The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell-cell trans-dimerization of Na,K-ATPase β1 subunits

Elmira Tokhtaeva, Haying Sun, Nimrod Deiss-Yehiely, Yi Wen, Pritin N. Soni, Nieves M. Gabrielli, Elizabeth A. Marcus, Karen M. Ridge, George Sachs, Mónica Vazquez-Levin, Jacob I. Sznajder, Olga Vagin, Laura A. Dada*

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

FXYD5 (also known as dysadherin), a regulatory subunit of the Na,K-ATPase, impairs intercellular adhesion by a poorly understood mechanism. Here, we determined whether FXYD5 disrupts the transdimerization of Na,K-ATPase molecules located in neighboring cells. Mutagenesis of the Na,K-ATPase β1 subunit identified four conserved residues, including Y199, that are crucial for the intercellular Na,K-ATPase trans-dimerization and adhesion. Modulation of expression of FXYD5 or of the β1 subunit with intact or mutated β11 binding sites demonstrated that the anti-adhesive effect of FXYD5 depends on the presence of Y199 in the β1 subunit. Immunodetection of the plasma membrane FXYD5 was prevented by the presence of O-glycans. Partial FXYD5 deglycosylation enabled antibody binding and showed that the protein level and the degree of O-glycosylation were greater in cancer than in normal cells. FXYD5-induced impairment of adhesion was abolished by both genetic and pharmacological inhibition of FXYD5 O-glycosylation. Therefore, the extracellular O-glycosylated domain of FXYD5 impairs adhesion by interfering with intercellular β11 interactions, suggesting that the ratio between FXYD5 and α11 heterodimer determines whether the Na,K-ATPase acts as a positive or negative regulator of intercellular adhesion.

Original languageEnglish (US)
Pages (from-to)2394-2406
Number of pages13
JournalJournal of cell science
Volume129
Issue number12
DOIs
Publication statusPublished - Jun 15 2016

    Fingerprint

Keywords

  • Cell adhesion
  • Cell-cell interaction
  • Epithelial cell adhesion molecule
  • Epithelium
  • FXYD5
  • NA,K-ATPase
  • O-glycosylation

ASJC Scopus subject areas

  • Cell Biology

Cite this