Transmembrane protein 116
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Transmembrane protein 116 is a protein in which in humans is encoded by the TMEM116 gene.[1] TMEM116 is a transmembrane protein with several hydrophobic transmembrane helices.[2] The protein is broadly expressed at low-to-moderate levels in human tissues, with relatively higher expression reported in the lungs, heart, and kidneys.[3] TMEM116 has been studied in non-small-cell lung cancer, where increased expression has led to cancer cell proliferation, migration, invasion, and metastasis.[4]
Gene
The human TMEM116 gene is located on chromosome 12 at 12q24.13.[1] The gene spans approximately 81,938 base pairs and contains 13 exons.[3] It is located near NAA25, ERP29, and MAPKAPK5.[1] The gene is also listed under the alias FLJ90167.[5]
Transcripts
TMEM116 has multiple alternatively spliced transcript variants. The longest RefSeq coding isoform is transcript variant 1, which encodes protein isoform 1.[6] Transcript variant 4 is longer at the mRNA level but encodes a shorter protein isoform.[3]
| Transcript variant | mRNA accession | mRNA length | Protein isoform | Protein accession | Protein length |
|---|---|---|---|---|---|
| Variant 1 | NM_001193531.2 | 1,534 bp | Isoform 1 | NP_001180460.1 | 337 aa |
| Variant 2 | NM_001193453.2 | 1,429 bp | Isoform 2 | NP_001180382.1 | 302 aa |
| Variant 3 | NM_138341.3 | 1,470 bp | Isoform 3 | NP_612350.1 | 245 aa |
| Variant 4 | NM_001294314.2 | 1,751 bp | Isoform 3 | NP_001281243.1 | 245 aa |
Protein
Isoforms and general properties
The longest human TMEM116 isoform contains 337 amino acids and has a predicted molecular mass of approximately 38 kDa and a predicted isoelectric point of about 8.8.[7] Sequence-composition analysis indicates that TMEM116 is enriched in hydrophobic residues, especially leucine, valine, isoleucine, phenylalanine, and methionine, consistent with its predicted membrane-associated structure.[8]
| Protein isoform | Accession | Length | Approximate molecular weight |
|---|---|---|---|
| Isoform 1 | NP_001180460.1 | 337 aa | ~38 kDa |
| Isoform 2 | NP_001180382.1 | 302 aa | ~34 kDa |
| Isoform 3 | NP_612350.1 / NP_001281243.1 | 245 aa | ~27 kDa |
Domains, motifs, and structure
TMEM116 is predicted to contain six transmembrane helices, supporting its annotation as a multi-pass membrane protein.[2] Computational analyses also identified short sequence motifs and predicted post-translational modification motifs.[9] Predicted structural models indicate that TMEM116 is composed primarily of alpha-helical regions.[10]
Gene-level regulation
Expression pattern
TMEM116 is expressed broadly across human tissues, generally at low-to-moderate RNA abundance.[3] RNA-seq and microarray expression datasets suggest relatively higher expression in the lungs, heart, and kidney.[11] The Human Protein Atlas reports TMEM116 as having evidence at the protein level and provides tissue and cell-type expression data for the gene.[5]
Experimental expression datasets
Microarray data from NCBI GEO support broad TMEM116 expression across normal tissues and altered expression in certain disease states. In non-small-cell lung cancer datasets, TMEM116 expression appears moderate-to-high in both lung adenocarcinoma and squamous cell carcinoma samples.[12] A separate study found that TMEM116 promotes cancer cell proliferation, migration, invasion, and lung metastasis in experimental models of non-small-cell lung cancer.[4]
Promoter and transcription factor binding
The promoter region upstream of the longest RefSeq transcript contains predicted transcription factor binding sites, including sites for factors associated with broadly active GC-rich promoters and cell proliferation, such as SP1, KLF5, E2F3, NRF1, and RREB1.[13]
Transcript-level regulation
The 5′ UTR of TMEM116 is predicted to form multiple stem-loop structures, which may influence translation efficiency.[14] The 3′ UTR is also predicted to form stem-loop structures and contains a major polyadenylation site.[14]
Protein-level regulation
Subcellular localization
TMEM116 is predicted to localize to cellular membranes, including intracellular membrane compartments. The Alliance of Genome Resources lists TMEM116 as associated with the endoplasmic reticulum membrane.[15] This localization is consistent with the predicted transmembrane topology of the protein.
Post-translational modifications
Post-translational modification sites in TMEM116 include several candidate phosphorylation and N-linked glycosylation sites.[16] Phosphorylation sites include multiple phosphoserines and a phosphothreonine.[16] Candidate N-linked glycosylation sites include multiple asparagines in the extracellular space.[8] These modifications may affect protein folding, stability, membrane trafficking, or protein-protein interactions.
Homology and evolution
Paralogs
There are no known paralogs of TMEM116.[1]
Orthologs
TMEM116 orthologs have been identified across mammals, birds, reptiles, amphibians, fish, and several invertebrate groups.[17] Sequence conservation is highest in vertebrates and is strongest within predicted transmembrane regions, suggesting that the membrane-spanning portions of the protein are under stronger evolutionary constraint than terminal or linker regions.[18]
| Major clade | Genus and species | Common name | Taxonomic group | Median divergence (MYA) | Accession | Length (aa) | Identity (%) |
|---|---|---|---|---|---|---|---|
| Mammalia | Homo sapiens | Human | Primates | 0 | NP_001180460.1 | 337 | 100.0 |
| Mammalia | Mus musculus | House mouse | Rodentia | 87 | NP_001155099.1 | 364 | 71.3 |
| Aves | Gallus gallus | Chicken | Galliformes | 319 | XP_015131033.2 | 467 | 58.1 |
| Reptilia | Emydura macquarii | Murray turtle | Testudines | 319 | XP_067395464.1 | 367 | 61.3 |
| Reptilia | Anolis carolinensis | Green anole | Squamata | 319 | XP_062814468.1 | 360 | 53.6 |
| Amphibia | Xenopus tropicalis | Western clawed frog | Anura | 352 | XP_031748588.1 | 335 | 42.2 |
| Sarcopterygii | Latimeria chalumnae | Coelacanth | Coelacanthiformes | 415 | XP_005996451.1 | 381 | 53.5 |
| Actinopterygii | Lepisosteus oculatus | Spotted gar | Lepisosteiformes | 429 | XP_015221646.2 | 367 | 52.3 |
| Actinopterygii | Danio rerio | Zebrafish | Cypriniformes | 429 | NP_001108179.1 | 361 | 43.7 |
| Chondrichthyes | Amblyraja radiata | Thorny skate | Rajiformes | 462 | XP_032899604.1 | 368 | 43.7 |
| Chondrichthyes | Leucoraja erinacea | Little skate | Rajiformes | 462 | XP_055511280.1 | 370 | 43.5 |
| Agnatha | Petromyzon marinus | Sea lamprey | Petromyzontiformes | 563 | XP_032827499.1 | 359 | 31.8 |
| Agnatha | Lethenteron reissneri | Far Eastern brook lamprey | Petromyzontiformes | 563 | XP_061428767.1 | 359 | 31.8 |
| Cephalochordata | Branchiostoma floridae | Florida lancelet | Cephalochordata | 581 | XP_035690447.1 | 393 | 27.9 |
| Cephalochordata | Branchiostoma belcheri | Belcher's lancelet | Cephalochordata | 581 | XP_019631464.1 | 389 | 26.8 |
| Hemichordata | Saccoglossus kowalevskii | Acorn worm | Enteropneusta | 619 | XP_002737077.1 | 385 | 31.2 |
| Hemichordata | Ptychodera flava | Acorn worm | Enteropneusta | 619 | XP_070558638.1 | 349 | 27.9 |
| Echinodermata | Patiria miniata | Bat star | Asteroidea | 619 | XP_038059563.1 | 390 | 33.0 |
| Echinodermata | Apostichopus japonicus | Japanese sea cucumber | Holothuroidea | 619 | XP_071849507.1 | 386 | 25.7 |
| Cnidaria | Nematostella vectensis | Starlet sea anemone | Anthozoa | 686 | XP_048582274.1 | 361 | 30.4 |
| Mollusca | Patella caerulea | Mediterranean limpet | Gastropoda | 686 | KAK6176690.1 | 353 | 27.4 |
| Mollusca | Haliotis rufescens | Red abalone | Gastropoda | 686 | XP_048239061.1 | 343 | 26.7 |
| Mollusca | Bradybaena similaris | Asian tramp snail | Gastropoda | 686 | BFZ08763.1 | 348 | 25.5 |
| Mollusca | Octopus bimaculoides | California two-spot octopus | Cephalopoda | 686 | XP_052822184.1 | 271 | 21.4 |
| Porifera | Sycon ciliatum | Calcareous sponge | Calcarea | 758 | XP_065183738.1 | 355 | 26.6 |
| Porifera | Amphimedon queenslandica | Queensland sponge | Demospongiae | 758 | XP_011404615.1 | 369 | 23.0 |
Interacting proteins
Large-scale protein–protein interaction studies have identified candidate TMEM116-associated proteins. BioPlex 3.0 reported TMEM116 interactions using affinity-purification mass spectrometry.[19] Candidate interactors include NRP1, IGHA1, LCN1, CLCN3, RETSAT, and PDZD8.
| Interactor | Full name | Identification method | Cellular Localization | Notes |
|---|---|---|---|---|
| NRP1 | Neuropilin 1 | Anti-tag co-immunoprecipitation | Plasma membrane | Transmembrane co-receptor involved in VEGF signaling, angiogenesis, and cell migration |
| IGHA1 | Immunoglobulin heavy constant alpha 1 | Anti-tag co-immunoprecipitation | Extracellular | Antibody-associated protein; may represent immune or secretory pathway association |
| LCN1 | Lipocalin 1 | Anti-tag co-immunoprecipitation | Extracellular | Secreted lipocalin protein |
| CLCN3 | Chloride voltage-gated channel 3 | Anti-tag co-immunoprecipitation | Plasma membrane | Intracellular membrane chloride/proton exchanger involved in vesicular ion homeostasis |
| RETSAT | Retinol saturase | Anti-tag co-immunoprecipitation | Endoplasmic Reticulum | Membrane-associated enzyme involved in retinoid metabolism |
| PDZD8 | PDZ domain containing 8 | Anti-tag co-immunoprecipitation | Endoplasmic Reticulum | ER-associated protein involved in membrane contact sites |
Clinical significance
TMEM116 has been most directly studied in non-small-cell lung cancer. Inactivation of TMEM116 reduced proliferation, migration, invasion, and lung metastasis in experimental lung cancer models.[4] TMEM116 deficiency inhibited PDK1–AKT–FOXO3A signaling, suggesting that TMEM116 may contribute to cancer progression through this pathway.[4] TMEM116 has also been discussed with other transmembrane proteins in relation to cancer-associated cellular processes.[20]
Suggested reading
- Zhang S, Dai H, Li W, Wang R, Wu H, Shen M, et al. (2021). "TMEM116 is required for lung cancer cell motility and metastasis through PDK1 signaling pathway". Cell Death & Disease. 12 (12). doi:10.1038/s41419-021-04369-1. PMC 8597531 Check
|pmc=value (help). PMID 34789718 Check|pmid=value (help). Unknown parameter|article-number=ignored (help) - Wesoly J, Pstrąg N, Deryło K, Michalec-Wawiorka B, Derebecka N, Nowicka H, et al. (2023). "Structural, topological, and functional characterization of transmembrane proteins TMEM213, 207, 116, 72 and 30B provides a potential link to ccRCC etiology". American Journal of Cancer Research. 13 (5): 1863–1882. PMC 10244102 Check
|pmc=value (help). PMID 37293153 Check|pmid=value (help). - Huttlin EL, Bruckner RJ, Navarrete-Perea J, Cannon JR, Baltier K, Gebreab F, et al. (2021). "Dual proteome-scale networks reveal cell-specific remodeling of the human interactome". Cell. 184 (11): 3022–3040.e28. doi:10.1016/j.cell.2021.04.011. PMC 8165030 Check
|pmc=value (help). PMID 33961781 Check|pmid=value (help).
References
- ↑ 1.0 1.1 1.2 1.3 "TMEM116 transmembrane protein 116 [Homo sapiens]". NCBI Gene. Retrieved 4 June 2026.
- ↑ 2.0 2.1 "TMEM116 Gene - Transmembrane Protein 116". GeneCards. Retrieved 4 June 2026.
- ↑ 3.0 3.1 3.2 3.3 "TMEM116 transmembrane protein 116 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2026-06-05.
- ↑ 4.0 4.1 4.2 4.3 Zhang S, Dai H, Li W, Wang R, Wu H, Shen M, et al. (2021). "TMEM116 is required for lung cancer cell motility and metastasis through PDK1 signaling pathway". Cell Death & Disease. 12 (12). doi:10.1038/s41419-021-04369-1. PMC 8597531 Check
|pmc=value (help). PMID 34789718 Check|pmid=value (help). Unknown parameter|article-number=ignored (help) - ↑ 5.0 5.1 "TMEM116 protein expression summary". The Human Protein Atlas. Retrieved 4 June 2026.
- ↑ "Homo sapiens transmembrane protein 116 (TMEM116), transcript variant 1, mRNA". NCBI Nucleotide. 12 June 2025. Retrieved 4 June 2026.
- ↑ "Expasy - Error". web.expasy.org. Retrieved 2026-06-05.
- ↑ 8.0 8.1 "TMEM116 Entry on PROTTER". PROTTER.
- ↑ EMBL-EBI; Institute, European Bioinformatics. "Job Dispatcher homepage | EMBL-EBI". www.ebi.ac.uk. Retrieved 2026-06-05.
- ↑ "Phyre 2 Results for Undefined". www.sbg.bio.ic.ac.uk. Retrieved 2026-06-05.
- ↑ "2894740 - GEO Profiles - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2026-06-05.
- ↑ "62812128 - GEO Profiles - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2026-06-05.
- ↑ "Casper J, Speir ML, Raney BJ, Perez G, Nassar LR, Lee CM, Hinrichs AS, Gonzalez JN, Fischer C, Diekhans M et al. The UCSC Genome Browser database: 2026 update. Nucleic Acids Res. 2025 Nov 18;. PMID: 41251146". genome.ucsc.edu. Retrieved 2026-06-05.
- ↑ 14.0 14.1 "UNA Fold entry on TMEM116". UNAFold.
- ↑ "TMEM116". Alliance of Genome Resources. Retrieved 4 June 2026.
- ↑ 16.0 16.1 "TMEM116 (human)". www.phosphosite.org. Retrieved 2026-06-05.
- ↑ "BLAST: Basic Local Alignment Search Tool". blast.ncbi.nlm.nih.gov. Retrieved 2026-06-05.
- ↑ EMBL-EBI; Institute, European Bioinformatics. "Job Dispatcher homepage | EMBL-EBI". www.ebi.ac.uk. Retrieved 2026-06-05.
- ↑ Huttlin EL, Bruckner RJ, Navarrete-Perea J, Cannon JR, Baltier K, Gebreab F, et al. (2021). "Dual proteome-scale networks reveal cell-specific remodeling of the human interactome". Cell. 184 (11): 3022–3040.e28. doi:10.1016/j.cell.2021.04.011. PMC 8165030 Check
|pmc=value (help). PMID 33961781 Check|pmid=value (help). - ↑ Wesoly J, Pstrąg N, Deryło K, Michalec-Wawiorka B, Derebecka N, Nowicka H, et al. (2023). "Structural, topological, and functional characterization of transmembrane proteins TMEM213, 207, 116, 72 and 30B provides a potential link to ccRCC etiology". American Journal of Cancer Research. 13 (5): 1863–1882. PMC 10244102 Check
|pmc=value (help). PMID 37293153 Check|pmid=value (help).
Category:Genes on human chromosome 12 Category:Human proteins Category:Transmembrane proteins
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