Affinage

TMEM219

Insulin-like growth factor-binding protein 3 receptor · UniProt Q86XT9

Length
240 aa
Mass
25.7 kDa
Annotated
2026-04-28
10 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM219 is a transmembrane death receptor that transduces pro-apoptotic signals in multiple epithelial cell types, functioning through two distinct ligand systems: IGFBP-3 and chitinase 3-like-1 (Chi3l1). Binding of IGFBP-3 to TMEM219 activates Caspase-8-dependent apoptosis in an IGF-independent manner and concurrently suppresses NF-κB signaling through caspase-mediated degradation of IκBα and p65 (PMID:21383009, PMID:23498137). In pancreatic beta cells and intestinal stem cells, IGFBP-3/TMEM219 signaling drives cell death and tissue loss; genetic ablation or pharmacological blockade of this interaction preserves cell viability, promotes regeneration, and ameliorates diabetes and colitis in preclinical models (PMID:35115561, PMID:40371646, PMID:40783087). TMEM219 also forms a complex with IL-13Rα2 to mediate Chi3l1-stimulated MAPK/Erk and Akt activation, HB-EGF production, and suppression of oxidant-induced apoptosis (PMID:27629921).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2011 High

    Identifying TMEM219 as the receptor for IGFBP-3 established that IGFBP-3's IGF-independent apoptotic and NF-κB-suppressive activities converge on a single transmembrane mediator, answering how extracellular IGFBP-3 signals intracellularly.

    Evidence siRNA knockdown, caspase inhibitor experiments, non-IGF-binding IGFBP-3 mutants, and transgenic mice in cell-based NF-κB assays

    PMID:21383009

    Open questions at the time
    • Structural basis of IGFBP-3/TMEM219 binding undefined
    • Downstream adaptor proteins linking TMEM219 to caspase activation not identified
    • Tissue-specific expression and function of TMEM219 not yet explored
  2. 2013 Medium

    Demonstrating that TMEM219 knockdown blocked IGFBP-3-induced apoptosis in carcinogen-transformed lung epithelial cells extended the receptor's functional relevance beyond the original cell systems.

    Evidence siRNA knockdown of IGFBP-3R with IGFBP-3 overexpression, NF-κB and apoptosis readouts in lung cancer cells

    PMID:23498137

    Open questions at the time
    • Single lab, single cell type; independent replication in additional cancer models lacking
    • Whether TMEM219 expression level predicts IGFBP-3 sensitivity in tumors untested
  3. 2016 High

    Discovery that TMEM219 physically interacts with IL-13Rα2 to transduce Chi3l1 signals revealed an unexpected second ligand-receptor axis for TMEM219, showing it participates in pro-survival MAPK/Erk and Akt signaling in addition to its pro-apoptotic IGFBP-3 function.

    Evidence Yeast two-hybrid, co-IP, bimolecular fluorescence complementation, fluorescence anisotropy nanodisc assays, null mutations and siRNA phenocopying

    PMID:27629921

    Open questions at the time
    • How TMEM219 integrates opposing pro-apoptotic (IGFBP-3) and pro-survival (Chi3l1) signals is unresolved
    • Stoichiometry and structure of the TMEM219/IL-13Rα2/Chi3l1 complex unknown
    • Relative dominance of each pathway in shared tissue contexts not tested
  4. 2022 High

    Genetic ablation and pharmacological blockade of TMEM219 in pancreatic beta cells prevented diabetes onset and enabled beta cell expansion, establishing TMEM219 as a death receptor governing beta cell homeostasis and identifying it as a therapeutic target in diabetes.

    Evidence TMEM219 knockout mice, in vitro and in vivo IGFBP-3/TMEM219 inhibition, preclinical diabetes models, patient cohort IGFBP-3 measurements

    PMID:35115561

    Open questions at the time
    • Precise intracellular signaling intermediates between TMEM219 and Caspase-8 in beta cells not fully mapped
    • Long-term safety of TMEM219 blockade on beta cell neoplasia risk unassessed
  5. 2024 Medium

    Identification of miR-129-2 as an upstream regulator of TMEM219 expression, and demonstration that TMEM219 signals through Caspase-8 in beta cell precursors, added a transcriptional regulatory layer and extended the pathway to developmental stages of the endocrine pancreas.

    Evidence miRNA mimic/inhibitor experiments, caspase-8 activity assays, pharmacological TMEM219 blockade in endocrine progenitor differentiation models

    PMID:38318298

    Open questions at the time
    • miR-129-2 regulation demonstrated in a single lab system; confirmation in vivo needed
    • Whether additional miRNAs or transcription factors regulate TMEM219 in other tissues is unknown
  6. 2025 High

    Tissue-specific conditional deletion of TMEM219 in intestinal stem cells and pharmacological blockade with ecto-TMEM219 or anti-TMEM219 monoclonal antibodies restored mucosal regeneration in Crohn's disease organoids and colitis models, confirming IGFBP-3/TMEM219 as the operative death axis in inflammatory bowel disease.

    Evidence TMEM219fl/flLGR5cre conditional knockout, ecto-TMEM219 and monoclonal antibody (Ent001) blockade, patient-derived organoids, DSS and T cell-mediated colitis models

    PMID:40371646 PMID:40783087

    Open questions at the time
    • Whether TMEM219 blockade alters intestinal tumor susceptibility long-term remains to be defined
    • Contribution of Chi3l1/IL-13Rα2 arm of TMEM219 signaling in the intestinal stem cell niche unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanism by which TMEM219 integrates its two ligand axes (pro-apoptotic IGFBP-3 and pro-survival Chi3l1/IL-13Rα2), the identity of intracellular adaptor proteins linking the receptor to Caspase-8, and the structural determinants of ligand selectivity remain unresolved.
  • No structural model of TMEM219 or its ligand-bound complexes exists
  • Intracellular adaptor(s) bridging TMEM219 cytoplasmic domain to caspase machinery not identified
  • Tissue-specific contexts determining whether TMEM219 signals death versus survival not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-5357801 Programmed Cell Death 5 R-HSA-162582 Signal Transduction 2
Partners
CASP8CHI3L1IGFBP3IL13RA2

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 TMEM219 is a direct binding partner of IL-13Rα2, forming a complex that mediates chitinase 3-like-1 (Chi3l1) signaling. Fluorescence anisotropy nanodisc assays confirmed direct physical interaction between TMEM219 and IL-13Rα2-Chi3l1 complexes. Null mutations or siRNA silencing of TMEM219 phenocopied IL-13Rα2 loss, decreasing Chi3l1-stimulated HB-EGF production, MAPK/Erk and PKB/Akt activation, and inhibiting Chi3l1-mediated suppression of oxidant-induced apoptosis and promotion of melanoma metastasis and TGF-β1 stimulation. Yeast two-hybrid, co-immunoprecipitation, co-localization, bimolecular fluorescence complementation, fluorescence anisotropy nanodisc assays, null mutation and siRNA knockdown with defined phenotypic readouts Nature Communications High 27629921
2011 TMEM219 (IGFBP-3R) acts as a receptor for IGFBP-3 and mediates IGF-independent apoptotic signaling: IGFBP-3 binding to IGFBP-3R activates caspases, which degrade IκBα and p65-NF-κB proteins, thereby negatively regulating NF-κB signaling cascades. Knockdown of IGFBP-3R with siRNA completely abolished IGFBP-3's inhibitory effects on NF-κB; non-IGF-binding IGFBP-3 mutants confirmed IGF-independence. siRNA knockdown, caspase inhibitor experiments, non-IGF-binding IGFBP-3 mutants, in vitro cell-based NF-κB signaling assays, in vivo transgenic mouse model The Journal of Biological Chemistry High 21383009
2022 TMEM219 functions as a death receptor expressed on pancreatic beta cells; its ligand IGFBP-3 signals through TMEM219 to induce beta cell loss and dysfunction. In vitro and in vivo IGFBP-3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells, prevented/delayed diabetes onset, and allowed beta cell expansion. Genetic ablation (TMEM219 knockout), in vitro IGFBP-3/TMEM219 inhibition, in vivo preclinical diabetes models, patient cohort studies with IGFBP-3 measurement Nature Communications High 35115561
2024 TMEM219 is expressed on pancreatic beta cell precursors and in fetal pancreas; its signaling negatively regulates beta cells at early stages and induces Caspase 8-mediated cell death. Pharmacological blockade of TMEM219 rescued beta cell precursor and proliferation markers and decreased cell death in islets and embryonic-derived endocrine progenitors. miR-129-2 was identified as an endogenous upstream regulator of TMEM219 expression: miR-129-2 mimic downregulated TMEM219, while miR-129-2 inhibitor induced TMEM219 overexpression and restored cell proliferation. Pharmacological TMEM219 blockade, miRNA mimic/inhibitor experiments, caspase 8 activity assays, in vitro endocrine progenitor differentiation models Frontiers in Endocrinology Medium 38318298
2025 TMEM219 mediates intestinal stem cell (ISC) death in Crohn's disease via Caspase-8 activation. Genetic tissue-specific deletion of TMEM219 in ISCs (TMEM219fl/flLGR5cre mice) revived mucosal regenerative abilities in vitro and in vivo. Pharmacological blockade with recombinant ecto-TMEM219 (blocking IGFBP-3/TMEM219 binding) restored self-renewal of ISCs in patient-derived mini-guts and ameliorated colitis in DSS-induced and T cell-mediated models. Tissue-specific conditional knockout (TMEM219fl/flLGR5cre), pharmacological blockade with ecto-TMEM219, patient-derived organoids (mini-guts), in vivo colitis models, caspase-8 activity assays The Journal of Clinical Investigation High 40371646
2013 TMEM219 (IGFBP-3R) is required for IGFBP-3-induced apoptosis in lung cancer cells: knockdown of IGFBP-3R hindered IGFBP-3-overexpression-induced NF-κB suppression and apoptosis in tobacco carcinogen-transformed lung epithelial cells. siRNA knockdown of IGFBP-3R, IGFBP-3 overexpression, NF-κB activity assays, apoptosis assays Lung Cancer Medium 23498137
2025 Monoclonal antibodies blocking IGFBP-3/TMEM219 interaction (anti-TMEM219 mAb Ent001) displaced IGFBP-3/TMEM219 binding, rescued ISC markers and function in patient-derived mini-guts from Crohn's disease patients, downregulated Caspase 8, and improved colitis and prevented inflammatory carcinogenesis in vivo, confirming that direct IGFBP-3/TMEM219 binding is the operative mechanism. Phage display-generated monoclonal antibodies, binding displacement assays, patient-derived organoids, in vivo DSS colitis and carcinogenesis models Pharmacological Research Medium 40783087
2025 The IGFBP-3/TMEM219 pathway mediates hepatocyte apoptosis during liver fibrosis progression: IGFBP-3 and TMEM219 gene expression increase coordinately with fibrosis stage, and this is associated with activation of caspase 3/7 and caspase 8 apoptotic pathways in the bile duct ligation rat model. RT-PCR gene expression analysis, immunofluorescence for caspase 3/7 and caspase 8, histopathology in bile duct ligation rat model Molecular Biology Reports Low 40853400

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 IL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector responses. Nature communications 115 27629921
2011 Insulin-like growth factor-binding protein-3 (IGFBP-3) blocks the effects of asthma by negatively regulating NF-κB signaling through IGFBP-3R-mediated activation of caspases. The Journal of biological chemistry 67 21383009
2022 The IGFBP3/TMEM219 pathway regulates beta cell homeostasis. Nature communications 47 35115561
2013 Tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone suppresses a newly identified anti-tumor IGFBP-3/IGFBP-3R system in lung cancer cells. Lung cancer (Amsterdam, Netherlands) 17 23498137
2024 TMEM219 regulates the transcription factor expression and proliferation of beta cells. Frontiers in endocrinology 9 38318298
2025 Xanthosomes loaded with recombinant TMEM219 for targeting IGFBP-3: A novel approach for targeted drug delivery to ameliorate liver fibrosis. Life sciences 4 40447257
2025 TMEM219 signaling promotes intestinal stem cell death and exacerbates colitis. The Journal of clinical investigation 3 40371646
2025 Targeting of the IGFBP3/TMEM219 pathway restores intestinal stem cells capability of healing mucosa in gastrointestinal autoimmune disorders. Pharmacological research 1 40783087
2025 Promoting mucosal healing by targeting TMEM219-dependent intestinal epithelial stem cell defects in inflammatory bowel disease. The Journal of clinical investigation 0 40371644
2025 Stage-specific role of IGFBP-3/TMEM219 pathway in liver fibrosis progression using a bile duct ligation rat model. Molecular biology reports 0 40853400