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J Cell Sci. 2012 Oct 1;125(Pt 19):4662-75. doi: 10.1242/jcs.110296. Epub 2012 Jul 13.

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

Author information

1
MRC Protein Phosphorylation Unit, James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. g.hoxhaj@dundee.ac.uk

Abstract

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 α1 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 α1 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 α1 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.

PMID:
22797923
PMCID:
PMC3500867
DOI:
10.1242/jcs.110296
[Indexed for MEDLINE]
Free PMC Article

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