Na/K-ATPase Tethers Phospholipase C and IP3 Receptor into a Calcium-regulatory Complex

Yuan, Zhaokan; Cai, Ting; Tian, Jiang; Ivanov, Alexander; Giovannucci, David R.; Xie, Zijian

doi:10.1091/mbc.e05-04-0295

Cited by 201 publications

(218 citation statements)

References 48 publications

(89 reference statements)

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“…These studies demonstrated that ouabain activated Src by stimulating the phosphorylation of Tyr-418 and that the activation of Src was required for ouabaininduced transactivation of EGF receptors and many other protein kinase and lipase cascades (4,8,31). Subsequently, we and others have found that the ␣1 Na/K-ATPase and Src co-localized in the plasma membrane and that they could be coimmunoprecipitated from cell lysates.…”

Section: Discussionmentioning

confidence: 88%

Expression of Mutant α1 Na/K-ATPase Defective in Conformational Transition Attenuates Src-mediated Signal Transduction*

Lai

Banerjee

et al. 2013

Journal of Biological Chemistry

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Background:We propose that Na/K-ATPase regulates Src in an E1/E2 conformation-dependent manner. Results: Expression of ␣1 mutants defective in E1/E2 transition altered both basal and stimuli-induced Src regulation. Conclusion: Na/K-ATPase is necessary for dynamic regulation of Src and Src-mediated pathways. Significance: This is the first demonstration that E1/E2 transition-defective mutants can affect both pumping and signaling functions of Na/K-ATPase.

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Section: Discussionmentioning

confidence: 88%

Expression of Mutant α1 Na/K-ATPase Defective in Conformational Transition Attenuates Src-mediated Signal Transduction*

Lai

Banerjee

et al. 2013

Journal of Biological Chemistry

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“…Previous reports indicate that Na,K-ATPase signal transduction stimulates proliferation in smooth muscle cells (11) and apoptosis in prostate cancer cells (12). Ouabain, an endogenously synthesized hormone (13,14), is Na,K-ATPase's ligand and forms a hormone-receptor complex capable of inducing mitogen-activated protein (MAP) kinase phosphorylation (15,16) and intracellular Ca 2ϩ signaling (17)(18)(19).…”

mentioning

confidence: 99%

Na,K-ATPase signal transduction triggers CREB activation and dendritic growth

Desfrère¹,

Karlsson²,

Hiyoshi³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic growth is pivotal in the neurogenesis of cortical neurons. The sodium pump, or Na,K-ATPase, is an evolutionarily conserved protein that, in addition to its central role in establishing the electrochemical gradient, has recently been reported to function as a receptor and signaling mediator. Although a large body of evidence points toward a dual function for the Na,K-ATPase, few biological implications of this signaling pathway have been described. Here we report that Na,K-ATPase signal transduction triggers dendritic growth as well as a transcriptional program dependent on cAMP response element binding protein (CREB) and cAMP response element (CRE)-mediated gene expression, primarily regulated via Ca 2+ /calmodulin-dependent protein (CaM) kinases. The signaling cascade mediating dendritic arbor growth also involves intracellular Ca 2+ oscillations and sustained phosphorylation of mitogen-activated protein (MAP) kinases. Thus, our results suggest a novel role for the Na,K-ATPase as a modulator of dendritic growth in developing neurons.

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“…Studies from many laboratories have now established that the binding of ouabain to this enzyme not only inhibits the ATPase activity but also stimulates protein tyrosine kinases such as Src (4,5). The activated Src in turn transactivates epidermal growth factor receptor, resulting in the assembly and activation of multiple signaling cascades such as the ERK1/2 2 and phospholipase C-␥/ protein kinase C pathways (5,6).…”

mentioning

confidence: 99%

Functional Characterization of Src-interacting Na/K-ATPase Using RNA Interference Assay

Liang

Cai

Tian

et al. 2006

Journal of Biological Chemistry

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149

228

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We have shown that the Na/K-ATPase and Src form a signaling receptor complex. Here we determined how alterations in the amount and properties of the Na/K-ATPase affect basal Src activity and ouabain-induced signal transduction. Several ␣1 subunit knockdown cell lines were generated by transfecting LLC-PK1 cells with a vector expressing ␣1-specific small interference RNA. Although the ␣1 knockdown resulted in significant decreases in Na/K-ATPase activity, it increased the basal Src activity and tyrosine phosphorylation of focal adhesion kinase, a Src effector. Concomitantly it also abolished ouabaininduced activation of Src and ERK1/2. When the knockdown cells were rescued by a rat ␣1, both Na/K-ATPase activity and the basal Src activity were restored. In addition, ouabain was able to stimulate Src and ERK1/2 in the rescued cells at a much higher concentration, consistent with the established differences in ouabain sensitivity between pig and rat ␣1. Finally both fluorescence resonance energy transfer analysis and co-immunoprecipitation assay indicated that the pumping-null rat ␣1 (D371E) mutant could also bind Src. Expression of this mutant restored the basal Src activity and focal adhesion kinase tyrosine phosphorylation. Taken together, the new findings suggest that LLC-PK1 cells contain a pool of Src-interacting Na/K-ATPase that not only regulates Src activity but also serves as a receptor for ouabain to activate protein kinases. Na/K-ATPase was discovered by Skou (1) as the molecular machinery of the cellular sodium pump. It belongs to a family of evolutionarily ancient ATPases that couple the hydrolysis of ATP to membrane ion translocation (2, 3). A major difference between the Na/K-ATPase and other ATPases is its ability to bind cardiotonic steroids such as ouabain. Studies from many laboratories have now established that the binding of ouabain to this enzyme not only inhibits the ATPase activity but also stimulates protein tyrosine kinases such as Src (4, 5). The activated Src in turn transactivates epidermal growth factor receptor, resulting in the assembly and activation of multiple signaling cascades such as the ERK1/2 2 and phospholipase C-␥/ protein kinase C pathways (5, 6).Because several laboratories have demonstrated that the activation of Src is essential for ouabain-induced changes in many cellular activities including the regulation of intracellular calcium, gene expression, and cell growth (6 -9), we have recently examined whether the Na/K-ATPase interacts directly with Src to form a functional signaling receptor (10). Using in vitro glutathione S-transferase pulldown assays we have identified that the second and the third intracellular domains of the Na/K-ATPase ␣1 subunit interact with the Src SH2 and the kinase domains, respectively. Functionally these interactions keep Src in an inactive state, and binding of ouabain to this inactive Na/K-ATPase⅐Src complex frees and then activates the associated Src (10). These new findings suggest that the cellular Src-interacting Na/K-ATPase may play an...

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Na/K-ATPase Tethers Phospholipase C and IP3 Receptor into a Calcium-regulatory Complex

Cited by 201 publications

References 48 publications

Expression of Mutant α1 Na/K-ATPase Defective in Conformational Transition Attenuates Src-mediated Signal Transduction*

Expression of Mutant α1 Na/K-ATPase Defective in Conformational Transition Attenuates Src-mediated Signal Transduction*

Na,K-ATPase signal transduction triggers CREB activation and dendritic growth

Functional Characterization of Src-interacting Na/K-ATPase Using RNA Interference Assay

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