Src-mediated Inter-receptor Cross-talk between the Na+/K+-ATPase and the Epidermal Growth Factor Receptor Relays the Signal from Ouabain to Mitogen-activated Protein Kinases

Haas, Michael; Wang, Haojie; Tian, Jiang; Xie, Zijian

doi:10.1074/jbc.m111357200

Cited by 264 publications

(292 citation statements)

References 24 publications

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“…Previous reports as well as our current study (Figures 2a-c) suggest that the binding of ouabain or TCTP to the Na,K-ATPase a subunit stimulates Src-mediated EGFR phosphorylation, resulting in phosphorylation of other tyrosine residues on EGFR independent of serum (Haas et al, 2002;Kometiani et al, 2005;Kim et al, 2009). Phosphorylation of Tyr992 on EGFR has been reported to result in activation of PLC-g-mediated downstream signaling (Emlet et al, 1997) and phosphorylation of a pair of tyrosines 1148 and 1173, providing a docking site for scaffold proteins such as Shc, involved in the MAP kinase signaling pathway (Zwick et al, 1999).…”

Section: Discussionsupporting

confidence: 80%

“…Also, ouabain-induced activation of EGFR is known to induce different downstream signaling events through binding to adaptor proteins (Haas et al, 2002). Therefore, we investigated whether TCTP-induced EGFR transactivation stimulates downstream signaling pathways different from those induced by ouabain.…”

Section: Tctp-induced Src Activation Mediates Egfr Transactivationmentioning

confidence: 99%

“…Partial inhibition of Na,K-ATPase by ouabain promotes Src kinase binding to Na,K-ATPase, with the formation of a signaling complex and transactivation of anti-epidermal growth factor receptor (EGFR), thereby activating different downstream signaling pathways (Haas et al, 2002;Tian et al, 2006). We previously reported that translationally controlled tumor protein (TCTP) binding to the cytoplasmic domain of Na, K-ATPase a subunit results in the activation of EGFR and its downstream signaling pathways related to cell survival and motility (Jung et al, 2004;Kim et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

et al. 2011

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Translationally controlled tumor protein (TCTP) is implicated in cell growth and malignant transformation. TCTP has been found to interact directly with the third cytoplasmic domain of the a subunit of Na,K-ATPase, but whether this interaction has a role in tumorigenesis is unclear. In this study, we examined TCTP-induced tumor progression signaling networks in human breast epithelial cells, using adenoviral infection. We found that TCTP (a) induces Src release from Na,K-ATPase a subunit and Src activation; (b) phosphorylates tyrosine residues 845, 992, 1086, 1148 and 1173 on anti-epidermal growth factor receptor (EGFR); (c) activates PI3K (phosphatidylinositol 3-kinase )-AKT, Ras-Raf-MEK-ERK1/2, Rac-PAK1/ 2, MKK3/6-p38 and phospholipase C (PLC)-c pathways; (d) enhances NADPH oxidase-dependent reactive oxygen species (ROS) generation; (e) stimulates cytoskeletal remodeling and cell motility and (f) upregulates matrix metalloproteinase (MMP) 3 and 13. These findings suggest that TCTP induces tumorigenesis through distinct multicellular signaling pathways involving Src-dependent EGFR transactivation, ROS generation and MMP expression.

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Section: Discussionsupporting

confidence: 80%

Section: Tctp-induced Src Activation Mediates Egfr Transactivationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

et al. 2011

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“…Western blot analysis showed that ouabain increased the amount of coprecipitated Na/K-ATPase in a time-dependent manner ( Figure 3D). We showed previously that Src activation and recruitment to the signaling Na/K-ATPase is essential for ouabain to evoke downstream cascades (Haas et al, 2002). To address the role of Src in the ouabain-induced recruitment of PLC-␥1, we first probed for Src in the above immunoprecipitates, showing that ouabain stimulated the formation of the Na/KATPase/Src/PLC-␥1 complex ( Figure 3D).…”

Section: Ouabain-activated Na/k-atpase Signaling Complex Can Recruit mentioning

confidence: 94%

“…Recent work from several laboratories indicates that the enzyme also functions as a signaltransducing receptor for both endogenous and exogenous cardiotonic steroids such as ouabain (Kometiani et al, 1998;Xie et al, 1999;Haas et al, 2000Haas et al, , 2002Liu et al, 2000;Aizman et al, 2001;Aydemir-Koksoy et al, 2001;Miyakawa-Naito et al, 2003). First, binding of ouabain to the signaling Na/KATPase activates multiple signaling pathways and regulates transcription and translation of many genes in cardiac myocytes and other cell types.…”

Section: Introductionmentioning

confidence: 99%

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

Yuan

Cai

Tian

et al. 2005

MBoC

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201

209

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We have shown that the caveolar Na/K-ATPase transmits ouabain signals via multiple signalplexes. To obtain the information on the composition of such complexes, we separated the Na/K-ATPase from the outer medulla of rat kidney into two different fractions by detergent treatment and density gradient centrifugation. Analysis of the light fraction indicated that both PLC-␥1 and IP3 receptors (isoforms 2 and 3, IP3R2 and IP3R3) were coenriched with the Na/K-ATPase, caveolin-1 and Src. GST pulldown assays revealed that the central loop of the Na/K-ATPase ␣1 subunit interacts with PLC-␥1, whereas the N-terminus binds IP3R2 and IP3R3, suggesting that the signaling Na/K-ATPase may tether PLC-␥1 and IP3 receptors together to form a Ca 2؉ -regulatory complex. This notion is supported by the following findings.

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Inhibition of epidermal growth factor signaling by the cardiac glycoside ouabain in medulloblastoma

Wolle

Lee

et al. 2014

Cancer Medicine

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Epidermal growth factor (EGF) signaling regulates cell growth, proliferation, and differentiation. Upon receptor binding, EGF triggers cascades of downstream signaling, including the MAPK and phosphoinositide-3-kinase (PI3K)/Akt signaling pathways. Aberrant expression/activation of EGFR is found in multiple human cancers, including medulloblastoma, the most prevalent pediatric brain cancer, and often has been associated with metastasis, poor prognosis, and resistance to chemotherapy. Na,K-ATPase is an ion pump well known for its role in intracellular ion homeostasis. Recent studies showed that Na,K-ATPase also functions as a signaling platform and revealed a role in EGFR, MAPK, and PI3K signaling. While both EGFR and Na,K-ATPase seem to modulate similar signaling pathways, cardiac glycosides that are steroid-like inhibitors of Na,K-ATPase, exhibit antiproliferative and proapoptotic properties in cancer cells. Thus, we sought to better understand the relationship between EGF and cardiac glycoside signaling. Here, we show that in medulloblastoma cells, both EGF and ouabain activate Erk1/2 and PI3K/Akt signaling. Nevertheless, in medulloblastoma cells ouabain did not transactivate EGFR as has been reported in various other cell lines. Indeed, ouabain inhibited EGF-induced Erk1/2 and Akt activation and, moreover, prevented EGF-induced formation of actin stress fibers and cell motility, probably by activating a stress signaling response. Na,K-ATPase has been proposed to act as a signaling scaffold and our studies suggest that in medulloblastoma cells Na,K-ATPase might act as a check point to integrate EGF-associated signaling pathways. Thus, Na,K-ATPase might serve as a valid target to develop novel therapeutic approaches in tumors with aberrant activation of the EGFR signaling cascades.

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Src-mediated Inter-receptor Cross-talk between the Na+/K+-ATPase and the Epidermal Growth Factor Receptor Relays the Signal from Ouabain to Mitogen-activated Protein Kinases

Abstract: Binding of ouabain to Na

Cited by 264 publications

References 24 publications

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

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

Inhibition of epidermal growth factor signaling by the cardiac glycoside ouabain in medulloblastoma

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