{"gene":"CMTM7","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2013,"finding":"CMTM7 promotes EGFR internalization in carcinoma cells, thereby suppressing downstream AKT signaling. Ectopic CMTM7 expression causes G1/S cell cycle arrest associated with upregulation of p27 and downregulation of CDK2 and CDK6.","method":"Ectopic expression in carcinoma cell lines, cell cycle analysis, Western blot for AKT/p27/CDK2/CDK6, EGFR internalization assay, nude mouse tumor formation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal cellular assays (proliferation, motility, EGFR internalization, signaling readouts, in vivo), single lab","pmids":["23893243"],"is_preprint":false},{"year":2015,"finding":"CMTM7 knockdown increases EGFR-AKT signaling by reducing EGFR internalization and degradation. Mechanistically, CMTM7 is required for activation of Rab5, a GTPase needed for early endosome fusion; loss of CMTM7 reduces GTP-Rab5 levels.","method":"Stable shRNA knockdown in NSCLC cells, EGFR internalization/degradation assays, Rab5 activation assay, Western blot for AKT phosphorylation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and molecular mechanism, multiple orthogonal methods, single lab","pmids":["26528697"],"is_preprint":false},{"year":2012,"finding":"CMTM7, a tetra-spanning membrane protein, physically associates with surface IgM (BCR) and with BLNK in a membrane fraction; this interaction is augmented after BCR ligation. CMTM7 recruits BLNK to the vicinity of Syk, enabling BLNK phosphorylation and downstream JNK/ERK activation. The C-terminal domain is required for membrane localization and for these functions, while N-terminal deletion mutants retain activity.","method":"RNAi knockdown in B cells, co-immunoprecipitation (CMTM7-BLNK and CMTM7-sIgM), rescue experiments with deletion mutants, tyrosine phosphorylation assays, JNK/ERK activation assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain-deletion mutagenesis rescue, multiple orthogonal functional readouts, mechanistic pathway placement","pmids":["22363743"],"is_preprint":false},{"year":2013,"finding":"CMTM7 is required for normal BCR expression and survival specifically in B-1a cells but not B-2 cells. Cmtm7(flox/+) heterozygous reduction leads to decreased BCR surface levels, increased spontaneous apoptosis, impaired IgM secretion, and poor LPS-induced proliferation in B-1a cells.","method":"Rag1−/− reconstitution with Cmtm7(flox/+) fetal liver cells, flow cytometry for BCR surface expression and cell death, serum IgM measurement, proliferation assays","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo reconstitution model, multiple functional readouts, single lab","pmids":["24080084"],"is_preprint":false},{"year":2019,"finding":"Cmtm7 knockout blocks B-1a cell development specifically at the transitional B-1a (TrB-1a) stage, causing slow proliferation and high cell death at that stage. This is a B-cell-intrinsic defect confirmed by bone marrow and fetal liver adoptive transfer and conditional knockout models. Cmtm7-deficient mice produce less IgM and IL-10 and are more susceptible to microbial sepsis.","method":"Cmtm7 global knockout mice, conditional knockout, bone marrow/fetal liver adoptive transfer, flow cytometry at developmental stages, IgM/IL-10 ELISA, sepsis model","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — full knockout + conditional knockout + adoptive transfer, multiple orthogonal assays establishing B-cell-intrinsic mechanism and developmental stage","pmids":["31081901"],"is_preprint":false},{"year":2020,"finding":"CMTM7 is required for TLR agonist-induced plasma cell differentiation in B-1 cells. Loss of Cmtm7 suppresses downregulation of Pax5 and upregulation of Xbp1, Irf4, and Prdm1 (transcription factors governing plasma cell fate), and inhibits p38 phosphorylation. A p38 inhibitor phenocopies Cmtm7 deficiency, placing CMTM7 upstream of p38 in B-1 cell terminal differentiation.","method":"Cmtm7 knockout mice, in vitro TLR stimulation, flow cytometry for plasma cell markers, Western blot for p38 phosphorylation, p38 inhibitor epistasis experiment, IgM/IL-10 ELISA","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout with epistasis (p38 inhibitor phenocopy), multiple molecular readouts, pathway placement upstream of p38, single lab with orthogonal methods","pmids":["32022930"],"is_preprint":false},{"year":2020,"finding":"In splenic B-1a cells, Cmtm7 knockout elevates surface CD5, CD80, and CD86 and enhances tonic BCR signaling at steady state. Cmtm7 deficiency promotes splenic B-1a apoptosis in situ, associated with downregulation of IL-5Rα. Cmtm7 also shapes the IgM heavy-chain repertoire differently in peritoneal vs. splenic B-1a cells.","method":"Cmtm7 knockout mice, flow cytometry, BCR signaling assays, Igμ repertoire sequencing, apoptosis assays in situ","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout with multiple cellular and molecular readouts, single lab","pmids":["32305130"],"is_preprint":false},{"year":2021,"finding":"Dual knockdown of CMTM6 and CMTM7 significantly reduces PD-L1 surface expression in mesenchymal breast cancer cells, indicating that CMTM7 contributes to maintaining cell-surface PD-L1 during EMT.","method":"siRNA dual knockdown of CMTM6 and CMTM7 in MCF-7Mes cells, flow cytometry for surface PD-L1","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment (dual KD), one readout, single lab; CMTM7-specific contribution not fully disentangled from CMTM6","pmids":["33803139"],"is_preprint":false},{"year":2023,"finding":"CMTM7 interacts with CTNNA1 (Catenin Alpha 1) and regulates Wnt/β-catenin signaling in breast cancer cells. A feedback loop comprising miR-182-5p, CMTM7, CTNNA1, β-catenin (CTNNB1), and TCF3 was identified; TCF3 transcriptionally activates miR-182-5p, which targets and represses CMTM7, while CMTM7 suppresses β-catenin/TCF3 output.","method":"Co-IP (CMTM7-CTNNA1 interaction), luciferase reporter assay (miR-182-5p targeting CMTM7; TCF3 promoter activity on miR-182-5p), ChIP analysis, Western blot, in vitro and in vivo functional assays","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct interaction, luciferase and ChIP for transcriptional circuit, multiple orthogonal methods, single lab","pmids":["36829181"],"is_preprint":false},{"year":2025,"finding":"CMTM7 inhibits TLR4 signaling in macrophages by promoting the interaction between Rab5 and its GEF Gapex5, generating GTP-Rab5, which facilitates TLR4 internalization and degradation, thereby suppressing downstream inflammatory signaling. Myeloid-conditional Cmtm7 knockout mice show exacerbated acute liver injury, and adoptive transfer of CMTM7-overexpressing macrophages is protective.","method":"Myeloid conditional Cmtm7 knockout mice, Rab5 activation assay (GTP-Rab5), co-immunoprecipitation (Rab5-Gapex5 interaction), TLR4 internalization/degradation assays, LPS/HMGB1 stimulation, adoptive transfer of CMTM7-overexpressing macrophages, ALI mouse model","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo, mechanistic Co-IP, GTPase activation assay, receptor internalization, adoptive transfer rescue; multiple orthogonal methods establishing mechanism","pmids":["40490565"],"is_preprint":false},{"year":2018,"finding":"SOX10 transcriptionally regulates CMTM7 expression in gastric cancer. Overexpression of SOX10 in CMTM7-silenced gastric cancer cells inhibits proliferation and tumor growth, placing CMTM7 downstream of SOX10 in this pathway.","method":"Bioinformatics, luciferase reporter assay (SOX10 binding to CMTM7 promoter), stable CMTM7 silencing, SOX10 overexpression in CMTM7-knockdown cells, proliferation and in vivo tumor assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter for transcriptional regulation plus epistasis rescue experiment, single lab","pmids":["30392914"],"is_preprint":false},{"year":2025,"finding":"SOX10 transcriptionally represses CMTM7 in pancreatic cancer (dual-luciferase assay). CMTM7 overexpression inhibits the Wnt/β-catenin pathway and induces ferroptosis in PC cells; silencing CMTM7 reverses the anti-tumor effects of SOX10 knockdown, placing CMTM7 downstream of SOX10 in a Wnt/β-catenin-ferroptosis axis.","method":"Dual-luciferase reporter assay, shRNA knockdown, CMTM7 overexpression, flow cytometry for apoptosis/ferroptosis markers, Wnt/β-catenin pathway Western blot, tumor-bearing mouse model","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase for direct transcriptional regulation, genetic epistasis (sh-SOX10 + CMTM7 silencing rescue), in vivo validation, single lab","pmids":["39754171"],"is_preprint":false}],"current_model":"CMTM7 is a tetra-spanning MARVEL-domain membrane protein that functions as a scaffold linking surface receptors to endocytic machinery: it bridges the BCR (sIgM) to the adaptor BLNK to initiate B-cell signaling, promotes Rab5 activation (via Gapex5-mediated GTP loading) to drive clathrin-mediated internalization and degradation of EGFR and TLR4, thereby suppressing oncogenic EGFR/AKT and inflammatory TLR4 signaling; in B-1a cells it is additionally required for developmental progression through the transitional stage and for TLR-induced plasma cell differentiation via p38 activation, while in cancer cells it also interacts with CTNNA1 to suppress Wnt/β-catenin signaling and is transcriptionally silenced by SOX10-driven miR-182-5p."},"narrative":{"mechanistic_narrative":"CMTM7 is a tetra-spanning membrane protein that acts as a scaffold coupling cell-surface receptors to intracellular signaling and endocytic machinery, with roles spanning B-cell development, innate immune regulation, and tumor suppression [PMID:22363743, PMID:40490565]. In B cells it physically associates with surface IgM (BCR) and the adaptor BLNK in the membrane, recruiting BLNK toward Syk to enable its phosphorylation and downstream JNK/ERK activation; its C-terminal domain is required for membrane localization and these functions [PMID:22363743]. A central mechanism of CMTM7 is promotion of Rab5 GTP-loading to drive clathrin-mediated receptor internalization and degradation: it is required for Rab5 activation that internalizes and degrades EGFR, thereby restraining downstream AKT signaling [PMID:26528697], and in macrophages it promotes the interaction between Rab5 and its GEF Gapex5 to generate GTP-Rab5, facilitating TLR4 internalization and degradation and suppressing inflammatory signaling [PMID:40490565]. In B-1a cells CMTM7 is required cell-intrinsically for developmental progression through the transitional B-1a stage and for normal BCR expression and survival [PMID:24080084, PMID:31081901], and it is required for TLR-induced plasma cell differentiation acting upstream of p38 to control Pax5 downregulation and Xbp1/Irf4/Prdm1 induction [PMID:32022930]. In cancer cells CMTM7 suppresses proliferation, with ectopic expression causing G1/S arrest via p27 upregulation and CDK2/CDK6 downregulation [PMID:23893243], and it interacts with CTNNA1 to suppress Wnt/β-catenin signaling [PMID:36829181]; its expression is controlled transcriptionally by SOX10 and by a miR-182-5p feedback loop [PMID:36829181, PMID:30392914, PMID:39754171].","teleology":[{"year":2012,"claim":"Established CMTM7 as a membrane scaffold in BCR signaling by showing it physically links surface IgM to the adaptor BLNK, answering how BLNK is positioned for Syk-dependent phosphorylation.","evidence":"RNAi knockdown, reciprocal Co-IP (CMTM7-BLNK, CMTM7-sIgM), domain-deletion rescue, and JNK/ERK activation assays in B cells","pmids":["22363743"],"confidence":"High","gaps":["Structural basis of the CMTM7-BLNK-sIgM assembly not resolved","Whether endocytic function connects to this scaffold role not addressed here"]},{"year":2013,"claim":"Linked CMTM7 to receptor endocytosis and tumor suppression by showing it promotes EGFR internalization and imposes G1/S arrest, defining a growth-suppressive function in carcinoma.","evidence":"Ectopic expression in carcinoma lines, EGFR internalization assay, cell cycle analysis, AKT/p27/CDK Western blot, nude mouse tumor formation","pmids":["23893243"],"confidence":"Medium","gaps":["Molecular mechanism linking CMTM7 to internalization not defined at this stage","Single lab, gain-of-function emphasis"]},{"year":2013,"claim":"Demonstrated B-cell-subset specificity by showing CMTM7 is required for normal BCR expression and survival selectively in B-1a but not B-2 cells.","evidence":"Rag1−/− reconstitution with Cmtm7(flox/+) fetal liver cells, flow cytometry, serum IgM, proliferation assays","pmids":["24080084"],"confidence":"Medium","gaps":["Mechanism of subset-restricted requirement unexplained","Heterozygous reduction rather than full knockout"]},{"year":2015,"claim":"Defined the molecular mechanism of CMTM7-driven EGFR turnover by identifying Rab5 GTPase activation as the required step for endosomal internalization and degradation.","evidence":"Stable shRNA knockdown in NSCLC cells, EGFR internalization/degradation assays, Rab5 activation (GTP-Rab5) assay, AKT phosphorylation Western blot","pmids":["26528697"],"confidence":"Medium","gaps":["How CMTM7 activates Rab5 (GEF link) not yet identified","Direct interaction with Rab5 not shown"]},{"year":2019,"claim":"Pinpointed the developmental stage of CMTM7 action by showing knockout blocks B-1a development at the transitional B-1a stage in a cell-intrinsic manner, with functional consequences for IgM/IL-10 and sepsis resistance.","evidence":"Global and conditional Cmtm7 knockout mice, bone marrow/fetal liver adoptive transfer, stage-resolved flow cytometry, ELISA, sepsis model","pmids":["31081901"],"confidence":"High","gaps":["Molecular trigger of the transitional-stage block unresolved","Connection to the BCR-scaffold mechanism not directly tested"]},{"year":2020,"claim":"Placed CMTM7 upstream of p38 in B-1 plasma cell differentiation by showing knockout impairs the transcription factor switch and p38 phosphorylation, with a p38 inhibitor phenocopying the loss.","evidence":"Cmtm7 knockout mice, TLR stimulation, plasma cell marker flow cytometry, p38 Western blot, p38 inhibitor epistasis, ELISA","pmids":["32022930"],"confidence":"High","gaps":["How CMTM7 activates p38 mechanistically unknown","Link between p38 and receptor scaffolding role not established"]},{"year":2020,"claim":"Extended CMTM7's B-1a role to steady-state homeostasis by showing knockout enhances tonic BCR signaling, alters activation markers, promotes splenic apoptosis, and shapes the IgM repertoire.","evidence":"Cmtm7 knockout mice, flow cytometry, BCR signaling assays, Igμ repertoire sequencing, in situ apoptosis assays","pmids":["32305130"],"confidence":"Medium","gaps":["Causal link between tonic signaling and apoptosis not dissected","Single lab"]},{"year":2023,"claim":"Identified a tumor-suppressive Wnt axis by showing CMTM7 binds CTNNA1 and sits in a miR-182-5p/TCF3 feedback loop that controls β-catenin output in breast cancer.","evidence":"Co-IP (CMTM7-CTNNA1), luciferase reporters, ChIP, Western blot, in vitro and in vivo functional assays","pmids":["36829181"],"confidence":"Medium","gaps":["Whether CTNNA1 binding is direct vs complex-mediated not fully resolved","Tissue generality of the loop untested"]},{"year":2025,"claim":"Resolved the long-standing question of how CMTM7 activates Rab5 by showing it promotes Rab5-Gapex5 (GEF) interaction to drive TLR4 internalization/degradation and suppress inflammation in macrophages.","evidence":"Myeloid conditional knockout mice, GTP-Rab5 assay, Co-IP (Rab5-Gapex5), TLR4 internalization/degradation assays, adoptive transfer rescue, acute liver injury model","pmids":["40490565"],"confidence":"High","gaps":["Whether the same Gapex5-Rab5 mechanism operates for EGFR not shown","Direct CMTM7-Gapex5 or CMTM7-Rab5 binding interface undefined"]},{"year":2025,"claim":"Reinforced SOX10-CMTM7 transcriptional control and linked CMTM7 to ferroptosis, showing SOX10 represses CMTM7 and that CMTM7 inhibits Wnt/β-catenin and induces ferroptosis in pancreatic cancer.","evidence":"Dual-luciferase reporter, shRNA knockdown, CMTM7 overexpression, ferroptosis flow cytometry, Wnt Western blot, tumor-bearing mouse model","pmids":["39754171"],"confidence":"Medium","gaps":["Mechanism connecting Wnt suppression to ferroptosis not defined","SOX10 acts as repressor here vs activator elsewhere—context dependence unexplained"]},{"year":null,"claim":"It remains unknown whether the BCR/BLNK scaffolding role, the Gapex5-Rab5 endocytic mechanism, and the developmental p38 and Wnt/ferroptosis functions reflect one unified biochemical activity of CMTM7 or distinct context-specific mechanisms.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CMTM7 or its interaction interfaces","Direct binding partners on the cytoplasmic face (Rab5, Gapex5) not biochemically mapped","Unifying mechanism across immune and cancer contexts not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,5,9]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,8,9]}],"complexes":[],"partners":["BLNK","IGHM","CTNNA1","RAB5A","GAPVD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96FZ5","full_name":"CKLF-like MARVEL transmembrane domain-containing protein 7","aliases":["Chemokine-like factor superfamily member 7"],"length_aa":175,"mass_kda":18.8,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q96FZ5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CMTM7","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/CMTM7","total_profiled":1310},"omim":[{"mim_id":"607890","title":"CKLF-LIKE MARVEL TRANSMEMBRANE DOMAIN-CONTAINING 7; CMTM7","url":"https://www.omim.org/entry/607890"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CMTM7"},"hgnc":{"alias_symbol":["FLJ30992"],"prev_symbol":["CKLFSF7"]},"alphafold":{"accession":"Q96FZ5","domains":[{"cath_id":"1.20.1440","chopping":"43-169","consensus_level":"high","plddt":80.3884,"start":43,"end":169}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FZ5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FZ5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FZ5-F1-predicted_aligned_error_v6.png","plddt_mean":69.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CMTM7","jax_strain_url":"https://www.jax.org/strain/search?query=CMTM7"},"sequence":{"accession":"Q96FZ5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96FZ5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96FZ5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FZ5"}},"corpus_meta":[{"pmid":"23893243","id":"PMC_23893243","title":"A novel 3p22.3 gene CMTM7 represses oncogenic EGFR signaling and inhibits cancer cell growth.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23893243","citation_count":67,"is_preprint":false},{"pmid":"34294040","id":"PMC_34294040","title":"Breast cancer cell-derived extracellular vesicles transfer miR-182-5p and promote breast carcinogenesis via the CMTM7/EGFR/AKT axis.","date":"2021","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/34294040","citation_count":47,"is_preprint":false},{"pmid":"26528697","id":"PMC_26528697","title":"CMTM7 knockdown increases tumorigenicity of human non-small cell lung cancer cells and EGFR-AKT signaling by reducing Rab5 activation.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26528697","citation_count":44,"is_preprint":false},{"pmid":"22363743","id":"PMC_22363743","title":"Identification of CMTM7 as a transmembrane linker of BLNK and the B-cell receptor.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22363743","citation_count":28,"is_preprint":false},{"pmid":"33803139","id":"PMC_33803139","title":"Epithelial to Mesenchymal Transition Regulates Surface PD-L1 via CMTM6 and CMTM7 Induction in Breast Cancer.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33803139","citation_count":27,"is_preprint":false},{"pmid":"30903681","id":"PMC_30903681","title":"Overexpression of CMTM7 inhibits cell growth and migration in liver cancer.","date":"2019","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30903681","citation_count":22,"is_preprint":false},{"pmid":"36829181","id":"PMC_36829181","title":"CMTM7 inhibits breast cancer progression by regulating Wnt/β-catenin signaling.","date":"2023","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/36829181","citation_count":21,"is_preprint":false},{"pmid":"24080084","id":"PMC_24080084","title":"A role for CMTM7 in BCR expression and survival in B-1a but not B-2 cells.","date":"2013","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24080084","citation_count":15,"is_preprint":false},{"pmid":"30392914","id":"PMC_30392914","title":"SOX10-dependent CMTM7 expression inhibits cell proliferation and tumor growth in gastric carcinoma.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30392914","citation_count":14,"is_preprint":false},{"pmid":"31081901","id":"PMC_31081901","title":"Cmtm7 knockout inhibits B-1a cell development at the transitional (TrB-1a) stage.","date":"2019","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31081901","citation_count":11,"is_preprint":false},{"pmid":"23981602","id":"PMC_23981602","title":"Change of CMTM7 expression, a potential tumor suppressor, is associated with poor clinical outcome in human non-small cell lung cancer.","date":"2013","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/23981602","citation_count":11,"is_preprint":false},{"pmid":"32022930","id":"PMC_32022930","title":"CMTM7 plays key roles in TLR-induced plasma cell differentiation and p38 activation in murine B-1 B cells.","date":"2020","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32022930","citation_count":9,"is_preprint":false},{"pmid":"35575054","id":"PMC_35575054","title":"CMTM6 and CMTM7: New leads for PD-L1 regulation in breast cancer cells undergoing EMT.","date":"2022","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35575054","citation_count":7,"is_preprint":false},{"pmid":"32111069","id":"PMC_32111069","title":"Interaction of the CMTM7 rs347134 Polymorphism with Dietary Patterns and the Risk of Obesity in Han Chinese Male Children.","date":"2020","source":"International journal of environmental research and public health","url":"https://pubmed.ncbi.nlm.nih.gov/32111069","citation_count":6,"is_preprint":false},{"pmid":"36568362","id":"PMC_36568362","title":"CMTM7 recognizes an immune-hot tumor microenvironment and predicts therapeutic response of immunotherapy in breast cancer well.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36568362","citation_count":5,"is_preprint":false},{"pmid":"39609464","id":"PMC_39609464","title":"CMTM7 shapes the chronic inflammatory and immunosuppressive tumor microenvironment in hepatocellular carcinoma as an M2 macrophage biomarker.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39609464","citation_count":2,"is_preprint":false},{"pmid":"40490565","id":"PMC_40490565","title":"CMTM7 inhibits TLR4 signaling pathway via promoting Rab5 activation and alleviates acute liver injury.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/40490565","citation_count":2,"is_preprint":false},{"pmid":"32305130","id":"PMC_32305130","title":"Essential role for Cmtm7 in cell-surface phenotype, BCR signaling, survival and Igμ repertoire of splenic B-1a cells.","date":"2020","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32305130","citation_count":1,"is_preprint":false},{"pmid":"39754171","id":"PMC_39754171","title":"Immune-related gene SOX10 affects ferroptosis in pancreatic cancer and facilitates tumor progression by targeting CMTM7-mediated Wnt/β-catenin signaling pathway.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/39754171","citation_count":1,"is_preprint":false},{"pmid":"18560448","id":"PMC_18560448","title":"[Preparation and characterization of monoclonal antibodies against CMTM7].","date":"2008","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18560448","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12109,"output_tokens":3482,"usd":0.044278,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10994,"output_tokens":3787,"usd":0.074823,"stage2_stop_reason":"end_turn"},"total_usd":0.119101,"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\": 2013,\n      \"finding\": \"CMTM7 promotes EGFR internalization in carcinoma cells, thereby suppressing downstream AKT signaling. Ectopic CMTM7 expression causes G1/S cell cycle arrest associated with upregulation of p27 and downregulation of CDK2 and CDK6.\",\n      \"method\": \"Ectopic expression in carcinoma cell lines, cell cycle analysis, Western blot for AKT/p27/CDK2/CDK6, EGFR internalization assay, nude mouse tumor formation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal cellular assays (proliferation, motility, EGFR internalization, signaling readouts, in vivo), single lab\",\n      \"pmids\": [\"23893243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CMTM7 knockdown increases EGFR-AKT signaling by reducing EGFR internalization and degradation. Mechanistically, CMTM7 is required for activation of Rab5, a GTPase needed for early endosome fusion; loss of CMTM7 reduces GTP-Rab5 levels.\",\n      \"method\": \"Stable shRNA knockdown in NSCLC cells, EGFR internalization/degradation assays, Rab5 activation assay, Western blot for AKT phosphorylation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and molecular mechanism, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26528697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CMTM7, a tetra-spanning membrane protein, physically associates with surface IgM (BCR) and with BLNK in a membrane fraction; this interaction is augmented after BCR ligation. CMTM7 recruits BLNK to the vicinity of Syk, enabling BLNK phosphorylation and downstream JNK/ERK activation. The C-terminal domain is required for membrane localization and for these functions, while N-terminal deletion mutants retain activity.\",\n      \"method\": \"RNAi knockdown in B cells, co-immunoprecipitation (CMTM7-BLNK and CMTM7-sIgM), rescue experiments with deletion mutants, tyrosine phosphorylation assays, JNK/ERK activation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain-deletion mutagenesis rescue, multiple orthogonal functional readouts, mechanistic pathway placement\",\n      \"pmids\": [\"22363743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CMTM7 is required for normal BCR expression and survival specifically in B-1a cells but not B-2 cells. Cmtm7(flox/+) heterozygous reduction leads to decreased BCR surface levels, increased spontaneous apoptosis, impaired IgM secretion, and poor LPS-induced proliferation in B-1a cells.\",\n      \"method\": \"Rag1−/− reconstitution with Cmtm7(flox/+) fetal liver cells, flow cytometry for BCR surface expression and cell death, serum IgM measurement, proliferation assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo reconstitution model, multiple functional readouts, single lab\",\n      \"pmids\": [\"24080084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cmtm7 knockout blocks B-1a cell development specifically at the transitional B-1a (TrB-1a) stage, causing slow proliferation and high cell death at that stage. This is a B-cell-intrinsic defect confirmed by bone marrow and fetal liver adoptive transfer and conditional knockout models. Cmtm7-deficient mice produce less IgM and IL-10 and are more susceptible to microbial sepsis.\",\n      \"method\": \"Cmtm7 global knockout mice, conditional knockout, bone marrow/fetal liver adoptive transfer, flow cytometry at developmental stages, IgM/IL-10 ELISA, sepsis model\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — full knockout + conditional knockout + adoptive transfer, multiple orthogonal assays establishing B-cell-intrinsic mechanism and developmental stage\",\n      \"pmids\": [\"31081901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CMTM7 is required for TLR agonist-induced plasma cell differentiation in B-1 cells. Loss of Cmtm7 suppresses downregulation of Pax5 and upregulation of Xbp1, Irf4, and Prdm1 (transcription factors governing plasma cell fate), and inhibits p38 phosphorylation. A p38 inhibitor phenocopies Cmtm7 deficiency, placing CMTM7 upstream of p38 in B-1 cell terminal differentiation.\",\n      \"method\": \"Cmtm7 knockout mice, in vitro TLR stimulation, flow cytometry for plasma cell markers, Western blot for p38 phosphorylation, p38 inhibitor epistasis experiment, IgM/IL-10 ELISA\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout with epistasis (p38 inhibitor phenocopy), multiple molecular readouts, pathway placement upstream of p38, single lab with orthogonal methods\",\n      \"pmids\": [\"32022930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In splenic B-1a cells, Cmtm7 knockout elevates surface CD5, CD80, and CD86 and enhances tonic BCR signaling at steady state. Cmtm7 deficiency promotes splenic B-1a apoptosis in situ, associated with downregulation of IL-5Rα. Cmtm7 also shapes the IgM heavy-chain repertoire differently in peritoneal vs. splenic B-1a cells.\",\n      \"method\": \"Cmtm7 knockout mice, flow cytometry, BCR signaling assays, Igμ repertoire sequencing, apoptosis assays in situ\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout with multiple cellular and molecular readouts, single lab\",\n      \"pmids\": [\"32305130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Dual knockdown of CMTM6 and CMTM7 significantly reduces PD-L1 surface expression in mesenchymal breast cancer cells, indicating that CMTM7 contributes to maintaining cell-surface PD-L1 during EMT.\",\n      \"method\": \"siRNA dual knockdown of CMTM6 and CMTM7 in MCF-7Mes cells, flow cytometry for surface PD-L1\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment (dual KD), one readout, single lab; CMTM7-specific contribution not fully disentangled from CMTM6\",\n      \"pmids\": [\"33803139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CMTM7 interacts with CTNNA1 (Catenin Alpha 1) and regulates Wnt/β-catenin signaling in breast cancer cells. A feedback loop comprising miR-182-5p, CMTM7, CTNNA1, β-catenin (CTNNB1), and TCF3 was identified; TCF3 transcriptionally activates miR-182-5p, which targets and represses CMTM7, while CMTM7 suppresses β-catenin/TCF3 output.\",\n      \"method\": \"Co-IP (CMTM7-CTNNA1 interaction), luciferase reporter assay (miR-182-5p targeting CMTM7; TCF3 promoter activity on miR-182-5p), ChIP analysis, Western blot, in vitro and in vivo functional assays\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct interaction, luciferase and ChIP for transcriptional circuit, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36829181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CMTM7 inhibits TLR4 signaling in macrophages by promoting the interaction between Rab5 and its GEF Gapex5, generating GTP-Rab5, which facilitates TLR4 internalization and degradation, thereby suppressing downstream inflammatory signaling. Myeloid-conditional Cmtm7 knockout mice show exacerbated acute liver injury, and adoptive transfer of CMTM7-overexpressing macrophages is protective.\",\n      \"method\": \"Myeloid conditional Cmtm7 knockout mice, Rab5 activation assay (GTP-Rab5), co-immunoprecipitation (Rab5-Gapex5 interaction), TLR4 internalization/degradation assays, LPS/HMGB1 stimulation, adoptive transfer of CMTM7-overexpressing macrophages, ALI mouse model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo, mechanistic Co-IP, GTPase activation assay, receptor internalization, adoptive transfer rescue; multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"40490565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SOX10 transcriptionally regulates CMTM7 expression in gastric cancer. Overexpression of SOX10 in CMTM7-silenced gastric cancer cells inhibits proliferation and tumor growth, placing CMTM7 downstream of SOX10 in this pathway.\",\n      \"method\": \"Bioinformatics, luciferase reporter assay (SOX10 binding to CMTM7 promoter), stable CMTM7 silencing, SOX10 overexpression in CMTM7-knockdown cells, proliferation and in vivo tumor assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter for transcriptional regulation plus epistasis rescue experiment, single lab\",\n      \"pmids\": [\"30392914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SOX10 transcriptionally represses CMTM7 in pancreatic cancer (dual-luciferase assay). CMTM7 overexpression inhibits the Wnt/β-catenin pathway and induces ferroptosis in PC cells; silencing CMTM7 reverses the anti-tumor effects of SOX10 knockdown, placing CMTM7 downstream of SOX10 in a Wnt/β-catenin-ferroptosis axis.\",\n      \"method\": \"Dual-luciferase reporter assay, shRNA knockdown, CMTM7 overexpression, flow cytometry for apoptosis/ferroptosis markers, Wnt/β-catenin pathway Western blot, tumor-bearing mouse model\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase for direct transcriptional regulation, genetic epistasis (sh-SOX10 + CMTM7 silencing rescue), in vivo validation, single lab\",\n      \"pmids\": [\"39754171\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CMTM7 is a tetra-spanning MARVEL-domain membrane protein that functions as a scaffold linking surface receptors to endocytic machinery: it bridges the BCR (sIgM) to the adaptor BLNK to initiate B-cell signaling, promotes Rab5 activation (via Gapex5-mediated GTP loading) to drive clathrin-mediated internalization and degradation of EGFR and TLR4, thereby suppressing oncogenic EGFR/AKT and inflammatory TLR4 signaling; in B-1a cells it is additionally required for developmental progression through the transitional stage and for TLR-induced plasma cell differentiation via p38 activation, while in cancer cells it also interacts with CTNNA1 to suppress Wnt/β-catenin signaling and is transcriptionally silenced by SOX10-driven miR-182-5p.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CMTM7 is a tetra-spanning membrane protein that acts as a scaffold coupling cell-surface receptors to intracellular signaling and endocytic machinery, with roles spanning B-cell development, innate immune regulation, and tumor suppression [#2, #9]. In B cells it physically associates with surface IgM (BCR) and the adaptor BLNK in the membrane, recruiting BLNK toward Syk to enable its phosphorylation and downstream JNK/ERK activation; its C-terminal domain is required for membrane localization and these functions [#2]. A central mechanism of CMTM7 is promotion of Rab5 GTP-loading to drive clathrin-mediated receptor internalization and degradation: it is required for Rab5 activation that internalizes and degrades EGFR, thereby restraining downstream AKT signaling [#1], and in macrophages it promotes the interaction between Rab5 and its GEF Gapex5 to generate GTP-Rab5, facilitating TLR4 internalization and degradation and suppressing inflammatory signaling [#9]. In B-1a cells CMTM7 is required cell-intrinsically for developmental progression through the transitional B-1a stage and for normal BCR expression and survival [#3, #4], and it is required for TLR-induced plasma cell differentiation acting upstream of p38 to control Pax5 downregulation and Xbp1/Irf4/Prdm1 induction [#5]. In cancer cells CMTM7 suppresses proliferation, with ectopic expression causing G1/S arrest via p27 upregulation and CDK2/CDK6 downregulation [#0], and it interacts with CTNNA1 to suppress Wnt/\\u03b2-catenin signaling [#8]; its expression is controlled transcriptionally by SOX10 and by a miR-182-5p feedback loop [#8, #10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established CMTM7 as a membrane scaffold in BCR signaling by showing it physically links surface IgM to the adaptor BLNK, answering how BLNK is positioned for Syk-dependent phosphorylation.\",\n      \"evidence\": \"RNAi knockdown, reciprocal Co-IP (CMTM7-BLNK, CMTM7-sIgM), domain-deletion rescue, and JNK/ERK activation assays in B cells\",\n      \"pmids\": [\"22363743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the CMTM7-BLNK-sIgM assembly not resolved\", \"Whether endocytic function connects to this scaffold role not addressed here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked CMTM7 to receptor endocytosis and tumor suppression by showing it promotes EGFR internalization and imposes G1/S arrest, defining a growth-suppressive function in carcinoma.\",\n      \"evidence\": \"Ectopic expression in carcinoma lines, EGFR internalization assay, cell cycle analysis, AKT/p27/CDK Western blot, nude mouse tumor formation\",\n      \"pmids\": [\"23893243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking CMTM7 to internalization not defined at this stage\", \"Single lab, gain-of-function emphasis\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated B-cell-subset specificity by showing CMTM7 is required for normal BCR expression and survival selectively in B-1a but not B-2 cells.\",\n      \"evidence\": \"Rag1\\u2212/\\u2212 reconstitution with Cmtm7(flox/+) fetal liver cells, flow cytometry, serum IgM, proliferation assays\",\n      \"pmids\": [\"24080084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of subset-restricted requirement unexplained\", \"Heterozygous reduction rather than full knockout\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the molecular mechanism of CMTM7-driven EGFR turnover by identifying Rab5 GTPase activation as the required step for endosomal internalization and degradation.\",\n      \"evidence\": \"Stable shRNA knockdown in NSCLC cells, EGFR internalization/degradation assays, Rab5 activation (GTP-Rab5) assay, AKT phosphorylation Western blot\",\n      \"pmids\": [\"26528697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CMTM7 activates Rab5 (GEF link) not yet identified\", \"Direct interaction with Rab5 not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pinpointed the developmental stage of CMTM7 action by showing knockout blocks B-1a development at the transitional B-1a stage in a cell-intrinsic manner, with functional consequences for IgM/IL-10 and sepsis resistance.\",\n      \"evidence\": \"Global and conditional Cmtm7 knockout mice, bone marrow/fetal liver adoptive transfer, stage-resolved flow cytometry, ELISA, sepsis model\",\n      \"pmids\": [\"31081901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of the transitional-stage block unresolved\", \"Connection to the BCR-scaffold mechanism not directly tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed CMTM7 upstream of p38 in B-1 plasma cell differentiation by showing knockout impairs the transcription factor switch and p38 phosphorylation, with a p38 inhibitor phenocopying the loss.\",\n      \"evidence\": \"Cmtm7 knockout mice, TLR stimulation, plasma cell marker flow cytometry, p38 Western blot, p38 inhibitor epistasis, ELISA\",\n      \"pmids\": [\"32022930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CMTM7 activates p38 mechanistically unknown\", \"Link between p38 and receptor scaffolding role not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended CMTM7's B-1a role to steady-state homeostasis by showing knockout enhances tonic BCR signaling, alters activation markers, promotes splenic apoptosis, and shapes the IgM repertoire.\",\n      \"evidence\": \"Cmtm7 knockout mice, flow cytometry, BCR signaling assays, Ig\\u03bc repertoire sequencing, in situ apoptosis assays\",\n      \"pmids\": [\"32305130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between tonic signaling and apoptosis not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a tumor-suppressive Wnt axis by showing CMTM7 binds CTNNA1 and sits in a miR-182-5p/TCF3 feedback loop that controls \\u03b2-catenin output in breast cancer.\",\n      \"evidence\": \"Co-IP (CMTM7-CTNNA1), luciferase reporters, ChIP, Western blot, in vitro and in vivo functional assays\",\n      \"pmids\": [\"36829181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CTNNA1 binding is direct vs complex-mediated not fully resolved\", \"Tissue generality of the loop untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the long-standing question of how CMTM7 activates Rab5 by showing it promotes Rab5-Gapex5 (GEF) interaction to drive TLR4 internalization/degradation and suppress inflammation in macrophages.\",\n      \"evidence\": \"Myeloid conditional knockout mice, GTP-Rab5 assay, Co-IP (Rab5-Gapex5), TLR4 internalization/degradation assays, adoptive transfer rescue, acute liver injury model\",\n      \"pmids\": [\"40490565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same Gapex5-Rab5 mechanism operates for EGFR not shown\", \"Direct CMTM7-Gapex5 or CMTM7-Rab5 binding interface undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reinforced SOX10-CMTM7 transcriptional control and linked CMTM7 to ferroptosis, showing SOX10 represses CMTM7 and that CMTM7 inhibits Wnt/\\u03b2-catenin and induces ferroptosis in pancreatic cancer.\",\n      \"evidence\": \"Dual-luciferase reporter, shRNA knockdown, CMTM7 overexpression, ferroptosis flow cytometry, Wnt Western blot, tumor-bearing mouse model\",\n      \"pmids\": [\"39754171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting Wnt suppression to ferroptosis not defined\", \"SOX10 acts as repressor here vs activator elsewhere\\u2014context dependence unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether the BCR/BLNK scaffolding role, the Gapex5-Rab5 endocytic mechanism, and the developmental p38 and Wnt/ferroptosis functions reflect one unified biochemical activity of CMTM7 or distinct context-specific mechanisms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CMTM7 or its interaction interfaces\", \"Direct binding partners on the cytoplasmic face (Rab5, Gapex5) not biochemically mapped\", \"Unifying mechanism across immune and cancer contexts not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 5, 9]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BLNK\", \"IGHM\", \"CTNNA1\", \"RAB5A\", \"GAPVD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}