Affinage

TMEM100

Transmembrane protein 100 · UniProt Q9NV29

Length
134 aa
Mass
14.4 kDa
Annotated
2026-06-10
28 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM100 is a small membrane-associated protein that operates as a downstream effector of BMP-ALK1 signaling to control vascular development and as a modulator of sensory ion channels in nociception. In the developing vasculature it is an arterial endothelial transcriptional target of BMP9/BMP10-ALK1 (ACVRL1) signaling, and its loss phenocopies ALK1 deficiency, producing embryonic lethality, impaired arterial endothelial differentiation, arteriovenous shunts, and weakened, abnormally elastinized vessels, with concomitant downregulation of Notch, Akt, and cell-adhesion/extracellular-matrix programs (PMID:22783020, PMID:20848592, PMID:25538155). TMEM100 also governs endothelial-to-mesenchymal transformation during cardiac cushion formation through calcineurin-NFATc1 signaling and is required for proper specification of lymphatic endothelial progenitors via Notch (PMID:25318679, PMID:32112176). In sensory neurons of the DRG and trigeminal ganglion, TMEM100 forms a trimeric complex with TRPA1 and TRPV1, weakening the TRPA1-TRPV1 association to release TRPA1 from TRPV1-mediated inhibition and thereby potentiate TRPA1 activity; this mechanism un-silences mechanically silent nociceptors and drives inflammatory pain, TMD pain, and itch, and a peptide mimicking a dominant-negative TMEM100 mutant suppresses persistent pain (PMID:25640077, PMID:37019973, PMID:37033371, PMID:36514220). TMEM100 additionally acts as a direct negative regulator of signaling kinases, binding TAK1 through its transmembrane segments to suppress TAK1-JNK/p38 signaling and protect against pathological cardiac hypertrophy (PMID:39261825). Beyond these established axes, reported roles in BMP7-dependent renal mesenchymal proliferation and as a methylation/miRNA-silenced tumor suppressor modulating MAPK, Wnt/β-catenin, TGF-β, and PI3K/AKT pathways in carcinomas remain less fully characterized in the available corpus (PMID:29247399, PMID:34687431, PMID:34422038).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2010 Medium

    Establishing where TMEM100 acts and what controls it: the question was whether TMEM100 has a defined expression domain tied to a known pathway, answered by mapping it to arterial endothelium downstream of ALK1.

    Evidence LacZ reporter knock-in and in situ analysis in Acvrl1-deficient mouse lungs

    PMID:20848592

    Open questions at the time
    • Did not establish a molecular function for TMEM100
    • Mechanism linking ALK1 to TMEM100 transcription unresolved
  2. 2012 High

    Whether TMEM100 is functionally required in the BMP-ALK1 vascular axis was unknown; genetic ablation placed it as an essential effector phenocopying ALK1 loss with Notch/Akt downregulation.

    Evidence Tmem100 null and endothelial conditional knockout mice with BMP9/BMP10 stimulation and pathway analysis

    PMID:22783020

    Open questions at the time
    • How TMEM100 mechanistically couples to Notch and Akt not defined
    • No direct protein partner identified in endothelium
  3. 2014 High

    The stage-specific and cellular consequences of TMEM100 loss were undefined; inducible knockout revealed defects across embryonic, neonatal, and adult vasculature and impaired EndMT via calcineurin-NFATc1.

    Evidence Tamoxifen-inducible conditional KO, retinal imaging, AVC explant culture with calcineurin rescue, NFATc1 immunofluorescence

    PMID:25318679 PMID:25538155

    Open questions at the time
    • Direct molecular link between TMEM100 and calcium/calcineurin signaling not established
    • Mechanism of ECM/elastin gene regulation unknown
  4. 2015 High

    TMEM100's molecular function was unknown until it was shown to act as a regulator of sensory ion channels by remodeling the TRPA1-TRPV1 complex to potentiate TRPA1 and modulate pain.

    Evidence Co-IP, single-channel electrophysiology in heterologous cells, Tmem100-deficient mice, and cell-permeable dominant-negative peptide

    PMID:25640077

    Open questions at the time
    • Structural basis of TMEM100 disrupting TRPA1-TRPV1 association not resolved
    • Whether this channel-modulatory role connects to its vascular function unknown
  5. 2017 Medium

    Whether TMEM100 participates in BMP signaling beyond the vasculature was tested in renal mesenchyme, identifying a TMEM100-BMP7-BMPR-II regulatory network controlling proliferation and apoptosis.

    Evidence siRNA double-knockdown epistasis (Tmem100, BMP7, BMPR-II) with EdU and annexin V assays in metanephric mesenchymal cells

    PMID:29247399

    Open questions at the time
    • No direct binding shown; regulation may be indirect
    • In vivo relevance not tested
  6. 2020 High

    TMEM100's role in lymphatic lineage commitment was undefined; reciprocal gain/loss models showed it tunes lymphatic endothelial progenitor specification through Notch.

    Evidence Tamoxifen-inducible KO and endothelial overexpression mice with NOTCH readouts

    PMID:32112176

    Open questions at the time
    • Direct mechanism linking TMEM100 to Notch activity not defined
    • Whether the same effector logic applies as in arterial endothelium unknown
  7. 2023 High

    Whether TMEM100 functionally drives pathological pain states was open; reciprocal KO and AAV overexpression established it as sufficient to un-silence nociceptors and necessary for inflammatory and TMD pain.

    Evidence RNA-seq, electrophysiology, TMEM100 KO and AAV overexpression in afferents, conditional neuronal KO, behavioral pain models

    PMID:37019973 PMID:37033371

    Open questions at the time
    • Upstream signals inducing TMEM100 in nociceptors not fully defined
    • Quantitative link between channel-complex remodeling and behavior incomplete
  8. 2024 High

    A new direct protein partner and signaling role were defined: TMEM100 binds TAK1 via its transmembrane domain to suppress TAK1-JNK/p38 signaling and protect against cardiac hypertrophy.

    Evidence Co-IP, domain-mapping mutagenesis, binding-defective mutant, AAV9 in vivo TAC model, TAK1 inhibitor epistasis

    PMID:39261825

    Open questions at the time
    • Whether TAK1 interaction operates in other tissues unknown
    • Structural detail of the transmembrane-mediated binding unresolved
  9. 2025 Low

    An additional inflammatory mechanism was proposed: TMEM100 binds PRDX1 and GNAI2 and disrupts their complex to inhibit NF-κB and attenuate acute lung injury.

    Evidence Co-IP and TMEM100 overexpression in LPS-induced ALI mouse model and PVECs (preprint)

    PMID:bio_10.1101_2025.10.24.684325

    Open questions at the time
    • Preprint, single-lab Co-IP without reconstitution or mutagenesis validation
    • Direct binding interfaces not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TMEM100 reconciles its distinct molecular activities — channel-complex remodeling, direct kinase inhibition, and BMP-ALK1 effector function — into a unified biochemical mechanism remains unresolved.
  • No structural model of TMEM100
  • Unclear whether a single biochemical activity underlies its multiple context-specific roles
  • Tumor-suppressor regulation via methylation/miRNA largely correlative

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2
Partners
GNAI2PRDX1TAK1TRPA1TRPV1
Complex memberships
TRPA1-TRPV1 channel complex

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 TMEM100 forms a trimeric complex with TRPA1 and TRPV1 in DRG neurons and selectively potentiates TRPA1 activity in a TRPV1-dependent manner by weakening the physical association between TRPA1 and TRPV1, thereby releasing TRPA1 from TRPV1-mediated inhibition. A mutant (Tmem100-3Q) exerts the opposite effect, enhancing TRPA1-TRPV1 association and strongly inhibiting TRPA1. A cell-permeable peptide containing the C-terminal sequence of Tmem100-3Q inhibits persistent pain. Co-immunoprecipitation, single-channel electrophysiology in heterologous system, Tmem100-deficient mice, cell-permeable peptide treatment Neuron High 25640077
2012 TMEM100 is a downstream target of BMP9/BMP10-ALK1 signaling in endothelial cells; Tmem100-null mice show embryonic lethality with impaired arterial endothelium differentiation and vascular morphogenesis phenocopying ALK1 deficiency, with down-regulation of Notch and Akt signaling. Endothelial-specific Cre-mediated deletion recapitulates null phenotypes. Tmem100 null mouse generation, endothelial-specific conditional knockout (Cre-mediated deletion), BMP9/BMP10 stimulation assays, signaling pathway analysis Proceedings of the National Academy of Sciences of the United States of America High 22783020
2010 TMEM100 is predominantly expressed in arterial endothelial cells of developing embryos, and its expression is downstream of ACVRL1 (ALK1) signaling, as it is downregulated in Acvrl1-deficient mouse lungs. LacZ reporter knock-in, conditional allele generation, immunohistochemistry, in situ expression analysis in Acvrl1-deficient mice Genesis (New York, N.Y. : 2000) Medium 20848592
2014 TMEM100 deficiency causes cardiovascular defects at embryonic stage, retinal vascular hyperbranching and dilated vessels at neonatal stage, and arteriovenous shunts and weakened vasculature with abnormal elastin layers in adults. Loss of TMEM100 downregulates cell adhesion/extracellular matrix genes including Mfap4 (associated with elastin fiber formation) in lung. Inducible conditional knockout mice (tamoxifen), retinal vascular imaging, gene expression analysis of lung tissue Cardiovascular research High 25538155
2014 Tmem100 deficiency causes impaired endothelial-mesenchymal transformation (EndMT) during atrioventricular cushion formation, associated with upregulation of VEGFA in AVC myocardium and loss of calcineurin-VEGF suppression. Tmem100-null endocardial cells fail to undergo EndMT in response to TGF-β2 and BMP2. NFATc1 nuclear translocation is absent in Tmem100-null endocardial cells, indicating impaired endocardial calcium signaling. Tmem100-null embryos, AVC explant culture, constitutively-active calcineurin rescue experiments, immunofluorescence for NFATc1 nuclear translocation, RT-PCR Developmental dynamics : an official publication of the American Association of Anatomists High 25318679
2020 TMEM100 is required for specification of lymphatic endothelial cell progenitors in the cardinal vein; loss increases LEC progenitor number while overexpression decreases it, with corresponding reciprocal changes in NOTCH signaling activity. Tamoxifen-inducible global Tmem100 KO, Tie2-Cre-driven endothelial TMEM100 overexpression mice, embryo phenotyping, NOTCH signaling readouts Angiogenesis High 32112176
2013 TMEM100 is a membrane-associated protein expressed in enteric neurons of the mouse and human gastrointestinal tract muscularis propria, co-localizing with the pan-neuronal marker PGP9.5 but not with glial marker S100β or interstitial cells of Cajal marker Kit. BMP4 co-localizes with TMEM100 in enteric neurons of the human colon. Western blotting (membrane fractionation), immunohistochemistry, immunofluorescence co-localization, mRNA expression Neuroscience Medium 23485812
2019 TMEM100 overexpression in LX-2 hepatic stellate cells downregulates IL-1β and IL-6 secretion, and TMEM100 expression changes are associated with modulation of MAPK signaling (ERK and JNK phosphorylation) in response to TNF-α. pEGFP-C2-TMEM100 transfection, ELISA for cytokines, Western blot for phospho-ERK and phospho-JNK Toxicology letters Low 30639579
2021 TMEM100 induces autophagy in NSCLC cells (A549) via inhibition of the PI3K/AKT signaling pathway, and inhibiting autophagy with bafilomycin A1 enhances TMEM100-induced apoptosis. TMEM100 overexpression in cell lines, bafilomycin A1 treatment, Western blot for PI3K/AKT pathway components, apoptosis assays Oncology reports Low 34184748
2021 HDAC6 represses TMEM100 expression via deacetylation modification on the TMEM100 promoter; HDAC6 knockdown or TMEM100 overexpression inhibits TGF-β1-induced EMT and suppresses Wnt/β-catenin signaling in NSCLC cells. HDAC6 knockdown, chromatin immunoprecipitation or promoter assay for deacetylation, EMT and Wnt/β-catenin signaling assays by Western blot Human cell Medium 34687431
2021 miR-106b directly downregulates TMEM100 expression in NSCLC; TMEM100 overexpression suppresses survivin expression and promotes apoptosis, while the oncogenic effects of miR-106b on cell survival are mitigated by restoration of TMEM100. Luciferase reporter assay (implied by 'directly downregulated'), TMEM100 overexpression/knockdown, colony formation, apoptosis assays, Western blot for survivin Oncology reports Low 34278505
2017 BMP7 plays a critical role in TMEM100-regulated cell proliferation and apoptosis in mouse metanephric mesenchymal cells; TMEM100 knockdown increases proliferation and apoptosis, and this effect is rescued by BMP7 knockdown. TMEM100 deficiency upregulates BMP7, while TMEM100 overexpression has the opposite effect. BMPR-II expression is regulated by BMP7 but not vice versa. siRNA knockdown of Tmem100, BMP7, and BMPR-II; EdU incorporation assay; annexin V apoptosis assay; qRT-PCR In vitro cellular & developmental biology. Animal Medium 29247399
2023 TMEM100 overexpression is required and sufficient to un-silence mechanically silent nociceptors during inflammation; mice lacking TMEM100 do not develop secondary mechanical hypersensitivity during knee joint inflammation, and AAV-mediated TMEM100 overexpression in articular afferents induces remote mechanical hypersensitivity without inflammation. RNA-sequencing, quantitative RT-PCR, electrophysiology, TMEM100 KO mice, AAV-mediated overexpression in afferents, behavioral pain assays Nature communications High 37019973
2023 TMEM100 co-expresses with TRPA1 and TRPV1 in trigeminal ganglion neurons innervating the TMJ and masseter muscle; TMEM100 upregulation after TMD pain enhances TRPA1 activity within the TRPA1-TRPV1 complex, and selective deletion of Tmem100 in TG neurons or local TMEM100 inhibition attenuates TMD pain. Mouse TMD pain models, conditional neuronal Tmem100 KO, local TMEM100 inhibitor injection, electrophysiology, immunofluorescence co-localization Frontiers in molecular neuroscience High 37033371
2022 TMEM100 upregulation in DRG neurons facilitates dry-skin-induced itch by enhancing TRPA1 channel function and expression; DRG-specific Tmem100 knockdown alleviates itch and rescues TRPA1 expression and functional changes without affecting TRPV1. AEW dry-skin mouse model, DRG-specific Tmem100 gene knockdown, behavioral itch assays, TRPA1/TRPV1 channel activity measurements, immunofluorescence Acta biochimica et biophysica Sinica Medium 36514220
2024 TMEM100 directly interacts with TAK1 via its transmembrane domain (amino acids 53-75 and 85-107) binding the C-terminal region of TAK1 (amino acids 1-300), and inhibits phosphorylation of TAK1 and its downstream molecules JNK and p38, thereby protecting against pathological cardiac hypertrophy. A TAK1-binding-defective TMEM100 mutant fails to inhibit the TAK1-JNK/p38 pathway. Co-immunoprecipitation, domain-mapping mutagenesis, AAV9-mediated TMEM100 overexpression in TAC mouse model, adenoviral TMEM100 in cardiomyocytes, TAK1 inhibitor (iTAK1) epistasis, Western blot for phospho-TAK1/JNK/p38, RNA-seq Cell communication and signaling : CCS High 39261825
2021 TMEM100 overexpression in colorectal cancer cells inhibits activation of the TGF-β signaling pathway, suppressing malignant progression. TMEM100 overexpression and knockdown in CRC cell lines, Western blot for TGF-β signaling components, MTT/colony/scratch/Transwell assays Gastroenterology research and practice Low 34422038
2020 BMP9 (but not BMP10) is the upstream modulator of TMEM100 in gastric cancer cells; HIF1α downregulation modulates TMEM100's effect on cell migration, invasion, and chemotherapy sensitivity. BMP9/BMP10 stimulation assays, HIF1α knockdown, TMEM100 overexpression/knockdown, migration/invasion assays, in vivo xenograft Biological chemistry Low 31188741
2025 TMEM100 interacts with both PRDX1 and GNAI2, disrupts the PRDX1-GNAI2 protein complex, and thereby inhibits LPS-induced NF-κB activation, attenuating lung inflammation and acute lung injury. Co-immunoprecipitation (TMEM100 with PRDX1 and GNAI2), TMEM100 overexpression in LPS-induced ALI mouse model and PVECs, NF-κB activation assays, proliferation/apoptosis assays bioRxivpreprint Low bio_10.1101_2025.10.24.684325
2024 TMEM100 promoter methylation suppresses its expression in esophageal squamous cell carcinoma; treatment with demethylating agent 5-AZA restores TMEM100 expression. TMEM100 overexpression inhibits MAPK pathway activation in ESCC cells. 5-AZA demethylating agent treatment, qRT-PCR, Western blot, GSEA/KEGG pathway enrichment analysis, overexpression functional assays World journal of clinical oncology Low 38689624

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Tmem100 Is a Regulator of TRPA1-TRPV1 Complex and Contributes to Persistent Pain. Neuron 153 25640077
2012 Tmem100, an ALK1 receptor signaling-dependent gene essential for arterial endothelium differentiation and vascular morphogenesis. Proceedings of the National Academy of Sciences of the United States of America 80 22783020
2010 Generation of mice with a conditional and reporter allele for Tmem100. Genesis (New York, N.Y. : 2000) 39 20848592
2014 Essential role for TMEM100 in vascular integrity but limited contributions to the pathogenesis of hereditary haemorrhagic telangiectasia. Cardiovascular research 35 25538155
2015 Novel roles of TMEM100: inhibition metastasis and proliferation of hepatocellular carcinoma. Oncotarget 26 25978032
2020 TMEM100 expression suppresses metastasis and enhances sensitivity to chemotherapy in gastric cancer. Biological chemistry 21 31188741
2020 TMEM100 is a key factor for specification of lymphatic endothelial progenitors. Angiogenesis 21 32112176
2014 Impairment of endothelial-mesenchymal transformation during atrioventricular cushion formation in Tmem100 null embryos. Developmental dynamics : an official publication of the American Association of Anatomists 16 25318679
2023 Role of TMEM100 in mechanically insensitive nociceptor un-silencing. Nature communications 15 37019973
2021 Histone deacetylase 6-mediated downregulation of TMEM100 expedites the development and progression of non-small cell lung cancer. Human cell 15 34687431
2023 The Role of IL-6 and TMEM100 in Lumbar Discogenic Pain and the Mechanism of the Glycine-Serine-Threonine Metabolic Axis: A Metabolomic and Molecular Biology Study. Journal of pain research 14 36815126
2021 TMEM100 induces cell death in non‑small cell lung cancer via the activation of autophagy and apoptosis. Oncology reports 14 34184748
2019 TMEM100 mediates inflammatory cytokines secretion in hepatic stellate cells and its mechanism research. Toxicology letters 14 30639579
2021 Tmem100- and Acta2-Lineage Cells Contribute to Implant Osseointegration in a Mouse Model. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 13 33528844
2013 Distribution of TMEM100 in the mouse and human gastrointestinal tract--a novel marker of enteric nerves. Neuroscience 13 23485812
2023 The Role of a Lung Vascular Endothelium Enriched Gene TMEM100. Biomedicines 11 36979916
2021 Functional expression of TRPA1 channel, TRPV1 channel and TMEM100 in human odontoblasts. Journal of molecular histology 9 34514518
2023 TMEM100, a regulator of TRPV1-TRPA1 interaction, contributes to temporomandibular disorder pain. Frontiers in molecular neuroscience 8 37033371
2021 TMEM100 negatively regulated by microRNA‑106b facilitates cellular apoptosis by suppressing survivin expression in NSCLC. Oncology reports 8 34278505
2021 TMEM100 Modulates TGF-β Signaling Pathway to Inhibit Colorectal Cancer Progression. Gastroenterology research and practice 8 34422038
2023 TMEM100 Regulates Neuropathic Pain by Reducing the Expression of Inflammatory Factors. Mediators of inflammation 7 37469758
2023 Diminished TMEM100 Expression in a Newborn With Acinar Dysplasia and a Novel TBX4 Variant: A Case Report. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 6 38044468
2017 BMP7 plays a critical role in TMEM100-inhibited cell proliferation and apoptosis in mouse metanephric mesenchymal cells in vitro. In vitro cellular & developmental biology. Animal 5 29247399
2022 Upregulation of DRG protein TMEM100 facilitates dry-skin-induced pruritus by enhancing TRPA1 channel function. Acta biochimica et biophysica Sinica 4 36514220
2024 TMEM100 acts as a TAK1 receptor that prevents pathological cardiac hypertrophy progression. Cell communication and signaling : CCS 3 39261825
2024 Regulation of TMEM100 expression by epigenetic modification, effects on proliferation and invasion of esophageal squamous carcinoma. World journal of clinical oncology 2 38689624
2021 Tmem100-BAC-EGFP mice to selectively mark and purify embryonic endothelial cells of large caliber arteries in mid-gestational vascular formation. Genesis (New York, N.Y. : 2000) 2 33651473
2025 Decreased Level of TMEM100 in Neonates With Lethal Lung Developmental Disorders due to Abnormalities in SHH-FOXF1 and TBX4-FGF10 Signaling Pathways. American journal of medical genetics. Part A 0 40145339

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