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The inositol pyrophosphate 5-InsP7 drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α.
Chin, Alfred C; Gao, Zhe; Riley, Andrew M; Furkert, David; Wittwer, Christopher; Dutta, Amit; Rojas, Tomas; Semenza, Evan R; Felder, Robin A; Pluznick, Jennifer L; Jessen, Henning J; Fiedler, Dorothea; Potter, Barry V L; Snyder, Solomon H; Fu, Chenglai.
Afiliación
  • Chin AC; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Gao Z; Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
  • Riley AM; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China.
  • Furkert D; Medicinal Chemistry and Drug Discovery, Department of Pharmacology, University of Oxford, Oxford, UK.
  • Wittwer C; Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
  • Dutta A; Institute of Organic Chemistry and CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany.
  • Rojas T; Institute of Organic Chemistry and CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany.
  • Semenza ER; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Felder RA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Pluznick JL; Department of Pathology, University of Virginia, Charlottesville, VA, USA.
  • Jessen HJ; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Fiedler D; Institute of Organic Chemistry and CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany.
  • Potter BVL; Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
  • Snyder SH; Medicinal Chemistry and Drug Discovery, Department of Pharmacology, University of Oxford, Oxford, UK.
  • Fu C; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ssnyder@jhmi.edu chenglaifu@tmu.edu.cn.
Sci Adv ; 6(44)2020 10.
Article en En | MEDLINE | ID: mdl-33115740
ABSTRACT
Sodium/potassium-transporting adenosine triphosphatase (Na+/K+-ATPase) is one of the most abundant cell membrane proteins and is essential for eukaryotes. Endogenous negative regulators have long been postulated to play an important role in regulating the activity and stability of Na+/K+-ATPase, but characterization of these regulators has been elusive. Mechanisms of regulating Na+/K+-ATPase homeostatic turnover are unknown. Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7), generated by inositol hexakisphosphate kinase 1 (IP6K1), promotes physiological endocytosis and downstream degradation of Na+/K+-ATPase-α1. Deletion of IP6K1 elicits a twofold enrichment of Na+/K+-ATPase-α1 in plasma membranes of multiple tissues and cell types. Using a suite of synthetic chemical biology tools, we found that 5-InsP7 binds the RhoGAP domain of phosphatidylinositol 3-kinase (PI3K) p85α to disinhibit its interaction with Na+/K+-ATPase-α1. This recruits adaptor protein 2 (AP2) and triggers the clathrin-mediated endocytosis of Na+/K+-ATPase-α1. Our study identifies 5-InsP7 as an endogenous negative regulator of Na+/K+-ATPase-α1.
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Texto completo: 1 Colección: 01-internacional Idioma: En Revista: Sci Adv Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Idioma: En Revista: Sci Adv Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos