TMEM219

Official Full Name

transmembrane protein 219

Organism

Homo sapiens

GeneID

124446

Background

Predicted to be involved in apoptotic process. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

IGFBP3R; IGFBP-3R;

Protein Sequence

MGNCQAGHNLHLCLAHHPPLVCATLILLLLGLSGLGLGSFLLTHRTGLRSPDIPQDWVSFLRSFGQLTLCPRNGTVTGKWRGSHVVGLLTTLNFGDGPDRNKTRTFQATVLGSQMGLKGSSAGQLVLITARVTTERTAGTCLYFSAVPGILPSSQPPISCSEEGAGNATLSPRMGEECVSVWSHEGLVLTKLLTSEELALCGSRLLVLGSFLLLFCGLLCCVTAMCFHPRRESHWSRTRL

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Detailed Information

The TMEM219 gene is located on human chromosome 9q31.3, consisting of six exons and encoding a transmembrane protein of 240 amino acids with an approximate molecular weight of 26 kDa. Two transcript variants have been identified, differing only in the 5′ untranslated region while encoding the same protein. The gene shows high expression in the lung, kidney, placenta, and small intestine. Its promoter contains a p53-binding site, suggesting regulation under DNA damage stress. Structurally, TMEM219 is a member of the tumor necrosis factor receptor (TNFR) superfamily, with an extracellular IgV-like domain, a single transmembrane region, and an intracellular death domain (DD).

Biological Function and Signaling Mechanisms

The principal function of TMEM219 is to act as a specific receptor for insulin-like growth factor-binding protein 3 (IGFBP-3), initiating a caspase-dependent apoptotic pathway:

Ligand Binding and Activation: Binding of IGFBP-3 to the extracellular domain of TMEM219 promotes receptor trimerization, recruitment of the adaptor protein FADD, and subsequent activation of caspase-8. Activated caspase-8 triggers a cascade leading to effector caspase-3/7 activation and apoptosis.

Crosstalk with IGF Signaling: IGFBP-3 can suppress IGF-1 survival signaling by sequestration, while TMEM219 provides an IGF-independent mechanism for apoptosis. Together, this dual role of the IGFBP-3/TMEM219 axis positions it as a key regulator of cell fate.

TMEM219 also modulates autophagy. Under nutrient deprivation, it inhibits autophagic flux via mTORC1 signaling, potentially through AMPK phosphorylation. In pancreatic β-cell homeostasis, TMEM219 deficiency increases autophagy and β-cell mass, highlighting its role in metabolic regulation.

Figure 1. Multiple downstream pathways regulated by IGFBP-3. (Naseri N, et al., 2025)

Metabolic Diseases

TMEM219 exerts dual effects in type 2 diabetes:

In the liver, hyperglycemia upregulates TMEM219 expression, enhancing caspase-3 activity and hepatocyte apoptosis, thereby aggravating insulin resistance.

In adipose tissue, TMEM219 mediates IGFBP-3–induced apoptosis of preadipocytes, limiting adipose expansion and contributing to lipotoxicity.

Elevated circulating IGFBP-3 levels in diabetes have been associated with microvascular complications, suggesting TMEM219 as a potential mediator.

Cancer Progression and Therapy Resistance

TMEM219 shows context-dependent roles in cancer:

Pro-tumor effects: In glioblastoma, TMEM219 promotes PD-L1 expression through STAT3 signaling, facilitating immune evasion. In breast cancer, its expression correlates with paclitaxel resistance.

Anti-tumor effects: In colorectal cancer, TMEM219 overexpression enhances 5-fluorouracil–induced apoptosis, whereas promoter methylation–mediated silencing contributes to chemoresistance.

These contrasting functions may depend on IGFBP-3 bioavailability and the repertoire of downstream adaptor proteins within the tumor microenvironment.

Genetic Disorders

Genome-wide association studies have linked TMEM219 to Hermansky-Pudlak syndrome (HPS), characterized by platelet dysfunction and pulmonary fibrosis. Impaired TMEM219-mediated clearance of apoptotic alveolar type II cells may contribute to collagen accumulation. In autism spectrum disorder (ASD), TMEM219 lies within a susceptibility region on 9q31, and missense variants such as p.R112Q may affect synaptic pruning, though the mechanisms remain unresolved.

Research Challenges and Therapeutic Perspectives

Two major challenges complicate TMEM219 research:

Signaling Complexity: IGFBP-3 also interacts with alternative receptors such as TGF-βRⅤ, and whether TMEM219 participates in non-apoptotic pathways, including inflammation, requires further investigation.
Model Limitations: TMEM219 knockout mice display mild phenotypes, possibly due to compensatory signaling pathways mitigating IGFBP-3 activity.

From a therapeutic perspective, strategies are emerging:

Monoclonal antibodies targeting TMEM219 (e.g., mAb-109) have shown efficacy in experimental diabetic nephropathy, reducing glomerulosclerosis.
Soluble TMEM219-Fc fusion proteins, acting as decoy receptors, have been shown to block IGFBP-3–mediated chemoresistance in breast cancer models.

Summary

TMEM219 is a multifunctional receptor that integrates apoptosis, autophagy, and metabolic regulation through its interaction with IGFBP-3. Its roles in diabetes, cancer, genetic syndromes, and potentially neurological disorders underscore its biological importance. Despite challenges in dissecting its signaling complexity, TMEM219 represents a promising therapeutic target with translational applications in metabolic disease and oncology.

Reference

Chen J, Fei S, Chan LWC, et al. Inflammatory signaling pathways in pancreatic β-cell: New insights into type 2 diabetes pathogenesis. Pharmacol Res. 2025 Jun;216:107776.
Cai Q, Dozmorov M, Oh Y. IGFBP-3/IGFBP-3 Receptor System as an Anti-Tumor and Anti-Metastatic Signaling in Cancer. Cells. 2020 May 20;9(5):1261.
Naseri N, Mofid MR. Role of IGFBP-3 in Human Diseases Relying on Different Cell Signaling Pathways. Adv Biomed Res. 2025 Feb 28;14:15.

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