| First Author | Hoxhaj G | Year | 2012 |
| Journal | J Cell Sci | Volume | 125 |
| Issue | Pt 19 | Pages | 4662-75 |
| PubMed ID | 22797923 | Mgi Jnum | J:199676 |
| Mgi Id | MGI:5504338 | Doi | 10.1242/jcs.110296 |
| Citation | Hoxhaj G, et al. (2012) ZNRF2 is released from membranes by growth factors and, together with ZNRF1, regulates the Na+/K+ATPase. J Cell Sci 125(Pt 19):4662-75 |
| abstractText | 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 alpha1 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 alpha1 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 alpha1 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. |
