primary endothelial cells is transcriptionally induced by Neisseria gonorrhoeae infection via NF-κB (p50/p65 heterodimer) activation. LPS from bacteria triggers TLR4-dependent NF-κB activation, upregulating CEACAM1 splice variants (CEACAM1-3L and CEACAM1-4L), which in turn increases Opa52-dependent neisserial binding.\",\n      \"method\": \"Gonococcal infection of HUVECs, NF-κB activation and nuclear translocation assays, NF-κB inhibitor experiments, RT-PCR for CEACAM1 splice variant expression, bacterial binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibitor approaches, multiple readouts, single lab\",\n      \"pmids\": [\"11306560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CEACAM1 is expressed on platelet surfaces and in intracellular pools, and negatively regulates platelet signaling through the GPVI/FcR-γ-chain collagen receptor. CEACAM1-null platelets show enhanced collagen-induced aggregation, adhesion, and granule secretion. CEACAM1's inhibitory function depends on its ITIM motifs that recruit SHP-1.\",\n      \"method\": \"Ceacam1-/- mouse platelets, platelet aggregation assays, collagen adhesion assays, granule secretion assays, intravital microscopy of mesenteric arterioles, pulmonary thromboembolism model, GPVI depletion experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ceacam1 KO mice with multiple orthogonal platelet function assays and in vivo thrombosis model, GPVI epistasis experiment\",\n      \"pmids\": [\"19008452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CEACAM1-long isoform engagement activates a PI3K-dependent Akt pathway in human monocytes, upregulating Bcl-2 and preventing caspase-3 activation. This confers survival signals to primary monocytes, distinct from ERK pathway signaling. PI3K inhibitor LY294002 blocked CEACAM1-dependent survival.\",\n      \"method\": \"CEACAM1-specific antibody and soluble CEACAM1 treatment of peripheral blood mononuclear cells/monocytes, apoptosis assays (annexin V, caspase-3), PI3K inhibitor experiments, Bcl-2 western blotting, ERK and Akt phosphorylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical readouts with pharmacological inhibition, primary cell system, single lab\",\n      \"pmids\": [\"17071610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CEACAM1 engagement on granulocytes delays spontaneous and Fas ligand-induced apoptosis. This anti-apoptotic effect requires CEACAM1-L tyrosine phosphorylation, SHP-1 association, and involves ERK1/2 and caspase-3 activation pathways.\",\n      \"method\": \"CEACAM1-specific antibody, Fab fragments, and soluble CEACAM1-Fc treatment of rat granulocytes; DNA fragmentation assays, annexin V staining, SHP-1 co-immunoprecipitation, ERK1/2 and caspase-3 activation assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal apoptosis assays with biochemical mechanism, single lab\",\n      \"pmids\": [\"15909305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CEACAM1-4S (short cytoplasmic isoform) directly associates with annexin II via its cytoplasmic domain (KD ~30 nM), confirmed by GST pull-down, reciprocal co-immunoprecipitation, surface plasmon resonance with oriented peptides, and co-localization in mammary epithelial cells in Matrigel. CEACAM1 also co-localizes with annexin II/p11 at plasma membrane and in secretory vesicles.\",\n      \"method\": \"GST pull-down assay, reciprocal co-immunoprecipitation, surface plasmon resonance with oriented CEACAM1-4S cytoplasmic domain peptides, confocal laser microscopy in 3D Matrigel culture\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with SPR KD measurement plus reciprocal co-IP plus confocal co-localization, multiple orthogonal methods single lab\",\n      \"pmids\": [\"14522961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CEACAM1-4S expression in MCF7 mammary carcinoma cells restores lumen formation in 3D Matrigel culture via apoptosis of central cells. Apoptosis involves Bax translocation to mitochondria and cytochrome c release into cytoplasm (intrinsic pathway), and is partially inhibited by caspase inhibitors. CEACAM1-4S localizes initially between cells and later exclusively apically in mature acini.\",\n      \"method\": \"3D Matrigel culture of MCF7 cells stably transfected with CEACAM1-4S, apoptosis assays (nuclear condensation, membrane blebbing, caspase activation, DNA laddering), Bax translocation and cytochrome c release assays, caspase inhibitor treatment, immunofluorescence localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular reconstitution with multiple orthogonal mechanistic readouts, 3D morphogenesis model\",\n      \"pmids\": [\"12522268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Homotypic CD66a (CEACAM1) interactions between melanoma cells and NK cells inhibit NK cell cytotoxicity via a class I MHC-independent mechanism. 721.221 cells expressing CD66a were protected from lysis by YTS cells and NK cells expressing CD66a; the inhibitory effect correlated with CD66a expression levels.\",\n      \"method\": \"NK cell cytotoxicity assays, redirected lysis experiments, transfection of 721.221 cells with CD66a, expression level correlation analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cytotoxicity assays with transfection controls and dose-response, single lab\",\n      \"pmids\": [\"11884449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM1 enhances melanoma cell invasion and migration, dependent on Tyr-488 within the full-length cytoplasmic CEACAM1 domain. CEACAM1 co-localizes and interacts with integrin β3 via the cytoplasmic domain. RGD peptides blocking integrin αvβ3 abolished CEACAM1-enhanced invasion, and integrin β3 expression induces CEACAM1 upregulation.\",\n      \"method\": \"Stable CEACAM1 transfection of melanocytic/melanoma cells, in vitro invasion and migration assays (Matrigel), anti-CEACAM1 antibody inhibition, RGD peptide blocking, Tyr-488 mutant analysis, co-immunoprecipitation of CEACAM1 with integrin β3\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis, co-IP, and functional invasion assays, multiple approaches, single lab\",\n      \"pmids\": [\"15509546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD66a (CEACAM1) and CD66b are the major galectin-3 receptors on human neutrophils, stored in intracellular gelatinase and specific granules. Galectin-3-Sepharose affinity chromatography from neutrophil granules isolated CD66a (160 kDa) and CD66b (100 kDa) as the primary binding proteins.\",\n      \"method\": \"Galectin-3-Sepharose affinity chromatography from neutrophil granule preparations, SDS-PAGE, immunoblotting, HL-60 cell differentiation model, subcellular fractionation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct affinity purification identifying binding partners plus subcellular fractionation, single lab\",\n      \"pmids\": [\"10553088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CEACAM1 cytoplasmic domain associates with paxillin in a tyrosine phosphorylation-dependent manner (requiring Tyr-488). CEACAM1-paxillin complexes co-immunoprecipitated from granulocytes, HT29 colon cells, and HUVECs, with co-localization at the plasma membrane, linking CEACAM1 to the actin cytoskeleton.\",\n      \"method\": \"Phosphorylated cytoplasmic domain pull-down from granulocyte extracts, co-immunoprecipitation from multiple cell types, confocal microscopy co-localization, Tyr-488 mutant analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down binding partner identification confirmed by co-IP across multiple cell types, site-directed mutagenesis, single lab\",\n      \"pmids\": [\"11035932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEACAM1 is induced by HCMV and influenza virus via their respective innate DNA/RNA sensors (IFI16 and RIG-I), mediated by IRF3 binding to an ISRE element in the human CEACAM1 promoter. Upon induction, CEACAM1 suppresses viral replication through an SHP-2-dependent process that inhibits mTOR-mediated protein biosynthesis.\",\n      \"method\": \"Virus infection assays (HCMV, influenza), innate sensor knockdown, IRF3 chromatin immunoprecipitation at CEACAM1 ISRE, SHP-2-dependent assays, mTOR activity assays, ex vivo human decidua organ culture\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing IRF3-ISRE interaction, SHP-2 functional link, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"27264178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEACAM1 or CEACAM5 expression in AZ-521 cells is necessary and sufficient to restore H. pylori type IV secretion system (T4SS)-dependent CagA translocation and phosphorylation. This defines an integrin-β1- and CEACAM1- or CEACAM5-dependent T4SS delivery pathway for CagA, independent of VacA.\",\n      \"method\": \"Transfection of CEACAM1 or CEACAM5 into AZ-521 cells, H. pylori infection, CagA translocation and phosphorylation assays, vinculin and cortactin dephosphorylation as functional readouts\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic reconstitution experiment with specific functional readouts, single lab\",\n      \"pmids\": [\"30321907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CEA induces CEACAM1-mediated apoptosis in HT29 colon cancer cells dependent on CEACAM1 cell surface abundance. Apoptosis triggers dual cleavage of CEACAM1-4L (at intracellular and extracellular sites) and activates caspases including caspase-1 and -3, as well as non-caspase proteases.\",\n      \"method\": \"CEA treatment of HT29/Jurkat/HEK293 cells, caspase activity assays, CEACAM1 cleavage detection, cell death assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined ligand (CEA), specific cleavage and caspase readouts, multiple cell lines, single lab\",\n      \"pmids\": [\"18278069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CEACAM1 intrinsic signaling promotes B cell survival via the BTK/Syk/NF-κB axis. CEACAM1 deficiency in Ceacam1-/- mice limits survival of proliferating B cells and prevents generation of protective antiviral neutralizing antibody responses during VSV infection.\",\n      \"method\": \"Ceacam1-/- mice, VSV infection model, B cell survival assays, BTK/Syk/NF-κB pathway analysis, antibody neutralization assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ceacam1 KO mouse with in vivo viral infection, mechanistic BTK/Syk/NF-κB pathway dissection, multiple readouts\",\n      \"pmids\": [\"25692415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEACAM1 is essential for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. Absence of CEACAM1 on virus-specific CD8+ T cells limits antiviral CD8+ T cell responses; anti-CEACAM1 antibody stabilizes Lck in the immunological synapse and prevents CD8+ T cell exhaustion in LCMV infection.\",\n      \"method\": \"LCMV infection of Ceacam1-/- mice, immunological synapse analysis, Lck recruitment assays, anti-CEACAM1 antibody treatment, CD8+ T cell proliferation and exhaustion assays in mouse and human cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ceacam1 KO mouse, defined molecular mechanism (Lck recruitment), multiple readouts, antibody validation in human cells, single lab with orthogonal methods\",\n      \"pmids\": [\"29967450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CEACAM1 is tyrosine-phosphorylated in endothelial cells upon VEGF treatment in a SHP-1- and Src-dependent manner. The long cytoplasmic domain of CEACAM1 is required for this phosphorylation and for VEGF-dependent nitric oxide (NO) production. CEACAM1 deficiency causes increased basal Akt and eNOS activation and defective VEGF-mediated vascular permeability.\",\n      \"method\": \"Ceacam1-/- mice, primary murine lung endothelial cells, VEGF stimulation, CEACAM1 phosphorylation assays, SHP-1/Src inhibitor experiments, eNOS/Akt phosphorylation assays, in vivo vascular permeability assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple biochemical pathway readouts in primary endothelial cells, single lab\",\n      \"pmids\": [\"21081647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CEACAM1 clustering in PC12 cells induces rapid transient CEACAM1 tyrosine dephosphorylation, reduced SHP-2 association, binding to the actin cytoskeleton, and activation of ERK1/2 (but not JNK or p38) MAPK signaling downstream.\",\n      \"method\": \"Antibody-induced CEACAM1 clustering on PC12 cell surface, tyrosine phosphorylation assays, SHP-2 co-immunoprecipitation, detergent fractionation for cytoskeletal association, ERK1/2/JNK/p38 activation assays\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical readouts with functional clustering stimulus, single lab\",\n      \"pmids\": [\"12108545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HIF-1α directly binds the polypyrimidine tract binding protein 1 (Ptbp1) promoter to transcriptionally regulate Ptbp1, which promotes alternative splicing of Ceacam1 toward the short cytoplasmic isoform (Ceacam1-S) during hypoxia/IRI. Ceacam1-S protects hepatocytes by repressing the ASK1/p-p38 cell death pathway. Established by ChIP and luciferase assays.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of HIF-1α at Ptbp1 promoter, luciferase reporter assays, adenoviral Ceacam1-S transfection into Ceacam1-deficient hepatocytes, morpholino-mediated isoform switching, warm IRI mouse model, human liver biopsy correlations\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP establishing direct HIF-1α/Ptbp1 binding, genetic reconstitution, morpholino isoform switching, in vitro and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37531413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Neutrophil CEACAM1-long (CC1-L) isoform determines susceptibility to NET formation by regulating the S1P-S1PR2/S1PR3 signaling axis and autophagy signaling. Ablation of CC1-L in recipient neutrophils aggravated hepatic ischemia-reperfusion injury in mouse OLT by promoting NETosis.\",\n      \"method\": \"Mouse OLT model with isoform-specific CC1-L ablation, S1PR2/S1PR3 pathway analysis, autophagy signaling assays, NET formation assays, human OLT patient cohort analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific KO in mouse OLT model with defined pathway, translational human cohort, single lab\",\n      \"pmids\": [\"36719377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"F. nucleatum CbpF (trimeric autotransporter adhesin) binds and activates CEACAM1 to inhibit CD4+ T cell function. Other fusobacterial trimeric autotransporter adhesins (fvcB, fvcC, fvcD) are not involved. Anti-CEACAM1 antibodies directed against the N-terminal domain block CbpF-CEACAM1 interaction.\",\n      \"method\": \"F. nucleatum deletion mutants lacking fvcA (CbpF)/fvcB/fvcC/fvcD, CEACAM1 binding assays, T cell functional inhibition assays, antibody blocking experiments\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined bacterial mutants with functional T cell assay, antibody blocking, single lab\",\n      \"pmids\": [\"34336716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"S. pyogenes R28 protein specifically targets human CEACAM1 via an IgI3-like fold domain that binds the N-terminal domain of CEACAM1. This interaction mediates bacterial adhesion to cervical cells, suppresses epithelial wound repair, and subverts innate immune responses. High-resolution structural analysis established the binding interface.\",\n      \"method\": \"High-resolution structural analysis of R28-CEACAM1 N-terminal domain interaction, bacterial adhesion assays to cervical cells, epithelial wound repair assays, innate immune response functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural determination of binding interface plus multiple functional assays, single lab\",\n      \"pmids\": [\"37080973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In liver transplantation (OLT), CEACAM1 deficiency in donor liver augments ischemia-reperfusion injury by enhancing ROS expression and HMGB1 translocation during cold storage via ASK1/p-p38 pathway upregulation. Adjunctive ASK1 inhibition alleviates IRI in CC1-KO livers by suppressing p-p38, ROS, and HMGB1.\",\n      \"method\": \"CC1-KO→WT mouse OLT model, ASK1/p38 pathway analysis, ROS and HMGB1 measurement, bone marrow-derived macrophage activation assays from hepatic flush, ASK1 siRNA in hepatocyte cultures, human donor liver biopsy correlations\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ceacam1 KO OLT model with defined ASK1/p38 pathway, siRNA knockdown, translational human data, single lab\",\n      \"pmids\": [\"32027621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Forced liver-specific CEACAM1 overexpression in mice prevents diet-induced hyperinsulinemia and insulin resistance by protecting hepatic insulin clearance. This is partly mediated by increased hepatic β-fatty acid oxidation and energy expenditure.\",\n      \"method\": \"Liver-specific inducible CEACAM1 transgenic mice on high-fat diet, insulin clearance assays, metabolic phenotyping, β-fatty acid oxidation measurements\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — liver-specific transgenic gain-of-function with mechanistic metabolic readouts, single lab\",\n      \"pmids\": [\"25972571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CEACAM1-Long (but not CEACAM1-Short or truncation mutants) intracellularly promotes Sox-2 expression in melanoma cells to enhance cell proliferation. This effect is not blocked by anti-CEACAM1 antibodies, indicating it is not mediated by homophilic intercellular interactions but by intracellular CEACAM1-L signaling.\",\n      \"method\": \"CEACAM1 knockdown and selective isoform/truncation mutant overexpression in melanoma cells, Sox-2 expression analysis, proliferation assays in vitro and xenograft in vivo, anti-CEACAM1 antibody blocking experiments, CEACAM1 promoter SNP analysis\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific genetic dissection with KD and OE, antibody blocking to define mechanism, in vivo xenograft confirmation, single lab\",\n      \"pmids\": [\"24931667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TIM-3 and CEACAM1 do not interact in cis or in trans, as shown by extensive binding studies and a T cell reporter platform. CEACAM1-mediated inhibition is confirmed but functions independently of TIM-3; TIM-3 cytoplasmic sequences can independently promote inhibitory signaling.\",\n      \"method\": \"T cell reporter platform, extensive cell-based and soluble protein binding assays for TIM-3/CEACAM1 interaction, flow cytometric co-expression analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative result from multiple binding assays using reporter system; contradicts PMID 25363763; single lab, lower confidence due to direct contradiction with structural study\",\n      \"pmids\": [\"32222966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM1-4S directly associates with and downregulates β1-integrin expression in mammary epithelial cells during 3D morphogenesis. Immuno-electron microscopy reveals CEACAM1-coated vesicles within lumena, and CEACAM1 is detected in breast milk lipid fractions.\",\n      \"method\": \"3D Matrigel culture, co-immunoprecipitation of CEACAM1 with β1-integrin, immuno-electron microscopy, breast milk lipid fractionation, immunohistochemistry\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP identifying interaction with functional downstream consequence, immuno-EM, single lab\",\n      \"pmids\": [\"15339048\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEACAM1 is a multifunctional transmembrane cell adhesion molecule whose inhibitory signaling is mediated by ITIM phosphorylation and recruitment of SHP-1/SHP-2 phosphatases; it forms cis and trans heterodimers with TIM-3 (established by crystallography) to regulate T cell tolerance, inhibits NK cell NKG2D-mediated cytolysis via SHP-1-dependent Vav1 dephosphorylation, suppresses T cell activation through ITIM/SHP-1-mediated dampening of TCR signaling, recruits Lck to the TCR immunological synapse to sustain CD8+ T cell responses, regulates platelet collagen-GPVI signaling, promotes hepatic insulin clearance as an insulin receptor substrate whose phosphorylation controls Shc binding and Ras/MAPK uncoupling, undergoes HIF-1α/Ptbp1-controlled alternative splicing to generate isoforms with distinct cytoprotective functions in ischemia-reperfusion injury, and is exploited by multiple bacterial pathogens (Neisseria, Helicobacter pylori, Fusobacterium, Streptococcus pyogenes) via direct binding to its N-terminal Ig domain to evade immunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEACAM1 is a transmembrane cell adhesion molecule that functions principally as an inhibitory immunoreceptor, regulating immune cell signaling, hepatic insulin metabolism, epithelial morphogenesis, and host responses to pathogens [#1, #7]. Its inhibitory output is encoded by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the long cytoplasmic-domain isoform; phosphorylation of the ITIM tyrosine (Y459/Y488) recruits the phosphatases SHP-1 and SHP-2, and mutation of this tyrosine abolishes inhibitory signaling [#2, #1]. Through this ITIM/SHP-1 module CEACAM1 dampens TCR-CD3 signaling and T cell proliferation and cytokine production [#1], inhibits NK cell NKG2D-mediated cytolysis via SHP-1-dependent dephosphorylation of Vav1 [#5], and negatively regulates platelet collagen responses through the GPVI/FcR-γ receptor [#10]. Trans-homophilic engagement of CEACAM1 induces cis-dimerization transmitted allosterically through the N-terminal Ig domain, and the monomer/dimer equilibrium of CEACAM1-L sets the balance of SHP-2 versus c-Src recruitment, with the short isoform CEACAM1-S antagonizing long-isoform homodimerization [#4]. Beyond inhibition, CEACAM1 provides positive and pro-survival signals: it recruits Lck into the TCR immunological synapse to sustain antiviral CD8+ T cell responses [#23], promotes B cell survival via the BTK/Syk/NF-κB axis [#22], and supports monocyte and granulocyte survival through PI3K/Akt and SHP-1-dependent pathways [#11, #12]. In the liver CEACAM1 is a substrate of the insulin receptor whose phosphorylation drives receptor-mediated insulin endocytosis and clearance; loss of this function causes insulin resistance, and hepatic overexpression protects against diet-induced hyperinsulinemia [#7, #31]. As an EGFR substrate, phosphorylated CEACAM1 sequesters Shc to uncouple EGFR from Ras/MAPK signaling [#8]. The short isoform CEACAM1-4S binds annexin II and downregulates β1-integrin to drive lumen formation and central-cell apoptosis during epithelial morphogenesis [#13, #14, #34], while HIF-1α/Ptbp1-controlled alternative splicing toward CEACAM1-S protects hepatocytes by repressing the ASK1/p-p38 death pathway in ischemia-reperfusion injury [#26, #30]. CEACAM1 is exploited as a receptor by multiple pathogens, including Neisseria, Helicobacter pylori, Fusobacterium nucleatum, and Streptococcus pyogenes, all binding its N-terminal Ig domain to subvert epithelial integrity and immune responses [#3, #20, #28, #29]. A structurally defined cis/trans heterodimer with TIM-3 has been reported as required for TIM-3-mediated T cell inhibition [#0], although a subsequent study found no detectable CEACAM1-TIM-3 interaction and concluded CEACAM1 inhibition operates independently of TIM-3 [#33].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing CEACAM1's binding partners on innate immune cells, the protein was identified as a major granule-stored galectin-3 receptor on neutrophils, an early clue to its extracellular ligand repertoire.\",\n      \"evidence\": \"galectin-3-Sepharose affinity chromatography from neutrophil granules with immunoblotting\",\n      \"pmids\": [\"10553088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence of galectin-3 binding not defined\", \"single lab affinity capture without binding kinetics\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"To define the molecular basis of CEACAM1 inhibitory signaling, the cytoplasmic Y459 motif was shown to be a functional ITIM requiring both SHP-1 and SHP-2 to suppress calcium influx.\",\n      \"evidence\": \"FcγRIIB-BGPa chimera in SHP-1/SHP-2-null DT40 B cells with Y-to-F mutagenesis and calcium assays\",\n      \"pmids\": [\"11493628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"studied in a chimeric receptor context, not native CEACAM1\", \"relative contributions of SHP-1 vs SHP-2 in physiological cells unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defining a metabolic role, CEACAM1 was identified as an insulin receptor substrate whose phosphorylation drives hepatic insulin clearance, linking the receptor to systemic insulin sensitivity.\",\n      \"evidence\": \"L-SACC1 dominant-negative S503A transgenic mice with insulin clearance and metabolic phenotyping\",\n      \"pmids\": [\"12128284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"primarily a review summarizing prior transfection data\", \"structural basis of insulin receptor docking not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"To explain epithelial morphogenetic functions, CEACAM1-4S was shown to bind annexin II directly and to restore lumen formation through intrinsic-pathway apoptosis of central acinar cells.\",\n      \"evidence\": \"GST pull-down, reciprocal co-IP, SPR (KD ~30 nM), and 3D Matrigel culture with Bax/cytochrome c readouts\",\n      \"pmids\": [\"14522961\", \"12522268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how cytoplasmic annexin II binding triggers apoptosis mechanistically unclear\", \"isoform-specific signaling downstream of CEACAM1-4S not fully mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Broadening the substrate concept, CEACAM1 was identified as an EGFR substrate that sequesters Shc to dampen Ras/MAPK proliferation, and as a Tyr-488-dependent promoter of melanoma invasion via integrin β3.\",\n      \"evidence\": \"co-IP with Shc and integrin β3, EGF stimulation, invasion assays, Tyr-488 mutagenesis, transgenic mice\",\n      \"pmids\": [\"15467833\", \"15509546\", \"15339048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"context-dependence of growth-suppressive vs invasion-promoting roles unresolved\", \"structural detail of Shc/integrin docking unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Reciprocal genetic approaches established CEACAM1 as a bona fide negative regulator of T cells, acting through long-isoform ITIMs and SHP-1 to restrain TCR-CD3 signaling, and as a PI3K/Akt-dependent survival factor in monocytes.\",\n      \"evidence\": \"CEACAM1 overexpression and conditional T cell deletion in mice; antibody/soluble-CEACAM1 treatment of monocytes with apoptosis and inhibitor assays\",\n      \"pmids\": [\"17081782\", \"17071610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how the same receptor switches between inhibitory and survival outputs unresolved\", \"monocyte survival mechanism is Medium-confidence and from a single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking CEACAM1 to host defense and hemostasis, the receptor was shown to negatively regulate TLR2-driven inflammation upon bacterial engagement and to inhibit platelet GPVI/collagen signaling, both via ITIM/SHP-1.\",\n      \"evidence\": \"bacterial infection of primary epithelial cells with pathway readouts; Ceacam1-/- platelet aggregation, adhesion, and in vivo thrombosis assays\",\n      \"pmids\": [\"18836450\", \"19008452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how pathogen binding couples to ITIM phosphorylation mechanistically unclear\", \"platelet ITIM kinase upstream of phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolving how trans engagement signals across the membrane, trans-homophilic binding was shown to induce cis-dimerization of CEACAM1-L allosterically, with the monomer/dimer equilibrium setting the SHP-2 vs c-Src balance.\",\n      \"evidence\": \"FRET, cross-linking, co-clustering and co-IP with CFP/YFP-tagged isoforms in epithelial monolayers\",\n      \"pmids\": [\"19948503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"physiological triggers shifting the equilibrium in vivo not defined\", \"SHP-1 binding not observed, leaving its in vivo role open\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining a tumor-immune evasion mechanism, NK-cell CEACAM1 was shown to inhibit NKG2D cytolysis via trans-homophilic interaction, NKG2D association, SHP-1 recruitment, and Vav1 dephosphorylation, complementing earlier evidence that tumor CEACAM1 retains NKG2D ligands intracellularly.\",\n      \"evidence\": \"NK cytolysis assays, reciprocal NKG2D-CEACAM1 co-IP, SHP-1 recruitment, Vav1 phosphorylation blotting; CEACAM1 silencing with surface-ligand flow cytometry\",\n      \"pmids\": [\"23696226\", \"22143889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism of NKG2D ligand intracellular retention unresolved\", \"relative importance of homophilic vs receptor-cis mechanisms in vivo unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A structurally defined CEACAM1-TIM-3 cis/trans heterodimer was reported as required for TIM-3-mediated T cell inhibition, proposing a co-receptor model for T cell tolerance.\",\n      \"evidence\": \"X-ray crystallography, co-IP, biophysical binding, and adoptive-transfer colitis with CEACAM1-deficient T cell reconstitution\",\n      \"pmids\": [\"25363763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"the interaction was later not reproduced (see 2020 entry)\", \"structural interface conditions vs cellular physiology not reconciled\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extending CEACAM1's survival role to humoral immunity and metabolism, intrinsic CEACAM1 signaling was shown to sustain B cell survival via BTK/Syk/NF-κB for antiviral antibody responses, and hepatic overexpression to protect insulin clearance.\",\n      \"evidence\": \"Ceacam1-/- mice with VSV infection and B cell survival assays; liver-specific CEACAM1 transgenic mice on high-fat diet\",\n      \"pmids\": [\"25692415\", \"25972571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how CEACAM1 couples to BTK/Syk activation mechanistically unclear\", \"link between hepatic insulin clearance and fatty-acid oxidation incompletely defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining antiviral and pathogen-cooperative roles, CEACAM1 was shown to be induced via IRF3 at an ISRE to suppress viral replication through SHP-2/mTOR, while also being required for H. pylori T4SS-dependent CagA delivery.\",\n      \"evidence\": \"IRF3 ChIP at CEACAM1 ISRE, SHP-2/mTOR functional assays, decidua organ culture; CEACAM1/CEACAM5 reconstitution in AZ-521 cells with CagA translocation assays\",\n      \"pmids\": [\"27264178\", \"30321907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how SHP-2 connects to mTOR inhibition mechanistically unresolved\", \"both single-lab studies awaiting independent confirmation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revising the inhibitory paradigm, CEACAM1 was found to act positively in CD8+ T cells by recruiting Lck into the immunological synapse to sustain antiviral responses and prevent exhaustion.\",\n      \"evidence\": \"LCMV infection of Ceacam1-/- mice, synapse imaging, Lck recruitment assays, anti-CEACAM1 antibody validation in human cells\",\n      \"pmids\": [\"29967450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular determinants of Lck recruitment by CEACAM1 not defined\", \"reconciliation of positive CD8 role with ITIM-based inhibition unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Directly challenging the 2014 model, a binding and reporter study found no detectable cis or trans CEACAM1-TIM-3 interaction and concluded CEACAM1 inhibition functions independently of TIM-3.\",\n      \"evidence\": \"T cell reporter platform with extensive cell-based and soluble-protein binding assays and co-expression analysis\",\n      \"pmids\": [\"32222966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"negative result directly contradicts the structural study\", \"single lab; conditions distinguishing the two outcomes not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining isoform-selective cytoprotection, HIF-1α/Ptbp1-driven splicing toward CEACAM1-S was shown to repress ASK1/p-p38-mediated hepatocyte death, while neutrophil CEACAM1-L modulates NETosis via S1PR2/S1PR3 in liver ischemia-reperfusion injury.\",\n      \"evidence\": \"HIF-1α ChIP, luciferase, adenoviral CEACAM1-S reconstitution and morpholino isoform switching in IRI models; isoform-specific CC1-L ablation in mouse OLT with S1PR pathway and NET assays; CC1-KO OLT ASK1/p38 analysis\",\n      \"pmids\": [\"37531413\", \"36719377\", \"32027621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how distinct cytoplasmic domains specify opposing cell-fate outcomes unresolved\", \"translation of isoform-switching strategy to human therapy untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cementing CEACAM1 as a convergent bacterial target, S. pyogenes R28 and F. nucleatum CbpF were shown to bind its N-terminal Ig domain to subvert epithelial repair and T cell function.\",\n      \"evidence\": \"high-resolution structural analysis of R28-CEACAM1 interface with adhesion/wound-repair/immune assays; defined F. nucleatum adhesin mutants with T cell inhibition and antibody blocking\",\n      \"pmids\": [\"37080973\", \"34336716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether diverse pathogens engage overlapping or distinct N-domain epitopes unresolved\", \"downstream signaling triggered by bacterial vs homophilic binding not compared\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CEACAM1 switches between inhibitory (ITIM/SHP) and activating/pro-survival (Lck, BTK/Syk, PI3K/Akt) outputs in the same cell, and whether the disputed TIM-3 partnership operates physiologically, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unifying model reconciling inhibitory and activating signaling\", \"CEACAM1-TIM-3 interaction unresolved between contradicting studies\", \"upstream kinases controlling ITIM phosphorylation in each cell type not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [4, 5, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 5, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 23, 4]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [3, 20, 28, 29]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 8, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 10, 13, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [13, 17, 34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 5, 22, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7, 8, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 20, 28, 29]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 14, 21, 30]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SHP-1\", \"SHP-2\", \"TIM-3\", \"NKG2D\", \"Shc\", \"annexin II\", \"integrin beta3\", \"paxillin\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}