TY  - JOUR
T1  - ZNRF2 is released from membranes by growth factors and with ZNRF1 regulates the Na+/K+ATPase
A1  - Hoxhaj,Gerta
A1  - Najafov,Ayaz
A1  - Toth,Rachel
A1  - Campbell,David G.
A1  - Prescott,Alan R.
A1  - MacKintosh,Carol
AU  - Hoxhaj,Gerta
AU  - Najafov,Ayaz
AU  - Toth,Rachel
AU  - Campbell,David G.
AU  - Prescott,Alan R.
AU  - MacKintosh,Carol
PY  - 2012/10/1
Y1  - 2012/10/1
N2  - 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. <br/><br/>
AB  - 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. <br/><br/>
KW  - Myristoyl switch
KW  - Protein trafficking
KW  - Ubiquitylation
KW  - Na+/K+ATPase
KW  - Na+ pump
KW  - Sodium pump
U2  - 10.1242/jcs.110296
DO  - 10.1242/jcs.110296
M1  - Article
JO  - Journal of Cell Science
JF  - Journal of Cell Science
SN  - 0021-9533
IS  - 19
VL  - 125
SP  - 4662
EP  - 4675
ER  -