Phosphorylation and ubiquitination are necessary for Na,K-ATPase endocytosis during hypoxia

Laura A. Dada, Lynn C. Welch, Guofei Zhou, Ronen Ben-Saadon, Aaron Ciechanover, Jacob I. Sznajder*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


As a cellular adaptative response, hypoxia decreases Na,K-ATPase activity by triggering the endocytosis of its α1 subunit in alveolar epithelial cells. Here, we present evidence that the ubiquitin conjugating system is important in the Na,K-ATPase endocytosis during hypoxia and that ubiquitination of Na,K-ATPase α1 subunit occurs at the basolateral membrane. Endocytosis and ubiquitination were prevented when the Ser 18 in the PKC phosphorylation motif of the Na,K-ATPase α1 subunit was mutated to an alanine, suggesting that phosphorylation at Ser-18 is required for ubiquitination. Mutation of the four lysines surrounding Ser 18 to arginine prevented Na,K-ATPase ubiquitination and endocytosis during hypoxia; however, only one of them was sufficient to restore hypoxia-induced endocytosis. We provide evidence that ubiquitination plays an important role in cellular adaptation to hypoxia by regulating Na,K-ATPase α1-subunit endocytosis.

Original languageEnglish (US)
Pages (from-to)1893-1898
Number of pages6
JournalCellular Signalling
Issue number9
StatePublished - Sep 2007


  • Endocytosis
  • Hypoxia
  • Na,K-ATPase
  • Phosphorylation
  • Ubiquitination

ASJC Scopus subject areas

  • Cell Biology


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