FXYD5 explained

FXYD domain-containing ion transport regulator 5 also named dysadherin (human) or RIC (mouse) is a protein that in humans is encoded by the FXYD5 gene.^[1]

Function

This gene encodes a member of a family of small membrane proteins that share a 35-amino acid signature sequence domain, beginning with the sequence PFXYD and containing 7 invariant and 6 highly conserved amino acids. The approved human gene nomenclature for the family is FXYD-domain containing ion transport regulator. Mouse FXYD5 has been termed RIC (Related to Ion Channel). FXYD2, also known as the gamma subunit of the Na,K-ATPase, regulates the properties of that enzyme. FXYD1 (phospholemman), FXYD2 (gamma), FXYD3 (MAT-8), FXYD4 (CHIF), and FXYD5 (RIC) have been shown to induce channel activity in experimental expression systems. Transmembrane topology has been established for two family members (FXYD1 and FXYD2), with the N-terminus extracellular and the C-terminus on the cytoplasmic side of the membrane. This gene product, FXYD5, has not been characterized as a protein. Two transcript variants have been found for this gene, and they are both predicted to encode the same protein.

Dysadherin is the gamma5 subunit of the human Na,K-ATPase. Of all the FXYD members, dysadherin is the only member that has a large extracellular sequence of 140 amino acids. Dysadherin has been observed to be over-expressed on the surface of cells that have down regulated levels of surface E-cadherin. CCL2 (bone homing cytokine)is a protein that is highly affected by silencing dysadherin expression. Dysadherin interferes with cell adhesion via beta1 subunit interactions.^[2] Dysadherin is a target for an extracellular antibody drug conjugate where the antibody to dysadherin is attached to a cardiac glycoside.^[3]

Clinical significance

Dysadherin has been found to be a marker for metastatic cancers and found up-regulated in multiple cancer types.

References

Further reading

• Nam JS, Hirohashi S, Wakefield LM . Dysadherin: a new player in cancer progression . Cancer Letters . 255 . 2 . 161–9 . October 2007 . 17442482 . 2094007 . 10.1016/j.canlet.2007.02.018 .
• Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee NH, Kirkness EF, Weinstock KG, Gocayne JD, White O . Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence . Nature . 377 . 6547 Suppl . 3–174 . September 1995 . 7566098 . .
• Sweadner KJ, Rael E . The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression . Genomics . 68 . 1 . 41–56 . August 2000 . 10950925 . 10.1006/geno.2000.6274 .
• Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, Fu G, Shen Y, Fan HY, Lu G, Zhong M, Xu XR, Han ZG, Zhang JW, Tao J, Huang QH, Zhou J, Hu GX, Gu J, Chen SJ, Chen Z . Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells . Genome Research . 10 . 10 . 1546–60 . October 2000 . 11042152 . 310934 . 10.1101/gr.140200 .
• Omasa T, Chen YG, Mantalaris A, Wu JH . A cDNA from human bone marrow encoding a protein exhibiting homology to the ATP1gamma1/PLM/MAT8 family of transmembrane proteins . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1517 . 2 . 307–10 . January 2001 . 11342114 . 10.1016/S0167-4781(00)00251-7 .
• Ino Y, Gotoh M, Sakamoto M, Tsukagoshi K, Hirohashi S . Dysadherin, a cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes metastasis . Proceedings of the National Academy of Sciences of the United States of America . 99 . 1 . 365–70 . January 2002 . 11756660 . 117566 . 10.1073/pnas.012425299 . 2002PNAS...99..365I . free .
• Sato H, Ino Y, Miura A, Abe Y, Sakai H, Ito K, Hirohashi S . Dysadherin: expression and clinical significance in thyroid carcinoma . The Journal of Clinical Endocrinology and Metabolism . 88 . 9 . 4407–12 . September 2003 . 12970317 . 10.1210/jc.2002-021757 .
• Shimada Y, Yamasaki S, Hashimoto Y, Ito T, Kawamura J, Soma T, Ino Y, Nakanishi Y, Sakamoto M, Hirohashi S, Imamura M . Clinical significance of dysadherin expression in gastric cancer patients . Clinical Cancer Research . 10 . 8 . 2818–23 . April 2004 . 15102690 . 10.1158/1078-0432.CCR-0633-03 . 6282644 .
• Shimada Y, Hashimoto Y, Kan T, Kawamura J, Okumura T, Soma T, Kondo K, Teratani N, Watanabe G, Ino Y, Sakamoto M, Hirohashi S, Imamura M . Prognostic significance of dysadherin expression in esophageal squamous cell carcinoma . Oncology . 67 . 1 . 73–80 . 2004 . 15459499 . 10.1159/000080289 . 34215274 .
• Shimamura T, Yasuda J, Ino Y, Gotoh M, Tsuchiya A, Nakajima A, Sakamoto M, Kanai Y, Hirohashi S . Dysadherin expression facilitates cell motility and metastatic potential of human pancreatic cancer cells . Cancer Research . 64 . 19 . 6989–95 . October 2004 . 15466191 . 10.1158/0008-5472.CAN-04-1166 . free .
• Wu D, Qiao Y, Kristensen GB, Li S, Troen G, Holm R, Nesland JM, Suo Z . Prognostic significance of dysadherin expression in cervical squamous cell carcinoma . Pathology & Oncology Research . 10 . 4 . 212–8 . 2005 . 15619642 . 10.1007/BF03033763 . 20804810 .
• Nishizawa A, Nakanishi Y, Yoshimura K, Sasajima Y, Yamazaki N, Yamamoto A, Hanada K, Kanai Y, Hirohashi S . Clinicopathologic significance of dysadherin expression in cutaneous malignant melanoma: immunohistochemical analysis of 115 patients . Cancer . 103 . 8 . 1693–700 . April 2005 . 15751018 . 10.1002/cncr.20984 . 39775698 . free .
• Batistatou A, Scopa CD, Ravazoula P, Nakanishi Y, Peschos D, Agnantis NJ, Hirohashi S, Charalabopoulos KA . Involvement of dysadherin and E-cadherin in the development of testicular tumours . British Journal of Cancer . 93 . 12 . 1382–7 . December 2005 . 16333245 . 2361540 . 10.1038/sj.bjc.6602880 .
• Batistatou A, Makrydimas G, Zagorianakou N, Zagorianakou P, Nakanishi Y, Agnantis NJ, Hirohashi S, Charalabopoulos K . Expression of dysadherin and E-cadherin in trophoblastic tissue in normal and abnormal pregnancies . Placenta . 28 . 5–6 . 590–2 . 2007 . 17084448 . 10.1016/j.placenta.2006.09.004 .
• Batistatou A, Peschos D, Tsanou H, Charalabopoulos A, Nakanishi Y, Hirohashi S, Agnantis NJ, Charalabopoulos K . In breast carcinoma dysadherin expression is correlated with invasiveness but not with E-cadherin . British Journal of Cancer . 96 . 9 . 1404–8 . May 2007 . 17437014 . 2360179 . 10.1038/sj.bjc.6603743 .

Notes and References

1. Web site: Entrez Gene: FXYD5 FXYD domain containing ion transport regulator 5 .
2. Tokhtaeva E, Sun H, Deiss-Yehiely N, Wen Y, Soni PN, Gabrielli NM, Marcus EA, Ridge KM, Sachs G, Vazquez-Levin M, Sznajder JI, Vagin O, Dada LA . The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell-cell trans-dimerization of Na,K-ATPase β1 subunits . Journal of Cell Science . 129 . 12 . 2394–406 . June 2016 . 27142834 . 4920254 . 10.1242/jcs.186148 .
3. Marshall DJ, Harried SS, Murphy JL, Hall CA, Shekhani MS, Pain C, Lyons CA, Chillemi A, Malavasi F, Pearce HL, Thorson JS, Prudent JR . Extracellular Antibody Drug Conjugates Exploiting the Proximity of Two Proteins . Molecular Therapy . 24 . 10 . 1760–1770 . October 2016 . 27434591 . 5112037 . 10.1038/mt.2016.119 .