Affinage

CMTM7

CKLF-like MARVEL transmembrane domain-containing protein 7 · UniProt Q96FZ5

Length
175 aa
Mass
18.8 kDa
Annotated
2026-06-09
20 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2012 High

    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

    PMID:22363743

    Open questions at the time
    • Structural basis of the CMTM7-BLNK-sIgM assembly not resolved
    • Whether endocytic function connects to this scaffold role not addressed here
  2. 2013 Medium

    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

    PMID:23893243

    Open questions at the time
    • Molecular mechanism linking CMTM7 to internalization not defined at this stage
    • Single lab, gain-of-function emphasis
  3. 2013 Medium

    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

    PMID:24080084

    Open questions at the time
    • Mechanism of subset-restricted requirement unexplained
    • Heterozygous reduction rather than full knockout
  4. 2015 Medium

    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

    PMID:26528697

    Open questions at the time
    • How CMTM7 activates Rab5 (GEF link) not yet identified
    • Direct interaction with Rab5 not shown
  5. 2019 High

    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

    PMID:31081901

    Open questions at the time
    • Molecular trigger of the transitional-stage block unresolved
    • Connection to the BCR-scaffold mechanism not directly tested
  6. 2020 High

    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

    PMID:32022930

    Open questions at the time
    • How CMTM7 activates p38 mechanistically unknown
    • Link between p38 and receptor scaffolding role not established
  7. 2020 Medium

    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

    PMID:32305130

    Open questions at the time
    • Causal link between tonic signaling and apoptosis not dissected
    • Single lab
  8. 2023 Medium

    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

    PMID:36829181

    Open questions at the time
    • Whether CTNNA1 binding is direct vs complex-mediated not fully resolved
    • Tissue generality of the loop untested
  9. 2025 High

    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

    PMID:40490565

    Open questions at the time
    • Whether the same Gapex5-Rab5 mechanism operates for EGFR not shown
    • Direct CMTM7-Gapex5 or CMTM7-Rab5 binding interface undefined
  10. 2025 Medium

    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

    PMID:39754171

    Open questions at the time
    • Mechanism connecting Wnt suppression to ferroptosis not defined
    • SOX10 acts as repressor here vs activator elsewhere—context dependence unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005768 endosome 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 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. Ectopic expression in carcinoma cell lines, cell cycle analysis, Western blot for AKT/p27/CDK2/CDK6, EGFR internalization assay, nude mouse tumor formation Oncogene Medium 23893243
2015 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. Stable shRNA knockdown in NSCLC cells, EGFR internalization/degradation assays, Rab5 activation assay, Western blot for AKT phosphorylation Oncotarget Medium 26528697
2012 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. RNAi knockdown in B cells, co-immunoprecipitation (CMTM7-BLNK and CMTM7-sIgM), rescue experiments with deletion mutants, tyrosine phosphorylation assays, JNK/ERK activation assays PloS one High 22363743
2013 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. Rag1−/− reconstitution with Cmtm7(flox/+) fetal liver cells, flow cytometry for BCR surface expression and cell death, serum IgM measurement, proliferation assays International immunology Medium 24080084
2019 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. Cmtm7 global knockout mice, conditional knockout, bone marrow/fetal liver adoptive transfer, flow cytometry at developmental stages, IgM/IL-10 ELISA, sepsis model International immunology High 31081901
2020 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. 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 European journal of immunology High 32022930
2020 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. Cmtm7 knockout mice, flow cytometry, BCR signaling assays, Igμ repertoire sequencing, apoptosis assays in situ Cellular immunology Medium 32305130
2021 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. siRNA dual knockdown of CMTM6 and CMTM7 in MCF-7Mes cells, flow cytometry for surface PD-L1 Cancers Low 33803139
2023 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. 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 Breast cancer research : BCR Medium 36829181
2025 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. 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 Cellular and molecular life sciences : CMLS High 40490565
2018 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. Bioinformatics, luciferase reporter assay (SOX10 binding to CMTM7 promoter), stable CMTM7 silencing, SOX10 overexpression in CMTM7-knockdown cells, proliferation and in vivo tumor assays Biochemical and biophysical research communications Medium 30392914
2025 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. Dual-luciferase reporter assay, shRNA knockdown, CMTM7 overexpression, flow cytometry for apoptosis/ferroptosis markers, Wnt/β-catenin pathway Western blot, tumor-bearing mouse model European journal of medical research Medium 39754171

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 A novel 3p22.3 gene CMTM7 represses oncogenic EGFR signaling and inhibits cancer cell growth. Oncogene 67 23893243
2021 Breast cancer cell-derived extracellular vesicles transfer miR-182-5p and promote breast carcinogenesis via the CMTM7/EGFR/AKT axis. Molecular medicine (Cambridge, Mass.) 47 34294040
2015 CMTM7 knockdown increases tumorigenicity of human non-small cell lung cancer cells and EGFR-AKT signaling by reducing Rab5 activation. Oncotarget 44 26528697
2012 Identification of CMTM7 as a transmembrane linker of BLNK and the B-cell receptor. PloS one 28 22363743
2021 Epithelial to Mesenchymal Transition Regulates Surface PD-L1 via CMTM6 and CMTM7 Induction in Breast Cancer. Cancers 27 33803139
2019 Overexpression of CMTM7 inhibits cell growth and migration in liver cancer. The Kaohsiung journal of medical sciences 22 30903681
2023 CMTM7 inhibits breast cancer progression by regulating Wnt/β-catenin signaling. Breast cancer research : BCR 21 36829181
2013 A role for CMTM7 in BCR expression and survival in B-1a but not B-2 cells. International immunology 15 24080084
2018 SOX10-dependent CMTM7 expression inhibits cell proliferation and tumor growth in gastric carcinoma. Biochemical and biophysical research communications 14 30392914
2019 Cmtm7 knockout inhibits B-1a cell development at the transitional (TrB-1a) stage. International immunology 11 31081901
2013 Change of CMTM7 expression, a potential tumor suppressor, is associated with poor clinical outcome in human non-small cell lung cancer. Chinese medical journal 11 23981602
2020 CMTM7 plays key roles in TLR-induced plasma cell differentiation and p38 activation in murine B-1 B cells. European journal of immunology 9 32022930
2022 CMTM6 and CMTM7: New leads for PD-L1 regulation in breast cancer cells undergoing EMT. Journal of cellular biochemistry 7 35575054
2020 Interaction of the CMTM7 rs347134 Polymorphism with Dietary Patterns and the Risk of Obesity in Han Chinese Male Children. International journal of environmental research and public health 6 32111069
2022 CMTM7 recognizes an immune-hot tumor microenvironment and predicts therapeutic response of immunotherapy in breast cancer well. Frontiers in genetics 5 36568362
2025 CMTM7 inhibits TLR4 signaling pathway via promoting Rab5 activation and alleviates acute liver injury. Cellular and molecular life sciences : CMLS 2 40490565
2024 CMTM7 shapes the chronic inflammatory and immunosuppressive tumor microenvironment in hepatocellular carcinoma as an M2 macrophage biomarker. Scientific reports 2 39609464
2025 Immune-related gene SOX10 affects ferroptosis in pancreatic cancer and facilitates tumor progression by targeting CMTM7-mediated Wnt/β-catenin signaling pathway. European journal of medical research 1 39754171
2020 Essential role for Cmtm7 in cell-surface phenotype, BCR signaling, survival and Igμ repertoire of splenic B-1a cells. Cellular immunology 1 32305130
2008 [Preparation and characterization of monoclonal antibodies against CMTM7]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 0 18560448

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