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FXYD3 (FXYD domain containing ion transport regulator 3)

Written2012-02Hiroto Yamamoto, Shinji Asano
Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan

(Note : for Links provided by Atlas : click)


Alias (NCBI)MAT8
HGNC Alias symbMAT-8
HGNC Previous namePLML
HGNC Previous nameFXYD domain-containing ion transport regulator 3
LocusID (NCBI) 5349
Atlas_Id 43704
Location 19q13.12  [Link to chromosome band 19q13]
Location_base_pair Starts at 35115823 and ends at 35124324 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping FXYD3.png]
Local_order Centromere, SCN1B, HPN, FXYD3, LGI4, FXYD1, FXYD7, FXYD5, Telomere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
FXYD3 (19q13.12)::TARM1 (19q13.42)FXYD3 (19q13.12)::ZNF202 (11q24.1)FXYD3 (19q13.12)::ZNFX1 (20q13.13)
Note FXYD3 is a member of the FXYD family proteins, which regulate Na+,K+-ATPase activity to precisely adjust the physiological ion balance of the tissue.


Note Morrison and Leder (1994) originally found that FXYD3 mRNA was overexpressed in murine breast cancer induced by neu or ras oncogenes, but not by c-myc or int-2. FXYD3 has two splicing variants (FXYD3a and FXYD3b). FXYD3a and 3b are short and long isoforms of FXYD3, respectively.
  Red boxes represent shared exons between FXYD3a and FXYD3b, and a white box represents an exon specific for FXYD3b.
Description DNA contains 8494 bp composed of 9 (FXYD3a) or 8 (FXYD3b) exons.
Transcription The FXYD3a mRNA has an in-frame deletion of 78 nucleotides in the coding sequence compared to the FXYD3b mRNA. FXYD3a mRNA is a major transcript product expressed in normal tissues as well as in breast, colon, stomach and pancreas cancer cells. Transcription of FXYD3 mRNA was down-regulated by TGF-b signaling in human mammary epithelial cells (Yamamoto et al., 2011).
Pseudogene No pseudogenes reported.


  Amino acid alignments of human FXYD3a and 3b proteins. An underline represents the FXYD (Phe-Xaa-Tyr-Asp) motif. A box represents the transmembrane segment. FXYD3b protein has 26 more amino acids in the cytoplasmic domain compared to FXYD3a protein.
Description FXYD3 is a member of the "FXYD" family proteins, which consist of seven members of small proteins and share a signature sequence of four amino acids "FXYD" located in the ectodomain close to the transmembrane segment. Human FXYD3 protein contains a hydrophobic domain at the N terminus encoding a cleavable signal peptide, and adopts a type I topology. On the other hand, mouse FXYD3 may have two transmembrane domains because of the lack of cleavable signal peptide.
Expression Mammary gland, lung, stomach, pancreas and intestine.
Localisation Plasma membrane and intracellular membrane compartment.
Function FXYD family proteins perform fine tuning of ion transport by associating with and modulating the pump activity of Na+,K+-ATPase molecules and modifying the activity of ion channels (Geering, 2006). FXYD3a slightly decreased the apparent affinity both for intracellular Na+ (up to 40%) and extracellular K+ (15 to 40%) of Na+,K+-ATPase whereas FXYD3b slightly increased the apparent affinity for intracellular Na+ (about 15%) and decreased the apparent affinity for extracellular K+ (up to 50%). Both FXYD3 isoforms induced a hyperpolarization-activated chloride current in Xenopus oocytes (Bibert et al., 2006). Two cysteine residues at cytoplasmic domain of FXYD3 were glutathionylated by oxidative stress. As a result, glutathionylation of subunit by oxidative stress was prevented and the pump activity of Na+,K+-ATPase was maintained (Bibert et al., 2011). FXYD3 is responsible for cancer cell proliferation. Suppression of FXYD3 expression caused a significant decrease in cellular proliferation of breast, prostate and pancreatic cancer cell lines. In colon cancer cell line Caco-2, silencing of FXYD3 mRNA with shRNA specific for FXYD3 increased the apoptosis rate and inhibited the differentiation to enterocyte-like phenotype (Bibert et al., 2009).
Homology FXYD family proteins have invariant amino acids in a signature sequence of FXYD motif and two conserved glycines and a serine residue (Sweadner and Rael, 2000). In mammals, this family contains seven members including FXYD1 (phospholemman), FXYD2 (the gamma-subunit of Na+,K+-ATPase), FXYD3 (Mat-8), FXYD4 (corticosteroid hormone-induced factor), FXYD5 (dysadherin), FXYD6 (phosphohippolin) and FXYD7. FXYD family proteins are expressed in specific tissues to regulate Na+,K+-ATPase activity, and precisely adjust the physiological ion balance of the tissues.


Somatic Okudela et al. (2009) showed that somatic mutation (D19H) occurred only in a lung cancer cell line, H2087. This mutation is very rare in lung cancer cell lines and primary lung cancers. Exogenous expression of wild-type FXYD3, but not the mutant (FXYD3/D19H), enhanced the cortical actin density in a lung cancer cell line, H1299. FXYD3/D19H distorted the outline of nuclear envelope in H1299 cells, suggesting that loss of FXYD3 function attenuates the integrity of the nuclear envelope and the cytoskeleton.

Implicated in

Entity Breast cancer
Note Down-regulation of FXYD3 mRNA via siRNA for FXYD3 decreased the proliferation of MCF-7 breast cancer cells.
Disease Yamamoto et al. (2009) reported that FXYD3 protein was overexpressed in human breast cancer specimens; invasive ductal carcinomas and intra-ductal carcinomas compared with surrounding normal mammary glands. On the other hand, FXYD3 expression was low in benign lesion specimens; mastopathy, fibroadenoma and phyllodes tumors. Distribution pattern of FXYD3 expression was divided into two groups. In one group, expression was observed mainly in the cytoplasm. In the other group, expression was observed both in the cytoplasm and at the cell surface.
Entity Pancreas cancer
Note Down-regulation of FXYD3 mRNA by stable antisense transfection decreased the proliferation of T3M4 pancreatic cancer cells.
Disease Kayed et al. (2006) reported that FXYD3 was overexpressed in pancreatic cancer, and contributed to its proliferative activity and malignancy. There was no significant difference in FXYD3 mRNA expression levels between chronic pancreatitis and normal pancreatic tissues whereas FXYD3 mRNA levels were 3.9-fold increased in pancreatic ductal adenocarcinoma cells compared to normal ductal cells. FXYD3 protein expression was almost absent in normal pancreatic tissues. In contrast, chronic pancreatitis and pancreatic ductal adenocarcinoma tissues showed up-regulation of FXYD3 protein which was expressed in cytoplasm and plasma membrane. Pancreas cancer cells that had metastasized to the liver and regional lymph nodes also exhibited strong expression of FXYD3 protein.
Entity Urothelial carcinoma
Disease Zhang et al. (2011) reported FXYD3 mRNA as a promising prognosis marker of renal and bladder urothelial carcinoma (UC). Microarray gene expression data showed that FXYD3 mRNA was increased in UC whereas it was not observed in normal kidney tissues and other type of tumors including papillary, oncocytoma, chromophobe, and clear cell renal carcinoma. FXYD3 protein was expressed in about 90% of UC from renal pelvis, and 63% of UC from bladder, however, it was not expressed in normal kidney and bladder stromal tissues.
Prognosis Martin-Aguilera et al. (2008) reported that a combination of FXYD3 and KRT20 (a member of the keratin family) genes yielded a 100% sensitivity and specificity differentiating lymph nodes with bladder UC dissemination from controls. However, there was no significantly worse survival of patients presenting qRT-PCR positive compared to negative lymph nodes after a median follow-up of 35 months.
Entity Lung cancer
Disease Okudela et al. (2009) reported that FXYD3 mRNA and protein levels were down-regulated in some lung cancer cell lines. Epigenetic modifications such as DNA methylation and histone acethylation seem to affect FXYD3 expression. In normal lung epithelial cells, FXYD3 protein was extensively expressed on the basolateral membrane of bronchial epithelial cells, and in cytoplasm where it was concentrated at the perinuclear site of alveolar epithelial cells. In lung cancer, particularly in poorly differentiated cancers, FXYD3 expression was low or faint. Down-regulation of FXYD3 was more prominent in large cell carcinomas and small cell carcinomas than in adenocarcinomas. FXYD3 expression was decreased significantly as the histological grade of squamous cell carcinoma progressed from well to poorly differentiated.
Entity Prostate cancer
Note Grzmil et al. (2004) reported that FXYD3 (MAT-8) plays an important role in cellular growth of prostate carcinomas. In prostate tumors (6 out of 11), FXYD3 mRNA expression was increased (> 2 times) up to 35-fold compared to normal tissues. FXYD3 mRNA was also expressed in prostate cancer cell lines, PC3, DU-145 and LNCaP. Silencing of FXYD3 mRNA via siRNA specific for FXYD3 led to significant decrease in proliferation of PC3 and LNCaP.
Entity Colon cancer
Disease Kayed et al. (2006) showed that FXYD3 mRNA expression was decreased in colon cancers (n=40) compared to normal colon tissues (n=27). Widegren et al. (2009) reported that FXYD3 seems to be involved in the development of the relatively earlier stages of colorectal cancers. FXYD3 protein expression was significantly higher in primary tumor compared to adjacent normal mucosa in the matched cases, while there was no significant difference in the expression between primary tumor and metastasis in the lymph nodes. FXYD3 protein expression was positively related to the expression of Ras, P53, Legumain and proliferative cell nuclear antigen. Although FXYD3 expression in Dukes stage A-C tumors was higher than that in stage D tumors, there was no relationship between FXYD3 expression and survival in the whole group of the patients.
Prognosis Loftas et al. (2009) reported that in rectal cancers, FXYD3 expression was a prognosis factor independent of tumor stage and differentiation in patients receiving preoperative radiotherapy: strong expression was associated with an unfavorable prognosis. In the primary tumors, FXYD3 expression was increased compared with normal mucosa. There were less tumor necrosis and a higher rate of developing distant metastasis after radiotherapy in tumors with high FXYD3 expression.
Entity Gastric cancer
Disease Zhu et al. (2010) reported that up-regulation of FXYD3 protein expression seems to be involved in tumorigenesis and invasion of gastric adenocarcinoma. FXYD3 protein was present in the cytoplasm of normal gastric epithelial cells as well as gastric cancer cells. The rate of FXYD3 strong expression was significantly higher in cancer (51% of 51) than in normal mucosa (10% of 29). FXYD3 was expressed strongly in ulcerative/infiltrating types of cancers compared to polypoid/fungating ones. However, FXYD3 expression was not correlated with patient's gender, age, tumor size, lymph node status and histological grade.
Entity Glioma
Disease Wang et al. (2009) reported that FXYD3 expression seems to be involved in glioma development. The frequency of strong FXYD3 expression was higher in the primary tumors compared to normal brain tissues. FXYD3 expression was significantly more increased in females than males, and in multiple site gliomas than single sites. There was no difference of FXYD3 expression regarding age, tumor location, size, histological type, and tumor grade.


A link between FXYD3 (Mat-8)-mediated Na,K-ATPase regulation and differentiation of Caco-2 intestinal epithelial cells.
Bibert S, Aebischer D, Desgranges F, Roy S, Schaer D, Kharoubi-Hess S, Horisberger JD, Geering K.
Mol Biol Cell. 2009 Feb;20(4):1132-40. Epub 2008 Dec 24.
PMID 19109419
FXYD proteins reverse inhibition of the Na+-K+ pump mediated by glutathionylation of its beta1 subunit.
Bibert S, Liu CC, Figtree GA, Garcia A, Hamilton EJ, Marassi FM, Sweadner KJ, Cornelius F, Geering K, Rasmussen HH.
J Biol Chem. 2011 May 27;286(21):18562-72. Epub 2011 Mar 30.
PMID 21454534
Structural and functional properties of two human FXYD3 (Mat-8) isoforms.
Bibert S, Roy S, Schaer D, Felley-Bosco E, Geering K.
J Biol Chem. 2006 Dec 22;281(51):39142-51. Epub 2006 Oct 31.
PMID 17077088
FXYD3 (Mat-8), a new regulator of Na,K-ATPase.
Crambert G, Li C, Claeys D, Geering K.
Mol Biol Cell. 2005 May;16(5):2363-71. Epub 2005 Mar 2.
PMID 15743908
FXYD proteins: new regulators of Na-K-ATPase.
Geering K.
Am J Physiol Renal Physiol. 2006 Feb;290(2):F241-50. (REVIEW)
PMID 16403837
Up-regulated expression of the MAT-8 gene in prostate cancer and its siRNA-mediated inhibition of expression induces a decrease in proliferation of human prostate carcinoma cells.
Grzmil M, Voigt S, Thelen P, Hemmerlein B, Helmke K, Burfeind P.
Int J Oncol. 2004 Jan;24(1):97-105.
PMID 14654946
FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth.
Kayed H, Kleeff J, Kolb A, Ketterer K, Keleg S, Felix K, Giese T, Penzel R, Zentgraf H, Buchler MW, Korc M, Friess H.
Int J Cancer. 2006 Jan 1;118(1):43-54.
PMID 16003754
Expression of FXYD-3 is an independent prognostic factor in rectal cancer patients with preoperative radiotherapy.
Loftas P, Onnesjo S, Widegren E, Adell G, Kayed H, Kleeff J, Zentgraf H, Sun XF.
Int J Radiat Oncol Biol Phys. 2009 Sep 1;75(1):137-42. Epub 2009 Mar 14.
PMID 19289258
Molecular lymph node staging in bladder urothelial carcinoma: impact on survival.
Marin-Aguilera M, Mengual L, Burset M, Oliver A, Ars E, Ribal MJ, Colomer D, Mellado B, Villavicencio H, Algaba F, Alcaraz A.
Eur Urol. 2008 Dec;54(6):1363-72. Epub 2008 May 7.
PMID 18486306
Mat-8, a novel phospholemman-like protein expressed in human breast tumors, induces a chloride conductance in Xenopus oocytes.
Morrison BW, Moorman JR, Kowdley GC, Kobayashi YM, Jones LR, Leder P.
J Biol Chem. 1995 Feb 3;270(5):2176-82.
PMID 7836447
Down-regulation of FXYD3 expression in human lung cancers: its mechanism and potential role in carcinogenesis.
Okudela K, Yazawa T, Ishii J, Woo T, Mitsui H, Bunai T, Sakaeda M, Shimoyamada H, Sato H, Tajiri M, Ogawa N, Masuda M, Sugimura H, Kitamura H.
Am J Pathol. 2009 Dec;175(6):2646-56. Epub 2009 Nov 5.
PMID 19893046
The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression.
Sweadner KJ, Rael E.
Genomics. 2000 Aug 15;68(1):41-56.
PMID 10950925
FXYD3 expression in gliomas and its clinicopathological significance.
Wang MW, Gu P, Zhang ZY, Zhu ZL, Geng Y, Kayed H, Zentgraf H, Sun XF.
Oncol Res. 2009;18(4):133-9.
PMID 20112499
Expression of FXYD3 protein in relation to biological and clinicopathological variables in colorectal cancers.
Widegren E, Onnesjo S, Arbman G, Kayed H, Zentgraf H, Kleeff J, Zhang H, Sun XF.
Chemotherapy. 2009;55(6):407-13. Epub 2009 Dec 2.
PMID 19955746
Down-regulation of FXYD3 is induced by transforming growth factor-beta signaling via ZEB1/deltaEF1 in human mammary epithelial cells.
Yamamoto H, Mukaisho K, Sugihara H, Hattori T, Asano S.
Biol Pharm Bull. 2011 Mar;34(3):324-9.
PMID 21372379
FXYD3: A Promising Biomarker for Urothelial Carcinoma.
Zhang Z, Pang ST, Kasper KA, Luan C, Wondergem B, Lin F, Chuang CK, Teh BT, Yang XJ.
Biomark Insights. 2011 Feb 15;6:17-26.
PMID 21499437
Expression and significance of FXYD-3 protein in gastric adenocarcinoma.
Zhu ZL, Zhao ZR, Zhang Y, Yang YH, Wang ZM, Cui DS, Wang MW, Kleeff J, Kayed H, Yan BY, Sun XF.
Dis Markers. 2010;28(2):63-9.
PMID 20364041


This paper should be referenced as such :
Yamamoto, H ; Asano, S
FXYD3 (FXYD domain containing ion transport regulator 3)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(7):471-475.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)FXYD3   4027
Entrez_Gene (NCBI)FXYD3    FXYD domain containing ion transport regulator 3
AliasesMAT8; PLML
GeneCards (Weizmann)FXYD3
Ensembl hg19 (Hinxton)ENSG00000089356 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000089356 [Gene_View]  ENSG00000089356 [Sequence]  chr19:35115823-35124324 [Contig_View]  FXYD3 [Vega]
ICGC DataPortalENSG00000089356
TCGA cBioPortalFXYD3
Genatlas (Paris)FXYD3
SOURCE (Princeton)FXYD3
Genetics Home Reference (NIH)FXYD3
Genomic and cartography
GoldenPath hg38 (UCSC)FXYD3  -     chr19:35115823-35124324 +  19q13.12   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FXYD3  -     19q13.12   [Description]    (hg19-Feb_2009)
GoldenPathFXYD3 - 19q13.12 [CytoView hg19]  FXYD3 - 19q13.12 [CytoView hg38]
Genome Data Viewer NCBIFXYD3 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AA298900 AK311689 AW250864 BC005238 BC090044
RefSeq transcript (Entrez)NM_001136007 NM_001136008 NM_001136009 NM_001136010 NM_001136011 NM_001136012 NM_001387349 NM_001387350 NM_001387352 NM_001387353 NM_001387354 NM_001387355 NM_005971 NM_021910
Consensus coding sequences : CCDS (NCBI)FXYD3
Gene ExpressionFXYD3 [ NCBI-GEO ]   FXYD3 [ EBI - ARRAY_EXPRESS ]   FXYD3 [ SEEK ]   FXYD3 [ MEM ]
Gene Expression Viewer (FireBrowse)FXYD3 [ Firebrowse - Broad ]
GenevisibleExpression of FXYD3 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5349
GTEX Portal (Tissue expression)FXYD3
Human Protein AtlasENSG00000089356-FXYD3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ14802   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ14802  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ14802
Domaine pattern : Prosite (Expaxy)FXYD (PS01310)   
Domains : Interpro (EBI)Ion-transport_regulator_FXYD   
Domain families : Pfam (Sanger)ATP1G1_PLM_MAT8 (PF02038)   
Domain families : Pfam (NCBI)pfam02038   
Conserved Domain (NCBI)FXYD3
AlphaFold pdb e-kbQ14802   
Human Protein Atlas [tissue]ENSG00000089356-FXYD3 [tissue]
Protein Interaction databases
IntAct (EBI)Q14802
Ontologies - Pathways
Ontology : AmiGOchloride channel activity  plasma membrane  integral component of plasma membrane  potassium ion transport  sodium ion transport  chloride transport  sodium channel regulator activity  ion transmembrane transport  extracellular exosome  regulation of cardiac conduction  regulation of sodium ion transmembrane transporter activity  
Ontology : EGO-EBIchloride channel activity  plasma membrane  integral component of plasma membrane  potassium ion transport  sodium ion transport  chloride transport  sodium channel regulator activity  ion transmembrane transport  extracellular exosome  regulation of cardiac conduction  regulation of sodium ion transmembrane transporter activity  
REACTOMEQ14802 [protein]
REACTOME PathwaysR-HSA-936837 [pathway]   
NDEx NetworkFXYD3
Atlas of Cancer Signalling NetworkFXYD3
Wikipedia pathwaysFXYD3
Orthology - Evolution
GeneTree (enSembl)ENSG00000089356
Phylogenetic Trees/Animal Genes : TreeFamFXYD3
Homologs : HomoloGeneFXYD3
Homology/Alignments : Family Browser (UCSC)FXYD3
Gene fusions - Rearrangements
Fusion : MitelmanFXYD3::TARM1 [19q13.12/19q13.42]  
Fusion : MitelmanFXYD3::ZNFX1 [19q13.12/20q13.13]  
Fusion : QuiverFXYD3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerFXYD3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FXYD3
Exome Variant ServerFXYD3
GNOMAD BrowserENSG00000089356
Varsome BrowserFXYD3
ACMGFXYD3 variants
Genomic Variants (DGV)FXYD3 [DGVbeta]
DECIPHERFXYD3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisFXYD3 
ICGC Data PortalFXYD3 
TCGA Data PortalFXYD3 
Broad Tumor PortalFXYD3
OASIS PortalFXYD3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICFXYD3  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DFXYD3
Mutations and Diseases : HGMDFXYD3
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)FXYD3
DoCM (Curated mutations)FXYD3
CIViC (Clinical Interpretations of Variants in Cancer)FXYD3
NCG (London)FXYD3
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry FXYD3
NextProtQ14802 [Medical]
Target ValidationFXYD3
Huge Navigator FXYD3 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDFXYD3
Pharm GKB GenePA28443
Clinical trialFXYD3
DataMed IndexFXYD3
PubMed34 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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