{"gene":"MCAM","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1997,"finding":"Enforced expression of MCAM/MUC18 in MCAM-negative primary cutaneous melanoma SB-2 cells increased homotypic adhesion, attachment to human endothelial cells, and invasiveness through Matrigel; anti-MCAM monoclonal antibody reversed these functions, establishing a direct functional role for MCAM in tumor cell adhesion and invasion.","method":"cDNA transfection in melanoma cells, homotypic adhesion assay, endothelial attachment assay, Matrigel invasion assay, antibody blocking, in vivo tumorigenicity/metastasis in nude mice","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (adhesion, invasion, in vivo metastasis) with both gain-of-function (transfection) and loss-of-function (antibody blockade) in the same study; independently corroborated by subsequent labs","pmids":["9187135"],"is_preprint":false},{"year":1997,"finding":"MCAM mediates homotypic cell adhesion through interaction with a heterophilic (non-MCAM) ligand in a divalent-cation-independent, temperature-sensitive manner; homophilic MCAM-MCAM interactions were not supported by mixed aggregation assays with MCAM-expressing and non-expressing cells.","method":"cDNA transfection of MCAM-negative melanoma lines, homotypic aggregation assay, mixed aggregation assay, glycosaminoglycan inhibition assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional adhesion assays with transfected cells, single lab, multiple cell lines tested","pmids":["9398060"],"is_preprint":false},{"year":1998,"finding":"The transcription factor AP-2 directly binds to four AP-2 binding sites in the MCAM/MUC18 promoter and represses MCAM expression; loss of AP-2 in metastatic melanoma cells correlates with MCAM upregulation, and re-expression of AP-2 downregulates MCAM mRNA and protein.","method":"EMSA (electrophoretic mobility shift assay), promoter-reporter (CAT) assay with AP-2 transfection, AP-2 dose-dependent repression assay, Western blot, in vivo tumorigenicity in nude mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct protein-DNA binding by EMSA, reporter assay with mutagenesis context, rescue experiments, multiple orthogonal methods in one rigorous study","pmids":["9632718"],"is_preprint":false},{"year":1996,"finding":"Cyclic AMP elevation upregulates cell-surface MCAM/MUC18 expression and mRNA levels, while phorbol ester treatment downregulates both, demonstrating that MCAM expression is regulated by PKC and cAMP signaling pathways.","method":"cAMP analogue and phorbol ester treatment, flow cytometry for surface expression, Northern blot for mRNA quantification","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pharmacological manipulation with protein and mRNA quantification, single lab, two orthogonal readouts","pmids":["8616875"],"is_preprint":false},{"year":2000,"finding":"The minimal MCAM promoter (-106/+22 bp) contains Sp-1 sites, AP-2 elements, and a CRE element; site-directed mutagenesis showed the CRE is a major transcriptional activator, while the AP-2 site at -23 bp has an inhibitory influence in AP-2-expressing cells, and AP-2 sites at -131 and -302 bp are activating.","method":"Deletion and site-directed mutagenesis of the MCAM promoter, promoter-reporter assay in melanoma/glioma/carcinoma cell lines","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis of promoter elements with functional reporter assays, single lab","pmids":["10938273"],"is_preprint":false},{"year":2003,"finding":"MelCAM/MCAM and AKT engage in reciprocal regulation in melanoma: pharmacological or dominant-negative inhibition of AKT reduces MelCAM expression, while overexpression of constitutively active AKT upregulates MelCAM; conversely, MelCAM overexpression activates endogenous AKT and inhibits pro-apoptotic BAD, increasing cell survival.","method":"Pharmacological AKT inhibition, constitutively active AKT overexpression, dominant-negative PI3K expression, Western blot for MelCAM/AKT/BAD, cell survival assay under stress","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic/pharmacological manipulation, multiple readouts (protein expression, survival), single lab","pmids":["14534536"],"is_preprint":false},{"year":2007,"finding":"The long cytoplasmic isoform MCAM-l (but not MCAM-s) promotes microvilli formation and enhances lymphocyte rolling and adhesion to endothelial monolayers and VCAM-1; mutagenesis identified serine 32 in the MCAM-l cytoplasmic tail (a putative PKC phosphorylation site) as required for MCAM-l–actin cytoskeleton interaction and microvilli induction; PKC inhibition abolished these effects.","method":"Isoform transfection into NK cell line NKL1, shear-stress adhesion assay, scanning electron microscopy, site-directed mutagenesis (S32), PKC inhibitor treatment (chelerythrine chloride), anti-MCAM antibody blockade","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis identifying specific residue, pharmacological confirmation, morphological (EM) and functional (adhesion under shear) orthogonal readouts, single rigorous study","pmids":["17982057"],"is_preprint":false},{"year":2006,"finding":"The long isoform MCAM-l is targeted to the basolateral membrane of polarized MDCK epithelial cells, while MCAM-s is targeted to the apical membrane; a single dileucine motif (positions 41-42) in the MCAM-l cytoplasmic domain is required for basolateral targeting.","method":"Transfection of MCAM isoform–GFP chimeras in polarized MDCK cells, confocal microscopy, site-directed mutagenesis of the dileucine motif","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis identifying specific motif, live-cell confocal imaging in polarized epithelial cells, single lab with orthogonal methods","pmids":["16756976"],"is_preprint":false},{"year":2001,"finding":"HEMCAM/CD146 expression in fibroblasts downregulates cell-surface levels of laminin-binding integrins α3β1, α6β1, α7β1, and fibronectin receptor α5β1; this downregulation occurs at a translational or post-translational level rather than at the transcriptional level, and both isoforms (HEMCAM-s and HEMCAM-l) inhibit integrin-dependent adhesion to laminin-1.","method":"Stable transfection of murine fibroblasts with HEMCAM isoforms, flow cytometry for integrin surface levels, immunoprecipitation, semi-quantitative PCR, Northern blot, cell adhesion/spreading assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (flow cytometry, immunoprecipitation, Northern/PCR, adhesion assay), isoform comparison, identifying translational/post-translational mechanism","pmids":["11329371"],"is_preprint":false},{"year":2012,"finding":"MCAM (CD146) is identified as a receptor for laminin-411 (an isoform of laminin expressed in vascular endothelial basement membranes); purified MCAM-Fc binds laminin-411 with an affinity of 27 nM; MCAM binding was undetectable in tissue from mice with targeted deletion of laminin-411 (confirming laminin-411 as a major tissue ligand); anti-MCAM antibody and soluble MCAM-Fc inhibited T cell adhesion to laminin-411 and reduced TH17 cell infiltration into the CNS in a mouse MS model.","method":"Solid-phase binding assay (MCAM-Fc to purified laminin), biolayer interferometry/affinity measurement (KD = 27 nM), laminin-411 knockout mouse tissue binding, in vitro T cell adhesion assay, in vivo EAE mouse model with antibody blockade","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding with affinity measurement, genetic (knockout) validation, in vitro and in vivo functional confirmation","pmids":["22792325"],"is_preprint":false},{"year":2014,"finding":"Laminin-421, but not laminin-411, binds MCAM (CD146) in solid-phase binding assays; a function-blocking anti-MCAM antibody inhibits tumor cell migration on laminin-421 but not laminin-411, demonstrating that MCAM specifically mediates laminin-421-dependent tumor cell migration.","method":"Solid-phase binding assay (multiple laminin isoforms vs. MCAM), function-blocking antibody to MCAM, tumor cell migration assay on laminin substrates","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and functional blockade, single lab, two orthogonal readouts","pmids":["24951930"],"is_preprint":false},{"year":2015,"finding":"CD146 is identified as a receptor for netrin-1; netrin-1 binds CD146 with high affinity, inducing endothelial cell activation and downstream signaling in a CD146-dependent manner; conditional knockout of cd146 in murine endothelium or disruption of netrin-CD146 interaction by anti-CD146 antibody blocks netrin-1-induced angiogenesis; CD146 knockdown in zebrafish phenocopies netrin-1 loss-of-function vascular defects.","method":"Binding affinity assay, CD146 conditional knockout in mouse endothelium, anti-CD146 antibody blockade, zebrafish knockdown of CD146 and netrin-1a, ectopic netrin-1 overexpression with CD146 knockdown","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 / Strong — receptor-ligand binding, genetic loss-of-function (conditional KO and zebrafish knockdown), antibody blockade, multiple species/models with orthogonal methods","pmids":["25656845"],"is_preprint":false},{"year":2009,"finding":"PAR1 mediates MCAM/MUC18 expression in metastatic melanoma via activation of PAFR and CREB phosphorylation; PAR1 silencing reduces PAFR expression and PAF production; PAFR silencing blocks MCAM expression; re-expression of PAFR in PAR1-silenced cells rescues MCAM expression; this PAR1-PAFR-MCAM pathway mediates melanoma adhesion to endothelial cells, transendothelial migration, and metastatic lung retention.","method":"shRNA silencing of PAR1 and PAFR, PAFR rescue in PAR1-silenced cells, CREB phosphorylation assay, ChIP for CREB binding to MCAM promoter, Western blot, transendothelial migration assay, in vivo metastasis model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (shRNA knockdown + rescue), ChIP demonstrating direct promoter binding, multiple functional readouts, in vivo validation","pmids":["19703903"],"is_preprint":false},{"year":2011,"finding":"MUC18/MCAM regulates Id-1 expression at the transcriptional level via ATF-3; MUC18 silencing upregulates ATF-3 which binds the Id-1 promoter (confirmed by ChIP) and represses Id-1; MUC18 rescue reverses Id-1 and ATF-3 expression patterns; Id-1 overexpression in MUC18-silenced cells restores MMP-2 expression and activity, linking the MUC18–ATF-3–Id-1 axis to melanoma invasion.","method":"Stable shRNA silencing of MUC18, cDNA microarray, ChIP for ATF-3 binding to Id-1 promoter, MUC18 rescue transfection, Id-1 overexpression rescue, MMP-2 activity assay (zymography)","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP with direct promoter binding validation, microarray plus individual gene rescue, functional enzyme activity readout, all in one rigorous study","pmids":["21467165"],"is_preprint":false},{"year":2012,"finding":"MCAM silencing in ovarian cancer cells increases apoptosis and reduces cell spreading and invasion; these effects are associated with dysregulation of small RhoGTPases RhoA and Cdc42, placing MCAM upstream of Rho GTPase signaling.","method":"RNA interference (siRNA) knockdown of MCAM in SKOV-3 cells, apoptosis assay, invasion assay, RhoA/Cdc42 activity measurement","journal":"Tumour biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RhoGTPase pathway placement via knockdown only, no rescue or direct interaction demonstrated","pmids":["22610942"],"is_preprint":false},{"year":2017,"finding":"CD146 functions as a co-receptor of PDGF receptor-β to mediate pericyte recruitment to cerebrovascular endothelial cells during blood-brain barrier development; pericyte-specific Cd146 deletion impairs pericyte coverage and BBB integrity; the attached pericytes in turn downregulate endothelial CD146 by secreting TGF-β1, promoting further BBB maturation; endothelial-specific Cd146 deletion reduces claudin-5 expression and causes BBB breakdown.","method":"Endothelial-specific and pericyte-specific Cd146 conditional knockout mice, TGF-β1 treatment experiments, immunofluorescence, BBB integrity assay, claudin-5 expression analysis","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO in two cell types with distinct phenotypes, ligand (TGF-β1) rescue experiment, multiple orthogonal readouts (pericyte coverage, permeability, claudin-5)","pmids":["28827364"],"is_preprint":false},{"year":2017,"finding":"CD146 on macrophages drives foam cell formation by promoting internalization of scavenger receptor CD36 during lipid uptake; macrophage-specific Cd146 deletion reduces complex plaques in ApoE−/− mice on high-fat diet, with lipid-loaded macrophages exiting plaques; blocking CD146 restores migratory capacity of macrophages toward CCL19/CCL21 that is reduced by oxLDL.","method":"Macrophage-specific Cd146 conditional knockout in ApoE−/− mice, CD36 internalization assay, anti-CD146 antibody treatment, oxLDL stimulation assay, transwell migration assay, atherosclerosis plaque analysis","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — macrophage-specific genetic knockout with clear phenotype, mechanistic link to CD36 internalization, antibody rescue, multiple orthogonal methods","pmids":["28084332"],"is_preprint":false},{"year":2017,"finding":"MCAM mediates chemoresistance in small-cell lung cancer via the PI3K/AKT/SOX2 signaling pathway; MCAM depletion reduces SOX2-dependent upregulation of MRP1/ABCC1 and reduces PI3K/AKT activity, sensitizing cells to chemotherapy; MCAM also modulates lactate production in a metabolic reprogramming context.","method":"MCAM depletion (siRNA/shRNA) in chemoresistant SCLC cells and PDX models, IC50 chemotherapy assay, PI3K/AKT pathway analysis, SOX2/MRP1 expression analysis, metabolomic profiling","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion with functional rescue potential, proteomic and metabolomic profiling, PDX model, single lab","pmids":["28646020"],"is_preprint":false},{"year":2017,"finding":"KDM3A positively regulates MCAM expression in Ewing Sarcoma through both a direct mechanism (modulation of H3K9 methylation at the MCAM promoter) and an indirect mechanism (via the Ets1 transcription factor); MCAM depletion inhibits cell migration and experimental metastasis and partially rescues impaired migration caused by KDM3A knockdown.","method":"Global gene expression profiling (microarray), KDM3A and MCAM siRNA/shRNA knockdown, MCAM rescue in KDM3A-depleted cells, H3K9 methylation analysis at MCAM promoter (ChIP), Ets1 mechanistic analysis, in vitro migration assay, in vivo experimental metastasis model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — epigenetic mechanism confirmed by ChIP, epistasis rescue experiments, in vivo validation, multiple orthogonal methods in one study","pmids":["28319067"],"is_preprint":false},{"year":2017,"finding":"MCAM (CD146) is required for VEGF-C-induced lymphatic sprouting; CD146 selectively activates p38 kinase downstream of VEGF-C to regulate sprouting, and also activates ERK to mediate VEGF-C-regulated proliferation and migration of lymphatic endothelial cells; CD146 knockdown in zebrafish phenocopies VEGF-C loss-of-function defects in lymphangiogenesis.","method":"CD146 knockdown in lymphatic endothelial cells (in vitro sprouting assay), p38 and ERK inhibition/activation, zebrafish CD146 knockdown and VEGF-C manipulation, in vivo lymphangiogenesis assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown in two systems (cell line and zebrafish), pathway kinase analysis, single lab","pmids":["28785085"],"is_preprint":false},{"year":2017,"finding":"MCAM is an independent receptor for FGF4 and a membrane anchor of PLC-γ, acting as an upstream receptor of NFAT and a constitutive activator of JNK; MCAM-mediated vesicular trafficking toward FGF4 and NFAT transcriptional response determines lumenogenesis, while MCAM-driven JNK activation (independently of FGF signals) is required for ciliogenesis; mcam-deficient zebrafish and Xenopus exhibit global left-right asymmetry defects.","method":"Receptor identification for FGF4 (binding assay), PLC-γ co-immunoprecipitation, NFAT reporter assay, JNK activation assay, mcam genetic loss-of-function in zebrafish and Xenopus, lumenogenesis and ciliogenesis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple receptor-ligand interactions validated by co-IP, reporter assays, and genetic loss-of-function in two independent model organisms with distinct phenotypic readouts","pmids":["28589943"],"is_preprint":false},{"year":2017,"finding":"Galectin-3 binds to N-linked glycans on CD146, inducing CD146 dimerization and subsequent AKT signaling activation; siRNA-mediated suppression of CD146 completely abolishes galectin-3-induced secretion of IL-6 and G-CSF from endothelial cells; galectin-3 binding site on CD146 is in Domain 5, which contains poly-N-acetyllactosamine sites.","method":"Galectin-3 affinity purification, co-localization (confocal microscopy), pull-down assay, gel filtration, biolayer interferometry (KD ~1.1 μM), mass spectrometry for N-glycosites, PNGase F treatment, domain deletion mutants, siRNA knockdown, cytokine ELISA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding with affinity measurement, domain-deletion mutagenesis, glycan site mapping by mass spectrometry, functional siRNA rescue, multiple orthogonal methods in one study","pmids":["28364041"],"is_preprint":false},{"year":2018,"finding":"CD146 mediates a cadherin switch during TGF-β-induced EMT: TGF-β induces CD146 expression; CD146 positively correlates with STAT3/Twist activation (which inhibits E-cadherin) and ERK pathway activation (which enhances N-cadherin); CD146-deficient MEFs exhibit decreased motility due to reversion of the cadherin switch.","method":"TGF-β-induced EMT model, CD146 overexpression and knockout (in MEFs), Western blot for STAT3/Twist/ERK/cadherins, cell motility assay, correlation with ovarian cancer patient outcome","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in primary MEFs and gain-of-function in cancer cells, pathway intermediaries measured, single lab","pmids":["29777784"],"is_preprint":false},{"year":2019,"finding":"CD146 and HIF-1α engage in cross-regulation in pulmonary artery smooth muscle cells: CD146 expression reinforces HIF-1α transcriptional program and vice versa; smooth-muscle-specific Cd146 genetic ablation mitigates pulmonary vascular remodeling in chronic hypoxic mice; anti-CD146 antibodies alleviate established pulmonary hypertension and enhance cardiac function in two rodent models.","method":"Smooth-muscle-specific Cd146 conditional knockout, chronic hypoxia mouse model, two pharmacological rodent PH models with anti-CD146 antibody treatment, HIF-1α pathway analysis, hemodynamic measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic KO, two independent disease models with antibody therapeutic intervention, multiple physiological and molecular readouts","pmids":["31391533"],"is_preprint":false},{"year":2019,"finding":"S100A8/A9 binds to MCAM (CD146) on breast cancer cell surface and activates ETV4 downstream; ETV4 transcriptionally upregulates ZEB1 to induce EMT; downregulation of MCAM or ETV4 represses EMT and reduces tumor growth and lung metastasis in vivo.","method":"Co-immunoprecipitation/binding assay (S100A8/A9–MCAM interaction), MCAM and ETV4 knockdown, ZEB1 promoter analysis, EMT marker assessment, in vivo xenograft tumor and metastasis models","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-ligand interaction, genetic epistasis (MCAM→ETV4→ZEB1), in vivo validation, single lab","pmids":["31100639"],"is_preprint":false},{"year":2019,"finding":"ZBTB7A directly binds to the MCAM promoter and transcriptionally represses MCAM expression; ZBTB7A downregulation results in marked upregulation of MCAM and enhanced melanoma cell invasion and metastasis; an inverse correlation between ZBTB7A and MCAM expression is validated in human melanoma specimens.","method":"ChIP demonstrating ZBTB7A binding to MCAM promoter, ZBTB7A knockdown/overexpression, invasion and metastasis assays, human melanoma tissue gene expression analysis","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP, functional genetic manipulation, single lab with two orthogonal methods","pmids":["25995384"],"is_preprint":false},{"year":2021,"finding":"CD146 directly interacts with the SH3 domain of coreceptor-free LCK via its cytoplasmic domain in T cells; CD146 forms monomers and dimers, with dimerized CD146 increasing after TCR ligation; increased dimerized CD146 recruits LCK and promotes LCK autophosphorylation, thereby initiating TCR signaling; CD146 deficiency in T cells substantially impairs thymocyte development and peripheral activation; in tumor models, CD146 deficiency impairs antitumor T cell responses.","method":"Co-immunoprecipitation (CD146–LCK SH3 domain interaction), CD146 cytoplasmic domain deletion analysis, native PAGE and crosslinking for dimer analysis, T cell-specific Cd146 conditional knockout mice, thymocyte development assay, TCR signaling assays, tumor models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct protein-protein interaction mapped to SH3 domain, dimerization-dependent LCK activation mechanism, T cell-specific KO with defined developmental and functional phenotypes, in vivo validation","pmids":["34491908"],"is_preprint":false},{"year":2018,"finding":"CD146 interacts with the CD146 ectodomain via galectin-3 binding; galectin-3 binds CD146 ectodomain with KD ~1.1 μM (biolayer interferometry); galectin-3 interaction requires N-glycans on CD146, with Domain 5 (containing poly-N-acetyllactosamine sites) as the binding site; CD146 knockdown significantly attenuates galectin-3-mediated endothelial cell migration.","method":"Galectin-3 pulldown assay, gel filtration, biolayer interferometry, N-glycan removal (PNGase F), domain deletion mutants, CD146 knockdown, endothelial cell migration assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding with affinity measurement, domain mapping, functional knockdown; overlaps mechanistically with PMID 28364041 from a different lab providing partial replication","pmids":["29741757"],"is_preprint":false},{"year":2021,"finding":"HERV-K dUTPase interaction with MCAM is necessary to upregulate VCAM1 in pulmonary arterial endothelial cells; MCAM engagement by HERV-K dUTPase activates p-p38/NF-κB and pERK1/2-ATF2 signaling to increase VCAM1, contributing to endothelial mesenchymal transition.","method":"HERV-K dUTPase overexpression in monocytes, extracellular vesicle application to endothelial cells, MCAM blockade/knockdown, p38/NF-κB and ERK/ATF2 pathway analysis, VCAM1 measurement, EndMT marker analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor engagement established by knockdown with functional rescue, signaling pathway intermediaries measured, single lab","pmids":["34185707"],"is_preprint":false},{"year":2023,"finding":"Netrin-1 induces formation of a CD146-Gαi1/3-Gab1 complex: Gαi1/3 associate with CD146 upon Netrin-1 stimulation, facilitating CD146 internalization, Gab1 recruitment, and downstream Akt-mTOR and Erk activation; silencing or knockout of Gαi1/3 inhibits Netrin-1-induced endothelial cell proliferation, migration, and tube formation; endothelial Gαi1/3 knockdown in mice inhibits Netrin-1-induced retinal angiogenesis.","method":"Co-immunoprecipitation (Gαi1/3–CD146 interaction), Gαi1/3 siRNA/shRNA and knockout in MEFs and endothelial cells, Gαi1/3 dominant-negative mutants, Gab1 knockout, CD146 internalization assay, Akt/ERK phosphorylation, HUVEC functional assays (proliferation, migration, tube formation), in vivo retinal angiogenesis (AAV shRNA delivery in mice)","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — complex formation by Co-IP, multiple genetic perturbations (KO, siRNA, dominant-negative), in vitro and in vivo orthogonal validation in two species","pmids":["37153740"],"is_preprint":false},{"year":2014,"finding":"MUC18 overexpression in airway epithelial cells promotes IL-8 production while inhibiting IFN-β expression after polyI:C stimulation or HRV infection; increased serine phosphorylation of MUC18 correlates with its pro-inflammatory function; ERK inhibition reduces MUC18 serine phosphorylation and IL-8 production, placing MUC18 in an ERK-dependent pro-inflammatory signaling pathway.","method":"Lentiviral MUC18 overexpression in primary airway epithelial cells, polyI:C stimulation and HRV infection, cytokine ELISA (IL-8, IFN-β), serine phosphorylation analysis, ERK inhibitor treatment","journal":"Journal of clinical & cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function overexpression with pharmacological validation (ERK inhibitor), dual cytokine readouts, single lab","pmids":["25478290"],"is_preprint":false},{"year":2012,"finding":"MUC18/CD146 amplifies proinflammatory responses in alveolar macrophages during bacterial infection; Muc18−/− mice show lower lung KC, TNF-α, and neutrophil recruitment after Mycoplasma pneumoniae infection; adenovirus-mediated MUC18 gene transfer into Muc18−/− alveolar macrophages restores KC production; MUC18 enhances NF-κB activation in macrophages.","method":"Muc18 knockout mice, intratracheal M. pneumoniae infection, cytokine/chemokine ELISA, adenoviral MUC18 gene transfer rescue, NF-κB activation assay","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with in vivo infection model, adenoviral rescue confirming the specific role of MUC18, NF-κB mechanistic link, multiple orthogonal readouts","pmids":["23256918"],"is_preprint":false},{"year":2022,"finding":"ST6GAL1-mediated α2,6-sialylation of MCAM inhibits MCAM interaction with galectin-3 and decreases MCAM expression on the cell surface, thereby suppressing HCC cell migration and invasion; sialylated MCAM levels negatively correlate with tumor malignancy in HCC patients.","method":"Metabolic labeling-based glycoproteomics, ST6GAL1 overexpression, co-immunoprecipitation (MCAM–galectin-3 after sialylation manipulation), flow cytometry for surface MCAM, migration/invasion assays in vitro, in vivo xenograft metastasis model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — glycoproteomics plus direct Co-IP of modified MCAM, functional in vitro and in vivo validation, single lab","pmids":["36528750"],"is_preprint":false},{"year":2022,"finding":"CD146 forms a co-receptor complex with integrin β1 and activates YAP signaling by regulating LATS1 phosphorylation; this drives nuclear translocation of YAP, promotes DNA damage repair, EMT, and stemness, and confers radioresistance; dual inhibition of CD146 and integrin β1 synergistically increases breast cancer sensitivity to radiotherapy.","method":"Co-immunoprecipitation (CD146–integrin β1), CD146 knockdown/overexpression, LATS1/YAP phosphorylation and localization analysis, DNA damage repair assay, in vitro and in vivo radioresistance models, dual inhibition experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating complex, mechanistic LATS1-YAP pathway analysis, functional in vivo validation, single lab","pmids":["35944750"],"is_preprint":false},{"year":2023,"finding":"CD146 acts as a protective shield against DCBLD2 protein degradation in breast phyllodes tumor cells; by preventing DCBLD2 degradation, CD146 activates the PI3K/AKT signaling pathway, enhancing malignant behaviors; this was demonstrated by co-immunoprecipitation and pull-down assays identifying the CD146–DCBLD2 interaction.","method":"Co-immunoprecipitation, pull-down assay (CD146–DCBLD2 interaction), transcriptome sequencing, proteomic analysis, DCBLD2 degradation assay, PI3K/AKT pathway analysis, organoid and PDX models with anti-CD146 antibody AA98","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-protein interaction by Co-IP and pulldown, functional pathway validation, in vivo organoid/PDX model, single lab","pmids":["37856423"],"is_preprint":false},{"year":2023,"finding":"CD146 inhibits TMEM176B (an immunoregulatory cation channel) activity in tumor-associated macrophages to facilitate NLRP3 inflammasome activation; CD146 expression in macrophages is negatively controlled by STAT3 signaling; CD146+ TAMs exert antitumor activity, and reducing this population promotes myeloid-derived suppressor cell recruitment via JNK signaling.","method":"Flow cytometry and single-cell analysis of CD146+ TAM subpopulation, CD146 and STAT3 knockdown/manipulation, TMEM176B inhibitor treatment, NLRP3 inflammasome activation assay, JNK signaling analysis, in vivo tumor models","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — STAT3-CD146 genetic regulation, mechanistic TMEM176B-NLRP3 link with pharmacological inhibitor, multiple in vivo models, single lab","pmids":["37308559"],"is_preprint":false},{"year":2014,"finding":"TNF-α upregulates endothelial CD146 expression through NF-κB transactivation; endothelial-specific Cd146 conditional knockout significantly ameliorates colitis severity and reduces tumor incidence in models of colitis-associated colorectal carcinogenesis; endothelial CD146 promotes both angiogenesis and proinflammatory leukocyte extravasation.","method":"Endothelial-specific Cd146 conditional knockout mice, TNF-α stimulation with NF-κB pathway analysis, two murine colitis models, colitis-associated carcinogenesis model, anti-CD146 antibody treatment","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — endothelial-specific genetic KO, transcription factor (NF-κB) mechanism, multiple disease models with antibody therapeutic confirmation, orthogonal readouts","pmids":["24767106"],"is_preprint":false},{"year":2018,"finding":"CD146 blockade specifically impedes T cell migration across the choroid plexus (CP) into the CNS; MCAM-expressing T cells migrate through the CP where laminin-411 is expressed in endothelial basement membranes; anti-MCAM antibody reduces in vitro transmigration of MCAM-expressing T cells across laminin α4-expressing barriers and delayed disease onset in CD4::Itga4−/− mice when VLA-4 is absent.","method":"Anti-MCAM antibody treatment in murine EAE and CP-dependent CNS inflammation models, T cell-specific α4-integrin conditional KO, in vitro human T cell transmigration assay through fibroblast-derived ECM and brain endothelial monolayer, laminin α4 detection in mouse and human CP tissue","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo models, genetic (conditional KO) plus antibody pharmacological approach, translation to human in vitro system, anatomical specificity (CP route) established","pmids":["30134924"],"is_preprint":false},{"year":1997,"finding":"MUC18/MCAM (CD146) is neo-expressed on human T cells upon activation (reaching maximum at day 3 post-PHA stimulation); MUC18/MCAM is expressed on CD3+ T cells in delayed-type hypersensitivity lesions, synovial fluid T cells in rheumatoid arthritis, and T leukemia cells, suggesting a role in activated T cell extravasation and homing.","method":"mAb characterization (molecular weight, cDNA-transfected L cell reactivity, N-terminal sequencing, immunoblot), flow cytometry of activated peripheral blood T cells, immunohistochemistry of tissue specimens","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple antibody validation methods, in vitro activation kinetics, in vivo tissue localization, single lab","pmids":["9036955"],"is_preprint":false},{"year":2014,"finding":"Semaphorin 3A (Sema3A) upregulates MelCAM/MCAM expression through a NRP-1–PTEN–FOXO3a pathway; FOXO3a directly regulates MelCAM at the transcriptional level (demonstrated by ChIP and EMSA), and Sema3A-induced NRP-1-mediated PTEN-dependent FOXO3a activation results in MelCAM upregulation, suppressing breast cancer cell migration, tumor growth, and angiogenesis.","method":"Sema3A treatment, NRP-1/PTEN/FOXO3a knockdown/overexpression, ChIP for FOXO3a binding to MelCAM promoter, EMSA, nuclear translocation analysis, in vivo tumor and angiogenesis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP and EMSA establishing direct transcription factor-promoter binding, genetic pathway manipulation, single lab","pmids":["24727891"],"is_preprint":false},{"year":2020,"finding":"SOX18 transcriptionally activates MCAM by directly binding to the MCAM promoter; MCAM knockdown decreases SOX18-mediated gastric cancer invasion and metastasis, while MCAM overexpression rescues the invasion/metastasis defect caused by SOX18 inhibition; CCL7-CCR1-ERK/ELK1-SOX18 forms a positive feedback loop that drives GC metastasis.","method":"ChIP for SOX18 binding to MCAM promoter, MCAM and CCL7 knockdown/overexpression in SOX18 manipulation context, in vitro invasion assay, in vivo metastasis models, ERK/ELK1 pathway analysis, CCR1 inhibitor treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct promoter binding, epistasis rescue experiments, in vivo validation, single lab","pmids":["32616889"],"is_preprint":false}],"current_model":"MCAM/CD146/MUC18 is a transmembrane immunoglobulin-superfamily glycoprotein that functions as a multifunctional signaling receptor and adhesion molecule: it acts as a high-affinity receptor for netrin-1 (activating Gαi1/3-Gab1-Akt-ERK signaling), VEGF-C (activating p38 and ERK for lymphangiogenesis), FGF4 (activating PLC-γ/NFAT for lumenogenesis), laminin-411/421, and galectin-3 (via N-glycans on Domain 5, inducing CD146 dimerization and AKT activation); its long cytoplasmic isoform (MCAM-l) uses serine 32 and a dileucine motif for basolateral targeting and PKC-dependent actin/microvilli regulation; in T cells, dimerized CD146 recruits and activates LCK via its SH3 domain to initiate TCR signaling; in macrophages it drives CD36 internalization and foam cell formation; in endothelial cells it co-receptors with PDGFR-β for pericyte recruitment and with integrin β1 for YAP-LATS1-mediated radioresistance; transcriptionally MCAM is regulated by AP-2 (repressor), CREB/cAMP, ZBTB7A (repressor), KDM3A (via H3K9 demethylation and Ets1), SOX18, and FOXO3a downstream of Sema3A; MCAM expression promotes EMT through CD146-STAT3/Twist/ERK-cadherin switch and the S100A8/A9-MCAM-ETV4-ZEB1 axis, and drives Id-1 expression via ATF-3 suppression to enhance MMP-2-dependent invasion."},"narrative":{"mechanistic_narrative":"MCAM (CD146/MUC18) is a transmembrane immunoglobulin-superfamily cell-surface receptor that integrates adhesion and growth-factor signaling to drive tumor invasion, vascular morphogenesis, and immune cell function [PMID:9187135, PMID:25656845]. As an adhesion molecule it engages heterophilic ligands—including the basement-membrane laminins 411 and 421 (KD ~27 nM for laminin-411)—to mediate cell attachment, T cell transmigration across vascular and choroid-plexus barriers into the CNS, and tumor cell migration [PMID:9398060, PMID:22792325, PMID:24951930, PMID:30134924]. MCAM functions as a multiligand signaling receptor: it binds netrin-1 to nucleate a Gαi1/3–Gab1 complex that drives CD146 internalization and Akt/mTOR–ERK-dependent angiogenesis [PMID:25656845, PMID:37153740], serves as an independent FGF4 receptor and PLC-γ anchor controlling NFAT-dependent lumenogenesis and JNK-dependent ciliogenesis [PMID:28589943], and is required for VEGF-C-induced lymphatic sprouting through p38 and ERK [PMID:28785085]. Galectin-3 binding to poly-N-acetyllactosamine N-glycans on Domain 5 induces CD146 dimerization and downstream AKT activation and endothelial cytokine secretion, a process antagonized by ST6GAL1-mediated α2,6-sialylation [PMID:28364041, PMID:29741757, PMID:36528750]. Two cytoplasmic isoforms are functionally distinct: the long isoform MCAM-l is targeted basolaterally via a dileucine motif and promotes PKC- and serine-32-dependent actin/microvilli remodeling and lymphocyte rolling, whereas the short isoform localizes apically [PMID:17982057, PMID:16756976]. In immune cells, activation-induced CD146 dimerization recruits and activates LCK through its SH3 domain to initiate TCR signaling and support thymocyte development and antitumor T cell responses, and MCAM amplifies NF-κB-dependent proinflammatory responses in macrophages and airway epithelium [PMID:34491908, PMID:23256918, PMID:25478290]. CD146 acts as a co-receptor with PDGFR-β for pericyte recruitment and blood-brain-barrier maturation and with integrin β1 for YAP-LATS1-driven radioresistance, and in macrophages it promotes CD36 internalization and foam cell formation in atherosclerosis [PMID:28827364, PMID:35944750, PMID:28084332]. MCAM expression promotes EMT and invasion through cadherin switching via STAT3/Twist and ERK, the S100A8/A9–MCAM–ETV4–ZEB1 axis, and an ATF-3–Id-1–MMP-2 axis [PMID:29777784, PMID:31100639, PMID:21467165]. Its transcription is repressed by AP-2 and ZBTB7A and activated by CRE/CREB, KDM3A-mediated H3K9 demethylation, SOX18, and Sema3A-driven FOXO3a [PMID:9632718, PMID:25995384, PMID:10938273, PMID:28319067, PMID:32616889, PMID:24727891].","teleology":[{"year":1997,"claim":"Established that MCAM is not merely a marker but a functional driver of tumor cell adhesion and invasion, defining its core biological role.","evidence":"Gain-of-function transfection plus antibody blockade in melanoma cells with adhesion, Matrigel invasion, and in vivo metastasis readouts","pmids":["9187135"],"confidence":"High","gaps":["Ligand identity for the adhesion function not defined","Signaling pathway downstream of MCAM not addressed"]},{"year":1997,"claim":"Determined that MCAM-mediated adhesion is heterophilic rather than homophilic, reframing the search for its binding partners toward non-MCAM ligands.","evidence":"Homotypic and mixed aggregation assays with MCAM-expressing and non-expressing transfected melanoma lines","pmids":["9398060"],"confidence":"Medium","gaps":["The heterophilic ligand itself was not identified","Single-lab functional inference without ligand isolation"]},{"year":1997,"claim":"Showed MCAM is induced on activated T cells and present in inflammatory lesions, extending its function from tumor biology to immune cell homing.","evidence":"mAb characterization, flow cytometry of activated T cells, immunohistochemistry of DTH/RA tissue","pmids":["9036955"],"confidence":"Medium","gaps":["Mechanistic role in extravasation inferred from localization, not tested","Ligand engaged on activated T cells unknown"]},{"year":2000,"claim":"Defined the cis-regulatory architecture of the MCAM promoter, resolving how transcription factors set expression levels in tumor cells.","evidence":"Promoter deletion and site-directed mutagenesis with reporter assays across multiple tumor cell lines; AP-2 binding shown directly by EMSA and CAT reporter rescue (1998)","pmids":["10938273","9632718","8616875"],"confidence":"High","gaps":["Endogenous physiological signals controlling each element not fully mapped","Chromatin context not examined"]},{"year":2001,"claim":"Revealed that MCAM modulates integrin surface levels post-transcriptionally, providing a mechanism for its regulation of laminin and fibronectin adhesion.","evidence":"Stable HEMCAM isoform transfection in fibroblasts with flow cytometry, immunoprecipitation, and adhesion assays","pmids":["11329371"],"confidence":"High","gaps":["Molecular mechanism of post-translational integrin downregulation undefined","Direct MCAM-integrin interaction not demonstrated here"]},{"year":2007,"claim":"Mapped isoform-specific cytoplasmic determinants (dileucine motif, serine 32) that route MCAM to distinct membrane domains and couple it to PKC-dependent actin remodeling.","evidence":"Isoform-GFP chimeras in polarized MDCK cells and NK cells, site-directed mutagenesis, PKC inhibition, scanning EM, shear-stress adhesion (2006-2007)","pmids":["16756976","17982057"],"confidence":"High","gaps":["Cytoskeletal adaptor linking MCAM-l tail to actin not identified","Kinase directly phosphorylating S32 not pinned down"]},{"year":2011,"claim":"Connected MCAM signaling to a transcriptional invasion program, showing it controls invasion via ATF-3-mediated Id-1 and MMP-2 regulation.","evidence":"shRNA silencing with rescue, microarray, ChIP for ATF-3 on Id-1 promoter, zymography in melanoma; AKT/BAD survival axis shown earlier (2003)","pmids":["21467165","14534536"],"confidence":"High","gaps":["How surface MCAM transmits signal to ATF-3 not resolved","Receptor proximal events upstream of this axis unknown"]},{"year":2012,"claim":"Identified laminin-411 as a high-affinity MCAM ligand with genetically validated specificity, supplying the long-sought heterophilic partner for MCAM-mediated T cell adhesion.","evidence":"Solid-phase binding with KD measurement, laminin-411 knockout tissue binding, EAE model with antibody blockade","pmids":["22792325"],"confidence":"High","gaps":["Structural basis of MCAM-laminin recognition not solved","Signaling consequences of laminin engagement not detailed"]},{"year":2014,"claim":"Extended the ligand repertoire to laminin-421 with isoform selectivity, and defined transcriptional regulators (Sema3A-FOXO3a) that can suppress MCAM in tumor contexts.","evidence":"Solid-phase binding and function-blocking antibody migration assays; ChIP/EMSA for FOXO3a; airway/macrophage inflammatory readouts","pmids":["24951930","24727891","25478290","23256918"],"confidence":"Medium","gaps":["Distinct downstream signaling for laminin-411 versus -421 not separated","Context determining MCAM pro- versus anti-tumor role unclear"]},{"year":2015,"claim":"Established MCAM as a bona fide netrin-1 receptor driving angiogenesis, transforming it from an adhesion molecule into a defined signaling receptor.","evidence":"Binding affinity assay, endothelial conditional knockout, antibody blockade, zebrafish phenocopy of netrin-1 loss","pmids":["25656845"],"confidence":"High","gaps":["Immediate cytoplasmic transducers were not yet defined (later resolved as Gαi1/3-Gab1)","Stoichiometry of netrin-CD146 complex unknown"]},{"year":2017,"claim":"Diversified MCAM into a multiligand receptor hub, showing it transduces FGF4 (PLC-γ/NFAT/JNK), VEGF-C (p38/ERK), and galectin-3 (dimerization/AKT) signals for distinct morphogenetic and inflammatory outputs.","evidence":"Receptor binding assays, co-IP, reporter and kinase assays, domain-deletion and glycan mapping, zebrafish/Xenopus loss-of-function; co-receptor roles with PDGFR-β and CD36-driven foam cell formation in conditional KO mice","pmids":["28589943","28785085","28364041","28827364","28084332","28646020","28319067"],"confidence":"High","gaps":["How a single receptor selects among multiple ligand-specific signaling outputs is unresolved","Whether ligands compete or cooperate at the cell surface not addressed"]},{"year":2019,"claim":"Defined CD146 as an amplifier of pathological vascular and inflammatory programs through HIF-1α cross-regulation, NF-κB-driven endothelial inflammation, and the S100A8/A9-ETV4-ZEB1 EMT axis.","evidence":"Cell-type-specific conditional knockouts, disease models with antibody therapy, co-IP, and epistasis rescue across pulmonary hypertension, colitis, and breast cancer","pmids":["31391533","29777784","31100639","24767106","25995384"],"confidence":"High","gaps":["Whether these axes share common proximal CD146 signaling not established","Tissue-specific determinants of CD146 output not defined"]},{"year":2021,"claim":"Resolved a direct cytoplasmic effector mechanism in T cells, showing dimerized CD146 recruits and activates LCK via its SH3 domain to initiate TCR signaling.","evidence":"Co-IP mapping to LCK SH3 domain, native PAGE/crosslinking dimer analysis, T cell-specific conditional KO with developmental and antitumor phenotypes; HERV-K dUTPase-MCAM endothelial signaling in parallel","pmids":["34491908","34185707"],"confidence":"High","gaps":["Trigger linking TCR ligation to CD146 dimerization not fully defined","Relationship between LCK recruitment and ectodomain ligands unclear"]},{"year":2023,"claim":"Filled in proximal signaling and protein-stability mechanisms, identifying the netrin-1-induced CD146-Gαi1/3-Gab1 complex, the CD146-integrin β1-YAP radioresistance axis, and CD146 stabilization of DCBLD2.","evidence":"Co-IP and pull-down, multiple genetic perturbations, in vitro and in vivo angiogenesis/radioresistance/tumor models; SOX18 and ST6GAL1 regulatory studies; CD146-TMEM176B-NLRP3 in TAMs","pmids":["37153740","35944750","37856423","32616889","36528750","37308559"],"confidence":"High","gaps":["Structural assembly of these CD146 complexes not solved","How sialylation, dimerization, and partner choice are coordinated in vivo unknown"]},{"year":null,"claim":"How a single receptor discriminates among its many ligands (netrin-1, FGF4, VEGF-C, laminins, galectin-3) and co-receptors (PDGFR-β, integrin β1) to select specific downstream programs remains the central open question.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of liganded CD146 complexes","Rules governing ligand-specific versus shared signaling outputs undefined","Mechanism coupling ectodomain ligand engagement to cytoplasmic LCK/Gαi1/3 effectors not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[11,20,19,21]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[11,20,29,26]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,9,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,15,33]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,7,11,21,26]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,20,29,26]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[9,10,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26,31,16,37,36]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,13,17,33,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[20,15,19,11]}],"complexes":[],"partners":["NTN1","FGF4","VEGFC","LGALS3","LCK","PDGFRB","ITGB1","DCBLD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43121","full_name":"Cell surface glycoprotein MUC18","aliases":["Cell surface glycoprotein P1H12","Melanoma cell adhesion molecule","Melanoma-associated antigen A32","Melanoma-associated antigen MUC18","S-endo 1 endothelial-associated antigen"],"length_aa":646,"mass_kda":71.6,"function":"Plays a role in cell adhesion, and in cohesion of the endothelial monolayer at intercellular junctions in vascular tissue. Its expression may allow melanoma cells to interact with cellular elements of the vascular system, thereby enhancing hematogeneous tumor spread. Could be an adhesion molecule active in neural crest cells during embryonic development. Acts as a surface receptor that triggers tyrosine phosphorylation of FYN and PTK2/FAK1, and a transient increase in the intracellular calcium concentration","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P43121/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MCAM","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MCAM","total_profiled":1310},"omim":[{"mim_id":"155735","title":"MELANOMA ADHESION MOLECULE; MCAM","url":"https://www.omim.org/entry/155735"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adipose tissue","ntpm":312.2},{"tissue":"blood vessel","ntpm":1211.4}],"url":"https://www.proteinatlas.org/search/MCAM"},"hgnc":{"alias_symbol":["MUC18","CD146","MelCAM","METCAM","HEMCAM"],"prev_symbol":[]},"alphafold":{"accession":"P43121","domains":[{"cath_id":"2.60.40.10","chopping":"33-132","consensus_level":"high","plddt":85.8907,"start":33,"end":132},{"cath_id":"2.60.40.10","chopping":"139-245","consensus_level":"high","plddt":95.0924,"start":139,"end":245},{"cath_id":"2.60.40.10","chopping":"251-340","consensus_level":"high","plddt":91.2637,"start":251,"end":340},{"cath_id":"2.60.40.10","chopping":"346-428","consensus_level":"high","plddt":93.3308,"start":346,"end":428},{"cath_id":"2.60.40.10","chopping":"434-515","consensus_level":"high","plddt":88.1939,"start":434,"end":515}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43121","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43121-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43121-F1-predicted_aligned_error_v6.png","plddt_mean":80.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MCAM","jax_strain_url":"https://www.jax.org/strain/search?query=MCAM"},"sequence":{"accession":"P43121","fasta_url":"https://rest.uniprot.org/uniprotkb/P43121.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43121/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43121"}},"corpus_meta":[{"pmid":"23266426","id":"PMC_23266426","title":"CD146, a multi-functional molecule beyond adhesion.","date":"2012","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/23266426","citation_count":236,"is_preprint":false},{"pmid":"9187135","id":"PMC_9187135","title":"Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis.","date":"1997","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9187135","citation_count":207,"is_preprint":false},{"pmid":"10451481","id":"PMC_10451481","title":"The role of CD146 (Mel-CAM) in biology and pathology.","date":"1999","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10451481","citation_count":202,"is_preprint":false},{"pmid":"28827364","id":"PMC_28827364","title":"CD146 coordinates brain endothelial cell-pericyte communication for blood-brain barrier development.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28827364","citation_count":168,"is_preprint":false},{"pmid":"28084332","id":"PMC_28084332","title":"Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis.","date":"2017","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28084332","citation_count":155,"is_preprint":false},{"pmid":"9632718","id":"PMC_9632718","title":"Loss of AP-2 results in up-regulation of MCAM/MUC18 and an increase in tumor growth and metastasis of human melanoma cells.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9632718","citation_count":131,"is_preprint":false},{"pmid":"12208768","id":"PMC_12208768","title":"Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma.","date":"2002","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12208768","citation_count":128,"is_preprint":false},{"pmid":"32782280","id":"PMC_32782280","title":"CD146, from a melanoma cell adhesion molecule to a signaling receptor.","date":"2020","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32782280","citation_count":122,"is_preprint":false},{"pmid":"8471835","id":"PMC_8471835","title":"Direct correlation between MUC18 expression and metastatic potential of human melanoma cells.","date":"1993","source":"Melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/8471835","citation_count":120,"is_preprint":false},{"pmid":"25656845","id":"PMC_25656845","title":"CD146 acts as a novel receptor for netrin-1 in promoting angiogenesis and vascular development.","date":"2015","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/25656845","citation_count":119,"is_preprint":false},{"pmid":"31391533","id":"PMC_31391533","title":"CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31391533","citation_count":112,"is_preprint":false},{"pmid":"19356677","id":"PMC_19356677","title":"Towards understanding the mode of action of the multifaceted cell adhesion receptor CD146.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19356677","citation_count":104,"is_preprint":false},{"pmid":"22792325","id":"PMC_22792325","title":"Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22792325","citation_count":101,"is_preprint":false},{"pmid":"9036955","id":"PMC_9036955","title":"MUC18/MCAM (CD146), an activation antigen of human T lymphocytes.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9036955","citation_count":100,"is_preprint":false},{"pmid":"17982057","id":"PMC_17982057","title":"Dual role of melanoma cell adhesion molecule (MCAM)/CD146 in lymphocyte endothelium interaction: MCAM/CD146 promotes rolling via microvilli induction in lymphocyte and is an endothelial adhesion receptor.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17982057","citation_count":99,"is_preprint":false},{"pmid":"8978830","id":"PMC_8978830","title":"HEMCAM, an adhesion molecule expressed by c-kit+ hemopoietic progenitors.","date":"1996","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8978830","citation_count":86,"is_preprint":false},{"pmid":"28646020","id":"PMC_28646020","title":"MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28646020","citation_count":85,"is_preprint":false},{"pmid":"11722842","id":"PMC_11722842","title":"Isolation and characterization of the major form of human MUC18 cDNA gene and correlation of MUC18 over-expression in prostate cancer cell lines and tissues with malignant progression.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11722842","citation_count":82,"is_preprint":false},{"pmid":"9284823","id":"PMC_9284823","title":"The cell-cell adhesion receptor Mel-CAM acts as a tumor suppressor in breast carcinoma.","date":"1997","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/9284823","citation_count":78,"is_preprint":false},{"pmid":"26753846","id":"PMC_26753846","title":"CD146/MCAM defines functionality of human bone marrow stromal stem cell populations.","date":"2016","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/26753846","citation_count":76,"is_preprint":false},{"pmid":"9398060","id":"PMC_9398060","title":"Melanoma progression-associated glycoprotein MUC18/MCAM mediates homotypic cell adhesion through interaction with a heterophilic ligand.","date":"1997","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/9398060","citation_count":74,"is_preprint":false},{"pmid":"7923217","id":"PMC_7923217","title":"MUC18, a melanoma-progression associated molecule, and its potential role in tumor vascularization and hematogenous spread.","date":"1994","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7923217","citation_count":74,"is_preprint":false},{"pmid":"31070478","id":"PMC_31070478","title":"CD146 (Cluster of Differentiation 146).","date":"2019","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31070478","citation_count":71,"is_preprint":false},{"pmid":"14534536","id":"PMC_14534536","title":"Reciprocal regulation of MelCAM and AKT in human melanoma.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/14534536","citation_count":70,"is_preprint":false},{"pmid":"28364041","id":"PMC_28364041","title":"Galectin-3 interacts with the cell-surface glycoprotein CD146 (MCAM, MUC18) and induces secretion of metastasis-promoting cytokines from vascular endothelial cells.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28364041","citation_count":68,"is_preprint":false},{"pmid":"19703903","id":"PMC_19703903","title":"Crosstalk between protease-activated receptor 1 and platelet-activating factor receptor regulates melanoma cell adhesion molecule (MCAM/MUC18) expression and melanoma metastasis.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19703903","citation_count":66,"is_preprint":false},{"pmid":"12632016","id":"PMC_12632016","title":"Expression of the cell adhesion molecule CD146/MCAM in non-small cell lung cancer.","date":"2003","source":"Analytical cellular pathology : the journal of the European Society for Analytical Cellular Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12632016","citation_count":65,"is_preprint":false},{"pmid":"26941359","id":"PMC_26941359","title":"Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells.","date":"2016","source":"Stem cells translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26941359","citation_count":62,"is_preprint":false},{"pmid":"24951930","id":"PMC_24951930","title":"Laminins 411 and 421 differentially promote tumor cell migration via α6β1 integrin and MCAM (CD146).","date":"2014","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/24951930","citation_count":62,"is_preprint":false},{"pmid":"28319067","id":"PMC_28319067","title":"The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28319067","citation_count":62,"is_preprint":false},{"pmid":"14980717","id":"PMC_14980717","title":"Ectopical expression of human MUC18 increases metastasis of human prostate cancer cells.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/14980717","citation_count":61,"is_preprint":false},{"pmid":"17024104","id":"PMC_17024104","title":"Immunization against MUC18/MCAM, a novel antigen that drives melanoma invasion and metastasis.","date":"2006","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/17024104","citation_count":54,"is_preprint":false},{"pmid":"24727891","id":"PMC_24727891","title":"Semaphorin 3A upregulates FOXO 3a-dependent MelCAM expression leading to attenuation of breast tumor growth and angiogenesis.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24727891","citation_count":53,"is_preprint":false},{"pmid":"22610942","id":"PMC_22610942","title":"MCAM is a novel metastasis marker and regulates spreading, apoptosis and invasion of ovarian cancer cells.","date":"2012","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22610942","citation_count":53,"is_preprint":false},{"pmid":"27406247","id":"PMC_27406247","title":"CD146 Expression Influences Periapical Cyst Mesenchymal Stem Cell Properties.","date":"2016","source":"Stem cell reviews and reports","url":"https://pubmed.ncbi.nlm.nih.gov/27406247","citation_count":52,"is_preprint":false},{"pmid":"31002939","id":"PMC_31002939","title":"CD146/MCAM distinguishes stem cell subpopulations with distinct migration and regenerative potential in degenerative intervertebral discs.","date":"2019","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/31002939","citation_count":51,"is_preprint":false},{"pmid":"31100639","id":"PMC_31100639","title":"Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness.","date":"2019","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/31100639","citation_count":51,"is_preprint":false},{"pmid":"33352759","id":"PMC_33352759","title":"Role of CD146 (MCAM) in Physiological and Pathological Angiogenesis-Contribution of New Antibodies for Therapy.","date":"2020","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/33352759","citation_count":50,"is_preprint":false},{"pmid":"29777784","id":"PMC_29777784","title":"CD146 mediates an E-cadherin-to-N-cadherin switch during TGF-β signaling-induced epithelial-mesenchymal transition.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29777784","citation_count":49,"is_preprint":false},{"pmid":"11329371","id":"PMC_11329371","title":"HEMCAM/CD146 downregulates cell surface expression of beta1 integrins.","date":"2001","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11329371","citation_count":48,"is_preprint":false},{"pmid":"31065511","id":"PMC_31065511","title":"CD146-Targeted Multimodal Image-Guided Photoimmunotherapy of Melanoma.","date":"2019","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/31065511","citation_count":47,"is_preprint":false},{"pmid":"10362144","id":"PMC_10362144","title":"Influence of MUC18/MCAM/CD146 expression on human melanoma growth and metastasis in SCID mice.","date":"1999","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10362144","citation_count":46,"is_preprint":false},{"pmid":"8292890","id":"PMC_8292890","title":"The progression associated antigen MUC18: a unique member of the immunoglobulin supergene family.","date":"1993","source":"Melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/8292890","citation_count":46,"is_preprint":false},{"pmid":"21450088","id":"PMC_21450088","title":"Up-regulation of METCAM/MUC18 promotes motility, invasion, and tumorigenesis of human breast cancer cells.","date":"2011","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21450088","citation_count":44,"is_preprint":false},{"pmid":"21334670","id":"PMC_21334670","title":"Enforced expression of METCAM/MUC18 increases tumorigenesis of human prostate cancer LNCaP cells in nude mice.","date":"2011","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/21334670","citation_count":40,"is_preprint":false},{"pmid":"18958886","id":"PMC_18958886","title":"Mouse CD146/MCAM is a marker of natural killer cell maturation.","date":"2008","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18958886","citation_count":40,"is_preprint":false},{"pmid":"37308559","id":"PMC_37308559","title":"A subpopulation of CD146+ macrophages enhances antitumor immunity by activating the NLRP3 inflammasome.","date":"2023","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37308559","citation_count":39,"is_preprint":false},{"pmid":"21467165","id":"PMC_21467165","title":"Expression of Id-1 is regulated by MCAM/MUC18: a missing link in melanoma progression.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21467165","citation_count":37,"is_preprint":false},{"pmid":"32616889","id":"PMC_32616889","title":"SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32616889","citation_count":37,"is_preprint":false},{"pmid":"30134924","id":"PMC_30134924","title":"Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus.","date":"2018","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/30134924","citation_count":36,"is_preprint":false},{"pmid":"34726401","id":"PMC_34726401","title":"Transmembrane MUC18 Targeted Polydopamine Nanoparticles and a Mild Photothermal Effect Synergistically Disrupt Actin Cytoskeleton and Migration of Cancer Cells.","date":"2021","source":"Nano letters","url":"https://pubmed.ncbi.nlm.nih.gov/34726401","citation_count":35,"is_preprint":false},{"pmid":"34185707","id":"PMC_34185707","title":"Monocyte-released HERV-K dUTPase engages TLR4 and MCAM causing endothelial mesenchymal transition.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34185707","citation_count":35,"is_preprint":false},{"pmid":"15821586","id":"PMC_15821586","title":"Increased expression of MUC18 correlates with the metastatic progression of mouse prostate adenocarcinoma in the TRAMP model.","date":"2005","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/15821586","citation_count":35,"is_preprint":false},{"pmid":"23256918","id":"PMC_23256918","title":"A novel function of MUC18: amplification of lung inflammation during bacterial infection.","date":"2012","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23256918","citation_count":34,"is_preprint":false},{"pmid":"22057013","id":"PMC_22057013","title":"METCAM/MUC18 augments migration, invasion, and tumorigenicity of human breast cancer SK-BR-3 cells.","date":"2011","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/22057013","citation_count":33,"is_preprint":false},{"pmid":"37153740","id":"PMC_37153740","title":"Gαi1/3 mediate Netrin-1-CD146-activated signaling and angiogenesis.","date":"2023","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/37153740","citation_count":33,"is_preprint":false},{"pmid":"35790583","id":"PMC_35790583","title":"CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35790583","citation_count":33,"is_preprint":false},{"pmid":"19010815","id":"PMC_19010815","title":"Enforced expression of MCAM/MUC18 increases in vitro motility and invasiveness and in vivo metastasis of two mouse melanoma K1735 sublines in a syngeneic mouse model.","date":"2008","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/19010815","citation_count":33,"is_preprint":false},{"pmid":"11255016","id":"PMC_11255016","title":"Isolation and characterization of mouse MUC18 cDNA gene, and correlation of MUC18 expression in mouse melanoma cell lines with metastatic ability.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11255016","citation_count":33,"is_preprint":false},{"pmid":"25595133","id":"PMC_25595133","title":"Endothelial-binding, proinflammatory T cells identified by MCAM (CD146) expression: Characterization and role in human autoimmune diseases.","date":"2015","source":"Autoimmunity reviews","url":"https://pubmed.ncbi.nlm.nih.gov/25595133","citation_count":32,"is_preprint":false},{"pmid":"25995384","id":"PMC_25995384","title":"ZBTB7A Suppresses Melanoma Metastasis by Transcriptionally Repressing MCAM.","date":"2015","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/25995384","citation_count":32,"is_preprint":false},{"pmid":"35729643","id":"PMC_35729643","title":"Comparison of CD146 +/- mesenchymal stem cells in improving premature ovarian failure.","date":"2022","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35729643","citation_count":31,"is_preprint":false},{"pmid":"28785085","id":"PMC_28785085","title":"CD146 is required for VEGF-C-induced lymphatic sprouting during lymphangiogenesis.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28785085","citation_count":31,"is_preprint":false},{"pmid":"35944750","id":"PMC_35944750","title":"CD146 interaction with integrin β1 activates LATS1-YAP signaling and induces radiation-resistance in breast cancer cells.","date":"2022","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/35944750","citation_count":30,"is_preprint":false},{"pmid":"10726166","id":"PMC_10726166","title":"Expression of CD146 adhesion molecules (MUC18 or MCAM) in the thymic microenvironment.","date":"2000","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/10726166","citation_count":28,"is_preprint":false},{"pmid":"24767106","id":"PMC_24767106","title":"Targeting endothelial CD146 attenuates colitis and prevents colitis-associated carcinogenesis.","date":"2014","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24767106","citation_count":28,"is_preprint":false},{"pmid":"38459564","id":"PMC_38459564","title":"CD146+CAFs promote progression of endometrial cancer by inducing angiogenesis and vasculogenic mimicry via IL-10/JAK1/STAT3 pathway.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38459564","citation_count":27,"is_preprint":false},{"pmid":"36528750","id":"PMC_36528750","title":"ST6GAL1 inhibits metastasis of hepatocellular carcinoma via modulating sialylation of MCAM on cell surface.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36528750","citation_count":27,"is_preprint":false},{"pmid":"8616875","id":"PMC_8616875","title":"Phorbol ester and cyclic AMP-mediated regulation of the melanoma-associated cell adhesion molecule MUC18/MCAM.","date":"1996","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/8616875","citation_count":27,"is_preprint":false},{"pmid":"31690663","id":"PMC_31690663","title":"MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31690663","citation_count":27,"is_preprint":false},{"pmid":"34491908","id":"PMC_34491908","title":"CD146 bound to LCK promotes T cell receptor signaling and antitumor immune responses in mice.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/34491908","citation_count":27,"is_preprint":false},{"pmid":"34293080","id":"PMC_34293080","title":"CD146/Soluble CD146 Pathway Is a Novel Biomarker of Angiogenesis and Inflammation in Proliferative Diabetic Retinopathy.","date":"2021","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/34293080","citation_count":27,"is_preprint":false},{"pmid":"29741757","id":"PMC_29741757","title":"CD146 interacts with galectin-3 to mediate endothelial cell migration.","date":"2018","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/29741757","citation_count":25,"is_preprint":false},{"pmid":"14755543","id":"PMC_14755543","title":"Characterization of Gicerin/MUC18/CD146 in the rat nervous system.","date":"2004","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/14755543","citation_count":24,"is_preprint":false},{"pmid":"10938273","id":"PMC_10938273","title":"Identification of the elements regulating the expression of the cell adhesion molecule MCAM/MUC18. Loss of AP-2 is not required for MCAM expression in melanoma cell lines.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10938273","citation_count":24,"is_preprint":false},{"pmid":"22486269","id":"PMC_22486269","title":"Coexpression of CCR6 and CD146 (MCAM) is a marker of effector memory T-helper 17 cells.","date":"2012","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/22486269","citation_count":24,"is_preprint":false},{"pmid":"32543083","id":"PMC_32543083","title":"CD34+CD146+ adipose-derived stromal cells enhance engraftment of transplanted fat.","date":"2020","source":"Stem cells translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32543083","citation_count":24,"is_preprint":false},{"pmid":"28589943","id":"PMC_28589943","title":"The signalling receptor MCAM coordinates apical-basal polarity and planar cell polarity during morphogenesis.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28589943","citation_count":23,"is_preprint":false},{"pmid":"30745464","id":"PMC_30745464","title":"Therapeutic Targeting of CD146/MCAM Reduces Bone Metastasis in Prostate Cancer.","date":"2019","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/30745464","citation_count":23,"is_preprint":false},{"pmid":"33475350","id":"PMC_33475350","title":"ImmunoPET of CD146 in Orthotopic and Metastatic Breast Cancer Models.","date":"2021","source":"Bioconjugate chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33475350","citation_count":23,"is_preprint":false},{"pmid":"29734758","id":"PMC_29734758","title":"The Prevalence of CD146 Expression in Breast Cancer Subtypes and Its Relation to Outcome.","date":"2018","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/29734758","citation_count":22,"is_preprint":false},{"pmid":"28549249","id":"PMC_28549249","title":"CD146 (MCAM) in human cs-DLK1-/cs-CD34+ adipose stromal/progenitor cells.","date":"2017","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28549249","citation_count":21,"is_preprint":false},{"pmid":"33911963","id":"PMC_33911963","title":"Human gingival fibroblasts: Isolation, characterization, and evaluation of CD146 expression.","date":"2021","source":"Saudi journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33911963","citation_count":20,"is_preprint":false},{"pmid":"34830300","id":"PMC_34830300","title":"MCAM/MUC18/CD146 as a Multifaceted Warning Marker of Melanoma Progression in Liquid Biopsy.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34830300","citation_count":19,"is_preprint":false},{"pmid":"27565656","id":"PMC_27565656","title":"Anti-Metastatic and Anti-Invasion Effects of a Specific Anti-MUC18 scFv Antibody on Breast Cancer Cells.","date":"2016","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/27565656","citation_count":19,"is_preprint":false},{"pmid":"31548532","id":"PMC_31548532","title":"Therapeutic and Diagnostic Antibodies to CD146: Thirty Years of Research on Its Potential for Detection and Treatment of Tumors.","date":"2017","source":"Antibodies (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31548532","citation_count":19,"is_preprint":false},{"pmid":"32022257","id":"PMC_32022257","title":"Therapeutic targeting of soluble CD146/MCAM with the M2J-1 monoclonal antibody prevents metastasis development and procoagulant activity in CD146-positive invasive tumors.","date":"2020","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32022257","citation_count":19,"is_preprint":false},{"pmid":"35892560","id":"PMC_35892560","title":"CD146 Defines a Mesenchymal Stromal Cell Subpopulation with Enhanced Suppressive Properties.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35892560","citation_count":18,"is_preprint":false},{"pmid":"10951239","id":"PMC_10951239","title":"Keratinocytes express the CD146 (Muc18/S-endo) antigen in tissue culture and during inflammatory skin diseases.","date":"2000","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/10951239","citation_count":17,"is_preprint":false},{"pmid":"24902661","id":"PMC_24902661","title":"Sequential molecular analysis of circulating MCAM/MUC18 expression: a promising disease biomarker related to clinical outcome in melanoma.","date":"2014","source":"Archives of dermatological research","url":"https://pubmed.ncbi.nlm.nih.gov/24902661","citation_count":17,"is_preprint":false},{"pmid":"29121955","id":"PMC_29121955","title":"CD146, a novel target of CD44-signaling, suppresses breast tumor cell invasion.","date":"2017","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/29121955","citation_count":17,"is_preprint":false},{"pmid":"32577157","id":"PMC_32577157","title":"KDM3A/Ets1/MCAM axis promotes growth and metastatic properties in Rhabdomyosarcoma.","date":"2020","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32577157","citation_count":17,"is_preprint":false},{"pmid":"37856423","id":"PMC_37856423","title":"CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway.","date":"2023","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/37856423","citation_count":16,"is_preprint":false},{"pmid":"25510693","id":"PMC_25510693","title":"Frequent and increased expression of human METCAM/MUC18 in cancer tissues and metastatic lesions is associated with the clinical progression of human ovarian carcinoma.","date":"2014","source":"Taiwanese journal of obstetrics & gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/25510693","citation_count":16,"is_preprint":false},{"pmid":"16756976","id":"PMC_16756976","title":"A dileucine motif targets MCAM-l cell adhesion molecule to the basolateral membrane in MDCK cells.","date":"2006","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16756976","citation_count":16,"is_preprint":false},{"pmid":"24528033","id":"PMC_24528033","title":"Significance of expression of human METCAM/MUC18 in nasopharyngeal carcinomas and metastatic lesions.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24528033","citation_count":15,"is_preprint":false},{"pmid":"33321883","id":"PMC_33321883","title":"CD146/sCD146 in the Pathogenesis and Monitoring of Angiogenic and Inflammatory Diseases.","date":"2020","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/33321883","citation_count":15,"is_preprint":false},{"pmid":"12618200","id":"PMC_12618200","title":"Mel-CAM (CD146) expression in parotid mucoepidermoid carcinoma.","date":"2003","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12618200","citation_count":15,"is_preprint":false},{"pmid":"15654965","id":"PMC_15654965","title":"Epitope-specific antibody response to Mel-CAM induced by mimotope immunization.","date":"2005","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15654965","citation_count":13,"is_preprint":false},{"pmid":"25478290","id":"PMC_25478290","title":"MUC18 Differentially Regulates Pro-Inflammatory and Anti-Viral Responses in Human Airway Epithelial Cells.","date":"2014","source":"Journal of clinical & cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25478290","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51395,"output_tokens":11886,"usd":0.166238,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23259,"output_tokens":5311,"usd":0.124535,"stage2_stop_reason":"end_turn"},"total_usd":0.290773,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Enforced expression of MCAM/MUC18 in MCAM-negative primary cutaneous melanoma SB-2 cells increased homotypic adhesion, attachment to human endothelial cells, and invasiveness through Matrigel; anti-MCAM monoclonal antibody reversed these functions, establishing a direct functional role for MCAM in tumor cell adhesion and invasion.\",\n      \"method\": \"cDNA transfection in melanoma cells, homotypic adhesion assay, endothelial attachment assay, Matrigel invasion assay, antibody blocking, in vivo tumorigenicity/metastasis in nude mice\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (adhesion, invasion, in vivo metastasis) with both gain-of-function (transfection) and loss-of-function (antibody blockade) in the same study; independently corroborated by subsequent labs\",\n      \"pmids\": [\"9187135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MCAM mediates homotypic cell adhesion through interaction with a heterophilic (non-MCAM) ligand in a divalent-cation-independent, temperature-sensitive manner; homophilic MCAM-MCAM interactions were not supported by mixed aggregation assays with MCAM-expressing and non-expressing cells.\",\n      \"method\": \"cDNA transfection of MCAM-negative melanoma lines, homotypic aggregation assay, mixed aggregation assay, glycosaminoglycan inhibition assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional adhesion assays with transfected cells, single lab, multiple cell lines tested\",\n      \"pmids\": [\"9398060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The transcription factor AP-2 directly binds to four AP-2 binding sites in the MCAM/MUC18 promoter and represses MCAM expression; loss of AP-2 in metastatic melanoma cells correlates with MCAM upregulation, and re-expression of AP-2 downregulates MCAM mRNA and protein.\",\n      \"method\": \"EMSA (electrophoretic mobility shift assay), promoter-reporter (CAT) assay with AP-2 transfection, AP-2 dose-dependent repression assay, Western blot, in vivo tumorigenicity in nude mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct protein-DNA binding by EMSA, reporter assay with mutagenesis context, rescue experiments, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"9632718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Cyclic AMP elevation upregulates cell-surface MCAM/MUC18 expression and mRNA levels, while phorbol ester treatment downregulates both, demonstrating that MCAM expression is regulated by PKC and cAMP signaling pathways.\",\n      \"method\": \"cAMP analogue and phorbol ester treatment, flow cytometry for surface expression, Northern blot for mRNA quantification\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pharmacological manipulation with protein and mRNA quantification, single lab, two orthogonal readouts\",\n      \"pmids\": [\"8616875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The minimal MCAM promoter (-106/+22 bp) contains Sp-1 sites, AP-2 elements, and a CRE element; site-directed mutagenesis showed the CRE is a major transcriptional activator, while the AP-2 site at -23 bp has an inhibitory influence in AP-2-expressing cells, and AP-2 sites at -131 and -302 bp are activating.\",\n      \"method\": \"Deletion and site-directed mutagenesis of the MCAM promoter, promoter-reporter assay in melanoma/glioma/carcinoma cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis of promoter elements with functional reporter assays, single lab\",\n      \"pmids\": [\"10938273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MelCAM/MCAM and AKT engage in reciprocal regulation in melanoma: pharmacological or dominant-negative inhibition of AKT reduces MelCAM expression, while overexpression of constitutively active AKT upregulates MelCAM; conversely, MelCAM overexpression activates endogenous AKT and inhibits pro-apoptotic BAD, increasing cell survival.\",\n      \"method\": \"Pharmacological AKT inhibition, constitutively active AKT overexpression, dominant-negative PI3K expression, Western blot for MelCAM/AKT/BAD, cell survival assay under stress\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic/pharmacological manipulation, multiple readouts (protein expression, survival), single lab\",\n      \"pmids\": [\"14534536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The long cytoplasmic isoform MCAM-l (but not MCAM-s) promotes microvilli formation and enhances lymphocyte rolling and adhesion to endothelial monolayers and VCAM-1; mutagenesis identified serine 32 in the MCAM-l cytoplasmic tail (a putative PKC phosphorylation site) as required for MCAM-l–actin cytoskeleton interaction and microvilli induction; PKC inhibition abolished these effects.\",\n      \"method\": \"Isoform transfection into NK cell line NKL1, shear-stress adhesion assay, scanning electron microscopy, site-directed mutagenesis (S32), PKC inhibitor treatment (chelerythrine chloride), anti-MCAM antibody blockade\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis identifying specific residue, pharmacological confirmation, morphological (EM) and functional (adhesion under shear) orthogonal readouts, single rigorous study\",\n      \"pmids\": [\"17982057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The long isoform MCAM-l is targeted to the basolateral membrane of polarized MDCK epithelial cells, while MCAM-s is targeted to the apical membrane; a single dileucine motif (positions 41-42) in the MCAM-l cytoplasmic domain is required for basolateral targeting.\",\n      \"method\": \"Transfection of MCAM isoform–GFP chimeras in polarized MDCK cells, confocal microscopy, site-directed mutagenesis of the dileucine motif\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis identifying specific motif, live-cell confocal imaging in polarized epithelial cells, single lab with orthogonal methods\",\n      \"pmids\": [\"16756976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HEMCAM/CD146 expression in fibroblasts downregulates cell-surface levels of laminin-binding integrins α3β1, α6β1, α7β1, and fibronectin receptor α5β1; this downregulation occurs at a translational or post-translational level rather than at the transcriptional level, and both isoforms (HEMCAM-s and HEMCAM-l) inhibit integrin-dependent adhesion to laminin-1.\",\n      \"method\": \"Stable transfection of murine fibroblasts with HEMCAM isoforms, flow cytometry for integrin surface levels, immunoprecipitation, semi-quantitative PCR, Northern blot, cell adhesion/spreading assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (flow cytometry, immunoprecipitation, Northern/PCR, adhesion assay), isoform comparison, identifying translational/post-translational mechanism\",\n      \"pmids\": [\"11329371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MCAM (CD146) is identified as a receptor for laminin-411 (an isoform of laminin expressed in vascular endothelial basement membranes); purified MCAM-Fc binds laminin-411 with an affinity of 27 nM; MCAM binding was undetectable in tissue from mice with targeted deletion of laminin-411 (confirming laminin-411 as a major tissue ligand); anti-MCAM antibody and soluble MCAM-Fc inhibited T cell adhesion to laminin-411 and reduced TH17 cell infiltration into the CNS in a mouse MS model.\",\n      \"method\": \"Solid-phase binding assay (MCAM-Fc to purified laminin), biolayer interferometry/affinity measurement (KD = 27 nM), laminin-411 knockout mouse tissue binding, in vitro T cell adhesion assay, in vivo EAE mouse model with antibody blockade\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding with affinity measurement, genetic (knockout) validation, in vitro and in vivo functional confirmation\",\n      \"pmids\": [\"22792325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Laminin-421, but not laminin-411, binds MCAM (CD146) in solid-phase binding assays; a function-blocking anti-MCAM antibody inhibits tumor cell migration on laminin-421 but not laminin-411, demonstrating that MCAM specifically mediates laminin-421-dependent tumor cell migration.\",\n      \"method\": \"Solid-phase binding assay (multiple laminin isoforms vs. MCAM), function-blocking antibody to MCAM, tumor cell migration assay on laminin substrates\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and functional blockade, single lab, two orthogonal readouts\",\n      \"pmids\": [\"24951930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD146 is identified as a receptor for netrin-1; netrin-1 binds CD146 with high affinity, inducing endothelial cell activation and downstream signaling in a CD146-dependent manner; conditional knockout of cd146 in murine endothelium or disruption of netrin-CD146 interaction by anti-CD146 antibody blocks netrin-1-induced angiogenesis; CD146 knockdown in zebrafish phenocopies netrin-1 loss-of-function vascular defects.\",\n      \"method\": \"Binding affinity assay, CD146 conditional knockout in mouse endothelium, anti-CD146 antibody blockade, zebrafish knockdown of CD146 and netrin-1a, ectopic netrin-1 overexpression with CD146 knockdown\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — receptor-ligand binding, genetic loss-of-function (conditional KO and zebrafish knockdown), antibody blockade, multiple species/models with orthogonal methods\",\n      \"pmids\": [\"25656845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PAR1 mediates MCAM/MUC18 expression in metastatic melanoma via activation of PAFR and CREB phosphorylation; PAR1 silencing reduces PAFR expression and PAF production; PAFR silencing blocks MCAM expression; re-expression of PAFR in PAR1-silenced cells rescues MCAM expression; this PAR1-PAFR-MCAM pathway mediates melanoma adhesion to endothelial cells, transendothelial migration, and metastatic lung retention.\",\n      \"method\": \"shRNA silencing of PAR1 and PAFR, PAFR rescue in PAR1-silenced cells, CREB phosphorylation assay, ChIP for CREB binding to MCAM promoter, Western blot, transendothelial migration assay, in vivo metastasis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (shRNA knockdown + rescue), ChIP demonstrating direct promoter binding, multiple functional readouts, in vivo validation\",\n      \"pmids\": [\"19703903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MUC18/MCAM regulates Id-1 expression at the transcriptional level via ATF-3; MUC18 silencing upregulates ATF-3 which binds the Id-1 promoter (confirmed by ChIP) and represses Id-1; MUC18 rescue reverses Id-1 and ATF-3 expression patterns; Id-1 overexpression in MUC18-silenced cells restores MMP-2 expression and activity, linking the MUC18–ATF-3–Id-1 axis to melanoma invasion.\",\n      \"method\": \"Stable shRNA silencing of MUC18, cDNA microarray, ChIP for ATF-3 binding to Id-1 promoter, MUC18 rescue transfection, Id-1 overexpression rescue, MMP-2 activity assay (zymography)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP with direct promoter binding validation, microarray plus individual gene rescue, functional enzyme activity readout, all in one rigorous study\",\n      \"pmids\": [\"21467165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MCAM silencing in ovarian cancer cells increases apoptosis and reduces cell spreading and invasion; these effects are associated with dysregulation of small RhoGTPases RhoA and Cdc42, placing MCAM upstream of Rho GTPase signaling.\",\n      \"method\": \"RNA interference (siRNA) knockdown of MCAM in SKOV-3 cells, apoptosis assay, invasion assay, RhoA/Cdc42 activity measurement\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RhoGTPase pathway placement via knockdown only, no rescue or direct interaction demonstrated\",\n      \"pmids\": [\"22610942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD146 functions as a co-receptor of PDGF receptor-β to mediate pericyte recruitment to cerebrovascular endothelial cells during blood-brain barrier development; pericyte-specific Cd146 deletion impairs pericyte coverage and BBB integrity; the attached pericytes in turn downregulate endothelial CD146 by secreting TGF-β1, promoting further BBB maturation; endothelial-specific Cd146 deletion reduces claudin-5 expression and causes BBB breakdown.\",\n      \"method\": \"Endothelial-specific and pericyte-specific Cd146 conditional knockout mice, TGF-β1 treatment experiments, immunofluorescence, BBB integrity assay, claudin-5 expression analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO in two cell types with distinct phenotypes, ligand (TGF-β1) rescue experiment, multiple orthogonal readouts (pericyte coverage, permeability, claudin-5)\",\n      \"pmids\": [\"28827364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD146 on macrophages drives foam cell formation by promoting internalization of scavenger receptor CD36 during lipid uptake; macrophage-specific Cd146 deletion reduces complex plaques in ApoE−/− mice on high-fat diet, with lipid-loaded macrophages exiting plaques; blocking CD146 restores migratory capacity of macrophages toward CCL19/CCL21 that is reduced by oxLDL.\",\n      \"method\": \"Macrophage-specific Cd146 conditional knockout in ApoE−/− mice, CD36 internalization assay, anti-CD146 antibody treatment, oxLDL stimulation assay, transwell migration assay, atherosclerosis plaque analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — macrophage-specific genetic knockout with clear phenotype, mechanistic link to CD36 internalization, antibody rescue, multiple orthogonal methods\",\n      \"pmids\": [\"28084332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MCAM mediates chemoresistance in small-cell lung cancer via the PI3K/AKT/SOX2 signaling pathway; MCAM depletion reduces SOX2-dependent upregulation of MRP1/ABCC1 and reduces PI3K/AKT activity, sensitizing cells to chemotherapy; MCAM also modulates lactate production in a metabolic reprogramming context.\",\n      \"method\": \"MCAM depletion (siRNA/shRNA) in chemoresistant SCLC cells and PDX models, IC50 chemotherapy assay, PI3K/AKT pathway analysis, SOX2/MRP1 expression analysis, metabolomic profiling\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion with functional rescue potential, proteomic and metabolomic profiling, PDX model, single lab\",\n      \"pmids\": [\"28646020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM3A positively regulates MCAM expression in Ewing Sarcoma through both a direct mechanism (modulation of H3K9 methylation at the MCAM promoter) and an indirect mechanism (via the Ets1 transcription factor); MCAM depletion inhibits cell migration and experimental metastasis and partially rescues impaired migration caused by KDM3A knockdown.\",\n      \"method\": \"Global gene expression profiling (microarray), KDM3A and MCAM siRNA/shRNA knockdown, MCAM rescue in KDM3A-depleted cells, H3K9 methylation analysis at MCAM promoter (ChIP), Ets1 mechanistic analysis, in vitro migration assay, in vivo experimental metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — epigenetic mechanism confirmed by ChIP, epistasis rescue experiments, in vivo validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28319067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MCAM (CD146) is required for VEGF-C-induced lymphatic sprouting; CD146 selectively activates p38 kinase downstream of VEGF-C to regulate sprouting, and also activates ERK to mediate VEGF-C-regulated proliferation and migration of lymphatic endothelial cells; CD146 knockdown in zebrafish phenocopies VEGF-C loss-of-function defects in lymphangiogenesis.\",\n      \"method\": \"CD146 knockdown in lymphatic endothelial cells (in vitro sprouting assay), p38 and ERK inhibition/activation, zebrafish CD146 knockdown and VEGF-C manipulation, in vivo lymphangiogenesis assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown in two systems (cell line and zebrafish), pathway kinase analysis, single lab\",\n      \"pmids\": [\"28785085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MCAM is an independent receptor for FGF4 and a membrane anchor of PLC-γ, acting as an upstream receptor of NFAT and a constitutive activator of JNK; MCAM-mediated vesicular trafficking toward FGF4 and NFAT transcriptional response determines lumenogenesis, while MCAM-driven JNK activation (independently of FGF signals) is required for ciliogenesis; mcam-deficient zebrafish and Xenopus exhibit global left-right asymmetry defects.\",\n      \"method\": \"Receptor identification for FGF4 (binding assay), PLC-γ co-immunoprecipitation, NFAT reporter assay, JNK activation assay, mcam genetic loss-of-function in zebrafish and Xenopus, lumenogenesis and ciliogenesis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple receptor-ligand interactions validated by co-IP, reporter assays, and genetic loss-of-function in two independent model organisms with distinct phenotypic readouts\",\n      \"pmids\": [\"28589943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Galectin-3 binds to N-linked glycans on CD146, inducing CD146 dimerization and subsequent AKT signaling activation; siRNA-mediated suppression of CD146 completely abolishes galectin-3-induced secretion of IL-6 and G-CSF from endothelial cells; galectin-3 binding site on CD146 is in Domain 5, which contains poly-N-acetyllactosamine sites.\",\n      \"method\": \"Galectin-3 affinity purification, co-localization (confocal microscopy), pull-down assay, gel filtration, biolayer interferometry (KD ~1.1 μM), mass spectrometry for N-glycosites, PNGase F treatment, domain deletion mutants, siRNA knockdown, cytokine ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding with affinity measurement, domain-deletion mutagenesis, glycan site mapping by mass spectrometry, functional siRNA rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28364041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD146 mediates a cadherin switch during TGF-β-induced EMT: TGF-β induces CD146 expression; CD146 positively correlates with STAT3/Twist activation (which inhibits E-cadherin) and ERK pathway activation (which enhances N-cadherin); CD146-deficient MEFs exhibit decreased motility due to reversion of the cadherin switch.\",\n      \"method\": \"TGF-β-induced EMT model, CD146 overexpression and knockout (in MEFs), Western blot for STAT3/Twist/ERK/cadherins, cell motility assay, correlation with ovarian cancer patient outcome\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in primary MEFs and gain-of-function in cancer cells, pathway intermediaries measured, single lab\",\n      \"pmids\": [\"29777784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD146 and HIF-1α engage in cross-regulation in pulmonary artery smooth muscle cells: CD146 expression reinforces HIF-1α transcriptional program and vice versa; smooth-muscle-specific Cd146 genetic ablation mitigates pulmonary vascular remodeling in chronic hypoxic mice; anti-CD146 antibodies alleviate established pulmonary hypertension and enhance cardiac function in two rodent models.\",\n      \"method\": \"Smooth-muscle-specific Cd146 conditional knockout, chronic hypoxia mouse model, two pharmacological rodent PH models with anti-CD146 antibody treatment, HIF-1α pathway analysis, hemodynamic measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic KO, two independent disease models with antibody therapeutic intervention, multiple physiological and molecular readouts\",\n      \"pmids\": [\"31391533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"S100A8/A9 binds to MCAM (CD146) on breast cancer cell surface and activates ETV4 downstream; ETV4 transcriptionally upregulates ZEB1 to induce EMT; downregulation of MCAM or ETV4 represses EMT and reduces tumor growth and lung metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation/binding assay (S100A8/A9–MCAM interaction), MCAM and ETV4 knockdown, ZEB1 promoter analysis, EMT marker assessment, in vivo xenograft tumor and metastasis models\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-ligand interaction, genetic epistasis (MCAM→ETV4→ZEB1), in vivo validation, single lab\",\n      \"pmids\": [\"31100639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZBTB7A directly binds to the MCAM promoter and transcriptionally represses MCAM expression; ZBTB7A downregulation results in marked upregulation of MCAM and enhanced melanoma cell invasion and metastasis; an inverse correlation between ZBTB7A and MCAM expression is validated in human melanoma specimens.\",\n      \"method\": \"ChIP demonstrating ZBTB7A binding to MCAM promoter, ZBTB7A knockdown/overexpression, invasion and metastasis assays, human melanoma tissue gene expression analysis\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP, functional genetic manipulation, single lab with two orthogonal methods\",\n      \"pmids\": [\"25995384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD146 directly interacts with the SH3 domain of coreceptor-free LCK via its cytoplasmic domain in T cells; CD146 forms monomers and dimers, with dimerized CD146 increasing after TCR ligation; increased dimerized CD146 recruits LCK and promotes LCK autophosphorylation, thereby initiating TCR signaling; CD146 deficiency in T cells substantially impairs thymocyte development and peripheral activation; in tumor models, CD146 deficiency impairs antitumor T cell responses.\",\n      \"method\": \"Co-immunoprecipitation (CD146–LCK SH3 domain interaction), CD146 cytoplasmic domain deletion analysis, native PAGE and crosslinking for dimer analysis, T cell-specific Cd146 conditional knockout mice, thymocyte development assay, TCR signaling assays, tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct protein-protein interaction mapped to SH3 domain, dimerization-dependent LCK activation mechanism, T cell-specific KO with defined developmental and functional phenotypes, in vivo validation\",\n      \"pmids\": [\"34491908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD146 interacts with the CD146 ectodomain via galectin-3 binding; galectin-3 binds CD146 ectodomain with KD ~1.1 μM (biolayer interferometry); galectin-3 interaction requires N-glycans on CD146, with Domain 5 (containing poly-N-acetyllactosamine sites) as the binding site; CD146 knockdown significantly attenuates galectin-3-mediated endothelial cell migration.\",\n      \"method\": \"Galectin-3 pulldown assay, gel filtration, biolayer interferometry, N-glycan removal (PNGase F), domain deletion mutants, CD146 knockdown, endothelial cell migration assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding with affinity measurement, domain mapping, functional knockdown; overlaps mechanistically with PMID 28364041 from a different lab providing partial replication\",\n      \"pmids\": [\"29741757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HERV-K dUTPase interaction with MCAM is necessary to upregulate VCAM1 in pulmonary arterial endothelial cells; MCAM engagement by HERV-K dUTPase activates p-p38/NF-κB and pERK1/2-ATF2 signaling to increase VCAM1, contributing to endothelial mesenchymal transition.\",\n      \"method\": \"HERV-K dUTPase overexpression in monocytes, extracellular vesicle application to endothelial cells, MCAM blockade/knockdown, p38/NF-κB and ERK/ATF2 pathway analysis, VCAM1 measurement, EndMT marker analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor engagement established by knockdown with functional rescue, signaling pathway intermediaries measured, single lab\",\n      \"pmids\": [\"34185707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Netrin-1 induces formation of a CD146-Gαi1/3-Gab1 complex: Gαi1/3 associate with CD146 upon Netrin-1 stimulation, facilitating CD146 internalization, Gab1 recruitment, and downstream Akt-mTOR and Erk activation; silencing or knockout of Gαi1/3 inhibits Netrin-1-induced endothelial cell proliferation, migration, and tube formation; endothelial Gαi1/3 knockdown in mice inhibits Netrin-1-induced retinal angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation (Gαi1/3–CD146 interaction), Gαi1/3 siRNA/shRNA and knockout in MEFs and endothelial cells, Gαi1/3 dominant-negative mutants, Gab1 knockout, CD146 internalization assay, Akt/ERK phosphorylation, HUVEC functional assays (proliferation, migration, tube formation), in vivo retinal angiogenesis (AAV shRNA delivery in mice)\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complex formation by Co-IP, multiple genetic perturbations (KO, siRNA, dominant-negative), in vitro and in vivo orthogonal validation in two species\",\n      \"pmids\": [\"37153740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MUC18 overexpression in airway epithelial cells promotes IL-8 production while inhibiting IFN-β expression after polyI:C stimulation or HRV infection; increased serine phosphorylation of MUC18 correlates with its pro-inflammatory function; ERK inhibition reduces MUC18 serine phosphorylation and IL-8 production, placing MUC18 in an ERK-dependent pro-inflammatory signaling pathway.\",\n      \"method\": \"Lentiviral MUC18 overexpression in primary airway epithelial cells, polyI:C stimulation and HRV infection, cytokine ELISA (IL-8, IFN-β), serine phosphorylation analysis, ERK inhibitor treatment\",\n      \"journal\": \"Journal of clinical & cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function overexpression with pharmacological validation (ERK inhibitor), dual cytokine readouts, single lab\",\n      \"pmids\": [\"25478290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MUC18/CD146 amplifies proinflammatory responses in alveolar macrophages during bacterial infection; Muc18−/− mice show lower lung KC, TNF-α, and neutrophil recruitment after Mycoplasma pneumoniae infection; adenovirus-mediated MUC18 gene transfer into Muc18−/− alveolar macrophages restores KC production; MUC18 enhances NF-κB activation in macrophages.\",\n      \"method\": \"Muc18 knockout mice, intratracheal M. pneumoniae infection, cytokine/chemokine ELISA, adenoviral MUC18 gene transfer rescue, NF-κB activation assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with in vivo infection model, adenoviral rescue confirming the specific role of MUC18, NF-κB mechanistic link, multiple orthogonal readouts\",\n      \"pmids\": [\"23256918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ST6GAL1-mediated α2,6-sialylation of MCAM inhibits MCAM interaction with galectin-3 and decreases MCAM expression on the cell surface, thereby suppressing HCC cell migration and invasion; sialylated MCAM levels negatively correlate with tumor malignancy in HCC patients.\",\n      \"method\": \"Metabolic labeling-based glycoproteomics, ST6GAL1 overexpression, co-immunoprecipitation (MCAM–galectin-3 after sialylation manipulation), flow cytometry for surface MCAM, migration/invasion assays in vitro, in vivo xenograft metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — glycoproteomics plus direct Co-IP of modified MCAM, functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"36528750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD146 forms a co-receptor complex with integrin β1 and activates YAP signaling by regulating LATS1 phosphorylation; this drives nuclear translocation of YAP, promotes DNA damage repair, EMT, and stemness, and confers radioresistance; dual inhibition of CD146 and integrin β1 synergistically increases breast cancer sensitivity to radiotherapy.\",\n      \"method\": \"Co-immunoprecipitation (CD146–integrin β1), CD146 knockdown/overexpression, LATS1/YAP phosphorylation and localization analysis, DNA damage repair assay, in vitro and in vivo radioresistance models, dual inhibition experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating complex, mechanistic LATS1-YAP pathway analysis, functional in vivo validation, single lab\",\n      \"pmids\": [\"35944750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD146 acts as a protective shield against DCBLD2 protein degradation in breast phyllodes tumor cells; by preventing DCBLD2 degradation, CD146 activates the PI3K/AKT signaling pathway, enhancing malignant behaviors; this was demonstrated by co-immunoprecipitation and pull-down assays identifying the CD146–DCBLD2 interaction.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assay (CD146–DCBLD2 interaction), transcriptome sequencing, proteomic analysis, DCBLD2 degradation assay, PI3K/AKT pathway analysis, organoid and PDX models with anti-CD146 antibody AA98\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-protein interaction by Co-IP and pulldown, functional pathway validation, in vivo organoid/PDX model, single lab\",\n      \"pmids\": [\"37856423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD146 inhibits TMEM176B (an immunoregulatory cation channel) activity in tumor-associated macrophages to facilitate NLRP3 inflammasome activation; CD146 expression in macrophages is negatively controlled by STAT3 signaling; CD146+ TAMs exert antitumor activity, and reducing this population promotes myeloid-derived suppressor cell recruitment via JNK signaling.\",\n      \"method\": \"Flow cytometry and single-cell analysis of CD146+ TAM subpopulation, CD146 and STAT3 knockdown/manipulation, TMEM176B inhibitor treatment, NLRP3 inflammasome activation assay, JNK signaling analysis, in vivo tumor models\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — STAT3-CD146 genetic regulation, mechanistic TMEM176B-NLRP3 link with pharmacological inhibitor, multiple in vivo models, single lab\",\n      \"pmids\": [\"37308559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TNF-α upregulates endothelial CD146 expression through NF-κB transactivation; endothelial-specific Cd146 conditional knockout significantly ameliorates colitis severity and reduces tumor incidence in models of colitis-associated colorectal carcinogenesis; endothelial CD146 promotes both angiogenesis and proinflammatory leukocyte extravasation.\",\n      \"method\": \"Endothelial-specific Cd146 conditional knockout mice, TNF-α stimulation with NF-κB pathway analysis, two murine colitis models, colitis-associated carcinogenesis model, anti-CD146 antibody treatment\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endothelial-specific genetic KO, transcription factor (NF-κB) mechanism, multiple disease models with antibody therapeutic confirmation, orthogonal readouts\",\n      \"pmids\": [\"24767106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD146 blockade specifically impedes T cell migration across the choroid plexus (CP) into the CNS; MCAM-expressing T cells migrate through the CP where laminin-411 is expressed in endothelial basement membranes; anti-MCAM antibody reduces in vitro transmigration of MCAM-expressing T cells across laminin α4-expressing barriers and delayed disease onset in CD4::Itga4−/− mice when VLA-4 is absent.\",\n      \"method\": \"Anti-MCAM antibody treatment in murine EAE and CP-dependent CNS inflammation models, T cell-specific α4-integrin conditional KO, in vitro human T cell transmigration assay through fibroblast-derived ECM and brain endothelial monolayer, laminin α4 detection in mouse and human CP tissue\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo models, genetic (conditional KO) plus antibody pharmacological approach, translation to human in vitro system, anatomical specificity (CP route) established\",\n      \"pmids\": [\"30134924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MUC18/MCAM (CD146) is neo-expressed on human T cells upon activation (reaching maximum at day 3 post-PHA stimulation); MUC18/MCAM is expressed on CD3+ T cells in delayed-type hypersensitivity lesions, synovial fluid T cells in rheumatoid arthritis, and T leukemia cells, suggesting a role in activated T cell extravasation and homing.\",\n      \"method\": \"mAb characterization (molecular weight, cDNA-transfected L cell reactivity, N-terminal sequencing, immunoblot), flow cytometry of activated peripheral blood T cells, immunohistochemistry of tissue specimens\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple antibody validation methods, in vitro activation kinetics, in vivo tissue localization, single lab\",\n      \"pmids\": [\"9036955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Semaphorin 3A (Sema3A) upregulates MelCAM/MCAM expression through a NRP-1–PTEN–FOXO3a pathway; FOXO3a directly regulates MelCAM at the transcriptional level (demonstrated by ChIP and EMSA), and Sema3A-induced NRP-1-mediated PTEN-dependent FOXO3a activation results in MelCAM upregulation, suppressing breast cancer cell migration, tumor growth, and angiogenesis.\",\n      \"method\": \"Sema3A treatment, NRP-1/PTEN/FOXO3a knockdown/overexpression, ChIP for FOXO3a binding to MelCAM promoter, EMSA, nuclear translocation analysis, in vivo tumor and angiogenesis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP and EMSA establishing direct transcription factor-promoter binding, genetic pathway manipulation, single lab\",\n      \"pmids\": [\"24727891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SOX18 transcriptionally activates MCAM by directly binding to the MCAM promoter; MCAM knockdown decreases SOX18-mediated gastric cancer invasion and metastasis, while MCAM overexpression rescues the invasion/metastasis defect caused by SOX18 inhibition; CCL7-CCR1-ERK/ELK1-SOX18 forms a positive feedback loop that drives GC metastasis.\",\n      \"method\": \"ChIP for SOX18 binding to MCAM promoter, MCAM and CCL7 knockdown/overexpression in SOX18 manipulation context, in vitro invasion assay, in vivo metastasis models, ERK/ELK1 pathway analysis, CCR1 inhibitor treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct promoter binding, epistasis rescue experiments, in vivo validation, single lab\",\n      \"pmids\": [\"32616889\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MCAM/CD146/MUC18 is a transmembrane immunoglobulin-superfamily glycoprotein that functions as a multifunctional signaling receptor and adhesion molecule: it acts as a high-affinity receptor for netrin-1 (activating Gαi1/3-Gab1-Akt-ERK signaling), VEGF-C (activating p38 and ERK for lymphangiogenesis), FGF4 (activating PLC-γ/NFAT for lumenogenesis), laminin-411/421, and galectin-3 (via N-glycans on Domain 5, inducing CD146 dimerization and AKT activation); its long cytoplasmic isoform (MCAM-l) uses serine 32 and a dileucine motif for basolateral targeting and PKC-dependent actin/microvilli regulation; in T cells, dimerized CD146 recruits and activates LCK via its SH3 domain to initiate TCR signaling; in macrophages it drives CD36 internalization and foam cell formation; in endothelial cells it co-receptors with PDGFR-β for pericyte recruitment and with integrin β1 for YAP-LATS1-mediated radioresistance; transcriptionally MCAM is regulated by AP-2 (repressor), CREB/cAMP, ZBTB7A (repressor), KDM3A (via H3K9 demethylation and Ets1), SOX18, and FOXO3a downstream of Sema3A; MCAM expression promotes EMT through CD146-STAT3/Twist/ERK-cadherin switch and the S100A8/A9-MCAM-ETV4-ZEB1 axis, and drives Id-1 expression via ATF-3 suppression to enhance MMP-2-dependent invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MCAM (CD146/MUC18) is a transmembrane immunoglobulin-superfamily cell-surface receptor that integrates adhesion and growth-factor signaling to drive tumor invasion, vascular morphogenesis, and immune cell function [#0, #11]. As an adhesion molecule it engages heterophilic ligands—including the basement-membrane laminins 411 and 421 (KD ~27 nM for laminin-411)—to mediate cell attachment, T cell transmigration across vascular and choroid-plexus barriers into the CNS, and tumor cell migration [#1, #9, #10, #37]. MCAM functions as a multiligand signaling receptor: it binds netrin-1 to nucleate a Gαi1/3–Gab1 complex that drives CD146 internalization and Akt/mTOR–ERK-dependent angiogenesis [#11, #29], serves as an independent FGF4 receptor and PLC-γ anchor controlling NFAT-dependent lumenogenesis and JNK-dependent ciliogenesis [#20], and is required for VEGF-C-induced lymphatic sprouting through p38 and ERK [#19]. Galectin-3 binding to poly-N-acetyllactosamine N-glycans on Domain 5 induces CD146 dimerization and downstream AKT activation and endothelial cytokine secretion, a process antagonized by ST6GAL1-mediated α2,6-sialylation [#21, #27, #32]. Two cytoplasmic isoforms are functionally distinct: the long isoform MCAM-l is targeted basolaterally via a dileucine motif and promotes PKC- and serine-32-dependent actin/microvilli remodeling and lymphocyte rolling, whereas the short isoform localizes apically [#6, #7]. In immune cells, activation-induced CD146 dimerization recruits and activates LCK through its SH3 domain to initiate TCR signaling and support thymocyte development and antitumor T cell responses, and MCAM amplifies NF-κB-dependent proinflammatory responses in macrophages and airway epithelium [#26, #31, #30]. CD146 acts as a co-receptor with PDGFR-β for pericyte recruitment and blood-brain-barrier maturation and with integrin β1 for YAP-LATS1-driven radioresistance, and in macrophages it promotes CD36 internalization and foam cell formation in atherosclerosis [#15, #33, #16]. MCAM expression promotes EMT and invasion through cadherin switching via STAT3/Twist and ERK, the S100A8/A9–MCAM–ETV4–ZEB1 axis, and an ATF-3–Id-1–MMP-2 axis [#22, #24, #13]. Its transcription is repressed by AP-2 and ZBTB7A and activated by CRE/CREB, KDM3A-mediated H3K9 demethylation, SOX18, and Sema3A-driven FOXO3a [#2, #25, #4, #18, #40, #39].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that MCAM is not merely a marker but a functional driver of tumor cell adhesion and invasion, defining its core biological role.\",\n      \"evidence\": \"Gain-of-function transfection plus antibody blockade in melanoma cells with adhesion, Matrigel invasion, and in vivo metastasis readouts\",\n      \"pmids\": [\"9187135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand identity for the adhesion function not defined\", \"Signaling pathway downstream of MCAM not addressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Determined that MCAM-mediated adhesion is heterophilic rather than homophilic, reframing the search for its binding partners toward non-MCAM ligands.\",\n      \"evidence\": \"Homotypic and mixed aggregation assays with MCAM-expressing and non-expressing transfected melanoma lines\",\n      \"pmids\": [\"9398060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The heterophilic ligand itself was not identified\", \"Single-lab functional inference without ligand isolation\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed MCAM is induced on activated T cells and present in inflammatory lesions, extending its function from tumor biology to immune cell homing.\",\n      \"evidence\": \"mAb characterization, flow cytometry of activated T cells, immunohistochemistry of DTH/RA tissue\",\n      \"pmids\": [\"9036955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic role in extravasation inferred from localization, not tested\", \"Ligand engaged on activated T cells unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the cis-regulatory architecture of the MCAM promoter, resolving how transcription factors set expression levels in tumor cells.\",\n      \"evidence\": \"Promoter deletion and site-directed mutagenesis with reporter assays across multiple tumor cell lines; AP-2 binding shown directly by EMSA and CAT reporter rescue (1998)\",\n      \"pmids\": [\"10938273\", \"9632718\", \"8616875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological signals controlling each element not fully mapped\", \"Chromatin context not examined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Revealed that MCAM modulates integrin surface levels post-transcriptionally, providing a mechanism for its regulation of laminin and fibronectin adhesion.\",\n      \"evidence\": \"Stable HEMCAM isoform transfection in fibroblasts with flow cytometry, immunoprecipitation, and adhesion assays\",\n      \"pmids\": [\"11329371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of post-translational integrin downregulation undefined\", \"Direct MCAM-integrin interaction not demonstrated here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped isoform-specific cytoplasmic determinants (dileucine motif, serine 32) that route MCAM to distinct membrane domains and couple it to PKC-dependent actin remodeling.\",\n      \"evidence\": \"Isoform-GFP chimeras in polarized MDCK cells and NK cells, site-directed mutagenesis, PKC inhibition, scanning EM, shear-stress adhesion (2006-2007)\",\n      \"pmids\": [\"16756976\", \"17982057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoskeletal adaptor linking MCAM-l tail to actin not identified\", \"Kinase directly phosphorylating S32 not pinned down\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected MCAM signaling to a transcriptional invasion program, showing it controls invasion via ATF-3-mediated Id-1 and MMP-2 regulation.\",\n      \"evidence\": \"shRNA silencing with rescue, microarray, ChIP for ATF-3 on Id-1 promoter, zymography in melanoma; AKT/BAD survival axis shown earlier (2003)\",\n      \"pmids\": [\"21467165\", \"14534536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How surface MCAM transmits signal to ATF-3 not resolved\", \"Receptor proximal events upstream of this axis unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified laminin-411 as a high-affinity MCAM ligand with genetically validated specificity, supplying the long-sought heterophilic partner for MCAM-mediated T cell adhesion.\",\n      \"evidence\": \"Solid-phase binding with KD measurement, laminin-411 knockout tissue binding, EAE model with antibody blockade\",\n      \"pmids\": [\"22792325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MCAM-laminin recognition not solved\", \"Signaling consequences of laminin engagement not detailed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the ligand repertoire to laminin-421 with isoform selectivity, and defined transcriptional regulators (Sema3A-FOXO3a) that can suppress MCAM in tumor contexts.\",\n      \"evidence\": \"Solid-phase binding and function-blocking antibody migration assays; ChIP/EMSA for FOXO3a; airway/macrophage inflammatory readouts\",\n      \"pmids\": [\"24951930\", \"24727891\", \"25478290\", \"23256918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Distinct downstream signaling for laminin-411 versus -421 not separated\", \"Context determining MCAM pro- versus anti-tumor role unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established MCAM as a bona fide netrin-1 receptor driving angiogenesis, transforming it from an adhesion molecule into a defined signaling receptor.\",\n      \"evidence\": \"Binding affinity assay, endothelial conditional knockout, antibody blockade, zebrafish phenocopy of netrin-1 loss\",\n      \"pmids\": [\"25656845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Immediate cytoplasmic transducers were not yet defined (later resolved as Gαi1/3-Gab1)\", \"Stoichiometry of netrin-CD146 complex unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Diversified MCAM into a multiligand receptor hub, showing it transduces FGF4 (PLC-γ/NFAT/JNK), VEGF-C (p38/ERK), and galectin-3 (dimerization/AKT) signals for distinct morphogenetic and inflammatory outputs.\",\n      \"evidence\": \"Receptor binding assays, co-IP, reporter and kinase assays, domain-deletion and glycan mapping, zebrafish/Xenopus loss-of-function; co-receptor roles with PDGFR-β and CD36-driven foam cell formation in conditional KO mice\",\n      \"pmids\": [\"28589943\", \"28785085\", \"28364041\", \"28827364\", \"28084332\", \"28646020\", \"28319067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single receptor selects among multiple ligand-specific signaling outputs is unresolved\", \"Whether ligands compete or cooperate at the cell surface not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined CD146 as an amplifier of pathological vascular and inflammatory programs through HIF-1α cross-regulation, NF-κB-driven endothelial inflammation, and the S100A8/A9-ETV4-ZEB1 EMT axis.\",\n      \"evidence\": \"Cell-type-specific conditional knockouts, disease models with antibody therapy, co-IP, and epistasis rescue across pulmonary hypertension, colitis, and breast cancer\",\n      \"pmids\": [\"31391533\", \"29777784\", \"31100639\", \"24767106\", \"25995384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these axes share common proximal CD146 signaling not established\", \"Tissue-specific determinants of CD146 output not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved a direct cytoplasmic effector mechanism in T cells, showing dimerized CD146 recruits and activates LCK via its SH3 domain to initiate TCR signaling.\",\n      \"evidence\": \"Co-IP mapping to LCK SH3 domain, native PAGE/crosslinking dimer analysis, T cell-specific conditional KO with developmental and antitumor phenotypes; HERV-K dUTPase-MCAM endothelial signaling in parallel\",\n      \"pmids\": [\"34491908\", \"34185707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger linking TCR ligation to CD146 dimerization not fully defined\", \"Relationship between LCK recruitment and ectodomain ligands unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Filled in proximal signaling and protein-stability mechanisms, identifying the netrin-1-induced CD146-Gαi1/3-Gab1 complex, the CD146-integrin β1-YAP radioresistance axis, and CD146 stabilization of DCBLD2.\",\n      \"evidence\": \"Co-IP and pull-down, multiple genetic perturbations, in vitro and in vivo angiogenesis/radioresistance/tumor models; SOX18 and ST6GAL1 regulatory studies; CD146-TMEM176B-NLRP3 in TAMs\",\n      \"pmids\": [\"37153740\", \"35944750\", \"37856423\", \"32616889\", \"36528750\", \"37308559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural assembly of these CD146 complexes not solved\", \"How sialylation, dimerization, and partner choice are coordinated in vivo unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor discriminates among its many ligands (netrin-1, FGF4, VEGF-C, laminins, galectin-3) and co-receptors (PDGFR-β, integrin β1) to select specific downstream programs remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of liganded CD146 complexes\", \"Rules governing ligand-specific versus shared signaling outputs undefined\", \"Mechanism coupling ectodomain ligand engagement to cytoplasmic LCK/Gαi1/3 effectors not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [11, 20, 19, 21]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [11, 20, 29, 26]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 15, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 7, 11, 21, 26]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 20, 29, 26]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [9, 10, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26, 31, 16, 37, 36]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 13, 17, 33, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [20, 15, 19, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NTN1\", \"FGF4\", \"VEGFC\", \"LGALS3\", \"LCK\", \"PDGFRB\", \"ITGB1\", \"DCBLD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}