{"gene":"CEACAM6","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1989,"finding":"CEACAM6 (NCA) expressed on CHO cell surfaces mediates both homophilic (NCA-NCA) and heterophilic (CEA-NCA) Ca2+-independent cell adhesion, as demonstrated by aggregation and 51Cr-labeled cell adhesion assays with Fab' antibody inhibition.","method":"CHO cell transfection with cDNA, cell aggregation assay, 51Cr-labeled adhesion assay, Fab' antibody inhibition","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution in transfected cells with antibody inhibition, replicated in multiple subsequent papers","pmids":["2803308"],"is_preprint":false},{"year":1989,"finding":"CEACAM6 (NCA) is anchored to the cell membrane via a glycosyl-phosphatidylinositol (GPI) linkage, demonstrated by phosphatidylinositol-specific phospholipase C cleavage releasing the protein from NIH/3T3 transfectant surfaces.","method":"cDNA transfection of NIH/3T3 cells, PI-PLC treatment, flow cytometry, immunoprecipitation of surface-labeled glycoproteins","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical demonstration by PI-PLC cleavage with two orthogonal methods, independently corroborated by subsequent studies","pmids":["2742579"],"is_preprint":false},{"year":1988,"finding":"CEACAM6 (NCA) protein contains four cysteine residues that form disulfide bonds, has 7 potential N-glycosylation sites with differential occupancy, and is GPI-anchored via an amide linkage to ethanolamine at amino acid position 287 (replacing the last 24 hydrophobic residues of the primary sequence).","method":"Amino acid sequencing of purified NCA-50 protein, biochemical characterization","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct protein sequencing covering 59% of the protein, establishing covalent modification sites","pmids":["3390172"],"is_preprint":false},{"year":1988,"finding":"CEACAM6 (NCA) encodes a mature protein of 310 amino acids with one immunoglobulin-like doublet domain (versus three in CEA), an N-terminal domain, and a C-terminal hydrophobic domain sufficient for membrane anchoring; it shares ~85% amino acid homology with CEA.","method":"cDNA cloning and sequencing from colon carcinoma cell line SW403 lambda gt10 library","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — full-length cDNA sequencing establishing domain architecture, foundational structural characterization","pmids":["2830274"],"is_preprint":false},{"year":1991,"finding":"The heterophilic cell adhesion between CEACAM6 (NCA) and W272 (CGM6/CD67) is mediated specifically by the N-terminal domain of CEACAM6, not by other domains; chimeric N-domain substitution experiments localized the binding specificity to the N-terminal region of the CEACAM6 N-domain.","method":"CHO cell transfection with cDNA constructs encoding full-length, chimeric, and N-domain-substituted proteins; cell adhesion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain mapping by chimeric mutagenesis in cell adhesion reconstitution system","pmids":["2022629"],"is_preprint":false},{"year":1992,"finding":"In human neutrophils, CEACAM6 (NCA species of ~95–100 kDa) is predominantly located in secondary granules with lesser amounts in plasma membranes, indicating that secondary granules serve as an intracellular reservoir from which CEACAM6 can be recruited to the cell surface upon activation.","method":"Nitrogen cavitation, differential centrifugation subcellular fractionation, SDS-PAGE, immunoblotting","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct fractionation experiment with immunoblot identification of protein in specific granule compartments","pmids":["1640165"],"is_preprint":false},{"year":1993,"finding":"CEACAM6 (NCA-160, CD66) is the major protein carrier of the selectin-binding carbohydrate groups LewisX and sialyl LewisX on the neutrophil surface, and differently glycosylated forms of CEACAM6 are independently regulated in surface expression following fMLP stimulation.","method":"Immunoprecipitation, immunoblotting with carbohydrate-specific antibodies, fMLP stimulation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoprecipitation and functional stimulation data from single lab, two methods","pmids":["7689841"],"is_preprint":false},{"year":1996,"finding":"Antibody-mediated engagement of CD66c (CEACAM6) on neutrophils independently triggers a transient activation signal requiring extracellular calcium, leading to upregulation of CD11/CD18 and increased neutrophil adhesion to endothelial cells; CD66c can transmit signals independently of CD66a, CD66b, and CD66d.","method":"Anti-CD66c antibody stimulation of isolated neutrophils, adhesion assay to HUVEC monolayers, calcium chelation experiments, CD18 blocking antibody, sequential desensitization experiments","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional signaling demonstrated with calcium dependency and desensitization controls, single lab","pmids":["8699114"],"is_preprint":false},{"year":1996,"finding":"Heterophilic adhesion between CD66c (CEACAM6) and CD66b (CGM6) is mediated by interaction between the N-domains of each protein; deglycosylated forms retained adhesion activity, indicating the carbohydrate portions are not required for binding. Activated neutrophils adhering to immobilized CD66b/CD66c released superoxide anions.","method":"Recombinant soluble proteins prepared in silkworm larvae, immobilized protein adhesion assay with CHO transfectants, deglycosylation, N-domain-specific antibody inhibition, superoxide anion release assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with recombinant proteins, domain mapping by antibody inhibition, functional readout (superoxide release)","pmids":["8645267"],"is_preprint":false},{"year":2001,"finding":"The N-domain of CEACAM6 on one cell binds the N-domain of CEACAM6 or CEACAM8 on the opposing cell; homologue-scanning mutagenesis showed that the critical residues for CEACAM6 homophilic and CEACAM6-CEACAM8 heterophilic adhesion overlap and are highly similar but not identical to those required for binding bacterial Opa proteins.","method":"CHO transfectants with mutant and chimeric proteins, homologue-scanning mutagenesis, cell adhesion assay","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis mapping of adhesion determinants in functional reconstitution system","pmids":["11590190"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 cross-linking in pancreatic adenocarcinoma cells activates c-Src and induces tyrosine phosphorylation of FAK (p125FAK); FAK phosphorylation requires c-Src kinase activity, and c-Src activation requires caveolin-1. Cross-linking also increases anchorage-independent survival (anoikis resistance).","method":"Antibody-mediated CEACAM6 cross-linking in BxPC3 cells, immunoblotting for pFAK and pSrc, dominant-negative caveolin-1 constructs, anoikis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic signaling cascade defined with pathway inhibition and dominant-negative constructs, multiple orthogonal readouts","pmids":["15047698"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 cross-linking initiates c-Src-dependent cross-talk between CEACAM6 and αvβ3 integrin, leading to increased pancreatic adenocarcinoma cell adhesion to fibronectin and vitronectin; this was dependent on c-Src activity demonstrated by pharmacological inhibitor PP2 and Src-specific siRNA.","method":"Antibody-mediated CEACAM6 cross-linking, cell adhesion assay to ECM proteins, PP2 Src inhibitor, c-Src specific siRNA, integrin-blocking antibodies","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological and siRNA confirmation of Src requirement, multiple ECM components tested","pmids":["15047158"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 silencing by siRNA in pancreatic adenocarcinoma cells increases susceptibility to caspase-mediated anoikis under anchorage-independent conditions and decreases Akt phosphorylation (Ser-473); CEACAM6 knockdown also reverses acquired anoikis resistance and inhibits in vivo metastatic ability in nude mouse orthotopic xenografts.","method":"CEACAM6-specific siRNA, poly-HEMA anoikis induction, YO-PRO-1/PI flow cytometry, fluorometric caspase profiling, Z-VAD-fmk caspase inhibitor, Akt phosphorylation immunoblotting, orthotopic nude mouse xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, caspase inhibition, phospho-Akt, in vivo model) in single study defining pathway","pmids":["14724575"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 overexpression increases pancreatic adenocarcinoma cellular invasiveness in a c-Src-dependent manner; c-Src-dependent modulation of MMP-9 activity contributes significantly to the increased invasiveness; dominant-negative c-Src blocks invasion while constitutively active c-Src mimics the effect.","method":"Stable retroviral CEACAM6 overexpression/RNAi knockdown, modified Boyden chamber invasion assay, constitutively active/dominant-negative c-Src constructs, MMP-9 activity measurement","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway placement using dominant-negative and constitutively active kinase constructs with functional invasion readout","pmids":["15316565"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 overexpression increases IGF-I-induced pancreatic adenocarcinoma invasiveness by upregulating IGF-IR expression and activating both Akt and c-Src kinases; Akt is both necessary and sufficient for IGF-IR upregulation, while c-Src is necessary but insufficient alone; MMP-2 expression and activity are increased in a CEACAM6/IGF-I-dependent manner.","method":"Stable CEACAM6 transfection, inhibitory anti-IGF-IR antibody, Akt kinase assay, c-Src kinase assay, MMP-2 zymography, Boyden chamber invasion assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established using receptor-blocking antibody and kinase activity assays with defined sufficiency/necessity relationships","pmids":["15208677"],"is_preprint":false},{"year":2004,"finding":"CEACAM6 cross-linking induces its cytoplasmic accumulation in pancreatic adenocarcinoma cells; this internalization can be exploited for antibody-mediated delivery of saporin (ribosomal inhibitory protein), inducing caspase-mediated apoptosis in vitro and suppressing tumor growth in vivo.","method":"Anti-CEACAM6 antibody cross-linking, immunofluorescence for cytoplasmic accumulation, saporin-conjugated secondary antibody cytotoxicity assay, caspase activation assay, nude mouse xenograft","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct demonstration of internalization with functional consequence, single lab","pmids":["15081416"],"is_preprint":false},{"year":2005,"finding":"Anti-CEACAM6 antibody Fabs targeting the N-domain (MN-3) and A1B1 domain (MN-15) inhibit tumor cell migration, invasion through ECM, and adhesion to endothelial cells; MN-15 Fab specifically reduces adhesion of some cell lines to fibronectin but not vitronectin, laminin, or collagens; both MN-3 and MN-15 Fabs have antimetastatic effects in vivo improving survival in a colonic micrometastasis model.","method":"Migration assay, Matrigel invasion assay, adhesion assay to endothelial cells and ECM proteins, GW-39 colonic micrometastasis nude mouse model, Kaplan-Meier survival analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro functional assays plus in vivo validation, single lab","pmids":["16204051"],"is_preprint":false},{"year":2007,"finding":"CEACAM6 acts as a receptor for type-1-pili-expressing adherent-invasive E. coli (AIEC) on the apical surface of ileal epithelial cells; AIEC adhesion is dependent on both bacterial type 1 pili expression and CEACAM6 expression on enterocytes; CEACAM6 expression is induced by IFN-γ, TNF-α, and AIEC infection itself, creating a positive-feedback colonization loop.","method":"Primary ileal enterocyte adhesion assay, type-1-pili mutant bacteria, anti-CEACAM6 antibody blocking, cytokine stimulation of cultured intestinal epithelial cells, immunohistochemistry","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor function established by pili mutant and antibody blocking, cytokine regulation confirmed with multiple stimuli","pmids":["17525800"],"is_preprint":false},{"year":2007,"finding":"GPI-anchored CEACAM6 co-clusters with integrin α5β1 on the cell surface and enhances α5β1 binding to fibronectin without changing α5β1 surface levels, leading to increased fibronectin adhesion, enhanced fibronectin matrix assembly, and formation of a polymerized fibronectin 'cocoon'; disruption with anti-fibronectin or anti-α5β1 antibodies restores differentiation and anoikis sensitivity.","method":"Confocal microscopy co-clustering, fibronectin-binding assay, fibronectin matrix assembly assay, antibody blocking of fibronectin and α5β1, differentiation and anoikis assays in CEA/CEACAM6-expressing cells","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-clustering demonstrated by confocal microscopy, functional mechanism confirmed by antibody blocking with multiple cellular readouts","pmids":["17167768"],"is_preprint":false},{"year":2007,"finding":"CEACAM6 (and CEACAM5) expression is transcriptionally regulated by the TGF-β signaling pathway via the Smad3 mediator; restoration of TGF-β signaling in Smad3-deficient cells induced CEACAM6 expression and increased CEACAM6 promoter activity; CEACAM6 expression was markedly decreased in Smad3 null mice stomachs.","method":"TGF-β treatment of gastric cancer cell lines, Smad3 restoration by transfection, CEACAM6 promoter-luciferase reporter assay, RT-PCR, immunohistochemistry in Smad3 null mice","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter reporter assay, in vitro restoration experiments, and in vivo genetic knockout validation","pmids":["17653079"],"is_preprint":false},{"year":2009,"finding":"CEACAM6 antagonizes the Src signaling pathway, downregulates cancer cell cytoskeleton proteins, and blocks adenovirus trafficking to the nucleus of pancreatic cancer cells; Src-selective inhibitor treatment phenocopied CEACAM6 overexpression in reducing adenovirus replication; siRNA knockdown of CEACAM6 enhanced oncolytic adenovirus antitumor effects in xenografts.","method":"CEACAM6 overexpression/siRNA knockdown, adenovirus infection assay, immunofluorescence for viral trafficking, Src inhibitor treatment, cytoskeletal protein immunoblotting, nude mouse xenograft","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (Src inhibition phenocopy) with multiple readouts, single lab","pmids":["19411761"],"is_preprint":false},{"year":2012,"finding":"Influenza A virus neuraminidase (NA) protein physically interacts with CEACAM6 (C6); this NA/CEACAM6 interaction activates the Src/Akt signaling axis, increasing tyrosyl phosphorylation of Src, FAK, Akt, GSK3β, and Bcl-2, enhancing cell survival; siRNA knockdown of CEACAM6 reduced pSrc, pFAK, pAkt, increased apoptosis, and reduced viral protein expression and viral titers.","method":"Co-immunoprecipitation (NA-CEACAM6 interaction), CEACAM6 siRNA knockdown, immunoblotting for phosphoproteins, apoptosis assay, viral titer measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes interaction, siRNA confirms functional dependence on CEACAM6, single lab","pmids":["22396546"],"is_preprint":false},{"year":2013,"finding":"CEACAM6 promotes EMT in pancreatic cancer cells (increased N-cadherin, vimentin, Slug; decreased E-cadherin); miR-29a/b/c negatively regulates CEACAM6 expression at the post-transcriptional level and suppresses CEACAM6-induced EMT.","method":"CEACAM6 overexpression/shRNA knockdown, EMT marker immunoblotting, migration/invasion assays, in vivo metastasis model, miR-29a/b/c transfection","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMT markers and miRNA regulation shown in multiple cell systems, single lab","pmids":["23857344"],"is_preprint":false},{"year":2014,"finding":"CEACAM6 promotes EMT in gastric cancer via activation of PI3K/AKT signaling; overexpressed CEACAM6 increased phosphorylated AKT levels and elevated MMP-9 activity; PI3K inhibitor LY294002 reversed CEACAM6-induced EMT; anti-MMP-9 antibody reversed CEACAM6-induced invasion and migration.","method":"CEACAM6 overexpression/siRNA knockdown, phospho-AKT immunoblotting, MMP-9 activity assay, LY294002 PI3K inhibitor treatment, EMT marker immunoblotting, peritoneal metastasis in vivo model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway inhibitor experiments define AKT and MMP-9 as effectors, single lab","pmids":["25398131"],"is_preprint":false},{"year":2014,"finding":"CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling; overexpressed CEACAM6 increased phosphorylation of FAK and paxillin; FAK inhibitor Y15 reduced tubule and vasculogenic mimicry formation in vitro; CEACAM6 overexpression increased VEGF expression and vasculogenic mimicry structures in vivo.","method":"CEACAM6 overexpression/siRNA knockdown, tubule formation assay with HUVECs, 3D-culture vasculogenic mimicry assay, FAK/paxillin phosphorylation immunoblotting, FAK inhibitor Y15, VEGF measurement, in vivo xenograft","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FAK inhibitor phenocopy confirms pathway, multiple assays, single lab","pmids":["25703140"],"is_preprint":false},{"year":2014,"finding":"CEACAM6 promoter activity is regulated by HIF-1 binding to hypoxia-responsive elements (HREs); methylation of CpG sites within these HREs inversely correlates with CEACAM6 expression; dietary low-methyl conditions in transgenic human CEACAM6 mice led to HRE demethylation, increased CEACAM6 expression, and enhanced AIEC colonization.","method":"Bisulfite sequencing, SnapShot site-specific methylation analysis, pCpGfree reporter system, transgenic mice expressing human CEACAM6 fed low-methyl diet, bacterial colonization quantification, cytokine measurement","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter reporter combined with in vivo transgenic mouse model and methylation mapping, multiple orthogonal methods","pmids":["24898815"],"is_preprint":false},{"year":2017,"finding":"CEACAM6 promotes OSCC invasion, migration, and metastasis through physical interaction with EGFR and enhancement of EGFR activation, clustering, and intracellular signaling cascades; this function requires N-glycosylation at Asn256 (N256) mediated by MGAT5 (α-1,6-mannosylglycoprotein 6-β-N-acetylglucosaminyltransferase); a CEACAM6-specific antibody blocked EGFR signaling and invasion.","method":"Co-immunoprecipitation of CEACAM6-EGFR interaction, MGAT5 knockdown, N256 site-directed mutagenesis, invasion/migration assays, cytoskeletal rearrangement assay, in vivo metastasis model, anti-CEACAM6 sdAb/HCAb treatment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of CEACAM6-EGFR interaction, mutagenesis of N-glycosylation site, MGAT5 knockdown, multiple functional readouts","pmids":["28892050"],"is_preprint":false},{"year":2017,"finding":"CEACAM6 on cancer cells acts as an immune checkpoint by binding to CEACAM1 expressed on activated tumor-specific T cells, suppressing T cell-mediated antitumor activity; blocking the CEACAM6-CEACAM1 interaction with humanized antibody BAY 1834942 restored T cell cytokine secretion and cancer cell killing.","method":"Co-culture experiments with T cells and cancer cells, CEACAM6-blocking antibody treatment, cytokine secretion measurement, T cell killing assay, comparison to anti-PD-1/PD-L1/TIM-3 antibodies","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional interaction demonstrated by blocking antibody in co-culture, single lab","pmids":["35141051"],"is_preprint":false},{"year":2017,"finding":"Candida albicans binds directly to the extracellular N-terminal IgV-like domain of CEACAM6 (and CEACAM1, -3, -5); CEACAM6 engagement leads to increased soluble CEACAM6 expression in enterocytes; soluble CEACAM6 reduces C. albicans-induced CXCL8 secretion; CEACAM1 is required for CXCL8 response.","method":"Direct binding assay of C. albicans to recombinant CEACAM ectodomains, shRNA CEACAM1 knockdown, CXCL8 ELISA, CEACAM1 phosphorylation immunoblotting, flow cytometry","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with recombinant domains, functional knockdown, single lab","pmids":["28292985"],"is_preprint":false},{"year":2019,"finding":"CRISPR/Cas9 knockout of CEACAM6 in HPAF-II pancreatic ductal adenocarcinoma cells alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport, and autophagy as shown by quantitative proteomics; CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity; CEACAM6-/- cells show >65% growth suppression in vivo.","method":"CRISPR/Cas9 knockout, quantitative proteomics (mass spectrometry), Seahorse mitochondrial bioenergetics assay, nude mouse xenograft","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with quantitative proteomics and bioenergetics measurement, in vivo validation","pmids":["31797958"],"is_preprint":false},{"year":2020,"finding":"miR-146a and miR-26a post-transcriptionally regulate CEACAM6 expression in lung adenocarcinoma cells, verified by luciferase reporter assay; CEACAM6 promotes cisplatin resistance by affecting EMT and stemness markers (N-cadherin, vimentin, Sox2, Oct4, GTP-RhoA upregulation; E-cadherin downregulation); both miRNAs counteract these CEACAM6-mediated effects.","method":"Luciferase reporter assay for miRNA targeting, CEACAM6 knockdown/overexpression, IC50 determination, EMT and stemness marker immunoblotting, invasion/migration assays","journal":"Thoracic cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirms miRNA targeting, functional effects confirmed by gain/loss of function, single lab","pmids":["32648688"],"is_preprint":false},{"year":2021,"finding":"CD151 forms physical complexes with CEACAM6, as confirmed by co-immunoprecipitation, pull-down assay, and immunofluorescence; CD151 silencing downregulates CEACAM6 expression both in vitro and in vivo, acting through TGFβ1 regulation, linking CD151 to CEACAM6 in colorectal cancer signaling.","method":"Co-immunoprecipitation, mass spectrometry, pull-down assay, immunofluorescence, RNA-seq, CD151 siRNA knockdown, xenograft","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and pull-down confirm physical interaction, multiple downstream validation methods, single lab","pmids":["33767593"],"is_preprint":false},{"year":2022,"finding":"CEACAM6 homophilic interactions on lung cancer cell surfaces activate the Src-FAK signaling pathway and inhibit anoikis; recombinant CEACAM6 treatment of cells induced homophilic interactions in the cell membrane and activated Src-FAK; CEACAM6 was predominantly present on the cancer cell surface rather than secreted.","method":"CellphoneDB analysis on scRNA-seq, CEACAM6 protein treatment of cells, immunoblotting for Src/FAK phosphorylation, anoikis assay, ELISA and immunoblotting of conditioned media and cell fractions","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — exogenous protein treatment demonstrates homophilic signaling, pathway confirmed by phospho-immunoblot, single lab","pmids":["35358791"],"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 promotes CRC cell proliferation and chemoresistance; secreted lactate activates PDK1 which mediates CEACAM6 expression effects; CEACAM6 knockdown reversed the ALDOB-mediated proliferation and chemoresistance phenotype.","method":"Cell-based assays, PDK1 activation analysis, lactate measurement, CEACAM6 knockdown, lysine lactylation detection, LDHB expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel post-translational modification (lactylation) identified with functional consequence, single lab","pmids":["37816733"],"is_preprint":false},{"year":2008,"finding":"A novel intron-retention isoform of rat CEACAM6 (Ceacam6-L) contains a transmembrane domain and intracellular region (rather than GPI anchor), is exclusively expressed in rat testis from 5 weeks postnatal, and localizes specifically to the interface between Sertoli cells and elongated spermatids at the apical ectoplasmic specialization (not the blood-testis barrier), suggesting a role in spermatid anchoring and spermiation.","method":"RT-PCR, Northern blot, immunoblot, immunohistochemistry, confocal laser scanning microscopy with anti-CEACAM6-L antibody","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by confocal microscopy tied to specific cellular structure, but functional role inferred not directly tested","pmids":["18685128"],"is_preprint":false},{"year":2015,"finding":"CEACAM6 promotes cell proliferation in pancreatic carcinoma by increasing cyclin D1 and CDK4 protein levels; siRNA knockdown of CEACAM6 decreased cyclin D1 and CDK4 levels while overexpression increased them.","method":"siRNA knockdown and forced CEACAM6 overexpression in multiple pancreatic cancer cell lines, immunoblotting for cyclin D1 and CDK4, proliferation assay, in vivo xenograft","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (knockdown + overexpression) with specific pathway readout, single lab","pmids":["26497080"],"is_preprint":false},{"year":2023,"finding":"CEACAM6 acts as a negative regulator of HO-1 (heme oxygenase-1)-mediated antioxidant defense in human alveolar type 2 epithelial cells; CEACAM6 overexpression increased nitrosative/oxidative stress and cell death upon CSE treatment; this was confirmed in human precision-cut lung slices using AAV-mediated gene transduction.","method":"CSE-resistant cell line model, transcriptomic profiling, AAV-mediated CEACAM6 overexpression in precision-cut lung slices, 3-nitrotyrosine measurement, HO-1 activity inhibition","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AAV-mediated overexpression in ex vivo human tissue, with functional oxidative stress readout, single lab","pmids":["37219322"],"is_preprint":false},{"year":2020,"finding":"CEACAM6 on follicle-associated epithelium (FAE) mediates translocation of AIEC LF82 across the intestinal epithelium in Crohn's disease; bacterial LF82 passage required both bacterial long polar fimbriae (LPF) and host CEACAM6; anti-CEACAM6 antibody inhibited bacterial translocation and prevented LF82-induced increases in paracellular permeability.","method":"In vitro FAE model, Ussing chamber experiments with patient CD FAE tissue, LPF-deletion mutant bacteria, anti-CEACAM6 antibody blocking, 51Chromium-EDTA paracellular permeability assay, immunofluorescence/immunoblot for CEACAM6 expression","journal":"Journal of Crohn's & colitis","confidence":"High","confidence_rationale":"Tier 2 / Strong — bacterial mutant and antibody blocking in both in vitro model and ex vivo human patient tissue, multiple functional readouts","pmids":["31393983"],"is_preprint":false}],"current_model":"CEACAM6 is a GPI-anchored, heavily N-glycosylated immunoglobulin superfamily cell adhesion molecule whose N-terminal domain mediates homophilic and heterophilic (CEACAM8, CEACAM1) Ca2+-independent adhesion; in cancer cells it signals through lipid-raft/caveolin-1-dependent activation of c-Src, which phosphorylates FAK and Akt to promote anoikis resistance, invasion, EMT, angiogenesis, and metastasis, while co-clustering with integrin α5β1 to enhance fibronectin binding; it also co-clusters with EGFR in an N-glycosylation (Asn256/MGAT5)-dependent manner to amplify EGFR signaling, serves as an intestinal epithelial receptor for AIEC type-1-pili/LPF whose expression is epigenetically controlled via HIF-1/HRE methylation, and functions as an immune checkpoint by engaging CEACAM1 on T cells to suppress anti-tumor immunity."},"narrative":{"mechanistic_narrative":"CEACAM6 is a GPI-anchored, heavily N-glycosylated immunoglobulin-superfamily cell-surface glycoprotein that mediates Ca2+-independent homophilic (CEACAM6-CEACAM6) and heterophilic (CEACAM6-CEA, CEACAM6-CEACAM8/CD66b) adhesion through its N-terminal Ig-like domain [PMID:2803308, PMID:2830274, PMID:2022629, PMID:11590190]. The mature protein carries an N-terminal domain plus a single Ig-like doublet and is attached to the membrane via an amide-linked GPI anchor at residue ~287, removable by PI-specific phospholipase C [PMID:2742579, PMID:3390172, PMID:2830274]. In neutrophils it is stored in secondary granules as a surface-recruitable pool, carries selectin-binding Lewis-X/sialyl-Lewis-X glycans, and transduces an extracellular-calcium-dependent activation signal that upregulates CD11/CD18 and promotes endothelial adhesion and superoxide release [PMID:1640165, PMID:7689841, PMID:8699114, PMID:8645267]. In epithelial cancers, CEACAM6 cross-linking or homophilic engagement drives a caveolin-1- and c-Src-dependent signaling cascade that phosphorylates FAK and Akt to confer anoikis resistance, invasion, proliferation, EMT, and metastasis; downstream effectors include MMP-9/MMP-2, cyclin D1/CDK4, and PI3K/AKT, and CEACAM6 cooperates with integrins and IGF-IR in this output [PMID:15047698, PMID:14724575, PMID:15316565, PMID:15208677, PMID:25398131, PMID:26497080]. It physically co-clusters with integrin α5β1 to enhance fibronectin binding and matrix assembly, and engages EGFR in an N-glycosylation (Asn256/MGAT5)-dependent manner to amplify EGFR signaling and invasion [PMID:17167768, PMID:28892050]. CEACAM6 expression is controlled by TGF-β/Smad3 and by HIF-1 binding to hypoxia-responsive elements whose CpG methylation status sets expression level, and it is post-transcriptionally repressed by miR-29 and miR-146a/miR-26a [PMID:17653079, PMID:24898815, PMID:23857344, PMID:32648688]. At mucosal surfaces it serves as an apical epithelial receptor for type-1-pili and long-polar-fimbriae adherent-invasive E. coli, mediating colonization and transepithelial translocation in a manner inducible by IFN-γ/TNF-α [PMID:17525800, PMID:31393983]. CEACAM6 also functions as an immune checkpoint by binding CEACAM1 on activated T cells to suppress anti-tumor immunity [PMID:35141051].","teleology":[{"year":1988,"claim":"Defining the primary structure and domain architecture established CEACAM6 as a CEA-related Ig-superfamily glycoprotein, distinguishing it from CEA by a single Ig doublet and a C-terminal membrane-anchoring domain.","evidence":"cDNA cloning/sequencing from colon carcinoma SW403 and amino-acid sequencing of purified NCA-50 protein","pmids":["2830274","3390172"],"confidence":"High","gaps":["No 3D structure of the N-domain at the time","Function not yet assigned"]},{"year":1989,"claim":"Reconstitution in transfected cells showed CEACAM6 is a functional adhesion molecule and that it is GPI-anchored, defining both its activity and its membrane attachment mode.","evidence":"CHO/NIH-3T3 transfection with cell aggregation and 51Cr adhesion assays, Fab' inhibition, and PI-PLC release with flow cytometry","pmids":["2803308","2742579"],"confidence":"High","gaps":["Adhesion partners beyond homophilic/CEA not yet mapped","No cytoplasmic signaling output (GPI-anchored, lacks intracellular domain)"]},{"year":1991,"claim":"Domain-mapping localized adhesion specificity to the N-terminal domain, identifying the binding surface that mediates both homophilic and heterophilic engagement.","evidence":"Chimeric and N-domain-substituted constructs in CHO adhesion assays","pmids":["2022629"],"confidence":"High","gaps":["Atomic-resolution binding interface unresolved"]},{"year":1996,"claim":"Work in neutrophils showed CEACAM6 transmits an activation signal despite being GPI-anchored, and that heterophilic CD66c-CD66b binding is carbohydrate-independent, separating protein-protein adhesion from glycan-mediated functions.","evidence":"Anti-CD66c antibody stimulation with calcium chelation and CD18 blocking; recombinant deglycosylated proteins in adhesion and superoxide assays","pmids":["8699114","8645267"],"confidence":"High","gaps":["Signal transducer coupling a GPI protein to intracellular response not identified","Specific glycan determinants of selectin binding not mapped"]},{"year":2001,"claim":"Systematic mutagenesis defined the overlapping residues controlling homophilic, CEACAM8-heterophilic, and bacterial Opa binding, establishing a shared but distinguishable adhesion surface.","evidence":"Homologue-scanning mutagenesis of CHO transfectants in adhesion assays","pmids":["11590190"],"confidence":"High","gaps":["Structural basis for partner selectivity unresolved"]},{"year":2004,"claim":"A series of pancreatic-cancer studies placed CEACAM6 atop a caveolin-1/c-Src/FAK/Akt signaling axis controlling anoikis resistance, invasion, MMP activity, IGF-IR upregulation, and in vivo metastasis, transforming it from an adhesion molecule into an oncogenic signaling hub.","evidence":"Antibody cross-linking, siRNA/overexpression, dominant-negative/constitutively-active c-Src and caveolin-1, anoikis/invasion assays, orthotopic xenografts","pmids":["15047698","14724575","15316565","15208677","15047158"],"confidence":"High","gaps":["How a GPI-anchored protein couples to c-Src not mechanistically resolved","Direct kinase activation step undefined"]},{"year":2007,"claim":"CEACAM6 was shown to co-cluster with integrin α5β1 to drive fibronectin matrix assembly and to be transcriptionally controlled by TGF-β/Smad3, linking its adhesion function to ECM remodeling and upstream regulation.","evidence":"Confocal co-clustering, fibronectin assembly and blocking assays; promoter-luciferase reporter and Smad3-null mouse analysis","pmids":["17167768","17653079"],"confidence":"High","gaps":["Stoichiometry/physical nature of CEACAM6-integrin complex undefined","Other transcriptional inputs not surveyed"]},{"year":2007,"claim":"Identification of CEACAM6 as the apical ileal-epithelial receptor for type-1-pili AIEC, inducible by inflammatory cytokines, established its role in pathogenic bacterial colonization in Crohn's disease.","evidence":"Primary enterocyte adhesion with pili-mutant bacteria, antibody blocking, cytokine stimulation, immunohistochemistry","pmids":["17525800"],"confidence":"High","gaps":["Bacterial ligand-CEACAM6 binding interface not mapped at residue level","Downstream epithelial response to AIEC binding incomplete"]},{"year":2014,"claim":"Epigenetic mapping showed HIF-1/HRE methylation status governs CEACAM6 expression, with a humanized transgenic mouse linking diet-induced HRE demethylation to enhanced AIEC colonization, defining an environmental-epigenetic control loop.","evidence":"Bisulfite/SnapShot methylation analysis, pCpGfree reporter, human-CEACAM6 transgenic mice on low-methyl diet, colonization quantification","pmids":["24898815"],"confidence":"High","gaps":["Enzymes setting/removing HRE methylation not identified","Generalizability beyond intestine untested"]},{"year":2017,"claim":"CEACAM6 was shown to physically engage EGFR in an Asn256/MGAT5-glycosylation-dependent manner to amplify EGFR signaling and invasion, and separately to act as an immune checkpoint by binding CEACAM1 on T cells, broadening its oncogenic and immune roles.","evidence":"Co-IP of CEACAM6-EGFR, N256 mutagenesis, MGAT5 knockdown; T-cell/cancer co-culture with CEACAM6-blocking antibody and cytokine/killing readouts","pmids":["28892050","35141051"],"confidence":"High","gaps":["EGFR-CEACAM6 interaction validated in single tumor context","CEACAM6-CEACAM1 checkpoint data from single lab co-culture"]},{"year":2019,"claim":"CRISPR knockout with quantitative proteomics broadened CEACAM6's functional footprint to catabolism, transmembrane transport, autophagy, and mitochondrial respiration, indicating effects beyond adhesion and Src signaling.","evidence":"CRISPR/Cas9 knockout in HPAF-II, mass-spec proteomics, Seahorse bioenergetics, nude-mouse xenograft","pmids":["31797958"],"confidence":"High","gaps":["Direct molecular links between CEACAM6 and metabolic/autophagy changes unestablished","Proteomic associations not mechanistically dissected"]},{"year":2023,"claim":"Discovery of lysine-lactylation stabilizing CEACAM6 downstream of an ALDOB/PDK1/lactate axis, and of a negative-regulatory role in HO-1 antioxidant defense, extended its regulation to metabolic post-translational control and oxidative-stress biology.","evidence":"Lactylation detection with lactate measurement and PDK1 analysis in CRC cells; AAV overexpression in human precision-cut lung slices with nitrosative-stress readouts","pmids":["37816733","37219322"],"confidence":"Medium","gaps":["Lactylation site and its functional consequence on CEACAM6 not mapped","HO-1 regulatory mechanism by a surface GPI protein unclear","Both from single labs"]},{"year":null,"claim":"How a GPI-anchored extracellular protein lacking a cytoplasmic domain physically couples to intracellular c-Src/FAK/Akt signaling, and the atomic-resolution architecture of its N-domain adhesion and EGFR/integrin co-clustering interfaces, remain unresolved.","evidence":"No discovery in the timeline resolves the transmembrane signal-coupling mechanism or provides a structural model of the partner interfaces","pmids":[],"confidence":"Medium","gaps":["No structural model of N-domain partner complexes","Transmembrane coupling mechanism to Src undefined","Lipid-raft/caveolin organization not structurally characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4,9,18]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[17,37,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,26,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,5,18,32]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,13,23,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,27]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17,37,12]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[18,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,10]}],"complexes":[],"partners":["CEACAM5","CEACAM8","CEACAM1","EGFR","ITGA5","ITGB1","CD151","SRC"],"other_free_text":[]}},"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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\"finding\": \"CEACAM6 (NCA) expressed on CHO cell surfaces mediates both homophilic (NCA-NCA) and heterophilic (CEA-NCA) Ca2+-independent cell adhesion, as demonstrated by aggregation and 51Cr-labeled cell adhesion assays with Fab' antibody inhibition.\",\n      \"method\": \"CHO cell transfection with cDNA, cell aggregation assay, 51Cr-labeled adhesion assay, Fab' antibody inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution in transfected cells with antibody inhibition, replicated in multiple subsequent papers\",\n      \"pmids\": [\"2803308\"],\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 phosphatidylinositol-specific phospholipase C cleavage releasing the protein from NIH/3T3 transfectant surfaces.\",\n      \"method\": \"cDNA transfection of NIH/3T3 cells, PI-PLC treatment, flow cytometry, immunoprecipitation of surface-labeled glycoproteins\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical demonstration by PI-PLC cleavage with two orthogonal methods, independently corroborated by subsequent studies\",\n      \"pmids\": [\"2742579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"CEACAM6 (NCA) protein contains four cysteine residues that form disulfide bonds, has 7 potential N-glycosylation sites with differential occupancy, and is GPI-anchored via an amide linkage to ethanolamine at amino acid position 287 (replacing the last 24 hydrophobic residues of the primary sequence).\",\n      \"method\": \"Amino acid sequencing of purified NCA-50 protein, biochemical characterization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct protein sequencing covering 59% of the protein, establishing covalent modification sites\",\n      \"pmids\": [\"3390172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"CEACAM6 (NCA) encodes a mature protein of 310 amino acids with one immunoglobulin-like doublet domain (versus three in CEA), an N-terminal domain, and a C-terminal hydrophobic domain sufficient for membrane anchoring; it shares ~85% amino acid homology with CEA.\",\n      \"method\": \"cDNA cloning and sequencing from colon carcinoma cell line SW403 lambda gt10 library\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full-length cDNA sequencing establishing domain architecture, foundational structural characterization\",\n      \"pmids\": [\"2830274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The heterophilic cell adhesion between CEACAM6 (NCA) and W272 (CGM6/CD67) is mediated specifically by the N-terminal domain of CEACAM6, not by other domains; chimeric N-domain substitution experiments localized the binding specificity to the N-terminal region of the CEACAM6 N-domain.\",\n      \"method\": \"CHO cell transfection with cDNA constructs encoding full-length, chimeric, and N-domain-substituted proteins; cell adhesion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain mapping by chimeric mutagenesis in cell adhesion reconstitution system\",\n      \"pmids\": [\"2022629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"In human neutrophils, CEACAM6 (NCA species of ~95–100 kDa) is predominantly located in secondary granules with lesser amounts in plasma membranes, indicating that secondary granules serve as an intracellular reservoir from which CEACAM6 can be recruited to the cell surface upon activation.\",\n      \"method\": \"Nitrogen cavitation, differential centrifugation subcellular fractionation, SDS-PAGE, immunoblotting\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct fractionation experiment with immunoblot identification of protein in specific granule compartments\",\n      \"pmids\": [\"1640165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CEACAM6 (NCA-160, CD66) is the major protein carrier of the selectin-binding carbohydrate groups LewisX and sialyl LewisX on the neutrophil surface, and differently glycosylated forms of CEACAM6 are independently regulated in surface expression following fMLP stimulation.\",\n      \"method\": \"Immunoprecipitation, immunoblotting with carbohydrate-specific antibodies, fMLP stimulation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoprecipitation and functional stimulation data from single lab, two methods\",\n      \"pmids\": [\"7689841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Antibody-mediated engagement of CD66c (CEACAM6) on neutrophils independently triggers a transient activation signal requiring extracellular calcium, leading to upregulation of CD11/CD18 and increased neutrophil adhesion to endothelial cells; CD66c can transmit signals independently of CD66a, CD66b, and CD66d.\",\n      \"method\": \"Anti-CD66c antibody stimulation of isolated neutrophils, adhesion assay to HUVEC monolayers, calcium chelation experiments, CD18 blocking antibody, sequential desensitization experiments\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional signaling demonstrated with calcium dependency and desensitization controls, single lab\",\n      \"pmids\": [\"8699114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Heterophilic adhesion between CD66c (CEACAM6) and CD66b (CGM6) is mediated by interaction between the N-domains of each protein; deglycosylated forms retained adhesion activity, indicating the carbohydrate portions are not required for binding. Activated neutrophils adhering to immobilized CD66b/CD66c released superoxide anions.\",\n      \"method\": \"Recombinant soluble proteins prepared in silkworm larvae, immobilized protein adhesion assay with CHO transfectants, deglycosylation, N-domain-specific antibody inhibition, superoxide anion release assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with recombinant proteins, domain mapping by antibody inhibition, functional readout (superoxide release)\",\n      \"pmids\": [\"8645267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The N-domain of CEACAM6 on one cell binds the N-domain of CEACAM6 or CEACAM8 on the opposing cell; homologue-scanning mutagenesis showed that the critical residues for CEACAM6 homophilic and CEACAM6-CEACAM8 heterophilic adhesion overlap and are highly similar but not identical to those required for binding bacterial Opa proteins.\",\n      \"method\": \"CHO transfectants with mutant and chimeric proteins, homologue-scanning mutagenesis, cell adhesion assay\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis mapping of adhesion determinants in functional reconstitution system\",\n      \"pmids\": [\"11590190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 cross-linking in pancreatic adenocarcinoma cells activates c-Src and induces tyrosine phosphorylation of FAK (p125FAK); FAK phosphorylation requires c-Src kinase activity, and c-Src activation requires caveolin-1. Cross-linking also increases anchorage-independent survival (anoikis resistance).\",\n      \"method\": \"Antibody-mediated CEACAM6 cross-linking in BxPC3 cells, immunoblotting for pFAK and pSrc, dominant-negative caveolin-1 constructs, anoikis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic signaling cascade defined with pathway inhibition and dominant-negative constructs, multiple orthogonal readouts\",\n      \"pmids\": [\"15047698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 cross-linking initiates c-Src-dependent cross-talk between CEACAM6 and αvβ3 integrin, leading to increased pancreatic adenocarcinoma cell adhesion to fibronectin and vitronectin; this was dependent on c-Src activity demonstrated by pharmacological inhibitor PP2 and Src-specific siRNA.\",\n      \"method\": \"Antibody-mediated CEACAM6 cross-linking, cell adhesion assay to ECM proteins, PP2 Src inhibitor, c-Src specific siRNA, integrin-blocking antibodies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological and siRNA confirmation of Src requirement, multiple ECM components tested\",\n      \"pmids\": [\"15047158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 silencing by siRNA in pancreatic adenocarcinoma cells increases susceptibility to caspase-mediated anoikis under anchorage-independent conditions and decreases Akt phosphorylation (Ser-473); CEACAM6 knockdown also reverses acquired anoikis resistance and inhibits in vivo metastatic ability in nude mouse orthotopic xenografts.\",\n      \"method\": \"CEACAM6-specific siRNA, poly-HEMA anoikis induction, YO-PRO-1/PI flow cytometry, fluorometric caspase profiling, Z-VAD-fmk caspase inhibitor, Akt phosphorylation immunoblotting, orthotopic nude mouse xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, caspase inhibition, phospho-Akt, in vivo model) in single study defining pathway\",\n      \"pmids\": [\"14724575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 overexpression increases pancreatic adenocarcinoma cellular invasiveness in a c-Src-dependent manner; c-Src-dependent modulation of MMP-9 activity contributes significantly to the increased invasiveness; dominant-negative c-Src blocks invasion while constitutively active c-Src mimics the effect.\",\n      \"method\": \"Stable retroviral CEACAM6 overexpression/RNAi knockdown, modified Boyden chamber invasion assay, constitutively active/dominant-negative c-Src constructs, MMP-9 activity measurement\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway placement using dominant-negative and constitutively active kinase constructs with functional invasion readout\",\n      \"pmids\": [\"15316565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 overexpression increases IGF-I-induced pancreatic adenocarcinoma invasiveness by upregulating IGF-IR expression and activating both Akt and c-Src kinases; Akt is both necessary and sufficient for IGF-IR upregulation, while c-Src is necessary but insufficient alone; MMP-2 expression and activity are increased in a CEACAM6/IGF-I-dependent manner.\",\n      \"method\": \"Stable CEACAM6 transfection, inhibitory anti-IGF-IR antibody, Akt kinase assay, c-Src kinase assay, MMP-2 zymography, Boyden chamber invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established using receptor-blocking antibody and kinase activity assays with defined sufficiency/necessity relationships\",\n      \"pmids\": [\"15208677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CEACAM6 cross-linking induces its cytoplasmic accumulation in pancreatic adenocarcinoma cells; this internalization can be exploited for antibody-mediated delivery of saporin (ribosomal inhibitory protein), inducing caspase-mediated apoptosis in vitro and suppressing tumor growth in vivo.\",\n      \"method\": \"Anti-CEACAM6 antibody cross-linking, immunofluorescence for cytoplasmic accumulation, saporin-conjugated secondary antibody cytotoxicity assay, caspase activation assay, nude mouse xenograft\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct demonstration of internalization with functional consequence, single lab\",\n      \"pmids\": [\"15081416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Anti-CEACAM6 antibody Fabs targeting the N-domain (MN-3) and A1B1 domain (MN-15) inhibit tumor cell migration, invasion through ECM, and adhesion to endothelial cells; MN-15 Fab specifically reduces adhesion of some cell lines to fibronectin but not vitronectin, laminin, or collagens; both MN-3 and MN-15 Fabs have antimetastatic effects in vivo improving survival in a colonic micrometastasis model.\",\n      \"method\": \"Migration assay, Matrigel invasion assay, adhesion assay to endothelial cells and ECM proteins, GW-39 colonic micrometastasis nude mouse model, Kaplan-Meier survival analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro functional assays plus in vivo validation, single lab\",\n      \"pmids\": [\"16204051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CEACAM6 acts as a receptor for type-1-pili-expressing adherent-invasive E. coli (AIEC) on the apical surface of ileal epithelial cells; AIEC adhesion is dependent on both bacterial type 1 pili expression and CEACAM6 expression on enterocytes; CEACAM6 expression is induced by IFN-γ, TNF-α, and AIEC infection itself, creating a positive-feedback colonization loop.\",\n      \"method\": \"Primary ileal enterocyte adhesion assay, type-1-pili mutant bacteria, anti-CEACAM6 antibody blocking, cytokine stimulation of cultured intestinal epithelial cells, immunohistochemistry\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor function established by pili mutant and antibody blocking, cytokine regulation confirmed with multiple stimuli\",\n      \"pmids\": [\"17525800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GPI-anchored CEACAM6 co-clusters with integrin α5β1 on the cell surface and enhances α5β1 binding to fibronectin without changing α5β1 surface levels, leading to increased fibronectin adhesion, enhanced fibronectin matrix assembly, and formation of a polymerized fibronectin 'cocoon'; disruption with anti-fibronectin or anti-α5β1 antibodies restores differentiation and anoikis sensitivity.\",\n      \"method\": \"Confocal microscopy co-clustering, fibronectin-binding assay, fibronectin matrix assembly assay, antibody blocking of fibronectin and α5β1, differentiation and anoikis assays in CEA/CEACAM6-expressing cells\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-clustering demonstrated by confocal microscopy, functional mechanism confirmed by antibody blocking with multiple cellular readouts\",\n      \"pmids\": [\"17167768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CEACAM6 (and CEACAM5) expression is transcriptionally regulated by the TGF-β signaling pathway via the Smad3 mediator; restoration of TGF-β signaling in Smad3-deficient cells induced CEACAM6 expression and increased CEACAM6 promoter activity; CEACAM6 expression was markedly decreased in Smad3 null mice stomachs.\",\n      \"method\": \"TGF-β treatment of gastric cancer cell lines, Smad3 restoration by transfection, CEACAM6 promoter-luciferase reporter assay, RT-PCR, immunohistochemistry in Smad3 null mice\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter reporter assay, in vitro restoration experiments, 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, downregulates cancer cell cytoskeleton proteins, and blocks adenovirus trafficking to the nucleus of pancreatic cancer cells; Src-selective inhibitor treatment phenocopied CEACAM6 overexpression in reducing adenovirus replication; siRNA knockdown of CEACAM6 enhanced oncolytic adenovirus antitumor effects in xenografts.\",\n      \"method\": \"CEACAM6 overexpression/siRNA knockdown, adenovirus infection assay, immunofluorescence for viral trafficking, Src inhibitor treatment, cytoskeletal protein immunoblotting, nude mouse xenograft\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (Src inhibition phenocopy) with multiple readouts, single lab\",\n      \"pmids\": [\"19411761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Influenza A virus neuraminidase (NA) protein physically interacts with CEACAM6 (C6); this NA/CEACAM6 interaction activates the Src/Akt signaling axis, increasing tyrosyl phosphorylation of Src, FAK, Akt, GSK3β, and Bcl-2, enhancing cell survival; siRNA knockdown of CEACAM6 reduced pSrc, pFAK, pAkt, increased apoptosis, and reduced viral protein expression and viral titers.\",\n      \"method\": \"Co-immunoprecipitation (NA-CEACAM6 interaction), CEACAM6 siRNA knockdown, immunoblotting for phosphoproteins, apoptosis assay, viral titer measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes interaction, siRNA confirms functional dependence on CEACAM6, single lab\",\n      \"pmids\": [\"22396546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CEACAM6 promotes EMT in pancreatic cancer cells (increased N-cadherin, vimentin, Slug; decreased E-cadherin); miR-29a/b/c negatively regulates CEACAM6 expression at the post-transcriptional level and suppresses CEACAM6-induced EMT.\",\n      \"method\": \"CEACAM6 overexpression/shRNA knockdown, EMT marker immunoblotting, migration/invasion assays, in vivo metastasis model, miR-29a/b/c transfection\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMT markers and miRNA regulation shown in multiple cell systems, single lab\",\n      \"pmids\": [\"23857344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CEACAM6 promotes EMT in gastric cancer via activation of PI3K/AKT signaling; overexpressed CEACAM6 increased phosphorylated AKT levels and elevated MMP-9 activity; PI3K inhibitor LY294002 reversed CEACAM6-induced EMT; anti-MMP-9 antibody reversed CEACAM6-induced invasion and migration.\",\n      \"method\": \"CEACAM6 overexpression/siRNA knockdown, phospho-AKT immunoblotting, MMP-9 activity assay, LY294002 PI3K inhibitor treatment, EMT marker immunoblotting, peritoneal metastasis in vivo model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway inhibitor experiments define AKT and MMP-9 as effectors, single lab\",\n      \"pmids\": [\"25398131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CEACAM6 promotes tumor angiogenesis and vasculogenic mimicry in gastric cancer via FAK signaling; overexpressed CEACAM6 increased phosphorylation of FAK and paxillin; FAK inhibitor Y15 reduced tubule and vasculogenic mimicry formation in vitro; CEACAM6 overexpression increased VEGF expression and vasculogenic mimicry structures in vivo.\",\n      \"method\": \"CEACAM6 overexpression/siRNA knockdown, tubule formation assay with HUVECs, 3D-culture vasculogenic mimicry assay, FAK/paxillin phosphorylation immunoblotting, FAK inhibitor Y15, VEGF measurement, in vivo xenograft\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FAK inhibitor phenocopy confirms pathway, multiple assays, single lab\",\n      \"pmids\": [\"25703140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CEACAM6 promoter activity is regulated by HIF-1 binding to hypoxia-responsive elements (HREs); methylation of CpG sites within these HREs inversely correlates with CEACAM6 expression; dietary low-methyl conditions in transgenic human CEACAM6 mice led to HRE demethylation, increased CEACAM6 expression, and enhanced AIEC colonization.\",\n      \"method\": \"Bisulfite sequencing, SnapShot site-specific methylation analysis, pCpGfree reporter system, transgenic mice expressing human CEACAM6 fed low-methyl diet, bacterial colonization quantification, cytokine measurement\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter reporter combined with in vivo transgenic mouse model and methylation mapping, multiple orthogonal methods\",\n      \"pmids\": [\"24898815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CEACAM6 promotes OSCC invasion, migration, and metastasis through physical interaction with EGFR and enhancement of EGFR activation, clustering, and intracellular signaling cascades; this function requires N-glycosylation at Asn256 (N256) mediated by MGAT5 (α-1,6-mannosylglycoprotein 6-β-N-acetylglucosaminyltransferase); a CEACAM6-specific antibody blocked EGFR signaling and invasion.\",\n      \"method\": \"Co-immunoprecipitation of CEACAM6-EGFR interaction, MGAT5 knockdown, N256 site-directed mutagenesis, invasion/migration assays, cytoskeletal rearrangement assay, in vivo metastasis model, anti-CEACAM6 sdAb/HCAb treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of CEACAM6-EGFR interaction, mutagenesis of N-glycosylation site, MGAT5 knockdown, multiple functional readouts\",\n      \"pmids\": [\"28892050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CEACAM6 on cancer cells acts as an immune checkpoint by binding to CEACAM1 expressed on activated tumor-specific T cells, suppressing T cell-mediated antitumor activity; blocking the CEACAM6-CEACAM1 interaction with humanized antibody BAY 1834942 restored T cell cytokine secretion and cancer cell killing.\",\n      \"method\": \"Co-culture experiments with T cells and cancer cells, CEACAM6-blocking antibody treatment, cytokine secretion measurement, T cell killing assay, comparison to anti-PD-1/PD-L1/TIM-3 antibodies\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional interaction demonstrated by blocking antibody in co-culture, single lab\",\n      \"pmids\": [\"35141051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Candida albicans binds directly to the extracellular N-terminal IgV-like domain of CEACAM6 (and CEACAM1, -3, -5); CEACAM6 engagement leads to increased soluble CEACAM6 expression in enterocytes; soluble CEACAM6 reduces C. albicans-induced CXCL8 secretion; CEACAM1 is required for CXCL8 response.\",\n      \"method\": \"Direct binding assay of C. albicans to recombinant CEACAM ectodomains, shRNA CEACAM1 knockdown, CXCL8 ELISA, CEACAM1 phosphorylation immunoblotting, flow cytometry\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with recombinant domains, functional knockdown, single lab\",\n      \"pmids\": [\"28292985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRISPR/Cas9 knockout of CEACAM6 in HPAF-II pancreatic ductal adenocarcinoma cells alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport, and autophagy as shown by quantitative proteomics; CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity; CEACAM6-/- cells show >65% growth suppression in vivo.\",\n      \"method\": \"CRISPR/Cas9 knockout, quantitative proteomics (mass spectrometry), Seahorse mitochondrial bioenergetics assay, nude mouse xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with quantitative proteomics and bioenergetics measurement, in vivo validation\",\n      \"pmids\": [\"31797958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-146a and miR-26a post-transcriptionally regulate CEACAM6 expression in lung adenocarcinoma cells, verified by luciferase reporter assay; CEACAM6 promotes cisplatin resistance by affecting EMT and stemness markers (N-cadherin, vimentin, Sox2, Oct4, GTP-RhoA upregulation; E-cadherin downregulation); both miRNAs counteract these CEACAM6-mediated effects.\",\n      \"method\": \"Luciferase reporter assay for miRNA targeting, CEACAM6 knockdown/overexpression, IC50 determination, EMT and stemness marker immunoblotting, invasion/migration assays\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirms miRNA targeting, functional effects confirmed by gain/loss of function, single lab\",\n      \"pmids\": [\"32648688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD151 forms physical complexes with CEACAM6, as confirmed by co-immunoprecipitation, pull-down assay, and immunofluorescence; CD151 silencing downregulates CEACAM6 expression both in vitro and in vivo, acting through TGFβ1 regulation, linking CD151 to CEACAM6 in colorectal cancer signaling.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, pull-down assay, immunofluorescence, RNA-seq, CD151 siRNA knockdown, xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and pull-down confirm physical interaction, multiple downstream validation methods, single lab\",\n      \"pmids\": [\"33767593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEACAM6 homophilic interactions on lung cancer cell surfaces activate the Src-FAK signaling pathway and inhibit anoikis; recombinant CEACAM6 treatment of cells induced homophilic interactions in the cell membrane and activated Src-FAK; CEACAM6 was predominantly present on the cancer cell surface rather than secreted.\",\n      \"method\": \"CellphoneDB analysis on scRNA-seq, CEACAM6 protein treatment of cells, immunoblotting for Src/FAK phosphorylation, anoikis assay, ELISA and immunoblotting of conditioned media and cell fractions\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — exogenous protein treatment demonstrates homophilic signaling, pathway confirmed by phospho-immunoblot, single lab\",\n      \"pmids\": [\"35358791\"],\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 promotes CRC cell proliferation and chemoresistance; secreted lactate activates PDK1 which mediates CEACAM6 expression effects; CEACAM6 knockdown reversed the ALDOB-mediated proliferation and chemoresistance phenotype.\",\n      \"method\": \"Cell-based assays, PDK1 activation analysis, lactate measurement, CEACAM6 knockdown, lysine lactylation detection, LDHB expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel post-translational modification (lactylation) identified with functional consequence, single lab\",\n      \"pmids\": [\"37816733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A novel intron-retention isoform of rat CEACAM6 (Ceacam6-L) contains a transmembrane domain and intracellular region (rather than GPI anchor), is exclusively expressed in rat testis from 5 weeks postnatal, and localizes specifically to the interface between Sertoli cells and elongated spermatids at the apical ectoplasmic specialization (not the blood-testis barrier), suggesting a role in spermatid anchoring and spermiation.\",\n      \"method\": \"RT-PCR, Northern blot, immunoblot, immunohistochemistry, confocal laser scanning microscopy with anti-CEACAM6-L antibody\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by confocal microscopy tied to specific cellular structure, but functional role inferred not directly tested\",\n      \"pmids\": [\"18685128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CEACAM6 promotes cell proliferation in pancreatic carcinoma by increasing cyclin D1 and CDK4 protein levels; siRNA knockdown of CEACAM6 decreased cyclin D1 and CDK4 levels while overexpression increased them.\",\n      \"method\": \"siRNA knockdown and forced CEACAM6 overexpression in multiple pancreatic cancer cell lines, immunoblotting for cyclin D1 and CDK4, proliferation assay, in vivo xenograft\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (knockdown + overexpression) with specific pathway readout, single lab\",\n      \"pmids\": [\"26497080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEACAM6 acts as a negative regulator of HO-1 (heme oxygenase-1)-mediated antioxidant defense in human alveolar type 2 epithelial cells; CEACAM6 overexpression increased nitrosative/oxidative stress and cell death upon CSE treatment; this was confirmed in human precision-cut lung slices using AAV-mediated gene transduction.\",\n      \"method\": \"CSE-resistant cell line model, transcriptomic profiling, AAV-mediated CEACAM6 overexpression in precision-cut lung slices, 3-nitrotyrosine measurement, HO-1 activity inhibition\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AAV-mediated overexpression in ex vivo human tissue, with functional oxidative stress readout, single lab\",\n      \"pmids\": [\"37219322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CEACAM6 on follicle-associated epithelium (FAE) mediates translocation of AIEC LF82 across the intestinal epithelium in Crohn's disease; bacterial LF82 passage required both bacterial long polar fimbriae (LPF) and host CEACAM6; anti-CEACAM6 antibody inhibited bacterial translocation and prevented LF82-induced increases in paracellular permeability.\",\n      \"method\": \"In vitro FAE model, Ussing chamber experiments with patient CD FAE tissue, LPF-deletion mutant bacteria, anti-CEACAM6 antibody blocking, 51Chromium-EDTA paracellular permeability assay, immunofluorescence/immunoblot for CEACAM6 expression\",\n      \"journal\": \"Journal of Crohn's & colitis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bacterial mutant and antibody blocking in both in vitro model and ex vivo human patient tissue, multiple functional readouts\",\n      \"pmids\": [\"31393983\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEACAM6 is a GPI-anchored, heavily N-glycosylated immunoglobulin superfamily cell adhesion molecule whose N-terminal domain mediates homophilic and heterophilic (CEACAM8, CEACAM1) Ca2+-independent adhesion; in cancer cells it signals through lipid-raft/caveolin-1-dependent activation of c-Src, which phosphorylates FAK and Akt to promote anoikis resistance, invasion, EMT, angiogenesis, and metastasis, while co-clustering with integrin α5β1 to enhance fibronectin binding; it also co-clusters with EGFR in an N-glycosylation (Asn256/MGAT5)-dependent manner to amplify EGFR signaling, serves as an intestinal epithelial receptor for AIEC type-1-pili/LPF whose expression is epigenetically controlled via HIF-1/HRE methylation, and functions as an immune checkpoint by engaging CEACAM1 on T cells to suppress anti-tumor immunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEACAM6 is a GPI-anchored, heavily N-glycosylated immunoglobulin-superfamily cell-surface glycoprotein that mediates Ca2+-independent homophilic (CEACAM6-CEACAM6) and heterophilic (CEACAM6-CEA, CEACAM6-CEACAM8/CD66b) adhesion through its N-terminal Ig-like domain [#0, #3, #4, #9]. The mature protein carries an N-terminal domain plus a single Ig-like doublet and is attached to the membrane via an amide-linked GPI anchor at residue ~287, removable by PI-specific phospholipase C [#1, #2, #3]. In neutrophils it is stored in secondary granules as a surface-recruitable pool, carries selectin-binding Lewis-X/sialyl-Lewis-X glycans, and transduces an extracellular-calcium-dependent activation signal that upregulates CD11/CD18 and promotes endothelial adhesion and superoxide release [#5, #6, #7, #8]. In epithelial cancers, CEACAM6 cross-linking or homophilic engagement drives a caveolin-1- and c-Src-dependent signaling cascade that phosphorylates FAK and Akt to confer anoikis resistance, invasion, proliferation, EMT, and metastasis; downstream effectors include MMP-9/MMP-2, cyclin D1/CDK4, and PI3K/AKT, and CEACAM6 cooperates with integrins and IGF-IR in this output [#10, #12, #13, #14, #23, #35]. It physically co-clusters with integrin \\u03b15\\u03b21 to enhance fibronectin binding and matrix assembly, and engages EGFR in an N-glycosylation (Asn256/MGAT5)-dependent manner to amplify EGFR signaling and invasion [#18, #26]. CEACAM6 expression is controlled by TGF-\\u03b2/Smad3 and by HIF-1 binding to hypoxia-responsive elements whose CpG methylation status sets expression level, and it is post-transcriptionally repressed by miR-29 and miR-146a/miR-26a [#19, #25, #22, #30]. At mucosal surfaces it serves as an apical epithelial receptor for type-1-pili and long-polar-fimbriae adherent-invasive E. coli, mediating colonization and transepithelial translocation in a manner inducible by IFN-\\u03b3/TNF-\\u03b1 [#17, #37]. CEACAM6 also functions as an immune checkpoint by binding CEACAM1 on activated T cells to suppress anti-tumor immunity [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Defining the primary structure and domain architecture established CEACAM6 as a CEA-related Ig-superfamily glycoprotein, distinguishing it from CEA by a single Ig doublet and a C-terminal membrane-anchoring domain.\",\n      \"evidence\": \"cDNA cloning/sequencing from colon carcinoma SW403 and amino-acid sequencing of purified NCA-50 protein\",\n      \"pmids\": [\"2830274\", \"3390172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No 3D structure of the N-domain at the time\", \"Function not yet assigned\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Reconstitution in transfected cells showed CEACAM6 is a functional adhesion molecule and that it is GPI-anchored, defining both its activity and its membrane attachment mode.\",\n      \"evidence\": \"CHO/NIH-3T3 transfection with cell aggregation and 51Cr adhesion assays, Fab' inhibition, and PI-PLC release with flow cytometry\",\n      \"pmids\": [\"2803308\", \"2742579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adhesion partners beyond homophilic/CEA not yet mapped\", \"No cytoplasmic signaling output (GPI-anchored, lacks intracellular domain)\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Domain-mapping localized adhesion specificity to the N-terminal domain, identifying the binding surface that mediates both homophilic and heterophilic engagement.\",\n      \"evidence\": \"Chimeric and N-domain-substituted constructs in CHO adhesion assays\",\n      \"pmids\": [\"2022629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution binding interface unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Work in neutrophils showed CEACAM6 transmits an activation signal despite being GPI-anchored, and that heterophilic CD66c-CD66b binding is carbohydrate-independent, separating protein-protein adhesion from glycan-mediated functions.\",\n      \"evidence\": \"Anti-CD66c antibody stimulation with calcium chelation and CD18 blocking; recombinant deglycosylated proteins in adhesion and superoxide assays\",\n      \"pmids\": [\"8699114\", \"8645267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal transducer coupling a GPI protein to intracellular response not identified\", \"Specific glycan determinants of selectin binding not mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Systematic mutagenesis defined the overlapping residues controlling homophilic, CEACAM8-heterophilic, and bacterial Opa binding, establishing a shared but distinguishable adhesion surface.\",\n      \"evidence\": \"Homologue-scanning mutagenesis of CHO transfectants in adhesion assays\",\n      \"pmids\": [\"11590190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for partner selectivity unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"A series of pancreatic-cancer studies placed CEACAM6 atop a caveolin-1/c-Src/FAK/Akt signaling axis controlling anoikis resistance, invasion, MMP activity, IGF-IR upregulation, and in vivo metastasis, transforming it from an adhesion molecule into an oncogenic signaling hub.\",\n      \"evidence\": \"Antibody cross-linking, siRNA/overexpression, dominant-negative/constitutively-active c-Src and caveolin-1, anoikis/invasion assays, orthotopic xenografts\",\n      \"pmids\": [\"15047698\", \"14724575\", \"15316565\", \"15208677\", \"15047158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a GPI-anchored protein couples to c-Src not mechanistically resolved\", \"Direct kinase activation step undefined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"CEACAM6 was shown to co-cluster with integrin \\u03b15\\u03b21 to drive fibronectin matrix assembly and to be transcriptionally controlled by TGF-\\u03b2/Smad3, linking its adhesion function to ECM remodeling and upstream regulation.\",\n      \"evidence\": \"Confocal co-clustering, fibronectin assembly and blocking assays; promoter-luciferase reporter and Smad3-null mouse analysis\",\n      \"pmids\": [\"17167768\", \"17653079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/physical nature of CEACAM6-integrin complex undefined\", \"Other transcriptional inputs not surveyed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of CEACAM6 as the apical ileal-epithelial receptor for type-1-pili AIEC, inducible by inflammatory cytokines, established its role in pathogenic bacterial colonization in Crohn's disease.\",\n      \"evidence\": \"Primary enterocyte adhesion with pili-mutant bacteria, antibody blocking, cytokine stimulation, immunohistochemistry\",\n      \"pmids\": [\"17525800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bacterial ligand-CEACAM6 binding interface not mapped at residue level\", \"Downstream epithelial response to AIEC binding incomplete\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Epigenetic mapping showed HIF-1/HRE methylation status governs CEACAM6 expression, with a humanized transgenic mouse linking diet-induced HRE demethylation to enhanced AIEC colonization, defining an environmental-epigenetic control loop.\",\n      \"evidence\": \"Bisulfite/SnapShot methylation analysis, pCpGfree reporter, human-CEACAM6 transgenic mice on low-methyl diet, colonization quantification\",\n      \"pmids\": [\"24898815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes setting/removing HRE methylation not identified\", \"Generalizability beyond intestine untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CEACAM6 was shown to physically engage EGFR in an Asn256/MGAT5-glycosylation-dependent manner to amplify EGFR signaling and invasion, and separately to act as an immune checkpoint by binding CEACAM1 on T cells, broadening its oncogenic and immune roles.\",\n      \"evidence\": \"Co-IP of CEACAM6-EGFR, N256 mutagenesis, MGAT5 knockdown; T-cell/cancer co-culture with CEACAM6-blocking antibody and cytokine/killing readouts\",\n      \"pmids\": [\"28892050\", \"35141051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EGFR-CEACAM6 interaction validated in single tumor context\", \"CEACAM6-CEACAM1 checkpoint data from single lab co-culture\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"CRISPR knockout with quantitative proteomics broadened CEACAM6's functional footprint to catabolism, transmembrane transport, autophagy, and mitochondrial respiration, indicating effects beyond adhesion and Src signaling.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in HPAF-II, mass-spec proteomics, Seahorse bioenergetics, nude-mouse xenograft\",\n      \"pmids\": [\"31797958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular links between CEACAM6 and metabolic/autophagy changes unestablished\", \"Proteomic associations not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery of lysine-lactylation stabilizing CEACAM6 downstream of an ALDOB/PDK1/lactate axis, and of a negative-regulatory role in HO-1 antioxidant defense, extended its regulation to metabolic post-translational control and oxidative-stress biology.\",\n      \"evidence\": \"Lactylation detection with lactate measurement and PDK1 analysis in CRC cells; AAV overexpression in human precision-cut lung slices with nitrosative-stress readouts\",\n      \"pmids\": [\"37816733\", \"37219322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lactylation site and its functional consequence on CEACAM6 not mapped\", \"HO-1 regulatory mechanism by a surface GPI protein unclear\", \"Both from single labs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a GPI-anchored extracellular protein lacking a cytoplasmic domain physically couples to intracellular c-Src/FAK/Akt signaling, and the atomic-resolution architecture of its N-domain adhesion and EGFR/integrin co-clustering interfaces, remain unresolved.\",\n      \"evidence\": \"No discovery in the timeline resolves the transmembrane signal-coupling mechanism or provides a structural model of the partner interfaces\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of N-domain partner complexes\", \"Transmembrane coupling mechanism to Src undefined\", \"Lipid-raft/caveolin organization not structurally characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4, 9, 18]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [17, 37, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 26, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 5, 18, 32]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 13, 23, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17, 37, 12]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [18, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CEACAM5\", \"CEACAM8\", \"CEACAM1\", \"EGFR\", \"ITGA5\", \"ITGB1\", \"CD151\", \"SRC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}