Alternative titles; symbols
HGNC Approved Gene Symbol: FXYD5
Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:35,154,735-35,169,881 (from NCBI)
FXYD5 interacts with and positively regulates the Na/K ATPase channel (see 182310) (Lubarski et al., 2005).
The gene family FXYD (pronounced fix-id) consists of small membrane proteins containing a core motif of 35 invariant and conserved amino acids centered on a single transmembrane span. By EST database searching and in silico analysis, Sweadner and Rael (2000) identified genes and protein sequences for 7 FXYD molecules in rodents and humans. The deduced FXYD5 protein, the largest of the 7, contains 178 amino acids and has a signal peptide. Sweadner and Rael (2000) noted that ESTs for FXYD5 are found in all tissues, suggesting ubiquitous expression.
Omasa et al. (2001) cloned a cDNA encoding a 115-amino acid protein, which they termed IWU-1, that is nearly identical to mouse Ric and to the C-terminal half of FXYD5. PCR analysis detected expression in a bone marrow cDNA library.
Ino et al. (2002) reported the cloning and characterization of a cancer-associated cell membrane glycoprotein, which they called dysadherin, recognized by a monoclonal antibody. The deduced 178-amino acid protein contains a putative signal sequence, a potential O-glycosylated extracellular domain, a single transmembrane domain, and a short cytoplasmic tail. The antigen distribution and results of transfection of the cDNA indicated that this antigen inactivates E-cadherin (CDH1; 192090) function in a posttranscriptional manner and plays an important role in tumor progression and metastasis.
By Western blot analysis, Lubarski et al. (2005) detected highest Fxyd5 expression in mouse kidney, intestine, spleen, and lung. Confocal immunofluorescence microscopy of mouse kidney detected Fxyd5 on basolateral membranes of connecting tubules, collecting tubules, and intercalated cells of collecting duct. It was also expressed on apical membranes in long thin limb of Henle loop. No expression of Fxyd5 was detected in blood vessels. Fxyd5 had an apparent molecular mass of 24 kD, and the mass was not sensitive to O- or N-deglycosylation.
To evaluate the association between dysadherin expression and E-cadherin expression in thyroid carcinoma, Sato et al. (2003) performed immunostaining in 51 papillary (see 188550), 10 follicular, and 31 undifferentiated carcinomas. Immunoreactivity for dysadherin, localized at cell-cell boundaries, was detected in 39 of 51 papillary carcinomas and in all 31 undifferentiated carcinomas but not in the follicular carcinomas or normal thyroid tissue controls. Dysadherin expression was significantly higher in undifferentiated carcinoma than in papillary carcinoma or follicular carcinoma and showed significant negative correlation with E-cadherin expression. The authors concluded that the degree of dysadherin expression was significantly associated with the prognosis and that a process involving increased dysadherin expression may lead to an adverse clinical outcome.
By coimmunoprecipitation and Western blot analyses of mouse kidney microsomes, Lubarski et al. (2005) found that Fxyd5 interacted directly with the alpha-1 subunit of the Na/K ATPase (ATP1A1; 182310). The immunopellets did not contain other FXYD proteins. Coexpression of mouse Fxyd5 with rat alpha-1 and pig beta-1 (ATP1B1; 182330) in Xenopus oocytes increased current density over that displayed by alpha-1 and beta-1 alone.
Lubarski-Gotliv et al. (2016) noted that knockdown of FXYD5 in human breast cancer cells or human renal cell carcinoma cells results in decreased expression of CCL2 (158105). They found that expression of mouse Fxyd5 in the mouse M1 epithelial cell line resulted in increased production of Ccl2 mRNA and protein in response to lipopolysaccharide (LPS), following an increase of Tnfr1 (TNFRSF1A; 191190) surface expression. Administration of LPS to mice induced secretion of Ccl2 and Tnfa (191160) in Fxyd5-expressing lung tissue, suggesting a role for FXYD5 in inflammation.
Hartz (2016) mapped the FXYD5 gene to chromosome 19q13.12 based on an alignment of the FXYD5 sequence (GenBank AF161462) with the genomic sequence (GRCh38).
Hartz, P. A. Personal Communication. Baltimore, Md. 5/10/2016.
Ino, Y., Gotoh, M., Sakamoto, M., Tsukagoshi, K., Hirohashi, S. Dysadherin, a cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes metastasis. Proc. Nat. Acad. Sci. 99: 365-370, 2002. [PubMed: 11756660] [Full Text: https://doi.org/10.1073/pnas.012425299]
Lubarski, I., Pihakaski-Maunsbach, K., Karlish, S. J. D., Maunsbach, A. B., Garty, H. Interaction with the Na,K-ATPase and tissue distribution of FXYD5 (related to ion channel). J. Biol. Chem. 280: 37717-37724, 2005. [PubMed: 16148001] [Full Text: https://doi.org/10.1074/jbc.M506397200]
Lubarski-Gotliv, I., Asher, C., Dada, L. A., Garty, H. FXYD5 protein has a pro-inflammatory role in epithelial cells. J. Biol. Chem. 291: 11072-11082, 2016. [PubMed: 27006401] [Full Text: https://doi.org/10.1074/jbc.M115.699041]
Omasa, T., Chen, Y.-G., Mantalaris, A., Wu, J. H. D. A cDNA from human bone marrow encoding a protein exhibiting homology to the ATP1-gamma-1/PLM/MAT8 family of transmembrane proteins. Biochim. Biophys. Acta 1517: 307-310, 2001. [PubMed: 11342114] [Full Text: https://doi.org/10.1016/s0167-4781(00)00251-7]
Sato, H., Ino, Y., Miura, A., Abe, Y., Sakai, H., Ito, K., Hirohashi, S. Dysadherin: expression and clinical significance in thyroid carcinoma. J. Clin. Endocr. Metab. 88: 4407-4412, 2003. [PubMed: 12970317] [Full Text: https://doi.org/10.1210/jc.2002-021757]
Sweadner, K. J., Rael, E. The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression. Genomics 68: 41-56, 2000. [PubMed: 10950925] [Full Text: https://doi.org/10.1006/geno.2000.6274]