SLC12A4 Gene

HGNC Family	Solute carriers (SLC)
Name	solute carrier family 12 (potassium/chloride transporter), member 4
Description	This gene encodes a member of the SLC12A transporter family. The encoded protein mediates the coupled movement of potassium and chloride ions across the plasma membrane. This gene is expressed ubiquitously. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2013]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nStudies in gynecological malignancies reveal that SLC12A4 (KCC1) plays a critical role in modulating cell invasiveness and proliferation. Growth factors such as insulin-like growth factor‑1 and ‑II stimulate KCC1 activity and mRNA expression via ERK1/2 MAPK and PI3K/AKT signaling cascades, thereby enhancing regulatory volume decrease and promoting cancer cell motility. In cervical and ovarian cancer models, interference with KCC1 function (for example, by dominant‑negative mutations) significantly reduces cell growth and invasion, underscoring its importance in tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n\nDisruption of ion homeostasis and cell volume control is another key function of SLC12A4. Acting as an electroneutral K+/Cl– cotransporter, KCC1 contributes to the regulation of intracellular chloride concentration and cell swelling. In osteoblasts, its activity indirectly triggers volume‑sensitive chloride channels following increases in intracellular KCl concentration, while in erythrocytes modest expression of KCC1 supports cell volume regulation and exhibits sensitivity to oxygen tension. Moreover, activation of basolateral KCC1 by Zn2+ via the ZnR/GPR39 receptor in colonocytes enhances chloride absorption, thereby alleviating fluid loss during diarrheal episodes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n\nAt the regulatory and structural levels, SLC12A4 is characterized as a ubiquitously expressed, “housekeeping” protein whose transcription is driven by a TATA-less promoter featuring an initiator element, downstream promoter element, and binding sites for transcription factors such as AP‑2 and Sp1. Its activity is further modulated by regulators including WNK3 kinase splice variants, which fine-tune cotransporter function. High‑resolution structural studies via cryo‑electron microscopy have uncovered an outward‑open conformation along with unique gating mechanisms, insights that not only enhance our understanding of its transport cycle but also open avenues for targeted therapeutic intervention in diseases where KCC1 function is aberrant."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Meng-Ru Shen, Cheng-Yang Chou, Keng-Fu Hsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "KCl cotransport is an important modulator of human cervical cancer growth and invasion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M308232200"}], "href": "https://doi.org/10.1074/jbc.M308232200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12902337"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12902337"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Meng-Ru Shen, Ai-Chien Lin, Yueh-Mei Hsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Insulin-like growth factor 1 stimulates KCl cotransport, which is necessary for invasion and proliferation of cervical cancer and ovarian cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M406706200"}], "href": "https://doi.org/10.1074/jbc.M406706200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15262997"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15262997"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "S Zhang, X Wu, T Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The up-regulation of KCC1 gene expression in cervical cancer cells by IGF-II through the ERK1/2MAPK and PI3K/AKT pathways and its significance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Gynaecol Oncol (2009)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19317253"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19317253"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Chao Shang, Yan-ming Lu, Li-rong Meng "}, {"type": "b", "children": [{"type": "t", "text": "KCC1 gene advances cell invasion ability by regulating ERK signaling pathway in endometrial cancer HEC-1B cell line."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Gynecol Cancer (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/IGC.0b013e318216a169"}], "href": "https://doi.org/10.1097/IGC.0b013e318216a169"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21666489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21666489"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Margot Bräuer, Eva Frei, Lutz Claes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Influence of K-Cl cotransporter activity on activation of volume-sensitive Cl- channels in human osteoblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00289.2002"}], "href": "https://doi.org/10.1152/ajpcell.00289.2002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12637262"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12637262"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Guo-Ping Zhou, Clara Wong, Robert Su, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human potassium chloride cotransporter 1 (SLC12A4) promoter is regulated by AP-2 and contains a functional downstream promoter element."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2003-01-0107"}], "href": "https://doi.org/10.1182/blood-2003-01-0107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14976052"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14976052"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Asif I Khan, Clare Drew, Sarah E Ball, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oxygen dependence of K(+)-Cl- cotransport in human red cell ghosts and sickle cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioelectrochemistry (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bioelechem.2003.07.005"}], "href": "https://doi.org/10.1016/j.bioelechem.2003.07.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15039017"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15039017"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Dao Pan, Theodosia A Kalfa, Daren Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "K-Cl cotransporter gene expression during human and murine erythroid differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.206516"}], "href": "https://doi.org/10.1074/jbc.M110.206516"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21733850"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21733850"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Laxmi Sunuwar, Hila Asraf, Mark Donowitz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Zn"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "2+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": "-sensing receptor, ZnR/GPR39, upregulates colonocytic Cl"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "-"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " absorption, via basolateral KCC1, and reduces fluid loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Mol Basis Dis (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2017.01.009"}], "href": "https://doi.org/10.1016/j.bbadis.2017.01.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28093242"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28093242"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Silvia Cruz-Rangel, Zesergio Melo, Norma Vázquez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Similar effects of all WNK3 variants on SLC12 cotransporters."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00070.2011"}], "href": "https://doi.org/10.1152/ajpcell.00070.2011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21613606"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21613606"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "A P Garneau, S Slimani, L E Tremblay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "K"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": "-Cl"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "-"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " cotransporter 1 (KCC1): a housekeeping membrane protein that plays key supplemental roles in hematopoietic and cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hematol Oncol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13045-019-0766-x"}], "href": "https://doi.org/10.1186/s13045-019-0766-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31296230"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31296230"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Yongxiang Zhao, Jiemin Shen, Qinzhe Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of the human cation-chloride cotransport KCC1 in an outward-open state."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2109083119"}], "href": "https://doi.org/10.1073/pnas.2109083119"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35759661"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35759661"}]}]}]}
Synonyms	CTC-479C5.17, hKCC1, KCC1
Proteins	S12A4_HUMAN
NCBI Gene ID	6560
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

SLC12A4 has 6,651 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 129 datasets.

Click the + buttons to view associations for SLC12A4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

SLC12A4 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 SLC12A4 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 SLC12A4 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 SLC12A4 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 SLC12A4 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 SLC12A4 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 SLC12A4 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 SLC12A4 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 SLC12A4 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 SLC12A4 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 SLC12A4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of SLC12A4 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 SLC12A4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with SLC12A4 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with SLC12A4 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of SLC12A4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of SLC12A4 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 SLC12A4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of SLC12A4 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing SLC12A4 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of SLC12A4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing SLC12A4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing SLC12A4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing SLC12A4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing SLC12A4 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 SLC12A4 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 SLC12A4 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 SLC12A4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with SLC12A4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with SLC12A4 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with SLC12A4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of SLC12A4 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by SLC12A4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DGIdb Drug Targets 2026	interacting drugs for SLC12A4 protein from the DGIdb Drug Targets 2026 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with SLC12A4 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 SLC12A4 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 SLC12A4 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 SLC12A4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with SLC12A4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for SLC12A4 protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at SLC12A4 gene from the ENCODE Histone Modification Site Profiles dataset.