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

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ZNRF2 is released from membranes by growth factors and with ZNRF1 regulates the Na+/K+ATPase. / Hoxhaj, Gerta; Najafov, Ayaz; Toth, Rachel; Campbell, David G.; Prescott, Alan R.; MacKintosh, Carol.

In: Journal of Cell Science, Vol. 125, No. 19, 01.10.2012, p. 4662-4675.

Research output: Contribution to journalArticle

Harvard

Hoxhaj, G, Najafov, A, Toth, R, Campbell, DG, Prescott, AR & MacKintosh, C 2012, 'ZNRF2 is released from membranes by growth factors and with ZNRF1 regulates the Na+/K+ATPase' Journal of Cell Science, vol 125, no. 19, pp. 4662-4675., 10.1242/jcs.110296

APA

Hoxhaj, G., Najafov, A., Toth, R., Campbell, D. G., Prescott, A. R., & MacKintosh, C. (2012). ZNRF2 is released from membranes by growth factors and with ZNRF1 regulates the Na+/K+ATPase. Journal of Cell Science, 125(19), 4662-4675. 10.1242/jcs.110296

Vancouver

Hoxhaj G, Najafov A, Toth R, Campbell DG, Prescott AR, MacKintosh C. ZNRF2 is released from membranes by growth factors and with ZNRF1 regulates the Na+/K+ATPase. Journal of Cell Science. 2012 Oct 1;125(19):4662-4675. Available from: 10.1242/jcs.110296

Author

Hoxhaj, Gerta; Najafov, Ayaz; Toth, Rachel; Campbell, David G.; Prescott, Alan R.; MacKintosh, Carol / ZNRF2 is released from membranes by growth factors and with ZNRF1 regulates the Na+/K+ATPase.

In: Journal of Cell Science, Vol. 125, No. 19, 01.10.2012, p. 4662-4675.

Research output: Contribution to journalArticle

Bibtex - Download

@article{42cd0294a9644ed384cb44bf987e3692,
title = "ZNRF2 is released from membranes by growth factors and with ZNRF1 regulates the Na+/K+ATPase",
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",
doi = "10.1242/jcs.110296",
volume = "125",
number = "19",
pages = "4662--4675",
journal = "Journal of Cell Science",
issn = "0021-9533",

}

RIS (suitable for import to EndNote) - Download

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 - 14-3-3 Proteins

KW - Amino Acid Sequence

KW - Animals

KW - Carrier Proteins

KW - Cytoplasm

KW - Gene Knockdown Techniques

KW - HEK293 Cells

KW - Humans

KW - Intercellular Signaling Peptides and Proteins

KW - Intracellular Membranes

KW - Isotope Labeling

KW - Mice

KW - Molecular Sequence Data

KW - Mutation

KW - Ouabain

KW - Phosphorylation

KW - Phosphoserine

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - Protein Subunits

KW - Protein Transport

KW - Sodium-Potassium-Exchanging ATPase

KW - Ubiquitin-Conjugating Enzymes

KW - Ubiquitin-Protein Ligases

KW - Ubiquitination

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 -

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