FXYD3 (FXYD domain containing ion transport regulator 3)

2012-02-01   Hiroto Yamamoto , Shinji Asano 

Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan

Identity

HGNC
LOCATION
19q13.12
LOCUSID
ALIAS
MAT8,PLML
FUSION GENES

DNA/RNA

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.
Atlas Image
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.

Proteins

Atlas Image
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 Na+,K+-ATPase beta1 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.

Mutations

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 name
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 name
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 name
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 name
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 name
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 name
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 name
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 patients gender, age, tumor size, lymph node status and histological grade.
Entity name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
191094192009A link between FXYD3 (Mat-8)-mediated Na,K-ATPase regulation and differentiation of Caco-2 intestinal epithelial cells.Bibert S et al
214545342011FXYD proteins reverse inhibition of the Na+-K+ pump mediated by glutathionylation of its beta1 subunit.Bibert S et al
170770882006Structural and functional properties of two human FXYD3 (Mat-8) isoforms.Bibert S et al
157439082005FXYD3 (Mat-8), a new regulator of Na,K-ATPase.Crambert G et al
164038372006FXYD proteins: new regulators of Na-K-ATPase.Geering K et al
146549462004Up-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 et al
160037542006FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth.Kayed H et al
192892582009Expression of FXYD-3 is an independent prognostic factor in rectal cancer patients with preoperative radiotherapy.Loftås P et al
184863062008Molecular lymph node staging in bladder urothelial carcinoma: impact on survival.Marín-Aguilera M et al
78364471995Mat-8, a novel phospholemman-like protein expressed in human breast tumors, induces a chloride conductance in Xenopus oocytes.Morrison BW et al
198930462009Down-regulation of FXYD3 expression in human lung cancers: its mechanism and potential role in carcinogenesis.Okudela K et al
109509252000The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression.Sweadner KJ et al
201124992009FXYD3 expression in gliomas and its clinicopathological significance.Wang MW et al
199557462009Expression of FXYD3 protein in relation to biological and clinicopathological variables in colorectal cancers.Widegren E et al
213723792011Down-regulation of FXYD3 is induced by transforming growth factor-β signaling via ZEB1/δEF1 in human mammary epithelial cells.Yamamoto H et al
214994372011FXYD3: A Promising Biomarker for Urothelial Carcinoma.Zhang Z et al
203640412010Expression and significance of FXYD-3 protein in gastric adenocarcinoma.Zhu ZL et al

Other Information

Locus ID:

NCBI: 5349
MIM: 604996
HGNC: 4027
Ensembl: ENSG00000089356

Variants:

dbSNP: 5349
ClinVar: 5349
TCGA: ENSG00000089356
COSMIC: FXYD3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000089356ENST00000344013Q14802
ENSG00000089356ENST00000346446Q14802
ENSG00000089356ENST00000435734Q14802
ENSG00000089356ENST00000603181Q14802
ENSG00000089356ENST00000603449Q14802
ENSG00000089356ENST00000603524S4R445
ENSG00000089356ENST00000604255Q14802
ENSG00000089356ENST00000604404Q14802
ENSG00000089356ENST00000604621Q14802
ENSG00000089356ENST00000604804S4R445
ENSG00000089356ENST00000605550S4R3M2
ENSG00000089356ENST00000605552Q14802
ENSG00000089356ENST00000605677Q14802

Expression (GTEx)

0
50
100
150
200
250
300

Pathways

PathwaySourceExternal ID
Muscle contractionREACTOMER-HSA-397014
Transmembrane transport of small moleculesREACTOMER-HSA-382551
Ion channel transportREACTOMER-HSA-983712
Ion transport by P-type ATPasesREACTOMER-HSA-936837
Cardiac conductionREACTOMER-HSA-5576891
Ion homeostasisREACTOMER-HSA-5578775

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
224308722012Tissue-based proteomics reveals FXYD3, S100A11 and GSTM3 as novel markers for regional lymph node metastasis in colon cancer.25
146549462004Up-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.22
160037542006FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth.20
162889232005Correlation of gene and protein structures in the FXYD family proteins.12
180007452007Structures of the FXYD regulatory proteins in lipid micelles and membranes.12
208053352010Translocation of Pseudomonas aeruginosa from the intestinal tract is mediated by the binding of ExoS to an Na,K-ATPase regulator, FXYD3.12
125356062003Expression and characterization of the FXYD ion transport regulators for NMR structural studies in lipid micelles and lipid bilayers.10
170770882006Structural and functional properties of two human FXYD3 (Mat-8) isoforms.10
174094962007Interaction of Mat-8 (FXYD-3) with Na+/K+-ATPase in colorectal cancer cells.8
195713762009FXYD3 protein involved in tumor cell proliferation is overproduced in human breast cancer tissues.8

Citation

Hiroto Yamamoto ; Shinji Asano

FXYD3 (FXYD domain containing ion transport regulator 3)

Atlas Genet Cytogenet Oncol Haematol. 2012-02-01

Online version: http://atlasgeneticsoncology.org/gene/43704/fxyd3