{"gene":"CEACAM6","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2007,"finding":"CEACAM6 acts as a receptor for adherent-invasive E. coli (AIEC) adhesion on the apical surface of ileal epithelial cells; AIEC adhesion is dependent on type 1 pili on the bacterial surface binding to CEACAM6, and IFN-γ or TNF-α stimulation increases CEACAM6 expression, promoting AIEC colonization.","method":"Primary ileal enterocyte adhesion assays, anti-CEACAM6 blocking, cytokine stimulation of cultured intestinal epithelial cells","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional blocking with antibodies, multiple cell systems, replicated in transgenic mouse model","pmids":["17525800"],"is_preprint":false},{"year":1988,"finding":"CEACAM6 (NCA) is encoded by a cDNA containing a 34-aa leader sequence, 310-aa mature protein with one immunoglobulin-like domain doublet (versus three in CEA), and a C-terminal hydrophobic domain; overall ~85% amino acid homology to CEA, supporting GPI-anchor membrane attachment.","method":"cDNA cloning and sequencing from SW403 colon carcinoma library; sequence comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct cDNA sequencing establishing domain architecture, foundational paper","pmids":["2830274"],"is_preprint":false},{"year":1989,"finding":"CEACAM6 (NCA) is anchored to the cell membrane via a glycosyl-phosphatidylinositol (GPI) linkage, demonstrated by release of surface NCA from transfected NIH/3T3 cells upon treatment with phosphatidylinositol-specific phospholipase C.","method":"Transfection of NCA cDNA into NIH/3T3 cells, PI-PLC treatment, flow cytometry and immunoprecipitation of surface glycoproteins","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — enzymatic cleavage assay with two orthogonal readouts (flow cytometry and immunoprecipitation)","pmids":["2742579"],"is_preprint":false},{"year":1991,"finding":"CEACAM6 (NCA) mediates specific Ca2+-independent heterotypic cell adhesion with W272 (CGM6/CEACAM8), and this adhesion is mediated by the N-terminal domain of NCA; W272-expressing cells showed no homotypic binding but bound cells expressing NCA via NCA's N-domain.","method":"CHO cell transfectants expressing NCA, CEA, W272 and chimeric N-domain constructs; cell aggregation assays; chimeric domain analysis in COS-1 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in transfected cells with chimeric domain mutagenesis establishing N-domain specificity","pmids":["2022629"],"is_preprint":false},{"year":1992,"finding":"CEACAM6 (NCA species ~95-100 kDa) is localized predominantly in secondary granules of neutrophils, with lesser amounts in plasma membrane and primary granules, suggesting secondary granules as the intracellular reservoir from which CEACAM6 is recruited to the cell surface upon neutrophil activation.","method":"Nitrogen cavitation, differential centrifugation, SDS-PAGE and immunoblotting of neutrophil subcellular fractions","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular fractionation with functional implication, clean biochemical method","pmids":["1640165"],"is_preprint":false},{"year":1996,"finding":"CEACAM6 (CD66c) antibody binding to neutrophils triggers a calcium-dependent signal that upregulates CD11/CD18 on the neutrophil surface and increases adhesion to HUVEC monolayers; CD66c signals independently from other CD66 family members.","method":"Neutrophil adhesion assays to HUVEC monolayers, CD18 blocking antibody, calcium chelation, sequential desensitization experiments","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays with blocking controls and desensitization establishing independent signaling","pmids":["8699114"],"is_preprint":false},{"year":2001,"finding":"The N-terminal domain (N-domain) of CEACAM6 mediates both homophilic (CEACAM6–CEACAM6) and heterophilic (CEACAM6–CEACAM8) cell adhesion; homologue-scanning mutagenesis revealed overlapping but non-identical critical residues for each interaction, similar to sites used by Neisseria Opa proteins.","method":"CHO transfectants expressing mutant and chimeric CEACAM6/CEACAM8 proteins; cell aggregation assays; homologue-scanning mutagenesis","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with functional readout in transfected cells","pmids":["11590190"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 cross-linking in pancreatic adenocarcinoma cells activates c-Src, induces caveolin-1-dependent tyrosine phosphorylation of FAK (p125FAK), and increases cellular resistance to anoikis; FAK phosphorylation requires c-Src kinase activity.","method":"Antibody-mediated cross-linking of CEACAM6 in BxPC3 cells, immunoblotting for phospho-FAK and phospho-Src, caveolin-1 dependence assessed, anoikis resistance quantified","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway dissection with multiple signaling readouts and dependence on caveolin-1","pmids":["15047698"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 cross-linking initiates c-Src-dependent cross-talk with αvβ3 integrin, leading to increased pancreatic adenocarcinoma cell adhesion to fibronectin and vitronectin ECM components; this effect is blocked by Src inhibitor PP2 or c-Src-specific siRNA.","method":"Antibody-mediated CEACAM6 cross-linking, ECM adhesion assays, Src kinase inhibitor PP2, c-Src siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — pharmacological and genetic inhibition of Src with functional ECM adhesion readout","pmids":["15047158"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 gene silencing by siRNA increases susceptibility to caspase-mediated anoikis in pancreatic adenocarcinoma cells under anchorage-independent conditions, decreases Akt phosphorylation at Ser-473, and inhibits in vivo metastatic ability in orthotopic mouse xenograft models.","method":"siRNA knockdown, YO-PRO-1/PI flow cytometry for anoikis, caspase fluorometric profiling, Z-VAD-fmk rescue, Akt immunoblotting, orthotopic nude mouse xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (siRNA, caspase profiling, chemical rescue, in vivo xenograft) with clear pathway placement","pmids":["14724575"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 overexpression in pancreatic adenocarcinoma increases invasiveness in a c-Src-dependent manner; c-Src mediates CEACAM6-dependent matrix metalloproteinase-9 (MMP-9) activation that contributes to enhanced invasion.","method":"Stable retroviral overexpression and RNAi knockdown, modified Boyden chamber invasion assay, constitutively active/dominant-negative c-Src constructs, MMP-9 activity assay","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 2 — gain- and loss-of-function with dominant-negative constructs establishing c-Src as mediator","pmids":["15316565"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 overexpression enhances IGF-I-induced invasiveness through upregulation of IGF-IR expression and increased Akt and c-Src kinase activities, as well as elevated MMP-2 expression; Akt is both necessary and sufficient for IGF-IR upregulation, while c-Src is necessary but not sufficient.","method":"Stable CEACAM6 overexpression in Capan2 cells, invasion assays toward IGF-I, anti-IGF-IR blocking antibody, Akt and c-Src inhibitors, MMP-2 zymography","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — pharmacological and antibody-based dissection of pathway components with epistasis","pmids":["15208677"],"is_preprint":false},{"year":2007,"finding":"CEACAM6 (and CEA) co-clusters with integrin α5β1 on the cell surface and enhances binding of integrin α5β1 to fibronectin without changing surface integrin levels, leading to increased fibronectin matrix assembly (polymerized fibronectin 'cocoon') and inhibition of cellular differentiation and anoikis; disruption of fibronectin binding or integrin α5β1 restores differentiation and anoikis.","method":"Confocal microscopy co-clustering analysis, fibronectin binding assays, antibody blocking of fibronectin and integrin α5β1, anoikis assays","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 — confocal co-localization combined with functional blocking antibodies and phenotypic rescue","pmids":["17167768"],"is_preprint":false},{"year":2007,"finding":"CEACAM5 and CEACAM6 promoters are activated by TGF-β signaling through Smad3; restoration of TGF-β signaling (via TGF-β type II receptor or Smad3) in non-responsive gastric cancer cell lines induced CEACAM5 and CEACAM6 expression, and CEA expression was markedly decreased in Smad3 null mice.","method":"Reporter assays for CEACAM5/CEACAM6 promoters, rescue of TGF-β signaling in receptor-mutant and Smad3-deficient cell lines, Smad3 knockout mouse gastric tissue analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — promoter reporter assay, cell rescue, and in vivo genetic knockout validation","pmids":["17653079"],"is_preprint":false},{"year":2009,"finding":"CEACAM6 antagonizes the Src signaling pathway in pancreatic cancer cells, downregulates cytoskeleton proteins, and blocks adenovirus trafficking to the nucleus; siRNA knockdown of CEACAM6 enhances adenoviral replication and antitumor effect of oncolytic adenovirus in vivo.","method":"CEACAM6 overexpression and siRNA knockdown, Src signaling immunoblotting, cytoskeleton protein analysis, adenovirus nuclear trafficking assays, mouse xenograft model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — gain/loss of function with multiple mechanistic readouts including viral trafficking and in vivo validation","pmids":["19411761"],"is_preprint":false},{"year":2012,"finding":"Influenza A virus neuraminidase (NA) protein interacts with CEACAM6 (C6) and activates the Src/Akt signaling axis (increased phosphorylation of Src, FAK, Akt, GSK3β, Bcl-2), enhancing host cell survival; siRNA knockdown of CEACAM6 reduces Src/FAK/Akt activation, increases apoptosis, and reduces viral titers.","method":"Co-immunoprecipitation of NA with CEACAM6, siRNA knockdown in human lung adenocarcinoma and normal bronchial epithelial cells, phospho-immunoblotting, apoptosis assays, viral titer measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — Co-IP for binding, siRNA knockdown with multiple pathway readouts, viral titer as functional output","pmids":["22396546"],"is_preprint":false},{"year":2013,"finding":"CEACAM6 promotes EMT and pancreatic cancer invasion and metastasis; miR-29a/b/c directly targets CEACAM6 and suppresses its expression at the post-transcriptional level, reducing EMT, migration, and invasion.","method":"CEACAM6 overexpression and shRNA knockdown, in vitro invasion/migration assays, in vivo metastasis models, miRNA transfection with EMT marker immunoblotting","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, miRNA-target relationship by functional rescue, no luciferase validation of direct binding cited in abstract","pmids":["23857344"],"is_preprint":false},{"year":2014,"finding":"CEACAM6 promotes EMT and invasion in gastric cancer via PI3K/AKT signaling; CEACAM6 overexpression increases N-cadherin, vimentin, Slug and MMP-9 while decreasing E-cadherin; PI3K inhibitor LY294002 reverses CEACAM6-induced EMT; anti-MMP-9 antibody reverses CEACAM6-induced invasion.","method":"CEACAM6 overexpression/silencing in GC cells, EMT marker immunoblotting, MMP-9 antibody blocking, PI3K inhibitor treatment, peritoneal metastasis in vivo model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (inhibitors, antibody blocking, in vivo), single lab","pmids":["25398131"],"is_preprint":false},{"year":2015,"finding":"CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling; CEACAM6 overexpression increases phosphorylation of FAK and paxillin, and FAK inhibitor Y15 reduces tubule and vasculogenic mimicry formation.","method":"CEACAM6 overexpression/silencing, HUVEC tubule formation assay, 3D-culture vasculogenic mimicry assay, FAK inhibitor Y15 treatment, paxillin and FAK phospho-immunoblotting, xenograft in vivo","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological FAK inhibition with functional rescue, in vivo validation, single lab","pmids":["25703140"],"is_preprint":false},{"year":2017,"finding":"CEACAM6 promotes OSCC invasion, migration, cytoskeletal rearrangement, and metastasis by interacting with EGFR and enhancing EGFR activation, clustering, and intracellular signaling; N-glycosylation of CEACAM6 at Asn256, mediated by MGAT5, is critical for this EGFR interaction and signaling.","method":"Anti-CEACAM6 antibody (TMU HCAb) that specifically recognizes glycosylated CEACAM6, MGAT5 manipulation, CEACAM6 N256 mutagenesis, invasion/migration assays, EGFR co-clustering analysis, in vivo metastasis model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1+2 — site-specific mutagenesis (N256) combined with glycosylation enzyme manipulation and functional rescue with specific antibody","pmids":["28892050"],"is_preprint":false},{"year":2008,"finding":"CEACAM6 suppression by siRNA reverses migration and invasion of oestrogen-deprived resistant breast cancer cells and significantly reduces phosphorylated Akt and c-Src expression, placing CEACAM6 upstream of Akt and c-Src in mediating invasion.","method":"siRNA knockdown, migration and invasion assays, phospho-Akt and phospho-c-Src immunoblotting","journal":"European journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — clean siRNA knockdown with multiple pathway readouts, single lab","pmids":["18614350"],"is_preprint":false},{"year":2010,"finding":"CEACAM6 cross-linking in B-cell precursor ALL cells activates Erk1/2, Akt, and p38 MAPK phosphorylation and upregulates integrin expression and integrin ligand (VCAM-1, ICAM-1) binding, but paradoxically increases apoptosis, unlike other GPI-anchored molecules such as CD24.","method":"Anti-CEACAM6 antibody cross-linking, flow cytometry for integrin expression and ligand binding, phospho-immunoblotting for Erk1/2/Akt/p38, apoptosis assays","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling readouts from defined cross-linking experiment, single lab","pmids":["20380867"],"is_preprint":false},{"year":2012,"finding":"CEACAM6 overexpression in HNSCC enhances tumor growth and tumor-initiating activity by activating AKT and suppressing caspase-3-mediated cell death; PI3K/AKT inhibitors selectively ablate CEACAM6-expressing HNSCC foci in xenograft models.","method":"shRNA knockdown and viral overexpression of CEACAM6, xenograft mouse model, AKT inhibitor treatment, caspase-3 immunoblotting","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — gain/loss of function with in vivo pharmacological rescue, single lab","pmids":["23021083"],"is_preprint":false},{"year":1990,"finding":"CEACAM6 (NCA-160, CD66c) is the predominant neutrophil surface carrier of CD15 (LewisX) and sialyl-LewisX carbohydrate antigens; NCA-90 and related NCAs do not express CD15.","method":"Immunoprecipitation and immunoblotting with anti-CD15 monoclonal antibody MC2; surface expression studies after fMLP stimulation","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — immunoprecipitation identifying the protein carrier of a functionally important carbohydrate antigen","pmids":["1694660"],"is_preprint":false},{"year":1993,"finding":"CEACAM6 (NCA-160, CD66c) is the major protein carrier of LewisX and sialyl LewisX groups on neutrophils that interact with vascular selectins E- and P-selectin; differently glycosylated forms of NCA are independently regulated on the cell surface.","method":"Immunoprecipitation and surface expression analysis after fMLP stimulation; flow cytometry for NCA species and sialyl/non-sialyl LewisX","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — immunoprecipitation identifying protein carrier and functional relevance to selectin interactions","pmids":["7689841"],"is_preprint":false},{"year":1996,"finding":"CD66b and CD66c (CEACAM6) mediate heterophilic cell adhesion through N-domain interactions; deglycosylated recombinant proteins retain adhesion activity (carbohydrate not required); CD66b/CD66c adhesion induces superoxide anion release from activated neutrophils.","method":"Soluble recombinant proteins from silkworm larvae, CHO transfectant adhesion assays, deglycosylation experiment, superoxide anion release assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — reconstituted adhesion with recombinant proteins and deglycosylation control establishing domain requirements","pmids":["8645267"],"is_preprint":false},{"year":2008,"finding":"A novel CEACAM6 isoform (CEACAM6-L) generated by intron retention encodes a protein with a transmembrane domain and intracellular region (unlike GPI-anchored CEACAM6), is exclusively expressed in rat testis starting at 5 weeks postnatal, and localizes to the interface between Sertoli cells and spermatids at apical ectoplasmic specializations, suggesting a role in spermatid anchoring.","method":"Differential display, RT-PCR, Northern blot, immunoblotting, confocal laser scanning microscopy/immunohistochemistry in rat testis","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by confocal microscopy tied to specific junction structure, novel isoform characterization","pmids":["18685128"],"is_preprint":false},{"year":2014,"finding":"HIF-1-responsive element (HRE) methylation in the CEACAM6 promoter inversely correlates with CEACAM6 expression; low-methyl diet causes HRE demethylation in transgenic CEACAM6-expressing mice, leading to abnormal gut CEACAM6 expression and enhanced AIEC colonization and inflammation.","method":"Bisulfite sequencing, site-specific methylation SnapShot, pCpGfree promoter reporter assay, Smad3 knockout mice, transgenic CEACAM6 mice on low-methyl diet, AIEC quantification","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1+2 — promoter reporter, methylation-specific sequencing, and in vivo transgenic mouse model with dietary intervention","pmids":["24898815"],"is_preprint":false},{"year":2017,"finding":"C. albicans binds directly to the extracellular N-terminal IgV-like domain of CEACAM6 (and CEACAM1, -3, -5); fungal binding to CEACAM1 and CEACAM6 in intestinal epithelial cells induces CEACAM1 tyrosine phosphorylation and alters epithelial immune responses (CXCL8 secretion); soluble CEACAM6 reduces C. albicans-induced CXCL8 secretion in CEACAM1-competent cells.","method":"Direct binding assay with C. albicans and recombinant CEACAM extracellular domains, shRNA knockdown of CEACAM1, CXCL8 ELISA, CEACAM1 phospho-tyrosine immunoblotting","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — direct binding established with recombinant proteins, functional consequence measured by cytokine secretion with genetic knockdown","pmids":["28292985"],"is_preprint":false},{"year":2021,"finding":"CEACAM6 on tumor cells suppresses anti-tumor T cell activity by interacting with CEACAM1 expressed on activated tumor-specific T cells; blocking CEACAM6-CEACAM1 interaction with the humanized antibody BAY 1834942 increases cytokine secretion by T cells and T cell-mediated cancer cell killing.","method":"T cell-cancer cell co-culture experiments, CEACAM6-blocking antibody (BAY 1834942), cytokine secretion assays, comparison with anti-PD-1/PD-L1/TIM-3 antibodies","journal":"Oncoimmunology","confidence":"High","confidence_rationale":"Tier 2 — functional blocking of specific CEACAM6-CEACAM1 interaction with defined immune readouts","pmids":["35141051"],"is_preprint":false},{"year":2022,"finding":"CEACAM6 homophilic interactions in the cancer cell membrane activate the Src-FAK signaling pathway and inhibit anoikis in lung adenocarcinoma; treatment with exogenous CEACAM6 protein induced homophilic interactions and Src-FAK activation.","method":"CellphoneDB single-cell RNA-seq analysis, CEACAM6 protein treatment, immunoblotting for Src-FAK pathway, anoikis assays, ELISA and immunoblotting of cell culture conditioned media","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein treatment establishing homophilic signaling mechanism with defined pathway readout","pmids":["35358791"],"is_preprint":false},{"year":2015,"finding":"CEACAM6 promotes cell proliferation in pancreatic carcinoma through regulation of cyclin D1 and CDK4 protein levels; CEACAM6 knockdown decreases cyclin D1 and CDK4, while overexpression increases them.","method":"siRNA knockdown and forced overexpression in pancreatic cell lines, immunoblotting for cyclin D1/CDK4, proliferation assays in vitro and xenograft in vivo","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional manipulation with defined downstream effector proteins, single lab","pmids":["26497080"],"is_preprint":false},{"year":2019,"finding":"CRISPR/Cas9 knockout of CEACAM6 in PDA cells alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport, and autophagy pathways; CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity, indicating a role in bioenergetic regulation.","method":"CRISPR/Cas9 KO, quantitative proteomics, mitochondrial bioenergetics (Seahorse assay), xenograft tumor growth","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with quantitative proteomics and direct bioenergetics measurement","pmids":["31797958"],"is_preprint":false},{"year":2023,"finding":"CEACAM6 protein stability is enhanced through lysine lactylation downstream of ALDOB-mediated lactagenesis; the ALDOB/PDK1/lactate/CEACAM6 axis controls CRC cell proliferation and chemoresistance via the Warburg effect.","method":"Cell-based assays, lactylation inhibition, PDK1 activation studies, gene silencing of ALDOB and CEACAM6, chemoresistance assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — pathway epistasis established by sequential gene silencing with defined PTM (lactylation) readout, single lab","pmids":["37816733"],"is_preprint":false},{"year":2021,"finding":"CD151 associates physically with CEACAM6 (confirmed by pulldown and immunofluorescence co-localization), and CD151 silencing downregulates CEACAM6 and TGFβ1 both in vitro and in vivo, placing CEACAM6 downstream of a CD151/TGFβ1 axis in colorectal cancer.","method":"Co-immunoprecipitation, mass spectrometry, pulldown assay, immunofluorescence, RNA-seq after CD151 knockdown, xenograft","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP/MS and pulldown establish physical interaction, RNA-seq and in vivo show downstream pathway regulation, single lab","pmids":["33767593"],"is_preprint":false},{"year":2023,"finding":"CEACAM6 acts as a negative regulator of HO-1-mediated antioxidant defense in human alveolar type 2 epithelial cells (hAEC2s); epithelium-specific CEACAM6 overexpression (via AAV) increases nitrosative/oxidative stress and cell death upon cigarette smoke extract treatment in human precision-cut lung slices.","method":"CSE-resistant cell line model, transcriptomics, AAV-mediated CEACAM6 overexpression in human precision-cut lung slices, HO-1 inhibition, 3-nitrotyrosine measurement","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 — AAV-mediated overexpression in ex vivo human tissue with mechanistic HO-1 pathway validation","pmids":["37219322"],"is_preprint":false}],"current_model":"CEACAM6 is a GPI-anchored, N-glycosylated cell surface immunoglobulin superfamily member that mediates homo- and heterophilic cell adhesion through its N-terminal domain; in cancer cells it drives anoikis resistance, invasion, and metastasis primarily by activating caveolin-1-dependent Src/FAK/AKT signaling, co-clustering with integrins (α5β1, αvβ3) to enhance ECM adhesion, and upregulating MMP-9 activity, while also promoting EMT via PI3K/AKT and inducing EGFR signaling in a manner dependent on N-glycosylation at Asn256; on the cell surface it functions as a pathogen receptor (AIEC type-1 pili, influenza NA, Candida), its expression is transcriptionally regulated by Smad3-mediated TGF-β signaling and by HIF-1 binding to promoter HREs whose methylation status determines expression level, and it can suppress anti-tumor T cell immunity through trans-interaction with CEACAM1 on T cells."},"narrative":{"teleology":[{"year":1988,"claim":"Establishing the molecular identity of CEACAM6 as a CEA family member with a truncated domain structure resolved the relationship between NCA and CEA and predicted GPI-anchoring based on C-terminal hydrophobicity.","evidence":"cDNA cloning and sequencing from SW403 colon carcinoma library","pmids":["2830274"],"confidence":"High","gaps":["GPI-anchor was predicted from sequence but not yet biochemically demonstrated","no functional role assigned"]},{"year":1989,"claim":"Demonstrating that CEACAM6 is tethered to the cell membrane via a GPI linkage established that it lacks an intracellular signaling domain, implying that downstream signaling must occur through lateral membrane interactions.","evidence":"PI-PLC release of NCA from transfected NIH/3T3 cells detected by flow cytometry and immunoprecipitation","pmids":["2742579"],"confidence":"High","gaps":["identity of signaling co-receptors unknown","no adhesion function yet tested"]},{"year":1991,"claim":"Mapping the adhesion specificity of CEACAM6 to its N-terminal domain established that this single domain mediates both homophilic and heterophilic (with CEACAM8) cell adhesion, defining CEACAM6 as an adhesion molecule.","evidence":"CHO transfectants with chimeric N-domain constructs in cell aggregation assays","pmids":["2022629","11590190","8645267"],"confidence":"High","gaps":["structural basis of N-domain binding interface unresolved","in vivo adhesion relevance not demonstrated"]},{"year":1992,"claim":"Localizing CEACAM6 to neutrophil secondary granules and identifying it as the major carrier of sialyl-LewisX selectin ligands revealed a role in neutrophil activation and leukocyte-endothelial interactions.","evidence":"Subcellular fractionation of neutrophils; immunoprecipitation with anti-CD15 antibody; neutrophil-HUVEC adhesion assays with calcium chelation","pmids":["1640165","1694660","7689841","8699114"],"confidence":"High","gaps":["precise mechanism of CEACAM6 signaling from GPI anchor on neutrophils unclear","selectin binding is indirect (via carbohydrate); direct protein-protein selectin interaction not shown"]},{"year":2004,"claim":"A burst of studies in pancreatic cancer revealed that CEACAM6 signals through caveolin-1-dependent c-Src to phosphorylate FAK and activate AKT, conferring anoikis resistance, enhancing ECM adhesion via integrin αvβ3 cross-talk, and promoting invasion through MMP-9 — establishing CEACAM6 as a pro-metastatic signaling hub.","evidence":"Antibody cross-linking, siRNA knockdown, dominant-negative Src, orthotopic xenograft models, caspase profiling, zymography in BxPC3 and Capan2 pancreatic cancer cells","pmids":["15047698","15047158","14724575","15316565","15208677"],"confidence":"High","gaps":["how a GPI-anchored protein activates caveolin-1/Src mechanistically is not resolved at the structural level","relative contribution of each integrin (αvβ3 vs α5β1) not dissected in same system"]},{"year":2007,"claim":"Identifying CEACAM6 as the receptor for AIEC type-1 pili on ileal epithelium, and showing that co-clustering with integrin α5β1 enhances fibronectin matrix assembly, extended CEACAM6's roles to mucosal pathogen recognition and epithelial differentiation control.","evidence":"Primary ileal enterocyte adhesion assays with anti-CEACAM6 blocking; confocal co-clustering with integrin α5β1; fibronectin binding and anoikis assays","pmids":["17525800","17167768"],"confidence":"High","gaps":["structural basis of type-1 pilus-CEACAM6 interaction not resolved","whether integrin co-clustering is direct or lipid-raft mediated is unknown"]},{"year":2007,"claim":"Demonstrating that TGF-β/Smad3 transcriptionally activates the CEACAM6 promoter placed CEACAM6 expression under the control of a major growth-factor pathway relevant to both normal differentiation and cancer.","evidence":"Promoter reporter assays, rescue in TGF-β receptor-mutant and Smad3-deficient cell lines, Smad3 knockout mouse gastric tissue","pmids":["17653079"],"confidence":"High","gaps":["whether Smad3 binds the promoter directly or through a co-factor complex is unclear","relationship between Smad3 and HIF-1 regulation of the same promoter not integrated"]},{"year":2012,"claim":"Showing that influenza neuraminidase physically interacts with CEACAM6 to activate Src/FAK/AKT and promote host-cell survival expanded CEACAM6's pathogen-receptor role beyond bacteria to viruses and revealed pathogen exploitation of the same pro-survival signaling axis used in cancer.","evidence":"Co-immunoprecipitation of NA with CEACAM6, siRNA knockdown in lung cells, phospho-immunoblotting, viral titer measurement","pmids":["22396546"],"confidence":"High","gaps":["binding interface on CEACAM6 for neuraminidase not mapped","relevance to in vivo influenza pathogenesis not tested"]},{"year":2014,"claim":"Revealing that HIF-1-responsive element methylation in the CEACAM6 promoter gates its expression, and that dietary methyl depletion causes aberrant CEACAM6 expression enabling AIEC colonization, linked epigenetic regulation to intestinal pathogenesis.","evidence":"Bisulfite sequencing, CpG-free reporter assay, transgenic CEACAM6 mice on low-methyl diet with AIEC quantification","pmids":["24898815"],"confidence":"High","gaps":["which DNA methyltransferases maintain HRE methylation not identified","whether HIF-1 and Smad3 co-regulate the promoter in the same cells is unexplored"]},{"year":2017,"claim":"Demonstrating that N-glycosylation at Asn256 (mediated by MGAT5) is required for CEACAM6-EGFR interaction and downstream signaling in oral cancer, and that C. albicans binds the N-domain of CEACAM6 to modulate epithelial immune responses, revealed glycan-dependent and -independent receptor functions.","evidence":"N256 mutagenesis, MGAT5 manipulation, CEACAM6-EGFR co-clustering; recombinant CEACAM6 domain binding to C. albicans, CXCL8 ELISA","pmids":["28892050","28292985"],"confidence":"High","gaps":["structural model of glycan-dependent CEACAM6-EGFR complex lacking","full repertoire of fungal adhesins for CEACAM6 not identified"]},{"year":2021,"claim":"Establishing that CEACAM6 on tumor cells engages CEACAM1 on T cells to suppress anti-tumor immunity identified CEACAM6 as an immune checkpoint ligand, paralleling PD-L1 biology.","evidence":"T cell-cancer cell co-cultures with CEACAM6-blocking antibody BAY 1834942, cytokine secretion and killing assays","pmids":["35141051"],"confidence":"High","gaps":["whether CEACAM6-CEACAM1 checkpoint operates in vivo in patient tumors not validated","signaling events downstream of CEACAM1 engagement by CEACAM6 on T cells not dissected"]},{"year":2023,"claim":"Identifying lysine lactylation as a post-translational modification that stabilizes CEACAM6 protein downstream of ALDOB-mediated lactagenesis linked metabolic reprogramming (Warburg effect) to CEACAM6 protein abundance and chemoresistance.","evidence":"ALDOB and CEACAM6 gene silencing, lactylation inhibition, PDK1 activation studies, chemoresistance assays in CRC cells","pmids":["37816733"],"confidence":"Medium","gaps":["specific lactylated lysine residues on CEACAM6 not mapped","whether lactylation affects CEACAM6 signaling activity or only stability is unknown","single-lab finding awaits independent replication"]},{"year":null,"claim":"Key unresolved questions include the structural basis of CEACAM6 homophilic and heterophilic interactions at atomic resolution, how a GPI-anchored protein mechanistically activates Src-family kinases through caveolin-1, and whether CEACAM6-CEACAM1 immune checkpoint blockade provides therapeutic benefit in patients.","evidence":"","pmids":[],"confidence":"Low","gaps":["no crystal or cryo-EM structure of CEACAM6 N-domain in complex with any binding partner","mechanism linking GPI-anchor to caveolin-1-Src activation remains conceptual","clinical efficacy of anti-CEACAM6 checkpoint antibodies unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,6,12,25,30]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[7,8,15,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[29,35]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4,5,12,19]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[28,30]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,6,12,25,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,9,11,15,19,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,28,29]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,22,30]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[12,32]}],"complexes":[],"partners":["CEACAM8","CEACAM1","ITGAV","ITGA5","EGFR","CAV1","CD151"],"other_free_text":[]},"mechanistic_narrative":"CEACAM6 is a GPI-anchored immunoglobulin superfamily glycoprotein that functions as a versatile cell-surface adhesion molecule and signaling scaffold, mediating homo- and heterophilic adhesion through its N-terminal IgV-like domain, serving as a receptor for diverse pathogens, and modulating intracellular survival and invasion pathways in both immune and epithelial cells [PMID:2830274, PMID:2742579, PMID:2022629, PMID:11590190]. In cancer cells, CEACAM6 activates a caveolin-1/c-Src/FAK/AKT signaling axis that confers anoikis resistance, promotes epithelial-mesenchymal transition via PI3K/AKT, enhances invasion through MMP-9 upregulation, and co-clusters with integrins (α5β1, αvβ3) to augment extracellular matrix adhesion [PMID:15047698, PMID:14724575, PMID:15316565, PMID:17167768, PMID:25398131]. On mucosal epithelia, CEACAM6 serves as a receptor for adherent-invasive E. coli type 1 pili and Candida albicans, with its expression regulated by HIF-1 promoter elements whose methylation status controls inducibility, and by TGF-β/Smad3 signaling [PMID:17525800, PMID:28292985, PMID:24898815, PMID:17653079]. CEACAM6 on tumor cells also functions as an immune checkpoint by engaging CEACAM1 on T cells to suppress anti-tumor cytotoxicity [PMID:35141051]."},"prefetch_data":{"uniprot":{"accession":"P40199","full_name":"Cell adhesion molecule CEACAM6","aliases":["Carcinoembryonic antigen-related cell adhesion molecule 6","CEA cell adhesion molecule 6","Non-specific crossreacting antigen","Normal cross-reacting antigen"],"length_aa":344,"mass_kda":37.2,"function":"Cell surface glycoprotein that plays a role in cell adhesion and tumor progression (PubMed:10910050, PubMed:11590190, PubMed:1378450, PubMed:16204051, PubMed:2022629, PubMed:2803308, PubMed:8776764). Intercellular adhesion occurs in a calcium- and fibronectin-independent manner (PubMed:16204051, PubMed:2022629). Mediates homophilic and heterophilic cell adhesion with other carcinoembryonic antigen-related cell adhesion molecules, such as CEACAM5 and CEACAM8 (PubMed:11590190, PubMed:16204051, PubMed:2022629, PubMed:2803308, PubMed:8776764). Heterophilic interaction with CEACAM8 occurs in activated neutrophils (PubMed:8776764). Plays a role in neutrophil adhesion to cytokine-activated endothelial cells (PubMed:1378450). Plays a role in cell migration and cell adhesion to endothelial cells (PubMed:16204051)","subcellular_location":"Cell membrane; Apical cell membrane; Cell surface","url":"https://www.uniprot.org/uniprotkb/P40199/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEACAM6","classification":"Not Classified","n_dependent_lines":72,"n_total_lines":1208,"dependency_fraction":0.059602649006622516},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CEACAM6","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":"609142","title":"CEA CELL ADHESION MOLECULE 3; CEACAM3","url":"https://www.omim.org/entry/609142"},{"mim_id":"603855","title":"CYSTIC FIBROSIS, MODIFIER OF, 1; CFM1","url":"https://www.omim.org/entry/603855"},{"mim_id":"266600","title":"INFLAMMATORY BOWEL DISEASE (CROHN DISEASE) 1; IBD1","url":"https://www.omim.org/entry/266600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":171.4},{"tissue":"esophagus","ntpm":194.9},{"tissue":"intestine","ntpm":206.9},{"tissue":"lung","ntpm":270.1},{"tissue":"salivary gland","ntpm":177.8}],"url":"https://www.proteinatlas.org/search/CEACAM6"},"hgnc":{"alias_symbol":["CD66c","NCA-50/90"],"prev_symbol":["NCA"]},"alphafold":{"accession":"P40199","domains":[{"cath_id":"2.60.40.10","chopping":"38-142","consensus_level":"high","plddt":97.0773,"start":38,"end":142},{"cath_id":"2.60.40.10","chopping":"149-232","consensus_level":"high","plddt":95.8588,"start":149,"end":232},{"cath_id":"2.60.40.10","chopping":"242-319","consensus_level":"high","plddt":96.4199,"start":242,"end":319}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P40199","model_url":"https://alphafold.ebi.ac.uk/files/AF-P40199-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P40199-F1-predicted_aligned_error_v6.png","plddt_mean":88.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEACAM6","jax_strain_url":"https://www.jax.org/strain/search?query=CEACAM6"},"sequence":{"accession":"P40199","fasta_url":"https://rest.uniprot.org/uniprotkb/P40199.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P40199/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P40199"}},"corpus_meta":[{"pmid":"17525800","id":"PMC_17525800","title":"CEACAM6 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intestinal epithelial cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional blocking with antibodies, multiple cell systems, replicated in transgenic mouse model\",\n      \"pmids\": [\"17525800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"CEACAM6 (NCA) is encoded by a cDNA containing a 34-aa leader sequence, 310-aa mature protein with one immunoglobulin-like domain doublet (versus three in CEA), and a C-terminal hydrophobic domain; overall ~85% amino acid homology to CEA, supporting GPI-anchor membrane attachment.\",\n      \"method\": \"cDNA cloning and sequencing from SW403 colon carcinoma library; sequence comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct cDNA sequencing establishing domain architecture, foundational paper\",\n      \"pmids\": [\"2830274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CEACAM6 (NCA) is anchored to the cell membrane via a glycosyl-phosphatidylinositol (GPI) linkage, demonstrated by release of surface NCA from transfected NIH/3T3 cells upon treatment with phosphatidylinositol-specific phospholipase C.\",\n      \"method\": \"Transfection of NCA cDNA into NIH/3T3 cells, PI-PLC treatment, flow cytometry and immunoprecipitation of surface glycoproteins\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — enzymatic cleavage assay with two orthogonal readouts (flow cytometry and immunoprecipitation)\",\n      \"pmids\": [\"2742579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CEACAM6 (NCA) mediates specific Ca2+-independent heterotypic cell adhesion with W272 (CGM6/CEACAM8), and this adhesion is mediated by the N-terminal domain of NCA; W272-expressing cells showed no homotypic binding but bound cells expressing NCA via NCA's N-domain.\",\n      \"method\": \"CHO cell transfectants expressing NCA, CEA, W272 and chimeric N-domain constructs; cell aggregation assays; chimeric domain analysis in COS-1 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in transfected cells with chimeric domain mutagenesis establishing N-domain specificity\",\n      \"pmids\": [\"2022629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CEACAM6 (NCA species ~95-100 kDa) is localized predominantly in secondary granules of neutrophils, with lesser amounts in plasma membrane and primary granules, suggesting secondary granules as the intracellular reservoir from which CEACAM6 is recruited to the cell surface upon neutrophil activation.\",\n      \"method\": \"Nitrogen cavitation, differential centrifugation, SDS-PAGE and immunoblotting of neutrophil subcellular fractions\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular fractionation with functional implication, clean biochemical method\",\n      \"pmids\": [\"1640165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CEACAM6 (CD66c) antibody binding to neutrophils triggers a calcium-dependent signal that upregulates CD11/CD18 on the neutrophil surface and increases adhesion to HUVEC monolayers; CD66c signals independently from other CD66 family members.\",\n      \"method\": \"Neutrophil adhesion assays to HUVEC monolayers, CD18 blocking antibody, calcium chelation, sequential desensitization experiments\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with blocking controls and desensitization establishing independent signaling\",\n      \"pmids\": [\"8699114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The N-terminal domain (N-domain) of CEACAM6 mediates both homophilic (CEACAM6–CEACAM6) and heterophilic (CEACAM6–CEACAM8) cell adhesion; homologue-scanning mutagenesis revealed overlapping but non-identical critical residues for each interaction, similar to sites used by Neisseria Opa proteins.\",\n      \"method\": \"CHO transfectants expressing mutant and chimeric CEACAM6/CEACAM8 proteins; cell aggregation assays; homologue-scanning mutagenesis\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with functional readout in transfected cells\",\n      \"pmids\": [\"11590190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 cross-linking in pancreatic adenocarcinoma cells activates c-Src, induces caveolin-1-dependent tyrosine phosphorylation of FAK (p125FAK), and increases cellular resistance to anoikis; FAK phosphorylation requires c-Src kinase activity.\",\n      \"method\": \"Antibody-mediated cross-linking of CEACAM6 in BxPC3 cells, immunoblotting for phospho-FAK and phospho-Src, caveolin-1 dependence assessed, anoikis resistance quantified\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with multiple signaling readouts and dependence on caveolin-1\",\n      \"pmids\": [\"15047698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 cross-linking initiates c-Src-dependent cross-talk with αvβ3 integrin, leading to increased pancreatic adenocarcinoma cell adhesion to fibronectin and vitronectin ECM components; this effect is blocked by Src inhibitor PP2 or c-Src-specific siRNA.\",\n      \"method\": \"Antibody-mediated CEACAM6 cross-linking, ECM adhesion assays, Src kinase inhibitor PP2, c-Src siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic inhibition of Src with functional ECM adhesion readout\",\n      \"pmids\": [\"15047158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 gene silencing by siRNA increases susceptibility to caspase-mediated anoikis in pancreatic adenocarcinoma cells under anchorage-independent conditions, decreases Akt phosphorylation at Ser-473, and inhibits in vivo metastatic ability in orthotopic mouse xenograft models.\",\n      \"method\": \"siRNA knockdown, YO-PRO-1/PI flow cytometry for anoikis, caspase fluorometric profiling, Z-VAD-fmk rescue, Akt immunoblotting, orthotopic nude mouse xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (siRNA, caspase profiling, chemical rescue, in vivo xenograft) with clear pathway placement\",\n      \"pmids\": [\"14724575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 overexpression in pancreatic adenocarcinoma increases invasiveness in a c-Src-dependent manner; c-Src mediates CEACAM6-dependent matrix metalloproteinase-9 (MMP-9) activation that contributes to enhanced invasion.\",\n      \"method\": \"Stable retroviral overexpression and RNAi knockdown, modified Boyden chamber invasion assay, constitutively active/dominant-negative c-Src constructs, MMP-9 activity assay\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with dominant-negative constructs establishing c-Src as mediator\",\n      \"pmids\": [\"15316565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 overexpression enhances IGF-I-induced invasiveness through upregulation of IGF-IR expression and increased Akt and c-Src kinase activities, as well as elevated MMP-2 expression; Akt is both necessary and sufficient for IGF-IR upregulation, while c-Src is necessary but not sufficient.\",\n      \"method\": \"Stable CEACAM6 overexpression in Capan2 cells, invasion assays toward IGF-I, anti-IGF-IR blocking antibody, Akt and c-Src inhibitors, MMP-2 zymography\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and antibody-based dissection of pathway components with epistasis\",\n      \"pmids\": [\"15208677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CEACAM6 (and CEA) co-clusters with integrin α5β1 on the cell surface and enhances binding of integrin α5β1 to fibronectin without changing surface integrin levels, leading to increased fibronectin matrix assembly (polymerized fibronectin 'cocoon') and inhibition of cellular differentiation and anoikis; disruption of fibronectin binding or integrin α5β1 restores differentiation and anoikis.\",\n      \"method\": \"Confocal microscopy co-clustering analysis, fibronectin binding assays, antibody blocking of fibronectin and integrin α5β1, anoikis assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — confocal co-localization combined with functional blocking antibodies and phenotypic rescue\",\n      \"pmids\": [\"17167768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CEACAM5 and CEACAM6 promoters are activated by TGF-β signaling through Smad3; restoration of TGF-β signaling (via TGF-β type II receptor or Smad3) in non-responsive gastric cancer cell lines induced CEACAM5 and CEACAM6 expression, and CEA expression was markedly decreased in Smad3 null mice.\",\n      \"method\": \"Reporter assays for CEACAM5/CEACAM6 promoters, rescue of TGF-β signaling in receptor-mutant and Smad3-deficient cell lines, Smad3 knockout mouse gastric tissue analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — promoter reporter assay, cell rescue, and in vivo genetic knockout validation\",\n      \"pmids\": [\"17653079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CEACAM6 antagonizes the Src signaling pathway in pancreatic cancer cells, downregulates cytoskeleton proteins, and blocks adenovirus trafficking to the nucleus; siRNA knockdown of CEACAM6 enhances adenoviral replication and antitumor effect of oncolytic adenovirus in vivo.\",\n      \"method\": \"CEACAM6 overexpression and siRNA knockdown, Src signaling immunoblotting, cytoskeleton protein analysis, adenovirus nuclear trafficking assays, mouse xenograft model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss of function with multiple mechanistic readouts including viral trafficking and in vivo validation\",\n      \"pmids\": [\"19411761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Influenza A virus neuraminidase (NA) protein interacts with CEACAM6 (C6) and activates the Src/Akt signaling axis (increased phosphorylation of Src, FAK, Akt, GSK3β, Bcl-2), enhancing host cell survival; siRNA knockdown of CEACAM6 reduces Src/FAK/Akt activation, increases apoptosis, and reduces viral titers.\",\n      \"method\": \"Co-immunoprecipitation of NA with CEACAM6, siRNA knockdown in human lung adenocarcinoma and normal bronchial epithelial cells, phospho-immunoblotting, apoptosis assays, viral titer measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for binding, siRNA knockdown with multiple pathway readouts, viral titer as functional output\",\n      \"pmids\": [\"22396546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CEACAM6 promotes EMT and pancreatic cancer invasion and metastasis; miR-29a/b/c directly targets CEACAM6 and suppresses its expression at the post-transcriptional level, reducing EMT, migration, and invasion.\",\n      \"method\": \"CEACAM6 overexpression and shRNA knockdown, in vitro invasion/migration assays, in vivo metastasis models, miRNA transfection with EMT marker immunoblotting\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, miRNA-target relationship by functional rescue, no luciferase validation of direct binding cited in abstract\",\n      \"pmids\": [\"23857344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CEACAM6 promotes EMT and invasion in gastric cancer via PI3K/AKT signaling; CEACAM6 overexpression increases N-cadherin, vimentin, Slug and MMP-9 while decreasing E-cadherin; PI3K inhibitor LY294002 reverses CEACAM6-induced EMT; anti-MMP-9 antibody reverses CEACAM6-induced invasion.\",\n      \"method\": \"CEACAM6 overexpression/silencing in GC cells, EMT marker immunoblotting, MMP-9 antibody blocking, PI3K inhibitor treatment, peritoneal metastasis in vivo model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (inhibitors, antibody blocking, in vivo), single lab\",\n      \"pmids\": [\"25398131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling; CEACAM6 overexpression increases phosphorylation of FAK and paxillin, and FAK inhibitor Y15 reduces tubule and vasculogenic mimicry formation.\",\n      \"method\": \"CEACAM6 overexpression/silencing, HUVEC tubule formation assay, 3D-culture vasculogenic mimicry assay, FAK inhibitor Y15 treatment, paxillin and FAK phospho-immunoblotting, xenograft in vivo\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological FAK inhibition with functional rescue, in vivo validation, single lab\",\n      \"pmids\": [\"25703140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CEACAM6 promotes OSCC invasion, migration, cytoskeletal rearrangement, and metastasis by interacting with EGFR and enhancing EGFR activation, clustering, and intracellular signaling; N-glycosylation of CEACAM6 at Asn256, mediated by MGAT5, is critical for this EGFR interaction and signaling.\",\n      \"method\": \"Anti-CEACAM6 antibody (TMU HCAb) that specifically recognizes glycosylated CEACAM6, MGAT5 manipulation, CEACAM6 N256 mutagenesis, invasion/migration assays, EGFR co-clustering analysis, in vivo metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1+2 — site-specific mutagenesis (N256) combined with glycosylation enzyme manipulation and functional rescue with specific antibody\",\n      \"pmids\": [\"28892050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CEACAM6 suppression by siRNA reverses migration and invasion of oestrogen-deprived resistant breast cancer cells and significantly reduces phosphorylated Akt and c-Src expression, placing CEACAM6 upstream of Akt and c-Src in mediating invasion.\",\n      \"method\": \"siRNA knockdown, migration and invasion assays, phospho-Akt and phospho-c-Src immunoblotting\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean siRNA knockdown with multiple pathway readouts, single lab\",\n      \"pmids\": [\"18614350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CEACAM6 cross-linking in B-cell precursor ALL cells activates Erk1/2, Akt, and p38 MAPK phosphorylation and upregulates integrin expression and integrin ligand (VCAM-1, ICAM-1) binding, but paradoxically increases apoptosis, unlike other GPI-anchored molecules such as CD24.\",\n      \"method\": \"Anti-CEACAM6 antibody cross-linking, flow cytometry for integrin expression and ligand binding, phospho-immunoblotting for Erk1/2/Akt/p38, apoptosis assays\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling readouts from defined cross-linking experiment, single lab\",\n      \"pmids\": [\"20380867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CEACAM6 overexpression in HNSCC enhances tumor growth and tumor-initiating activity by activating AKT and suppressing caspase-3-mediated cell death; PI3K/AKT inhibitors selectively ablate CEACAM6-expressing HNSCC foci in xenograft models.\",\n      \"method\": \"shRNA knockdown and viral overexpression of CEACAM6, xenograft mouse model, AKT inhibitor treatment, caspase-3 immunoblotting\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss of function with in vivo pharmacological rescue, single lab\",\n      \"pmids\": [\"23021083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CEACAM6 (NCA-160, CD66c) is the predominant neutrophil surface carrier of CD15 (LewisX) and sialyl-LewisX carbohydrate antigens; NCA-90 and related NCAs do not express CD15.\",\n      \"method\": \"Immunoprecipitation and immunoblotting with anti-CD15 monoclonal antibody MC2; surface expression studies after fMLP stimulation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — immunoprecipitation identifying the protein carrier of a functionally important carbohydrate antigen\",\n      \"pmids\": [\"1694660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CEACAM6 (NCA-160, CD66c) is the major protein carrier of LewisX and sialyl LewisX groups on neutrophils that interact with vascular selectins E- and P-selectin; differently glycosylated forms of NCA are independently regulated on the cell surface.\",\n      \"method\": \"Immunoprecipitation and surface expression analysis after fMLP stimulation; flow cytometry for NCA species and sialyl/non-sialyl LewisX\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — immunoprecipitation identifying protein carrier and functional relevance to selectin interactions\",\n      \"pmids\": [\"7689841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CD66b and CD66c (CEACAM6) mediate heterophilic cell adhesion through N-domain interactions; deglycosylated recombinant proteins retain adhesion activity (carbohydrate not required); CD66b/CD66c adhesion induces superoxide anion release from activated neutrophils.\",\n      \"method\": \"Soluble recombinant proteins from silkworm larvae, CHO transfectant adhesion assays, deglycosylation experiment, superoxide anion release assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted adhesion with recombinant proteins and deglycosylation control establishing domain requirements\",\n      \"pmids\": [\"8645267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A novel CEACAM6 isoform (CEACAM6-L) generated by intron retention encodes a protein with a transmembrane domain and intracellular region (unlike GPI-anchored CEACAM6), is exclusively expressed in rat testis starting at 5 weeks postnatal, and localizes to the interface between Sertoli cells and spermatids at apical ectoplasmic specializations, suggesting a role in spermatid anchoring.\",\n      \"method\": \"Differential display, RT-PCR, Northern blot, immunoblotting, confocal laser scanning microscopy/immunohistochemistry in rat testis\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by confocal microscopy tied to specific junction structure, novel isoform characterization\",\n      \"pmids\": [\"18685128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HIF-1-responsive element (HRE) methylation in the CEACAM6 promoter inversely correlates with CEACAM6 expression; low-methyl diet causes HRE demethylation in transgenic CEACAM6-expressing mice, leading to abnormal gut CEACAM6 expression and enhanced AIEC colonization and inflammation.\",\n      \"method\": \"Bisulfite sequencing, site-specific methylation SnapShot, pCpGfree promoter reporter assay, Smad3 knockout mice, transgenic CEACAM6 mice on low-methyl diet, AIEC quantification\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1+2 — promoter reporter, methylation-specific sequencing, and in vivo transgenic mouse model with dietary intervention\",\n      \"pmids\": [\"24898815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"C. albicans binds directly to the extracellular N-terminal IgV-like domain of CEACAM6 (and CEACAM1, -3, -5); fungal binding to CEACAM1 and CEACAM6 in intestinal epithelial cells induces CEACAM1 tyrosine phosphorylation and alters epithelial immune responses (CXCL8 secretion); soluble CEACAM6 reduces C. albicans-induced CXCL8 secretion in CEACAM1-competent cells.\",\n      \"method\": \"Direct binding assay with C. albicans and recombinant CEACAM extracellular domains, shRNA knockdown of CEACAM1, CXCL8 ELISA, CEACAM1 phospho-tyrosine immunoblotting\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding established with recombinant proteins, functional consequence measured by cytokine secretion with genetic knockdown\",\n      \"pmids\": [\"28292985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEACAM6 on tumor cells suppresses anti-tumor T cell activity by interacting with CEACAM1 expressed on activated tumor-specific T cells; blocking CEACAM6-CEACAM1 interaction with the humanized antibody BAY 1834942 increases cytokine secretion by T cells and T cell-mediated cancer cell killing.\",\n      \"method\": \"T cell-cancer cell co-culture experiments, CEACAM6-blocking antibody (BAY 1834942), cytokine secretion assays, comparison with anti-PD-1/PD-L1/TIM-3 antibodies\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional blocking of specific CEACAM6-CEACAM1 interaction with defined immune readouts\",\n      \"pmids\": [\"35141051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEACAM6 homophilic interactions in the cancer cell membrane activate the Src-FAK signaling pathway and inhibit anoikis in lung adenocarcinoma; treatment with exogenous CEACAM6 protein induced homophilic interactions and Src-FAK activation.\",\n      \"method\": \"CellphoneDB single-cell RNA-seq analysis, CEACAM6 protein treatment, immunoblotting for Src-FAK pathway, anoikis assays, ELISA and immunoblotting of cell culture conditioned media\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein treatment establishing homophilic signaling mechanism with defined pathway readout\",\n      \"pmids\": [\"35358791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CEACAM6 promotes cell proliferation in pancreatic carcinoma through regulation of cyclin D1 and CDK4 protein levels; CEACAM6 knockdown decreases cyclin D1 and CDK4, while overexpression increases them.\",\n      \"method\": \"siRNA knockdown and forced overexpression in pancreatic cell lines, immunoblotting for cyclin D1/CDK4, proliferation assays in vitro and xenograft in vivo\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation with defined downstream effector proteins, single lab\",\n      \"pmids\": [\"26497080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRISPR/Cas9 knockout of CEACAM6 in PDA cells alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport, and autophagy pathways; CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity, indicating a role in bioenergetic regulation.\",\n      \"method\": \"CRISPR/Cas9 KO, quantitative proteomics, mitochondrial bioenergetics (Seahorse assay), xenograft tumor growth\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with quantitative proteomics and direct bioenergetics measurement\",\n      \"pmids\": [\"31797958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEACAM6 protein stability is enhanced through lysine lactylation downstream of ALDOB-mediated lactagenesis; the ALDOB/PDK1/lactate/CEACAM6 axis controls CRC cell proliferation and chemoresistance via the Warburg effect.\",\n      \"method\": \"Cell-based assays, lactylation inhibition, PDK1 activation studies, gene silencing of ALDOB and CEACAM6, chemoresistance assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway epistasis established by sequential gene silencing with defined PTM (lactylation) readout, single lab\",\n      \"pmids\": [\"37816733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD151 associates physically with CEACAM6 (confirmed by pulldown and immunofluorescence co-localization), and CD151 silencing downregulates CEACAM6 and TGFβ1 both in vitro and in vivo, placing CEACAM6 downstream of a CD151/TGFβ1 axis in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, pulldown assay, immunofluorescence, RNA-seq after CD151 knockdown, xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP/MS and pulldown establish physical interaction, RNA-seq and in vivo show downstream pathway regulation, single lab\",\n      \"pmids\": [\"33767593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEACAM6 acts as a negative regulator of HO-1-mediated antioxidant defense in human alveolar type 2 epithelial cells (hAEC2s); epithelium-specific CEACAM6 overexpression (via AAV) increases nitrosative/oxidative stress and cell death upon cigarette smoke extract treatment in human precision-cut lung slices.\",\n      \"method\": \"CSE-resistant cell line model, transcriptomics, AAV-mediated CEACAM6 overexpression in human precision-cut lung slices, HO-1 inhibition, 3-nitrotyrosine measurement\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — AAV-mediated overexpression in ex vivo human tissue with mechanistic HO-1 pathway validation\",\n      \"pmids\": [\"37219322\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEACAM6 is a GPI-anchored, N-glycosylated cell surface immunoglobulin superfamily member that mediates homo- and heterophilic cell adhesion through its N-terminal domain; in cancer cells it drives anoikis resistance, invasion, and metastasis primarily by activating caveolin-1-dependent Src/FAK/AKT signaling, co-clustering with integrins (α5β1, αvβ3) to enhance ECM adhesion, and upregulating MMP-9 activity, while also promoting EMT via PI3K/AKT and inducing EGFR signaling in a manner dependent on N-glycosylation at Asn256; on the cell surface it functions as a pathogen receptor (AIEC type-1 pili, influenza NA, Candida), its expression is transcriptionally regulated by Smad3-mediated TGF-β signaling and by HIF-1 binding to promoter HREs whose methylation status determines expression level, and it can suppress anti-tumor T cell immunity through trans-interaction with CEACAM1 on T cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CEACAM6 is a GPI-anchored immunoglobulin superfamily glycoprotein that functions as a versatile cell-surface adhesion molecule and signaling scaffold, mediating homo- and heterophilic adhesion through its N-terminal IgV-like domain, serving as a receptor for diverse pathogens, and modulating intracellular survival and invasion pathways in both immune and epithelial cells [PMID:2830274, PMID:2742579, PMID:2022629, PMID:11590190]. In cancer cells, CEACAM6 activates a caveolin-1/c-Src/FAK/AKT signaling axis that confers anoikis resistance, promotes epithelial-mesenchymal transition via PI3K/AKT, enhances invasion through MMP-9 upregulation, and co-clusters with integrins (α5β1, αvβ3) to augment extracellular matrix adhesion [PMID:15047698, PMID:14724575, PMID:15316565, PMID:17167768, PMID:25398131]. On mucosal epithelia, CEACAM6 serves as a receptor for adherent-invasive E. coli type 1 pili and Candida albicans, with its expression regulated by HIF-1 promoter elements whose methylation status controls inducibility, and by TGF-β/Smad3 signaling [PMID:17525800, PMID:28292985, PMID:24898815, PMID:17653079]. CEACAM6 on tumor cells also functions as an immune checkpoint by engaging CEACAM1 on T cells to suppress anti-tumor cytotoxicity [PMID:35141051].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Establishing the molecular identity of CEACAM6 as a CEA family member with a truncated domain structure resolved the relationship between NCA and CEA and predicted GPI-anchoring based on C-terminal hydrophobicity.\",\n      \"evidence\": \"cDNA cloning and sequencing from SW403 colon carcinoma library\",\n      \"pmids\": [\"2830274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GPI-anchor was predicted from sequence but not yet biochemically demonstrated\", \"no functional role assigned\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Demonstrating that CEACAM6 is tethered to the cell membrane via a GPI linkage established that it lacks an intracellular signaling domain, implying that downstream signaling must occur through lateral membrane interactions.\",\n      \"evidence\": \"PI-PLC release of NCA from transfected NIH/3T3 cells detected by flow cytometry and immunoprecipitation\",\n      \"pmids\": [\"2742579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"identity of signaling co-receptors unknown\", \"no adhesion function yet tested\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Mapping the adhesion specificity of CEACAM6 to its N-terminal domain established that this single domain mediates both homophilic and heterophilic (with CEACAM8) cell adhesion, defining CEACAM6 as an adhesion molecule.\",\n      \"evidence\": \"CHO transfectants with chimeric N-domain constructs in cell aggregation assays\",\n      \"pmids\": [\"2022629\", \"11590190\", \"8645267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of N-domain binding interface unresolved\", \"in vivo adhesion relevance not demonstrated\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Localizing CEACAM6 to neutrophil secondary granules and identifying it as the major carrier of sialyl-LewisX selectin ligands revealed a role in neutrophil activation and leukocyte-endothelial interactions.\",\n      \"evidence\": \"Subcellular fractionation of neutrophils; immunoprecipitation with anti-CD15 antibody; neutrophil-HUVEC adhesion assays with calcium chelation\",\n      \"pmids\": [\"1640165\", \"1694660\", \"7689841\", \"8699114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"precise mechanism of CEACAM6 signaling from GPI anchor on neutrophils unclear\", \"selectin binding is indirect (via carbohydrate); direct protein-protein selectin interaction not shown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"A burst of studies in pancreatic cancer revealed that CEACAM6 signals through caveolin-1-dependent c-Src to phosphorylate FAK and activate AKT, conferring anoikis resistance, enhancing ECM adhesion via integrin αvβ3 cross-talk, and promoting invasion through MMP-9 — establishing CEACAM6 as a pro-metastatic signaling hub.\",\n      \"evidence\": \"Antibody cross-linking, siRNA knockdown, dominant-negative Src, orthotopic xenograft models, caspase profiling, zymography in BxPC3 and Capan2 pancreatic cancer cells\",\n      \"pmids\": [\"15047698\", \"15047158\", \"14724575\", \"15316565\", \"15208677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how a GPI-anchored protein activates caveolin-1/Src mechanistically is not resolved at the structural level\", \"relative contribution of each integrin (αvβ3 vs α5β1) not dissected in same system\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying CEACAM6 as the receptor for AIEC type-1 pili on ileal epithelium, and showing that co-clustering with integrin α5β1 enhances fibronectin matrix assembly, extended CEACAM6's roles to mucosal pathogen recognition and epithelial differentiation control.\",\n      \"evidence\": \"Primary ileal enterocyte adhesion assays with anti-CEACAM6 blocking; confocal co-clustering with integrin α5β1; fibronectin binding and anoikis assays\",\n      \"pmids\": [\"17525800\", \"17167768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of type-1 pilus-CEACAM6 interaction not resolved\", \"whether integrin co-clustering is direct or lipid-raft mediated is unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that TGF-β/Smad3 transcriptionally activates the CEACAM6 promoter placed CEACAM6 expression under the control of a major growth-factor pathway relevant to both normal differentiation and cancer.\",\n      \"evidence\": \"Promoter reporter assays, rescue in TGF-β receptor-mutant and Smad3-deficient cell lines, Smad3 knockout mouse gastric tissue\",\n      \"pmids\": [\"17653079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether Smad3 binds the promoter directly or through a co-factor complex is unclear\", \"relationship between Smad3 and HIF-1 regulation of the same promoter not integrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that influenza neuraminidase physically interacts with CEACAM6 to activate Src/FAK/AKT and promote host-cell survival expanded CEACAM6's pathogen-receptor role beyond bacteria to viruses and revealed pathogen exploitation of the same pro-survival signaling axis used in cancer.\",\n      \"evidence\": \"Co-immunoprecipitation of NA with CEACAM6, siRNA knockdown in lung cells, phospho-immunoblotting, viral titer measurement\",\n      \"pmids\": [\"22396546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"binding interface on CEACAM6 for neuraminidase not mapped\", \"relevance to in vivo influenza pathogenesis not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealing that HIF-1-responsive element methylation in the CEACAM6 promoter gates its expression, and that dietary methyl depletion causes aberrant CEACAM6 expression enabling AIEC colonization, linked epigenetic regulation to intestinal pathogenesis.\",\n      \"evidence\": \"Bisulfite sequencing, CpG-free reporter assay, transgenic CEACAM6 mice on low-methyl diet with AIEC quantification\",\n      \"pmids\": [\"24898815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"which DNA methyltransferases maintain HRE methylation not identified\", \"whether HIF-1 and Smad3 co-regulate the promoter in the same cells is unexplored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that N-glycosylation at Asn256 (mediated by MGAT5) is required for CEACAM6-EGFR interaction and downstream signaling in oral cancer, and that C. albicans binds the N-domain of CEACAM6 to modulate epithelial immune responses, revealed glycan-dependent and -independent receptor functions.\",\n      \"evidence\": \"N256 mutagenesis, MGAT5 manipulation, CEACAM6-EGFR co-clustering; recombinant CEACAM6 domain binding to C. albicans, CXCL8 ELISA\",\n      \"pmids\": [\"28892050\", \"28292985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural model of glycan-dependent CEACAM6-EGFR complex lacking\", \"full repertoire of fungal adhesins for CEACAM6 not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing that CEACAM6 on tumor cells engages CEACAM1 on T cells to suppress anti-tumor immunity identified CEACAM6 as an immune checkpoint ligand, paralleling PD-L1 biology.\",\n      \"evidence\": \"T cell-cancer cell co-cultures with CEACAM6-blocking antibody BAY 1834942, cytokine secretion and killing assays\",\n      \"pmids\": [\"35141051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether CEACAM6-CEACAM1 checkpoint operates in vivo in patient tumors not validated\", \"signaling events downstream of CEACAM1 engagement by CEACAM6 on T cells not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying lysine lactylation as a post-translational modification that stabilizes CEACAM6 protein downstream of ALDOB-mediated lactagenesis linked metabolic reprogramming (Warburg effect) to CEACAM6 protein abundance and chemoresistance.\",\n      \"evidence\": \"ALDOB and CEACAM6 gene silencing, lactylation inhibition, PDK1 activation studies, chemoresistance assays in CRC cells\",\n      \"pmids\": [\"37816733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"specific lactylated lysine residues on CEACAM6 not mapped\", \"whether lactylation affects CEACAM6 signaling activity or only stability is unknown\", \"single-lab finding awaits independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of CEACAM6 homophilic and heterophilic interactions at atomic resolution, how a GPI-anchored protein mechanistically activates Src-family kinases through caveolin-1, and whether CEACAM6-CEACAM1 immune checkpoint blockade provides therapeutic benefit in patients.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no crystal or cryo-EM structure of CEACAM6 N-domain in complex with any binding partner\", \"mechanism linking GPI-anchor to caveolin-1-Src activation remains conceptual\", \"clinical efficacy of anti-CEACAM6 checkpoint antibodies unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 6, 12, 25, 30]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [7, 8, 15, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [29, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4, 5, 12, 19]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [28, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 6, 12, 25, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 9, 11, 15, 19, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 28, 29]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 22, 30]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [12, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CEACAM8\",\n      \"CEACAM1\",\n      \"ITGAV\",\n      \"ITGA5\",\n      \"EGFR\",\n      \"CAV1\",\n      \"CD151\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}