@article{42cd0294a9644ed384cb44bf987e3692,
title = "ZNRF2 is released from membranes by growth factors and with ZNRF1 regulates the Na+/K+ATPase",
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 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. ",
keywords = "14-3-3 Proteins, Amino Acid Sequence, Animals, Carrier Proteins, Cytoplasm, Gene Knockdown Techniques, HEK293 Cells, Humans, Intercellular Signaling Peptides and Proteins, Intracellular Membranes, Isotope Labeling, Mice, Molecular Sequence Data, Mutation, Ouabain, Phosphorylation, Phosphoserine, Protein Binding, Protein Structure, Tertiary, Protein Subunits, Protein Transport, Sodium-Potassium-Exchanging ATPase, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination",
author = "Gerta Hoxhaj and Ayaz Najafov and Rachel Toth and Campbell, {David G.} and Prescott, {Alan R.} and Carol MacKintosh",
year = "2012",
month = oct,
day = "1",
doi = "10.1242/jcs.110296",
language = "English",
volume = "125",
pages = "4662--4675",
journal = "Journal of Cell Science",
issn = "0021-9533",
publisher = "Company of Biologists Ltd",
number = "19",
}