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ZNRF2 is released from membranes by growth factors and with ZNRF1 regulates the Na+/K+ATPase

ZNRF2 is released from membranes by growth factors and with ZNRF1 regulates the Na+/K+ATPase

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  • Gerta Hoxhaj
  • Ayaz Najafov
  • Rachel Toth
  • David G. Campbell
  • Alan R. Prescott
  • Carol MacKintosh

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Original languageEnglish
Pages (from-to)4662-4675
Number of pages14
JournalJournal of Cell Science
Issue number19
StatePublished - 1 Oct 2012


Here, we describe a phosphorylation-based reverse myristoyl switch for mammalian ZNRF2, and show that this E3 ubiquitin ligase and its sister protein ZNRF1 regulate the Na+/K+ pump (Na+/K+ATPase). N-myristoylation localizes ZNRF1 and ZNRF2 to intracellular membranes and enhances their activity. However, when ZNRF2 is phosphorylated in response to agonists including insulin and growth factors, it binds to 14-3-3 and is released into the cytosol. On membranes, ZNRF1 and ZNRF2 interact with the Na+/K+ATPase a1 subunit via their UBZ domains, while their RING domains interact with E2 proteins, predominantly Ubc13 that, together with Uev1a, mediates formation of Lys63-ubiquitin linkages. ZNRF1 and ZNRF2 can ubiquitylate the cytoplasmic loop encompassing the nucleotide-binding and phosphorylation regions of the Na+/K+ATPase a1 subunit. Ouabain, a Na+/K+ATPase inhibitor and therapeutic cardiac glycoside, decreases ZNRF1 protein levels, whereas knockdown of ZNRF2 inhibits the ouabain-induced decrease of cell surface and total Na+/K+ATPase a1 levels. Thus, ZNRF1 and ZNRF2 are new players in regulation of the ubiquitous Na+/K+ATPase that is tuned to changing demands in many physiological contexts.



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