Affinage

TMEM25

Transmembrane protein 25 · UniProt Q86YD3

Length
366 aa
Mass
39.3 kDa
Annotated
2026-06-10
11 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM25 is a single-pass transmembrane immunoglobulin-superfamily protein that functions as a negative regulator of receptor signaling across epithelial, neuronal, and tumor contexts (PMID:37095176, PMID:31424425, PMID:38177906). In triple-negative breast cancer cells it physically associates with monomeric EGFR and suppresses ligand-independent EGFR-mediated phosphorylation of STAT3; its loss permits basal STAT3 activation and tumor progression, and AAV-mediated restoration reverses this in vivo (PMID:37095176). In neurons TMEM25 localizes to late endosomes, binds the NMDA receptor subunit NR2B, and accelerates its lysosomal degradation, thereby dampening neuronal excitability and constraining seizure phenotypes (PMID:31424425). In epithelial cells it localizes to tight junctions, where its C-terminal cytoplasmic tail engages Par3 through a PDZ interaction while its N-terminal extracellular domain binds claudin-1 and claudin-2 to suppress claudin cis- and trans-oligomerization and attenuate tight-junction strand formation; Par3 binding in turn weakens the TMEM25–claudin association (PMID:38177906). A distinct role in neural progenitors couples TMEM25 to Akt-dependent cell cycle progression supporting cortical expansion (PMID:37846797). TMEM25 is epigenetically silenced by CpG island hypermethylation in colorectal cancer, consistent with a tumor-suppressive function (PMID:23324576).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2013 Medium

    Established that TMEM25 expression is lost in cancer through a defined epigenetic mechanism, framing it as a candidate tumor suppressor before any molecular function was known.

    Evidence Whole-genome methylation scan and methylation-specific melting analysis correlated with RT-PCR expression across 133 colorectal cancer samples

    PMID:23324576

    Open questions at the time
    • No functional manipulation of methylation to prove causality
    • No molecular function for TMEM25 defined at this stage
    • Tumor-suppressive role inferred from correlation only
  2. 2019 High

    Defined the first mechanistic role for TMEM25 by showing it drives lysosomal turnover of an NMDA receptor subunit, answering how it controls neuronal excitability.

    Evidence Late-endosome co-localization, reciprocal Co-IP with NR2B, lysosomal pH assays, NR2B turnover Western blots, electrophysiology, and in vivo epilepsy models with knockdown/overexpression

    PMID:31424425

    Open questions at the time
    • Mechanism by which TMEM25 targets NR2B to lysosomes is not resolved
    • Whether TMEM25 directly alters lysosomal acidification or acts indirectly is unclear
  3. 2023 High

    Showed TMEM25 restrains ligand-independent EGFR–STAT3 signaling, explaining how its loss promotes tumor progression and tying the methylation silencing to a concrete oncogenic pathway.

    Evidence Reciprocal Co-IP with monomeric EGFR, TMEM25-KO cells and mice, phospho-STAT3 immunoblotting, and AAV rescue in vivo

    PMID:37095176

    Open questions at the time
    • Structural basis for TMEM25 selectivity for monomeric versus dimeric EGFR not defined
    • Whether the EGFR-suppressive role generalizes beyond TNBC is untested
  4. 2023 High

    Resolved how TMEM25 modulates epithelial barrier assembly by mapping distinct extracellular (claudin) and cytoplasmic (Par3/PDZ) interactions to tight-junction strand formation.

    Evidence Tight-junction immunofluorescence, reciprocal Co-IP for Par3 and claudin-1/2, domain-deletion mutagenesis, claudin oligomerization assays, and TJ assembly kinetics under knockdown/overexpression

    PMID:38177906

    Open questions at the time
    • How the three signaling roles (EGFR, NR2B, claudin/Par3) relate within a single cell is unknown
    • Stoichiometry of the TMEM25–claudin–Par3 interplay not quantified
  5. 2023 Medium

    Linked TMEM25 to neural progenitor proliferation via Akt signaling, indicating a developmental role distinct from its suppressive functions elsewhere.

    Evidence In vitro NPC proliferation assays, in vivo mouse cortical electroporation with bRG and upper-layer neuron counting, and knockdown in human NPCs with RNA-seq and pharmacological Akt readouts

    PMID:37846797

    Open questions at the time
    • Akt pathway placement is pharmacological, not biochemically reconstituted
    • Upstream extracellular signal and direct receptor are not identified
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown whether TMEM25's context-specific roles share a unifying biochemical activity or reflect independent partner-dependent functions.
  • No structure of TMEM25 or its complexes
  • No unifying biochemical activity assigned to the Ig domain
  • Relationship between endosomal, tight-junction, and EGFR roles unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 1
Localization
GO:0005768 endosome 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1500931 Cell-Cell communication 1

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 TMEM25 physically associates with monomeric EGFR and suppresses ligand-independent EGFR monomer-mediated phosphorylation of STAT3 at basal state; loss of TMEM25 allows monomeric EGFR to phosphorylate STAT3 independently of ligand binding, enhancing basal STAT3 activation and promoting TNBC progression. AAV-mediated TMEM25 restoration suppressed STAT3 activation in vivo. Co-immunoprecipitation, loss-of-function (TMEM25-KO cells and mice), AAV overexpression rescue, phospho-STAT3 immunoblotting, electrophysiology Nature Communications High 37095176
2019 TMEM25 localizes to late endosomes in neurons, physically interacts with the NMDA receptor NR2B subunit (co-localized to late endosome compartments), induces acidification changes in lysosome compartments, and accelerates lysosomal degradation of NR2B, thereby modulating neuronal excitability. TMEM25 overexpression attenuated epileptic seizure phenotypes while knockdown exacerbated them. Subcellular fractionation/immunofluorescence co-localization to late endosomes, Co-immunoprecipitation (TMEM25–NR2B interaction), lysosomal pH assays, Western blot for NR2B protein levels, electrophysiology, in vivo KD/OE in epilepsy mouse models The Journal of Clinical Investigation High 31424425
2023 TMEM25 localizes to tight junctions in epithelial cells and binds Par3 via a PDZ-mediated interaction with its C-terminal cytoplasmic tail. Via its N-terminal extracellular domain, TMEM25 associates with claudin-1 and claudin-2 and suppresses their cis- and trans-oligomerizations, thereby attenuating tight junction strand formation. Par3 binding to TMEM25 attenuates TMEM25–claudin association, modulating claudin oligomerization. Depletion of TMEM25 accelerates TJ development, while overexpression (but not C-terminally deleted mutant) delays it. Immunofluorescence localization to tight junctions, Co-immunoprecipitation (TMEM25–Par3 and TMEM25–claudin-1/2), domain deletion mutagenesis (C-terminal and N-terminal truncations), siRNA knockdown and overexpression with TJ assembly kinetics assay, claudin oligomerization assays EMBO Reports High 38177906
2023 TMEM25 overexpression in mouse ventricular cortical progenitors promoted proliferation of basal radial glia (bRG) and increased upper-layer neuron numbers in vivo. Knockdown of TMEM25 in human neural progenitor cells inhibited cell cycle progression via repression of Akt signaling, suggesting TMEM25 receives extracellular signals to promote NPC expansion through an Akt-dependent pathway. In vitro NPC proliferation assays (overexpression), in vivo mouse cortical electroporation (bRG expansion, upper-layer neuron counting), TMEM25 knockdown in human NPCs with RNA-seq and pharmacological Akt pathway assays FEBS Letters Medium 37846797
2013 CpG island hypermethylation of TMEM25 is inversely correlated with reduced TMEM25 expression in colorectal cancer tissue, demonstrating that epigenetic silencing via DNA methylation is a mechanism of TMEM25 downregulation in cancer. Whole-genome methylation scan, methylation-specific high-resolution melting analysis (133 CRC samples), expression quantification by RT-PCR, correlation analysis of methylation vs. expression Disease Markers Medium 23324576
2004 TMEM25 was identified as a member of the immunoglobulin superfamily containing a C-2 type immunoglobulin domain (codons 42–112). The gene encodes two isoforms by alternative exon skipping: isoform 1 (366 aa, transmembrane) and isoform 2 (322 aa, secreted). Human TMEM25 shares 91% amino acid identity with mouse Tmem25. In silico bioinformatics analysis of cDNA sequences (BC042896, AY358919, AK002841), domain homology prediction Oncology Reports Low 15254712

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 TMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression. Nature communications 52 37095176
2013 TMEM25 is a candidate biomarker methylated and down-regulated in colorectal cancer. Disease markers 51 23324576
2019 TMEM25 modulates neuronal excitability and NMDA receptor subunit NR2B degradation. The Journal of clinical investigation 26 31424425
2004 Identification and characterization of human TMEM25 and mouse Tmem25 genes in silico. Oncology reports 17 15254712
2017 [Effects of lncRNA RP11-770J1.3 and TMEM25 expression on paclitaxel resistance in human breast cancer cells]. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 14 29256224
2021 Meta-Analyses of Splicing and Expression Quantitative Trait Loci Identified Susceptibility Genes of Glioma. Frontiers in genetics 11 33936159
2022 Whole Exome Sequencing in Two Southeast Asian Families With Atypical Femur Fractures. JBMR plus 7 35991532
2023 TMEM25 is a Par3-binding protein that attenuates claudin assembly during tight junction development. EMBO reports 5 38177906
2024 Multidimensional comprehensive and integrated analysis of the potential function of TMEM25 in renal clear cell carcinoma with low expression status. Aging 3 38189809
2024 Transmembrane protein 25 abrogates monomeric EGFR-driven STAT3 activation in triple-negative breast cancer. MedComm 3 38532948
2023 Human-biased TMEM25 expression promotes expansion of neural progenitor cells to alter cortical structure in the developing brain. FEBS letters 0 37846797

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