TM9SF4 Gene

Name	transmembrane 9 superfamily protein member 4
Description	Involved in several processes, including positive regulation of protein localization; regulation of intracellular pH; and vacuolar proton-transporting V-type ATPase complex assembly. Located in Golgi apparatus and early endosome. [provided by Alliance of Genome Resources, Mar 2025]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTM9SF4 is a multifunctional transmembrane protein that plays a critical role in regulating cellular pH homeostasis in cancer cells. It associates with the vacuolar ATPase complex by interacting with its ATP6V1H subunit, thereby enhancing V‑ATPase assembly and activity to establish an inverted pH gradient—characterized by cytosolic alkalization and extracellular acidification—that promotes tumor aggressiveness and invasive behavior. Furthermore, TM9SF4 is enriched in acidic vesicles where it supports atypical feeding mechanisms such as tumor cannibalism, a phenomenon associated with metastatic potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n \nTM9SF4 also functions as an important modulator of cell survival pathways. Under nutrient starvation, it facilitates the inactivation of mTOR by directly interacting with the kinase, thereby promoting autophagic flux that protects cells from apoptosis. In addition, its elevated expression in chemoresistant cancer models helps alleviate endoplasmic reticulum stress by reducing protein misfolding, which in turn supports malignant cell survival. These functions, together with its overexpression in metastatic melanoma and select hematological malignancies, underscore an oncogenic role for TM9SF4."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n \nBeyond its roles in pH regulation and stress responses, TM9SF4 contributes to intracellular protein trafficking and cytoskeletal dynamics. It regulates the sorting of transmembrane domains at the endoplasmic reticulum–Golgi interface, ensuring the proper localization of proteins with glycine‐rich transmembrane domains. In parallel, a cleaved N‑terminal fragment of TM9SF4 can bind to F‑actin, inducing actin oxidation and enhancing cofilin‑mediated actin disassembly, which in turn modulates cell migration and metastasis. In addition, genetic studies have linked TM9SF4 polymorphisms to inflammatory bowel disease, highlighting its broader impact on inflammatory processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "F Lozupone, M Borghi, F Marzoli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2014.437"}], "href": "https://doi.org/10.1038/onc.2014.437"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25659576"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25659576"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Francesco Lozupone, Maurizio Perdicchio, Daria Brambilla, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human homologue of Dictyostelium discoideum phg1A is expressed by human metastatic melanoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/embor.2009.236"}], "href": "https://doi.org/10.1038/embor.2009.236"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19893578"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19893578"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lei Sun, Zhaoyue Meng, Yifei Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TM9SF4 is a novel factor promoting autophagic flux under amino acid starvation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cdd.2017.166"}], "href": "https://doi.org/10.1038/cdd.2017.166"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29125601"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29125601"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yifei Zhu, Mingxu Xie, Zhaoyue Meng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Knockdown of TM9SF4 boosts ER stress to trigger cell death of chemoresistant breast cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-019-0846-y"}], "href": "https://doi.org/10.1038/s41388-019-0846-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31249383"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31249383"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Rosa Paolillo, Isabella Spinello, Maria Teresa Quaranta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human TM9SF4 Is a New Gene Down-Regulated by Hypoxia and Involved in Cell Adhesion of Leukemic Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0126968"}], "href": "https://doi.org/10.1371/journal.pone.0126968"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25961573"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25961573"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Alexandre Vernay, Otmane Lamrabet, Jackie Perrin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TM9SF4 levels determine sorting of transmembrane domains in the early secretory pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.220830"}], "href": "https://doi.org/10.1242/jcs.220830"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30301779"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30301779"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Zhaoyue Meng, Zhichao Li, Mingxu Xie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TM9SF4 is an F-actin disassembly factor that promotes tumor progression and metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-022-33276-y"}], "href": "https://doi.org/10.1038/s41467-022-33276-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36175399"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36175399"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Mingxu Xie, Joyce Wing Yan Mak, Hongyan Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TM9SF4 Is a Crucial Regulator of Inflammation and ER Stress in Inflammatory Bowel Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Gastroenterol Hepatol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jcmgh.2022.04.002"}], "href": "https://doi.org/10.1016/j.jcmgh.2022.04.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35398597"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35398597"}]}]}]}
Synonyms	DJ836N17.2
Proteins	TM9S4_HUMAN
NCBI Gene ID	9777
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

TM9SF4 has 5,843 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 108 datasets.

Click the + buttons to view associations for TM9SF4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

TM9SF4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of TM9SF4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of TM9SF4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of TM9SF4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of TM9SF4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of TM9SF4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of TM9SF4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of TM9SF4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of TM9SF4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of TM9SF4 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of TM9SF4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of TM9SF4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of TM9SF4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with TM9SF4 protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of TM9SF4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of TM9SF4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of TM9SF4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of TM9SF4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing TM9SF4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing TM9SF4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing TM9SF4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with TM9SF4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with TM9SF4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of TM9SF4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with TM9SF4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Disease Associations	diseases associated with TM9SF4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by TM9SF4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with TM9SF4 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with TM9SF4 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with TM9SF4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with TM9SF4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with TM9SF4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with TM9SF4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at TM9SF4 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of TM9SF4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of TM9SF4 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing TM9SF4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of TM9SF4 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with TM9SF4 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing TM9SF4 from the GeneSigDB Published Gene Signatures dataset.
	GEO Signatures of Differentially Expressed Genes for Diseases	disease perturbations changing expression of TM9SF4 gene from the GEO Signatures of Differentially Expressed Genes for Diseases dataset.