Is Phosphorylation of the α1 Subunit at Ser-16 Involved in the Control of Na,K-ATPase Activity by Phorbol Ester–activated Protein Kinase C?

Féraille, Eric; Béguin, Pascal; Carranza, M. L.; Gonin, Sandrine; Rousselot, M; Martin, Pierre‐Yves; Favre, H; Geering, Käthi

doi:10.1091/mbc.11.1.39

Cited by 27 publications

(16 citation statements)

References 48 publications

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“…Tyrosine phosphorylation of Na ϩ ,K ϩ -ATPase ␣ 1 -and ␣ 2 -subunits in response to insulin by an unidentified kinase has been previously reported (47,48). Src phosphorylates the Na (40,49).…”

Section: Discussionmentioning

confidence: 93%

Cardiotonic Steroids Stimulate Glycogen Synthesis in Human Skeletal Muscle Cells via a Src- and ERK1/2-dependent Mechanism

Kotova

Al-Khalili

Talia

et al. 2006

Journal of Biological Chemistry

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The cardiotonic steroid, ouabain, a specific inhibitor of Na ؉ ,K ؉ -ATPase, initiates protein-protein interactions that lead to an increase in growth and proliferation in different cell types. We explored the effects of ouabain on glucose metabolism in human skeletal muscle cells (HSMC) and clarified the mechanisms of ouabain signal transduction. In HSMC, ouabain increased glycogen synthesis in a concentration-dependent manner reaching the maximum at 100 nM. The effect of ouabain was additive to the effect of insulin and was independent of phosphatidylinositol 3-kinase inhibitor LY294002 but was abolished in the presence of a MEK1/2 inhibitor (PD98059) or a Src inhibitor (PP2). Ouabain increased Src-dependent tyrosine phosphorylation of ␣ 1 -and ␣ 2 -subunits of Na ؉ ,K ؉ -ATPase and promoted interaction of ␣ 1 -and ␣ 2 -subunits with Src, as assessed by co-immunoprecipitation with Src. Phosphorylation of ERK1/2 and GSK3␣/␤, as well as p90rsk activity, was increased in response to ouabain in HSMC, and these responses were prevented in the presence of PD98059 and PP2. Incubation of HSMC with 100 nM ouabain increased phosphorylation of the ␣-subunits of the Na-pump at a MAPK-specific Thr-Pro motif. Ouabain treatment decreased the surface abundance of ␣ 2 -subunit, whereas abundance of the ␣ 1 -subunit was unchanged. Marinobufagenin, an endogenous vertebrate bufadienolide cardiotonic steroid, increased glycogen synthesis in HSMC at 10 nM concentration, similarly to 100 nM ouabain. In conclusion, ouabain and marinobufagenin stimulate glycogen synthesis in skeletal muscle. This effect is mediated by activation of a Src-, ERK1/2-, p90rsk-, and GSK3-dependent signaling pathway.

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Section: Discussionmentioning

confidence: 93%

Cardiotonic Steroids Stimulate Glycogen Synthesis in Human Skeletal Muscle Cells via a Src- and ERK1/2-dependent Mechanism

Kotova

Al-Khalili

Talia

et al. 2006

Journal of Biological Chemistry

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“…Previous studies on PKCdependent modulation of ionic channels indicate that PKC modulates channel activity not only by the modulation of the intrinsic channel properties but also by the regulation of receptor/channel trafficking. Modulation of intrinsic channel properties by PKC involves usually direct phosphorylation of the channel protein (38,39). On the other hand, PKC-dependent regulation of channel trafficking involves diverse mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C-dependent Enhancement of Activity of Rat Brain NCKX2 Heterologously Expressed in HEK293 Cells

Lee

Visser

Lee

et al. 2006

Journal of Biological Chemistry

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Different members of the Na؉ /Ca 2؉ ؉K ؉ exchanger (NCKX) family are present in distinct brain regions, suggesting that they may have cell-specific functions. Many neuronal channels and transporters are regulated via phosphorylation. Regulation of the rat brain NCKXs by protein kinases, however, has not been described. Here, we report an increase in NCKX2 activity in response to protein kinase C (PKC) activation. Outward current of NCKX2 heterologously expressed in HEK293 cells was enhanced by ␤-phorbol dibutyrate (PDBu), whereas PDBu had little effect on activity of NCKX3 or NCKX4. The PDBu-induced enhancement (PIE) of NCKX2 activity was abolished by PKC inhibitors and significantly reduced when the dominant negative mutant of PKC⑀ (K437R) was overexpressed. Moreover, PDBu accelerated the decay rate of the Ca 2؉ transient at the calyx of Held, where NCKX is the major Ca 2؉ -clearance mechanism. Intracellular perfusion with alkaline phosphatase completely inhibited PIE. Consistently, ␤-phorbol myristate acetate (PMA), but not 4␣-PMA, induced a 3-fold stimulation of 32 P incorporation into NCKX2 expressed in HEK293 cells. To investigate the sites involved, PIE of wild-type NCKX2 was compared with mutant NCKX2 in which the three putative PKC consensus sites were replaced with alanine, either individually or in combination. Double-site mutation involving Thr-476 (T166A/ T476A and T476A/S504A) disrupted PIE, whereas single mutation of Thr-166, Thr-476, or Ser-504 or the double mutant T166A/S504A failed to completely prevent PIE. These findings suggest that PKC-mediated activation of NCKX2 is sensitive to mutation of multiple PKC consensus sites via a mechanism that may involve several phosphorylation events.

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“…Movement of the Na,K-ATPase between the plasma membrane and intracellular compartments have either required kinase activation (Chibalin et al, 1998 or not (Beron et al, 1997;Feraille et al, 2000). In renal epithelia, stimulation of Na,K-ATPase activity due to an increase in the amount of molecules present at the plasma membrane has been reported to be the consequence of activating PKC-␤, whereas DA inhibited Na,K-ATPase activity by activating PKC- (Efendiev et al, 1999(Efendiev et al, , 2000 or PKA (Carranza et al, 1996).…”

Section: Nak-atpase and Protein Kinase Cmentioning

confidence: 99%

Dopamine-induced Exocytosis of Na,K-ATPase Is Dependent on Activation of Protein Kinase C-ε and -δ

Ridge

Dada

Lecuona

et al. 2002

MBoC

101

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The purpose of this study was to define mechanisms by which dopamine (DA) regulates the Na,K-ATPase in alveolar epithelial type 2 (AT2) cells. The Na,K-ATPase activity increased by twofold in cells incubated with either 1 microM DA or a dopaminergic D(1) agonist, fenoldopam, but not with the dopaminergic D(2) agonist quinpirole. The increase in activity paralleled an increase in Na,K-ATPase alpha1 and beta1 protein abundance in the basolateral membrane (BLM) of AT2 cells. This increase in protein abundance was mediated by the exocytosis of Na,K-pumps from late endosomal compartments into the BLM. Down-regulation of diacylglycerol-sensitive types of protein kinase C (PKC) by pretreatment with phorbol 12-myristate 13-acetate or inhibition with bisindolylmaleimide prevented the DA-mediated increase in Na,K-ATPase activity and exocytosis of Na,K-pumps to the BLM. Preincubation of AT2 cells with either 2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl)maleimide (Gö6983), a selective inhibitor of PKC-delta, or isozyme-specific inhibitor peptides for PKC-delta or PKC-epsilon inhibited the DA-mediated increase in Na,K-ATPase. PKC-delta and PKC-epsilon, but not PKC-alpha or -beta, translocated from the cytosol to the membrane fraction after exposure to DA. PKC-delta- and PKC-epsilon-specific peptide agonists increased Na,K-ATPase protein abundance in the BLM. Accordingly, dopamine increased Na,K-ATPase activity in alveolar epithelial cells through the exocytosis of Na,K-pumps from late endosomes into the basolateral membrane in a mechanism-dependent activation of the novel protein kinase C isozymes PKC-delta and PKC-epsilon.

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Is Phosphorylation of the α1 Subunit at Ser-16 Involved in the Control of Na,K-ATPase Activity by Phorbol Ester–activated Protein Kinase C?

Cited by 27 publications

References 48 publications

Cardiotonic Steroids Stimulate Glycogen Synthesis in Human Skeletal Muscle Cells via a Src- and ERK1/2-dependent Mechanism

Cardiotonic Steroids Stimulate Glycogen Synthesis in Human Skeletal Muscle Cells via a Src- and ERK1/2-dependent Mechanism

Protein Kinase C-dependent Enhancement of Activity of Rat Brain NCKX2 Heterologously Expressed in HEK293 Cells

Dopamine-induced Exocytosis of Na,K-ATPase Is Dependent on Activation of Protein Kinase C-ε and -δ

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