{"gene":"CMTM4","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2017,"finding":"CMTM4 associates with the PD-L1 protein at the cell surface, reduces PD-L1 ubiquitination, and increases PD-L1 protein half-life without affecting PD-L1 transcription. CMTM4 shares this function with CMTM6 (demonstrated by genetic complementation in CMTM6-deficient cells), and interference with CMTM4 expression impairs PD-L1 protein expression.","method":"Haploid genetic screen, genetic complementation, co-immunoprecipitation, ubiquitination assay, protein half-life (cycloheximide chase), flow cytometry, siRNA knockdown","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (genetic screen, complementation, Co-IP, ubiquitination, half-life assay) in a single rigorous study replicated independently","pmids":["28813410"],"is_preprint":false},{"year":2022,"finding":"CMTM4 is a constitutive subunit of the IL-17 receptor: it associates with IL-17 receptor subunit C (IL-17RC), mediates IL-17RC stability, glycosylation, and plasma membrane localization. CMTM4-deficient mouse and human cell lines are largely unresponsive to IL-17A due to inability to assemble the IL-17R signaling complex. CMTM4-deficient mice show severe defects in immune cell recruitment following IL-17A administration and resistance to experimental psoriasis.","method":"Co-immunoprecipitation, CRISPR/Cas9 knockout cell lines, in vivo mouse models (experimental psoriasis, EAE), IL-17A stimulation assays, glycosylation analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KO cell lines and in vivo mouse models, multiple orthogonal methods, published in high-impact peer-reviewed journal","pmids":["36271145"],"is_preprint":false},{"year":2018,"finding":"CMTM4 colocalizes with Rab4+ and Rab7+ endocytic vesicles and with membrane-bound and internalized VE-cadherin. CMTM4 overexpression enhances VE-cadherin internalization and promotes rapid recycling (EEA1+, Rab4+, Rab11+, Rab7+ vesicles), while CMTM4 knockdown decreases VE-cadherin internalization. CMTM4 promotes endothelial barrier function and vascular sprouting.","method":"siRNA knockdown, adenovirus-mediated overexpression, intracellular colocalization staining, 3D vascular sprouting assay, zebrafish morpholino injection, transendothelial electrical resistance (TEER) assay","journal":"Angiogenesis","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (colocalization, functional sprouting assay, TEER, in vivo zebrafish), single lab","pmids":["30097810"],"is_preprint":false},{"year":2010,"finding":"CMTM4-v1 and CMTM4-v2 are distributed on the cell membrane and across the cytoplasm. Overexpression of either isoform inhibits HeLa cell growth by inducing G2/M phase accumulation without inducing apoptosis.","method":"Overexpression in HeLa cells, flow cytometry (cell cycle analysis), subcellular localization (immunofluorescence)","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, overexpression with cell cycle readout and localization, two isoforms tested","pmids":["20213316"],"is_preprint":false},{"year":2015,"finding":"Restoration of CMTM4 in 786-O ccRCC cells suppresses cell growth by inducing G2/M cell cycle arrest and upregulation of p21, and inhibits cell migration. Knockdown of CMTM4 produces the opposite effects. CMTM4 overexpression inhibits tumor xenograft growth in nude mice.","method":"Overexpression and siRNA knockdown, CCK-8/cell counting, wound healing/transwell assay, flow cytometry, Western blot (p21), xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain- and loss-of-function with multiple readouts and in vivo validation, single lab","pmids":["26474560"],"is_preprint":false},{"year":2019,"finding":"CMTM4 suppresses PI3K/Akt signaling in pancreatic cancer cells via downregulation of PAK4. miR-5703 (from pancreatic stellate cell-derived exosomes) directly binds the 3'UTR of CMTM4 mRNA to downregulate its expression, promoting PC cell proliferation.","method":"Luciferase 3'UTR reporter assay, siRNA knockdown, CMTM4 overexpression, Western blot (PAK4, p-AKT), in vivo xenograft model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — 3'UTR reporter, gain/loss-of-function with pathway readout (PAK4/PI3K-Akt), in vivo validation, single lab","pmids":["32585413"],"is_preprint":false},{"year":2019,"finding":"CMTM4 overexpression in colorectal cancer SW480 cells decreases phosphorylation levels of AKT, ERK1/2, and STAT3, while CMTM4 knockdown in HT29 cells elevates these. Pathway inhibitor experiments validate that these three signaling pathways contribute to CMTM4's anti-proliferative and anti-migratory effects.","method":"Overexpression and siRNA knockdown, Western blot (p-AKT, p-ERK1/2, p-STAT3), pharmacological inhibitors, proliferation and migration assays","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain/loss-of-function with pathway readout and inhibitor validation, single lab","pmids":["31435638"],"is_preprint":false},{"year":2019,"finding":"CMTM4 knockout mice generated by CRISPR-Cas9 show reduced testicular daily sperm production, lower epididymal sperm motility, abnormal sperm morphology, sub-fertile phenotype, and reduced acrosome reactions. Quantitative proteomics identified 139 downregulated proteins in KO testes enriched for sperm motility and acrosome reaction functions.","method":"CRISPR-Cas9 knockout mice, Western blot, immunohistochemistry, sperm motility/morphology analysis, in vitro fertilization assay, acrosome reaction assay, quantitative mass spectrometry proteomics","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO model with multiple orthogonal functional readouts and quantitative proteomics, rigorous in vivo study","pmids":["30867229"],"is_preprint":false},{"year":2021,"finding":"CMTM4 is the major regulator of PD-L1 in liver cancer (HCC and ICC) context. CMTM4 stabilizes PD-L1 through post-translational mechanisms. In vivo, Cmtm4 suppression in immunocompetent mice inhibited HCC growth and increased CD8+ T-cell infiltration. CMTM4 depletion sensitized HCC tumors to anti-PD-L1 treatment.","method":"siRNA knockdown in multiple HCC/ICC cell lines, Western blot, in vivo syngeneic mouse model, flow cytometry (CD8+ T cells), anti-PD-L1 combination therapy","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple cell lines, in vivo model, combination immunotherapy data, single lab","pmids":["34558800"],"is_preprint":false},{"year":2022,"finding":"CMTM4 interacts with CXCR4, alters its glycosylation pattern, and slows CXCR4 trafficking from the endoplasmic reticulum to the plasma membrane without affecting overall cell surface expression or CXCR4 internalization/degradation in the absence of ligand. Altered CXCR4 trafficking reduces ligand-induced CXCR4 degradation and affects AKT but not ERK1/2 activation downstream of CXCR4.","method":"Co-immunoprecipitation, synchronized ER-release trafficking assay, glycosylation analysis, CXCR4 internalization/degradation assay, Western blot (AKT, ERK1/2), zebrafish cmtm4 morpholino","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ER-release assay, multiple signaling readouts, in vivo zebrafish, single lab","pmids":["36044337"],"is_preprint":false},{"year":2024,"finding":"CMTM4 directly binds IL-17RC in lymphatic endothelial cells (LECs). CMTM4 knockdown abrogates IL-17A plus TNF-α-induced NF-κB signaling and CXC chemokine (CXCL1/2/3/5) secretion. LEC-specific CMTM4 overexpression in Prox1-CreERT2 mice promotes neutrophil drainage and alleviates immune pathological responses.","method":"Co-immunoprecipitation (CMTM4–IL-17RC binding), siRNA knockdown, NF-κB signaling assay, cytokine/chemokine ELISA, adeno-associated virus LEC-specific overexpression in mice, in vivo inflammation/infection models","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct binding by Co-IP, in vitro signaling readout, in vivo conditional overexpression model, single lab","pmids":["38754839"],"is_preprint":false},{"year":2025,"finding":"CMTM4 promotes EGFR recycling and prevents Rab-dependent EGFR degradation, thereby sustaining EGF signaling post-translationally. CMTM4 knockout reduces NF-κB, mTOR, and PI3K/Akt pathway activation in lung carcinoma and decreases EGF-stimulated production of inflammatory cytokines (G-CSF), leading to reduced PMN-MDSC recruitment. CMTM4 KO sensitizes tumor cells to EGFR inhibitors.","method":"CMTM4 knockout, Western blot (NF-κB, mTOR, PI3K/Akt, EGFR), EGFR recycling/degradation assay (Rab-dependent), cytokine profiling, MDSC flow cytometry, EGFR inhibitor sensitivity assay, in vivo syngeneic tumor models, siRNA-liposome in vivo delivery","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with multiple signaling readouts and EGFR trafficking mechanistic assay, in vivo validation, single lab","pmids":["39948411"],"is_preprint":false},{"year":2025,"finding":"CMTM4 interacts with and stabilizes PHB2 (prohibitin 2) through post-translational modification. This CMTM4–PHB2 interaction activates the STING/TBK1/STAT6 pathway, promoting nuclear translocation of STAT6 which binds CCL2 and IL-6 promoters to upregulate their transcription, thereby driving MDSC recruitment (via CCL2/CCR2 and IL-6/GP130 axes) and immune suppression in cervical cancer.","method":"Co-immunoprecipitation (CMTM4–PHB2), chromatin immunoprecipitation (ChIP-qPCR for STAT6 at CCL2/IL-6 promoters), nuclear fractionation, Western blot (STING/TBK1/STAT6), siRNA knockdown, in vivo therapeutic models with anti-PD-1","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-qPCR, nuclear translocation, multiple pathway readouts; single lab","pmids":["40514067"],"is_preprint":false},{"year":2025,"finding":"In sepsis, CMTM4 promotes PD-L1-mediated macrophage apoptosis by enhancing STAT2 phosphorylation rather than by directly binding PD-L1. CMTM4 inhibition reduces macrophage apoptosis.","method":"Co-immunoprecipitation (protein-protein interactions), ChIP-qPCR, Western blot (p-STAT2), flow cytometry (apoptosis), transcriptomic sequencing, in vitro macrophage model (THP-1 and C57BL/6 mice)","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ChIP-qPCR, functional apoptosis readout; explicitly distinguishes indirect (STAT2-mediated) from direct PD-L1 binding; single lab","pmids":["40122504"],"is_preprint":false},{"year":2025,"finding":"Cmtm4 deletion in mice downregulates IL-17RC expression and suppresses downstream NF-κB activation and NOX1 levels in the context of H. pylori-induced gastric carcinogenesis, inhibiting GC development and precancerous lesion formation.","method":"Cmtm4 knockout mice, H. pylori infection model, Western blot (IL-17RC, NF-κB, NOX1), immunohistochemistry, DNA damage analysis","journal":"Pathology international","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vivo KO model with mechanistic pathway readout, single lab","pmids":["40432275"],"is_preprint":false},{"year":2024,"finding":"Cmtm4 deficiency in mice exacerbates DSS-induced colitis and causes gut microbiome dysbiosis. CMTM4 deficiency suppresses S100a8/9 expression in vitro via the IL-17 pathway, whereas elevated S100a8/9 in vivo is attributable to microbial dysbiosis. Blocking S100a8/9 receptor RAGE reverses phenotypes associated with CMTM4 deficiency.","method":"Cmtm4 knockout mice, DSS colitis model, cohousing experiment (microbiome transfer), in vitro IL-17 stimulation, RAGE inhibitor, Western blot, 16S microbiome analysis","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KO model, cohousing causal experiment, pharmacological intervention, in vitro mechanistic validation; single lab","pmids":["38575111"],"is_preprint":false},{"year":2025,"finding":"Exosomal CMTM4 from ovarian cancer cells is internalized by macrophages, activates the NF-κB pathway in tumor-associated macrophages (TAMs), promotes M2 polarization, and enhances secretion of TGF-β1 and CXCL12 while upregulating ICAM1 expression to facilitate cancer metastasis. Eltrombopag was identified as a CMTM4 inhibitor in vivo.","method":"Exosome isolation/internalization assay, macrophage polarization assay, NF-κB pathway Western blot, cytokine ELISA (TGF-β1, CXCL12), ICAM1 expression analysis, CMTM4 knockdown, in vivo OC models, drug screening","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — exosome uptake functional assay, NF-κB/cytokine mechanistic readout, in vivo validation; single lab","pmids":["40433989"],"is_preprint":false},{"year":2015,"finding":"miR-205 inhibits apoptosis in renal HK-2 cells by directly binding to the 3'UTR of CMTM4 mRNA and inhibiting its expression; CMTM4 is identified as a pro-apoptotic target gene whose suppression mediates the anti-apoptotic effect of miR-205.","method":"Luciferase 3'UTR reporter assay, Western blot, RT-PCR, flow cytometry (apoptosis), miR-205 mimic/inhibitor overexpression","journal":"Iranian journal of basic medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, luciferase reporter and Western blot only, limited mechanistic follow-up beyond miRNA targeting","pmids":["26730338"],"is_preprint":false},{"year":2024,"finding":"CMTM4 overexpression in gastric cancer AGS cells upregulates STAT1 and enriches STAT1 signaling pathway activity (identified by TMT proteomics and confirmed by Western blot), associated with inhibition of proliferation, induction of apoptosis, and G1/S arrest.","method":"Overexpression in AGS cells, TMT quantitative proteomics, Western blot (STAT1), flow cytometry (apoptosis, cell cycle), CCK-8/clonogenic assay","journal":"Journal of gastrointestinal oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, proteomics with Western blot confirmation but no direct mechanistic link established between CMTM4 and STAT1","pmids":["39279978"],"is_preprint":false}],"current_model":"CMTM4 is a tetra-transmembrane MARVEL-domain protein that functions as a multi-context regulator of membrane protein stability and trafficking: it stabilizes PD-L1 by reducing its ubiquitination and extending its half-life (shared with CMTM6); constitutively associates with IL-17RC to mediate its glycosylation, stability, and plasma membrane localization, making it an essential subunit of the IL-17 receptor signaling complex; promotes EGFR recycling and prevents Rab-dependent EGFR degradation to sustain EGF/NF-κB/PI3K-Akt signaling; regulates VE-cadherin endocytic recycling to control angiogenic sprouting and endothelial barrier function; and interacts with CXCR4 to alter its glycosylation and ER-to-plasma-membrane trafficking, with downstream effects on AKT signaling."},"narrative":{"mechanistic_narrative":"CMTM4 is a tetra-transmembrane MARVEL-domain protein that acts as a post-translational regulator of membrane protein stability, glycosylation, and endocytic trafficking across immune, vascular, and oncogenic contexts [PMID:28813410, PMID:36271145, PMID:30097810]. It binds PD-L1 at the cell surface and extends its half-life by reducing PD-L1 ubiquitination without altering transcription, a function it shares redundantly with CMTM6 [PMID:28813410]; in liver cancer this stabilization is the dominant route to PD-L1 protein expression, and CMTM4 loss promotes CD8+ T-cell infiltration and sensitizes tumors to anti-PD-L1 therapy [PMID:34558800]. CMTM4 is a constitutive subunit of the IL-17 receptor complex, associating with IL-17RC to mediate its glycosylation, stability, and plasma-membrane localization so that CMTM4-deficient cells cannot assemble a functional IL-17 signaling complex or respond to IL-17A [PMID:36271145], a requirement that extends to lymphatic endothelial NF-κB/chemokine output and to IL-17RC-dependent NF-κB/NOX1 signaling in gastric carcinogenesis [PMID:38754839, PMID:40432275]. More broadly, CMTM4 governs the trafficking itinerary of partner receptors: it controls VE-cadherin internalization and Rab-dependent recycling to support endothelial barrier function and vascular sprouting [PMID:30097810], promotes EGFR recycling while preventing its Rab-dependent degradation to sustain EGF-driven NF-κB/mTOR/PI3K-Akt signaling [PMID:39948411], and interacts with CXCR4 to alter its glycosylation and ER-to-plasma-membrane trafficking with selective downstream effects on AKT [PMID:36044337]. Across multiple cancer cell models, modulating CMTM4 tunes proliferation and migration through PI3K/Akt, ERK, and STAT signaling [PMID:32585413, PMID:31435638].","teleology":[{"year":2010,"claim":"Established the first cellular consequence of CMTM4 expression, framing it as a growth regulator before any molecular partner was known.","evidence":"Overexpression of two isoforms in HeLa cells with cell-cycle and localization readouts","pmids":["20213316"],"confidence":"Medium","gaps":["No molecular target or binding partner identified","Phenotype rests on overexpression alone"]},{"year":2015,"claim":"Extended the growth-suppressive role to a tumor context and linked it to a defined effector, showing CMTM4 restoration drives G2/M arrest, p21 induction, and reduced migration.","evidence":"Gain- and loss-of-function in 786-O ccRCC cells plus xenografts","pmids":["26474560"],"confidence":"Medium","gaps":["Mechanism connecting CMTM4 to p21 not resolved","No physical partner identified"]},{"year":2017,"claim":"Resolved a direct molecular mechanism: CMTM4 binds PD-L1 and stabilizes it post-translationally by limiting ubiquitination, redundantly with CMTM6.","evidence":"Haploid genetic screen, complementation, Co-IP, ubiquitination and cycloheximide-chase assays","pmids":["28813410"],"confidence":"High","gaps":["Structural basis of the CMTM4–PD-L1 interaction unresolved","Does not address non-PD-L1 client proteins"]},{"year":2018,"claim":"Showed CMTM4 acts on endocytic trafficking, controlling VE-cadherin internalization and recycling to set endothelial barrier and sprouting behavior.","evidence":"Knockdown/overexpression with Rab/EEA1 colocalization, TEER, 3D sprouting, and zebrafish morpholino","pmids":["30097810"],"confidence":"High","gaps":["Direct CMTM4–VE-cadherin binding not demonstrated","Molecular step linking CMTM4 to Rab machinery unknown"]},{"year":2019,"claim":"Connected CMTM4 to oncogenic signaling cascades, showing it suppresses PI3K/Akt (via PAK4), ERK, and STAT3 and is itself silenced by tumor-microenvironment miRNAs.","evidence":"3'UTR luciferase reporters, gain/loss-of-function and pathway Western blots in pancreatic and colorectal cancer cells with xenografts","pmids":["32585413","31435638"],"confidence":"Medium","gaps":["Whether signaling effects are direct or downstream of receptor-stabilization roles unclear","No physical partner mediating these pathway changes identified"]},{"year":2019,"claim":"Defined a physiological requirement in vivo, showing CMTM4 is needed for normal spermatogenesis and fertility.","evidence":"CRISPR-Cas9 knockout mice with sperm phenotyping, IVF, acrosome assays, and quantitative testis proteomics","pmids":["30867229"],"confidence":"High","gaps":["Molecular partner driving the testicular phenotype not identified","Link between CMTM4 and the 139 downregulated proteins is correlative"]},{"year":2021,"claim":"Demonstrated the PD-L1-stabilizing function is therapeutically actionable, with CMTM4 being the dominant PD-L1 regulator in liver cancer.","evidence":"siRNA across HCC/ICC lines, syngeneic mouse model, CD8+ T-cell profiling, anti-PD-L1 combination","pmids":["34558800"],"confidence":"Medium","gaps":["Post-translational mechanism not dissected beyond prior PD-L1 model","Single-lab in vivo evidence"]},{"year":2022,"claim":"Identified CMTM4 as a constitutive IL-17 receptor subunit, making it essential for IL-17RC stability, glycosylation, surface localization, and IL-17A responsiveness.","evidence":"Reciprocal Co-IP, CRISPR KO human and mouse cells, psoriasis/EAE mouse models","pmids":["36271145"],"confidence":"High","gaps":["Stoichiometry within the assembled IL-17R complex not defined","How CMTM4 mediates IL-17RC glycosylation mechanistically unresolved"]},{"year":2022,"claim":"Generalized the trafficking-regulator role to CXCR4, showing CMTM4 alters its glycosylation and slows ER-to-plasma-membrane transit with selective AKT effects.","evidence":"Co-IP, synchronized ER-release trafficking assay, glycosylation and signaling readouts, zebrafish morpholino","pmids":["36044337"],"confidence":"Medium","gaps":["Surface CXCR4 levels unchanged, leaving the functional consequence partly unclear","Basis for AKT-selective (vs ERK) effect unknown"]},{"year":2024,"claim":"Extended the IL-17R partnership into lymphatic endothelium, showing CMTM4 directly binds IL-17RC to drive NF-κB-dependent chemokine secretion and modulate inflammatory drainage.","evidence":"Co-IP, knockdown NF-κB/cytokine assays, LEC-specific AAV overexpression in Prox1-CreERT2 mice","pmids":["38754839"],"confidence":"Medium","gaps":["Single-lab in vivo model","Does not establish whether glycosylation role applies in LECs"]},{"year":2024,"claim":"Linked CMTM4 to intestinal homeostasis, separating a cell-intrinsic IL-17/S100a8/9 effect from microbiome-driven effects in colitis.","evidence":"KO mice, DSS colitis, cohousing microbiome transfer, RAGE inhibition, in vitro IL-17 stimulation","pmids":["38575111"],"confidence":"Medium","gaps":["Causal chain between CMTM4 loss and dysbiosis not fully resolved","Single-lab study"]},{"year":2025,"claim":"Established CMTM4 as a controller of EGFR recycling that sustains pro-tumor inflammatory signaling and confers EGFR-inhibitor sensitivity upon its loss.","evidence":"Knockout with Rab-dependent EGFR trafficking/degradation assays, signaling Westerns, MDSC profiling, syngeneic tumor models, in vivo siRNA","pmids":["39948411"],"confidence":"Medium","gaps":["Direct CMTM4–EGFR binding not shown","Which Rab steps CMTM4 acts on not pinpointed"]},{"year":2025,"claim":"Expanded the partner repertoire to PHB2 and to STAT2, implicating CMTM4 in STING/STAT6-driven chemokine transcription and in PD-L1-associated macrophage apoptosis through indirect signaling.","evidence":"Co-IP, ChIP-qPCR, nuclear fractionation, apoptosis flow cytometry across cervical cancer and sepsis models","pmids":["40514067","40122504"],"confidence":"Medium","gaps":["PHB2 and STAT2 mechanisms each rest on single studies","STAT2-mediated PD-L1 effect explicitly distinguished from direct binding, leaving the connecting step open"]},{"year":2025,"claim":"Showed CMTM4 itself can act extracellularly via exosomes to reprogram macrophages, broadening it from an intracellular regulator to an intercellular signal.","evidence":"Exosome internalization assays, macrophage polarization, NF-κB/cytokine readouts, in vivo ovarian cancer models, drug screening","pmids":["40433989"],"confidence":"Medium","gaps":["Mechanism by which exosomal CMTM4 activates macrophage NF-κB undefined","Single-lab study"]},{"year":null,"claim":"Whether CMTM4's many context-specific activities reflect a single unifying biochemical function (e.g., chaperoning/regulating glycosylation and trafficking of multiple transmembrane clients) versus distinct mechanisms per partner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CMTM4 or its client interactions","Direct binding established only for a subset of reported partners","Enzymatic vs scaffolding basis of glycosylation effects unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,9,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,10,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11,5,6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,11]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,9]}],"complexes":["IL-17 receptor complex"],"partners":["CD274","IL17RC","CXCR4","PHB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IZR5","full_name":"CKLF-like MARVEL transmembrane domain-containing protein 4","aliases":["Chemokine-like factor superfamily member 4"],"length_aa":234,"mass_kda":25.8,"function":"Acts as a backup for CMTM6 to regulate plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. May protect PD-L1/CD274 from being polyubiquitinated and targeted for degradation","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q8IZR5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CMTM4","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CMTM4","total_profiled":1310},"omim":[{"mim_id":"607889","title":"CKLF-LIKE MARVEL TRANSMEMBRANE DOMAIN-CONTAINING 6; CMTM6","url":"https://www.omim.org/entry/607889"},{"mim_id":"607887","title":"CKLF-LIKE MARVEL TRANSMEMBRANE DOMAIN-CONTAINING 4; CMTM4","url":"https://www.omim.org/entry/607887"},{"mim_id":"605402","title":"CD274 MOLECULE; CD274","url":"https://www.omim.org/entry/605402"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CMTM4"},"hgnc":{"alias_symbol":[],"prev_symbol":["CKLFSF4"]},"alphafold":{"accession":"Q8IZR5","domains":[{"cath_id":"1.20.120","chopping":"48-193","consensus_level":"high","plddt":86.2271,"start":48,"end":193}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZR5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZR5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZR5-F1-predicted_aligned_error_v6.png","plddt_mean":73.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CMTM4","jax_strain_url":"https://www.jax.org/strain/search?query=CMTM4"},"sequence":{"accession":"Q8IZR5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IZR5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IZR5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZR5"}},"corpus_meta":[{"pmid":"28813410","id":"PMC_28813410","title":"Identification of CMTM6 and CMTM4 as PD-L1 protein regulators.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28813410","citation_count":575,"is_preprint":false},{"pmid":"32585413","id":"PMC_32585413","title":"Pancreatic stellate cells derived exosomal miR-5703 promotes pancreatic cancer by downregulating CMTM4 and activating PI3K/Akt pathway.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/32585413","citation_count":80,"is_preprint":false},{"pmid":"30097810","id":"PMC_30097810","title":"CMTM4 regulates angiogenesis by promoting cell surface recycling of VE-cadherin to endothelial adherens junctions.","date":"2018","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/30097810","citation_count":68,"is_preprint":false},{"pmid":"26474560","id":"PMC_26474560","title":"CMTM4 is frequently downregulated and functions as a tumour suppressor in clear cell renal cell carcinoma.","date":"2015","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/26474560","citation_count":52,"is_preprint":false},{"pmid":"20213316","id":"PMC_20213316","title":"Identification and characterization of CMTM4, a novel gene with inhibitory effects on HeLa cell growth through Inducing G2/M phase accumulation.","date":"2010","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/20213316","citation_count":43,"is_preprint":false},{"pmid":"34558800","id":"PMC_34558800","title":"Inhibition of CMTM4 Sensitizes Cholangiocarcinoma and Hepatocellular Carcinoma to T Cell-Mediated Antitumor Immunity Through PD-L1.","date":"2021","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/34558800","citation_count":31,"is_preprint":false},{"pmid":"29180877","id":"PMC_29180877","title":"Clinical significance of CMTM4 expression in hepatocellular carcinoma.","date":"2017","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29180877","citation_count":28,"is_preprint":false},{"pmid":"31435638","id":"PMC_31435638","title":"CMTM4 inhibits cell proliferation and migration via AKT, ERK1/2, and STAT3 pathway in colorectal cancer.","date":"2019","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/31435638","citation_count":27,"is_preprint":false},{"pmid":"36271145","id":"PMC_36271145","title":"CMTM4 is a subunit of the IL-17 receptor and mediates autoimmune pathology.","date":"2022","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36271145","citation_count":22,"is_preprint":false},{"pmid":"34061408","id":"PMC_34061408","title":"CMTM4 regulates epithelial-mesenchymal transition and PD-L1 expression in head and neck squamous cell carcinoma.","date":"2021","source":"Molecular 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disease","url":"https://pubmed.ncbi.nlm.nih.gov/35220395","citation_count":18,"is_preprint":false},{"pmid":"38754839","id":"PMC_38754839","title":"LECs regulate neutrophil clearance through IL-17RC/CMTM4/NF-κB axis at sites of inflammation or infection.","date":"2024","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38754839","citation_count":14,"is_preprint":false},{"pmid":"32596272","id":"PMC_32596272","title":"Expression Analysis of Canine CMTM6 and CMTM4 as Potential Regulators of the PD-L1 Protein in Canine Cancers.","date":"2020","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/32596272","citation_count":13,"is_preprint":false},{"pmid":"26730338","id":"PMC_26730338","title":"MicroRNA-205 inhibits renal cells apoptosis via targeting CMTM4.","date":"2015","source":"Iranian journal of basic medical 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signaling and drug sensitivity by CMTM4.","date":"2025","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/39948411","citation_count":2,"is_preprint":false},{"pmid":"18177617","id":"PMC_18177617","title":"[Preparation, purification and characterization of the polyclonal antibody against human CMTM4].","date":"2008","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18177617","citation_count":2,"is_preprint":false},{"pmid":"39279978","id":"PMC_39279978","title":"CMTM4 inhibits gastric tumorigenesis and metastasis.","date":"2024","source":"Journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39279978","citation_count":1,"is_preprint":false},{"pmid":"40432275","id":"PMC_40432275","title":"Cmtm4 Deficiency Inhibits Helicobacter pylori-Induced Gastric Carcinogenesis.","date":"2025","source":"Pathology 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/39839608","citation_count":0,"is_preprint":false},{"pmid":"40122504","id":"PMC_40122504","title":"CMTM4 promotes PD-L1-mediated macrophage apoptosis by enhancing STAT2 phosphorylation in sepsis.","date":"2025","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40122504","citation_count":0,"is_preprint":false},{"pmid":"42254028","id":"PMC_42254028","title":"Research progress of CMTM4 in the tumor immune microenvironment and immunotherapy.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/42254028","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18017,"output_tokens":5373,"usd":0.067323,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13626,"output_tokens":4513,"usd":0.090478,"stage2_stop_reason":"end_turn"},"total_usd":0.157801,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"CMTM4 associates with the PD-L1 protein at the cell surface, reduces PD-L1 ubiquitination, and increases PD-L1 protein half-life without affecting PD-L1 transcription. CMTM4 shares this function with CMTM6 (demonstrated by genetic complementation in CMTM6-deficient cells), and interference with CMTM4 expression impairs PD-L1 protein expression.\",\n      \"method\": \"Haploid genetic screen, genetic complementation, co-immunoprecipitation, ubiquitination assay, protein half-life (cycloheximide chase), flow cytometry, siRNA knockdown\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (genetic screen, complementation, Co-IP, ubiquitination, half-life assay) in a single rigorous study replicated independently\",\n      \"pmids\": [\"28813410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CMTM4 is a constitutive subunit of the IL-17 receptor: it associates with IL-17 receptor subunit C (IL-17RC), mediates IL-17RC stability, glycosylation, and plasma membrane localization. CMTM4-deficient mouse and human cell lines are largely unresponsive to IL-17A due to inability to assemble the IL-17R signaling complex. CMTM4-deficient mice show severe defects in immune cell recruitment following IL-17A administration and resistance to experimental psoriasis.\",\n      \"method\": \"Co-immunoprecipitation, CRISPR/Cas9 knockout cell lines, in vivo mouse models (experimental psoriasis, EAE), IL-17A stimulation assays, glycosylation analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KO cell lines and in vivo mouse models, multiple orthogonal methods, published in high-impact peer-reviewed journal\",\n      \"pmids\": [\"36271145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CMTM4 colocalizes with Rab4+ and Rab7+ endocytic vesicles and with membrane-bound and internalized VE-cadherin. CMTM4 overexpression enhances VE-cadherin internalization and promotes rapid recycling (EEA1+, Rab4+, Rab11+, Rab7+ vesicles), while CMTM4 knockdown decreases VE-cadherin internalization. CMTM4 promotes endothelial barrier function and vascular sprouting.\",\n      \"method\": \"siRNA knockdown, adenovirus-mediated overexpression, intracellular colocalization staining, 3D vascular sprouting assay, zebrafish morpholino injection, transendothelial electrical resistance (TEER) assay\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (colocalization, functional sprouting assay, TEER, in vivo zebrafish), single lab\",\n      \"pmids\": [\"30097810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CMTM4-v1 and CMTM4-v2 are distributed on the cell membrane and across the cytoplasm. Overexpression of either isoform inhibits HeLa cell growth by inducing G2/M phase accumulation without inducing apoptosis.\",\n      \"method\": \"Overexpression in HeLa cells, flow cytometry (cell cycle analysis), subcellular localization (immunofluorescence)\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, overexpression with cell cycle readout and localization, two isoforms tested\",\n      \"pmids\": [\"20213316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Restoration of CMTM4 in 786-O ccRCC cells suppresses cell growth by inducing G2/M cell cycle arrest and upregulation of p21, and inhibits cell migration. Knockdown of CMTM4 produces the opposite effects. CMTM4 overexpression inhibits tumor xenograft growth in nude mice.\",\n      \"method\": \"Overexpression and siRNA knockdown, CCK-8/cell counting, wound healing/transwell assay, flow cytometry, Western blot (p21), xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain- and loss-of-function with multiple readouts and in vivo validation, single lab\",\n      \"pmids\": [\"26474560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CMTM4 suppresses PI3K/Akt signaling in pancreatic cancer cells via downregulation of PAK4. miR-5703 (from pancreatic stellate cell-derived exosomes) directly binds the 3'UTR of CMTM4 mRNA to downregulate its expression, promoting PC cell proliferation.\",\n      \"method\": \"Luciferase 3'UTR reporter assay, siRNA knockdown, CMTM4 overexpression, Western blot (PAK4, p-AKT), in vivo xenograft model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — 3'UTR reporter, gain/loss-of-function with pathway readout (PAK4/PI3K-Akt), in vivo validation, single lab\",\n      \"pmids\": [\"32585413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CMTM4 overexpression in colorectal cancer SW480 cells decreases phosphorylation levels of AKT, ERK1/2, and STAT3, while CMTM4 knockdown in HT29 cells elevates these. Pathway inhibitor experiments validate that these three signaling pathways contribute to CMTM4's anti-proliferative and anti-migratory effects.\",\n      \"method\": \"Overexpression and siRNA knockdown, Western blot (p-AKT, p-ERK1/2, p-STAT3), pharmacological inhibitors, proliferation and migration assays\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain/loss-of-function with pathway readout and inhibitor validation, single lab\",\n      \"pmids\": [\"31435638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CMTM4 knockout mice generated by CRISPR-Cas9 show reduced testicular daily sperm production, lower epididymal sperm motility, abnormal sperm morphology, sub-fertile phenotype, and reduced acrosome reactions. Quantitative proteomics identified 139 downregulated proteins in KO testes enriched for sperm motility and acrosome reaction functions.\",\n      \"method\": \"CRISPR-Cas9 knockout mice, Western blot, immunohistochemistry, sperm motility/morphology analysis, in vitro fertilization assay, acrosome reaction assay, quantitative mass spectrometry proteomics\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO model with multiple orthogonal functional readouts and quantitative proteomics, rigorous in vivo study\",\n      \"pmids\": [\"30867229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CMTM4 is the major regulator of PD-L1 in liver cancer (HCC and ICC) context. CMTM4 stabilizes PD-L1 through post-translational mechanisms. In vivo, Cmtm4 suppression in immunocompetent mice inhibited HCC growth and increased CD8+ T-cell infiltration. CMTM4 depletion sensitized HCC tumors to anti-PD-L1 treatment.\",\n      \"method\": \"siRNA knockdown in multiple HCC/ICC cell lines, Western blot, in vivo syngeneic mouse model, flow cytometry (CD8+ T cells), anti-PD-L1 combination therapy\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple cell lines, in vivo model, combination immunotherapy data, single lab\",\n      \"pmids\": [\"34558800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CMTM4 interacts with CXCR4, alters its glycosylation pattern, and slows CXCR4 trafficking from the endoplasmic reticulum to the plasma membrane without affecting overall cell surface expression or CXCR4 internalization/degradation in the absence of ligand. Altered CXCR4 trafficking reduces ligand-induced CXCR4 degradation and affects AKT but not ERK1/2 activation downstream of CXCR4.\",\n      \"method\": \"Co-immunoprecipitation, synchronized ER-release trafficking assay, glycosylation analysis, CXCR4 internalization/degradation assay, Western blot (AKT, ERK1/2), zebrafish cmtm4 morpholino\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ER-release assay, multiple signaling readouts, in vivo zebrafish, single lab\",\n      \"pmids\": [\"36044337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CMTM4 directly binds IL-17RC in lymphatic endothelial cells (LECs). CMTM4 knockdown abrogates IL-17A plus TNF-α-induced NF-κB signaling and CXC chemokine (CXCL1/2/3/5) secretion. LEC-specific CMTM4 overexpression in Prox1-CreERT2 mice promotes neutrophil drainage and alleviates immune pathological responses.\",\n      \"method\": \"Co-immunoprecipitation (CMTM4–IL-17RC binding), siRNA knockdown, NF-κB signaling assay, cytokine/chemokine ELISA, adeno-associated virus LEC-specific overexpression in mice, in vivo inflammation/infection models\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct binding by Co-IP, in vitro signaling readout, in vivo conditional overexpression model, single lab\",\n      \"pmids\": [\"38754839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CMTM4 promotes EGFR recycling and prevents Rab-dependent EGFR degradation, thereby sustaining EGF signaling post-translationally. CMTM4 knockout reduces NF-κB, mTOR, and PI3K/Akt pathway activation in lung carcinoma and decreases EGF-stimulated production of inflammatory cytokines (G-CSF), leading to reduced PMN-MDSC recruitment. CMTM4 KO sensitizes tumor cells to EGFR inhibitors.\",\n      \"method\": \"CMTM4 knockout, Western blot (NF-κB, mTOR, PI3K/Akt, EGFR), EGFR recycling/degradation assay (Rab-dependent), cytokine profiling, MDSC flow cytometry, EGFR inhibitor sensitivity assay, in vivo syngeneic tumor models, siRNA-liposome in vivo delivery\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with multiple signaling readouts and EGFR trafficking mechanistic assay, in vivo validation, single lab\",\n      \"pmids\": [\"39948411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CMTM4 interacts with and stabilizes PHB2 (prohibitin 2) through post-translational modification. This CMTM4–PHB2 interaction activates the STING/TBK1/STAT6 pathway, promoting nuclear translocation of STAT6 which binds CCL2 and IL-6 promoters to upregulate their transcription, thereby driving MDSC recruitment (via CCL2/CCR2 and IL-6/GP130 axes) and immune suppression in cervical cancer.\",\n      \"method\": \"Co-immunoprecipitation (CMTM4–PHB2), chromatin immunoprecipitation (ChIP-qPCR for STAT6 at CCL2/IL-6 promoters), nuclear fractionation, Western blot (STING/TBK1/STAT6), siRNA knockdown, in vivo therapeutic models with anti-PD-1\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-qPCR, nuclear translocation, multiple pathway readouts; single lab\",\n      \"pmids\": [\"40514067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In sepsis, CMTM4 promotes PD-L1-mediated macrophage apoptosis by enhancing STAT2 phosphorylation rather than by directly binding PD-L1. CMTM4 inhibition reduces macrophage apoptosis.\",\n      \"method\": \"Co-immunoprecipitation (protein-protein interactions), ChIP-qPCR, Western blot (p-STAT2), flow cytometry (apoptosis), transcriptomic sequencing, in vitro macrophage model (THP-1 and C57BL/6 mice)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ChIP-qPCR, functional apoptosis readout; explicitly distinguishes indirect (STAT2-mediated) from direct PD-L1 binding; single lab\",\n      \"pmids\": [\"40122504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cmtm4 deletion in mice downregulates IL-17RC expression and suppresses downstream NF-κB activation and NOX1 levels in the context of H. pylori-induced gastric carcinogenesis, inhibiting GC development and precancerous lesion formation.\",\n      \"method\": \"Cmtm4 knockout mice, H. pylori infection model, Western blot (IL-17RC, NF-κB, NOX1), immunohistochemistry, DNA damage analysis\",\n      \"journal\": \"Pathology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vivo KO model with mechanistic pathway readout, single lab\",\n      \"pmids\": [\"40432275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cmtm4 deficiency in mice exacerbates DSS-induced colitis and causes gut microbiome dysbiosis. CMTM4 deficiency suppresses S100a8/9 expression in vitro via the IL-17 pathway, whereas elevated S100a8/9 in vivo is attributable to microbial dysbiosis. Blocking S100a8/9 receptor RAGE reverses phenotypes associated with CMTM4 deficiency.\",\n      \"method\": \"Cmtm4 knockout mice, DSS colitis model, cohousing experiment (microbiome transfer), in vitro IL-17 stimulation, RAGE inhibitor, Western blot, 16S microbiome analysis\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KO model, cohousing causal experiment, pharmacological intervention, in vitro mechanistic validation; single lab\",\n      \"pmids\": [\"38575111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Exosomal CMTM4 from ovarian cancer cells is internalized by macrophages, activates the NF-κB pathway in tumor-associated macrophages (TAMs), promotes M2 polarization, and enhances secretion of TGF-β1 and CXCL12 while upregulating ICAM1 expression to facilitate cancer metastasis. Eltrombopag was identified as a CMTM4 inhibitor in vivo.\",\n      \"method\": \"Exosome isolation/internalization assay, macrophage polarization assay, NF-κB pathway Western blot, cytokine ELISA (TGF-β1, CXCL12), ICAM1 expression analysis, CMTM4 knockdown, in vivo OC models, drug screening\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — exosome uptake functional assay, NF-κB/cytokine mechanistic readout, in vivo validation; single lab\",\n      \"pmids\": [\"40433989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-205 inhibits apoptosis in renal HK-2 cells by directly binding to the 3'UTR of CMTM4 mRNA and inhibiting its expression; CMTM4 is identified as a pro-apoptotic target gene whose suppression mediates the anti-apoptotic effect of miR-205.\",\n      \"method\": \"Luciferase 3'UTR reporter assay, Western blot, RT-PCR, flow cytometry (apoptosis), miR-205 mimic/inhibitor overexpression\",\n      \"journal\": \"Iranian journal of basic medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, luciferase reporter and Western blot only, limited mechanistic follow-up beyond miRNA targeting\",\n      \"pmids\": [\"26730338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CMTM4 overexpression in gastric cancer AGS cells upregulates STAT1 and enriches STAT1 signaling pathway activity (identified by TMT proteomics and confirmed by Western blot), associated with inhibition of proliferation, induction of apoptosis, and G1/S arrest.\",\n      \"method\": \"Overexpression in AGS cells, TMT quantitative proteomics, Western blot (STAT1), flow cytometry (apoptosis, cell cycle), CCK-8/clonogenic assay\",\n      \"journal\": \"Journal of gastrointestinal oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, proteomics with Western blot confirmation but no direct mechanistic link established between CMTM4 and STAT1\",\n      \"pmids\": [\"39279978\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CMTM4 is a tetra-transmembrane MARVEL-domain protein that functions as a multi-context regulator of membrane protein stability and trafficking: it stabilizes PD-L1 by reducing its ubiquitination and extending its half-life (shared with CMTM6); constitutively associates with IL-17RC to mediate its glycosylation, stability, and plasma membrane localization, making it an essential subunit of the IL-17 receptor signaling complex; promotes EGFR recycling and prevents Rab-dependent EGFR degradation to sustain EGF/NF-κB/PI3K-Akt signaling; regulates VE-cadherin endocytic recycling to control angiogenic sprouting and endothelial barrier function; and interacts with CXCR4 to alter its glycosylation and ER-to-plasma-membrane trafficking, with downstream effects on AKT signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CMTM4 is a tetra-transmembrane MARVEL-domain protein that acts as a post-translational regulator of membrane protein stability, glycosylation, and endocytic trafficking across immune, vascular, and oncogenic contexts [#0, #1, #2]. It binds PD-L1 at the cell surface and extends its half-life by reducing PD-L1 ubiquitination without altering transcription, a function it shares redundantly with CMTM6 [#0]; in liver cancer this stabilization is the dominant route to PD-L1 protein expression, and CMTM4 loss promotes CD8+ T-cell infiltration and sensitizes tumors to anti-PD-L1 therapy [#8]. CMTM4 is a constitutive subunit of the IL-17 receptor complex, associating with IL-17RC to mediate its glycosylation, stability, and plasma-membrane localization so that CMTM4-deficient cells cannot assemble a functional IL-17 signaling complex or respond to IL-17A [#1], a requirement that extends to lymphatic endothelial NF-\\u03baB/chemokine output and to IL-17RC-dependent NF-\\u03baB/NOX1 signaling in gastric carcinogenesis [#10, #14]. More broadly, CMTM4 governs the trafficking itinerary of partner receptors: it controls VE-cadherin internalization and Rab-dependent recycling to support endothelial barrier function and vascular sprouting [#2], promotes EGFR recycling while preventing its Rab-dependent degradation to sustain EGF-driven NF-\\u03baB/mTOR/PI3K-Akt signaling [#11], and interacts with CXCR4 to alter its glycosylation and ER-to-plasma-membrane trafficking with selective downstream effects on AKT [#9]. Across multiple cancer cell models, modulating CMTM4 tunes proliferation and migration through PI3K/Akt, ERK, and STAT signaling [#5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the first cellular consequence of CMTM4 expression, framing it as a growth regulator before any molecular partner was known.\",\n      \"evidence\": \"Overexpression of two isoforms in HeLa cells with cell-cycle and localization readouts\",\n      \"pmids\": [\"20213316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular target or binding partner identified\", \"Phenotype rests on overexpression alone\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the growth-suppressive role to a tumor context and linked it to a defined effector, showing CMTM4 restoration drives G2/M arrest, p21 induction, and reduced migration.\",\n      \"evidence\": \"Gain- and loss-of-function in 786-O ccRCC cells plus xenografts\",\n      \"pmids\": [\"26474560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CMTM4 to p21 not resolved\", \"No physical partner identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved a direct molecular mechanism: CMTM4 binds PD-L1 and stabilizes it post-translationally by limiting ubiquitination, redundantly with CMTM6.\",\n      \"evidence\": \"Haploid genetic screen, complementation, Co-IP, ubiquitination and cycloheximide-chase assays\",\n      \"pmids\": [\"28813410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the CMTM4\\u2013PD-L1 interaction unresolved\", \"Does not address non-PD-L1 client proteins\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CMTM4 acts on endocytic trafficking, controlling VE-cadherin internalization and recycling to set endothelial barrier and sprouting behavior.\",\n      \"evidence\": \"Knockdown/overexpression with Rab/EEA1 colocalization, TEER, 3D sprouting, and zebrafish morpholino\",\n      \"pmids\": [\"30097810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CMTM4\\u2013VE-cadherin binding not demonstrated\", \"Molecular step linking CMTM4 to Rab machinery unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected CMTM4 to oncogenic signaling cascades, showing it suppresses PI3K/Akt (via PAK4), ERK, and STAT3 and is itself silenced by tumor-microenvironment miRNAs.\",\n      \"evidence\": \"3'UTR luciferase reporters, gain/loss-of-function and pathway Western blots in pancreatic and colorectal cancer cells with xenografts\",\n      \"pmids\": [\"32585413\", \"31435638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether signaling effects are direct or downstream of receptor-stabilization roles unclear\", \"No physical partner mediating these pathway changes identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a physiological requirement in vivo, showing CMTM4 is needed for normal spermatogenesis and fertility.\",\n      \"evidence\": \"CRISPR-Cas9 knockout mice with sperm phenotyping, IVF, acrosome assays, and quantitative testis proteomics\",\n      \"pmids\": [\"30867229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partner driving the testicular phenotype not identified\", \"Link between CMTM4 and the 139 downregulated proteins is correlative\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated the PD-L1-stabilizing function is therapeutically actionable, with CMTM4 being the dominant PD-L1 regulator in liver cancer.\",\n      \"evidence\": \"siRNA across HCC/ICC lines, syngeneic mouse model, CD8+ T-cell profiling, anti-PD-L1 combination\",\n      \"pmids\": [\"34558800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Post-translational mechanism not dissected beyond prior PD-L1 model\", \"Single-lab in vivo evidence\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified CMTM4 as a constitutive IL-17 receptor subunit, making it essential for IL-17RC stability, glycosylation, surface localization, and IL-17A responsiveness.\",\n      \"evidence\": \"Reciprocal Co-IP, CRISPR KO human and mouse cells, psoriasis/EAE mouse models\",\n      \"pmids\": [\"36271145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry within the assembled IL-17R complex not defined\", \"How CMTM4 mediates IL-17RC glycosylation mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized the trafficking-regulator role to CXCR4, showing CMTM4 alters its glycosylation and slows ER-to-plasma-membrane transit with selective AKT effects.\",\n      \"evidence\": \"Co-IP, synchronized ER-release trafficking assay, glycosylation and signaling readouts, zebrafish morpholino\",\n      \"pmids\": [\"36044337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Surface CXCR4 levels unchanged, leaving the functional consequence partly unclear\", \"Basis for AKT-selective (vs ERK) effect unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the IL-17R partnership into lymphatic endothelium, showing CMTM4 directly binds IL-17RC to drive NF-\\u03baB-dependent chemokine secretion and modulate inflammatory drainage.\",\n      \"evidence\": \"Co-IP, knockdown NF-\\u03baB/cytokine assays, LEC-specific AAV overexpression in Prox1-CreERT2 mice\",\n      \"pmids\": [\"38754839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vivo model\", \"Does not establish whether glycosylation role applies in LECs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked CMTM4 to intestinal homeostasis, separating a cell-intrinsic IL-17/S100a8/9 effect from microbiome-driven effects in colitis.\",\n      \"evidence\": \"KO mice, DSS colitis, cohousing microbiome transfer, RAGE inhibition, in vitro IL-17 stimulation\",\n      \"pmids\": [\"38575111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain between CMTM4 loss and dysbiosis not fully resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established CMTM4 as a controller of EGFR recycling that sustains pro-tumor inflammatory signaling and confers EGFR-inhibitor sensitivity upon its loss.\",\n      \"evidence\": \"Knockout with Rab-dependent EGFR trafficking/degradation assays, signaling Westerns, MDSC profiling, syngeneic tumor models, in vivo siRNA\",\n      \"pmids\": [\"39948411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CMTM4\\u2013EGFR binding not shown\", \"Which Rab steps CMTM4 acts on not pinpointed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the partner repertoire to PHB2 and to STAT2, implicating CMTM4 in STING/STAT6-driven chemokine transcription and in PD-L1-associated macrophage apoptosis through indirect signaling.\",\n      \"evidence\": \"Co-IP, ChIP-qPCR, nuclear fractionation, apoptosis flow cytometry across cervical cancer and sepsis models\",\n      \"pmids\": [\"40514067\", \"40122504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PHB2 and STAT2 mechanisms each rest on single studies\", \"STAT2-mediated PD-L1 effect explicitly distinguished from direct binding, leaving the connecting step open\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed CMTM4 itself can act extracellularly via exosomes to reprogram macrophages, broadening it from an intracellular regulator to an intercellular signal.\",\n      \"evidence\": \"Exosome internalization assays, macrophage polarization, NF-\\u03baB/cytokine readouts, in vivo ovarian cancer models, drug screening\",\n      \"pmids\": [\"40433989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which exosomal CMTM4 activates macrophage NF-\\u03baB undefined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether CMTM4's many context-specific activities reflect a single unifying biochemical function (e.g., chaperoning/regulating glycosylation and trafficking of multiple transmembrane clients) versus distinct mechanisms per partner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CMTM4 or its client interactions\", \"Direct binding established only for a subset of reported partners\", \"Enzymatic vs scaffolding basis of glycosylation effects unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 9, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 10, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11, 5, 6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [\"IL-17 receptor complex\"],\n    \"partners\": [\"CD274\", \"IL17RC\", \"CXCR4\", \"PHB2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}