Role of Insulin in Regulation of Na<sup>+</sup>-/K<sup>+</sup>-Dependent ATPase Activity and Pump Function in Corneal Endothelial Cells

Hatou, Shin; Yamada, Masakazu; Akune, Yoko; Mochizuki, Hidetaka; Shiraishi, Atsushi; Joko, Takeshi; Nishida, Teruo; Tsubota, Kazuo

doi:10.1167/iovs.09-4027

Cited by 40 publications

(32 citation statements)

References 55 publications

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“…The pump is also regulated acutely; for example the skeletal muscle Na + /K + ATPase activity is enhanced by insulin to clear blood K + after a meal, and by adrenaline and contraction to prevent fatigue (Ewart and Klip, 1995;Hatou et al, 2010). Demands for the Na + / K + ATPase also change markedly during nerve excitation, renal blood filtration and breathing, and Na + /K + ATPases are highly regulated in context-dependent ways by adrenaline, dopamine, thyroid hormone, aldosterone, catecholamines and insulin (reviewed by Comellas et al, 2010;Ewart and Klip, 1995).…”

Section: Discussionmentioning

confidence: 99%

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

Hoxhaj

Najafov

Toth

et al. 2012

Journal of Cell Science

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SummaryHere, 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.

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Section: Discussionmentioning

confidence: 99%

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

Hoxhaj

Najafov

Toth

et al. 2012

Journal of Cell Science

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“…During an effective decellularization process the endothelium of the cornea is completely removed. The corneal endothelium is essential for maintaining human vision by regulating the hydration state of the stroma by way of Na+/K+- ATPase pump functioning (46)(47)(48). Once the cornea is denuded of the endothelium it undergoes extensive swelling (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Dextran Preserves Native Corneal Structure During Decellularization

Lynch

Wilson

Ahearne

2016

Tissue Engineering Part C: Methods

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“…Because some agents produce multiple changes in ␣1 subunit phosphorylation, in some cases, it can be difficult to conclude that specific phosphorylation sites are causal for changes in Na,K-ATPase activity. The PKC inhibitor GF109203X blocked insulin-promoted increases in Na,K-ATPase activity and decreases in Ser 23 ␣1 subunit phosphorylation in mouse corneal endothelial cells (40). These observations led investigators to suggest that the insulin receptor tyrosine kinase promoted a PKCmediated activation of Ser/Thr phosphatase, although contributions from tyrosine phosphorylation were not assessed in these studies.…”

Section: Sequencementioning

confidence: 98%

Regulation and Identification of Na,K-ATPase α1 Subunit Phosphorylation in Rat Parotid Acinar Cells

Soltoff

Asara

Hedden

2010

Journal of Biological Chemistry

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The stimulation of fluid and electrolyte secretion in salivary cells results in ionic changes that promote rapid increases in the activity of the Na,K-ATPase. In many cell systems, there are conflicting findings concerning the regulation of the phosphorylation of the Na,K-ATPase ␣ subunit, which is the catalytic moiety. Initially, we investigated the phosphorylation sites on the ␣1 subunit in native rat parotid acinar cells using tandem mass spectrometry and identified The Na,K-ATPase, or sodium pump, is an important ion transport protein that maintains the electrochemical gradient across the plasma membrane of eukaryotic cells. It is an integral plasma membrane protein that transports three Na ϩ ions for every two K ϩ ions, an event that consumes one molecule of ATP. As such, it participates in fluid and electrolyte secretion and cell volume regulation and is part of a network of ion transporters that regulate cellular ionic changes during basal, stimulated, and pathological conditions. The basic functional unit of the Na,K-ATPase protein consists of an ␣ subunit responsible for the catalytic activity, a glycosylated ␤ subunit, and in some cells, an FXYD protein. There are multiple isoforms of ␣ and ␤ subunits (1) and different FXYD proteins (2).Although it has been known for decades that the Na,KATPase activity is regulated by the intracellular and extracellular ionic composition, regulation can also occur by the phosphorylation of the ␣ subunit by various kinases (for review, see Ref.3). The ␤ subunit and FXYD proteins may also play regulatory roles under some conditions. Various studies demonstrated that Ser 943 , a site on the ␣ subunit C terminus, was a target for PKA phosphorylation, and Ser 16 and Ser 23 on the N terminus were identified as PKC phosphorylation sites (4 -7). In addition to contrasting results obtained from different species and differences between in vitro and intact cells (below), investigators have used different numbering of the ␣ subunit amino acids because the first five are cleaved during biosynthesis and production of the mature protein. There are conflicting studies concerning the effects of different kinases on the ␣ subunit phosphorylation and Na,KATPase activity. The phosphorylation of the ␣ subunit by PKC on Ser 23 and unspecified sites stimulated the Na,K-ATPase activity in intact cells (9, 10), in some cases due to its enhanced insertion into the plasma membrane (11). Alternatively, the PKC-mediated phosphorylation of ␣ produced a reduction in Na,K-ATPase activity due to its endocytosis and internalization (12)(13)(14). In some studies, the ␣ subunit was preferentially phosphorylated by members of the classical PKC family (cPKC: 2 ␣, ␤, ␥) when compared with novel PKC family members (nPKC: ␦, ⑀, ) (11, 15). However, both cPKC (PKC␤I) and nPKC (PKC␦) proteins were reported to regulate ␣ subunit phosphorylation (16), and PKC, an atypical PKC family member, also phosphorylated the ␣ subunit on Ser 23 (13). In addition to PKC, other kinases were reported to phosphorylate the ␣ s...

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Role of Insulin in Regulation of Na⁺-/K⁺-Dependent ATPase Activity and Pump Function in Corneal Endothelial Cells

Cited by 40 publications

References 55 publications

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

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

Dextran Preserves Native Corneal Structure During Decellularization

Regulation and Identification of Na,K-ATPase α1 Subunit Phosphorylation in Rat Parotid Acinar Cells

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Role of Insulin in Regulation of Na+-/K+-Dependent ATPase Activity and Pump Function in Corneal Endothelial Cells

Cited by 40 publications

References 55 publications

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

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

Dextran Preserves Native Corneal Structure During Decellularization

Regulation and Identification of Na,K-ATPase α1 Subunit Phosphorylation in Rat Parotid Acinar Cells

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Role of Insulin in Regulation of Na⁺-/K⁺-Dependent ATPase Activity and Pump Function in Corneal Endothelial Cells