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Article: Human ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinase
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TitleHuman ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinase
 
AuthorsWu, W1
Dong, MQ1
Wu, XG1
Sun, HY1
Tse, HF1
Lau, CP1
Li, GR1
 
KeywordsEGFR kinase
Ion channel modulation
Protein tyrosine kinase
Protein tyrosine phosphorylation
Signal transduction
 
Issue Date2012
 
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/bbamcr
 
CitationBiochimica Et Biophysica Acta - Molecular Cell Research, 2012, v. 1823 n. 2, p. 282-289 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.bbamcr.2011.10.010
 
AbstractHuman ether á-go-go gene potassium channels (hEAG1 or Kv10.1) are expressed in brain and various human cancers and play a role in neuronal excitement and tumor progression. However, the functional regulation of hEAG channels by signal transduction is not fully understood. The present study was therefore designed to investigate whether hEAG1 channels are regulated by protein tyrosine kinases (PTKs) in HEK 293 cells stably expressing hEAG1 gene using whole-cell patch voltage-clamp, immunoprecipitation, Western blot, and mutagenesis approaches. We found that the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556 (10μM), but not the platelet growth factor receptor (PDGFR) kinase inhibitor AG1295 (10μM) or the Src-family inhibitor PP2 (10μM), can inhibit hEAG1 current, and the inhibitory effect can be reversed by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate. Immunoprecipitation and Western blot analysis revealed that tyrosine phosphorylation level of hEAG1 channels was reduced by AG556, and the reduction was significantly countered by orthovanadate. The hEAG1 mutants Y90A, Y344A and Y485A, but not Y376A and Y479A, exhibited reduced response to AG556. Interestingly, the inhibition effect of AG556 was lost in triple mutant hEAG1 channels at Y90, Y344, and Y485 with alanine. These results demonstrate for the first time that hEAG1 channel activity is regulated by EGFR kinase at the tyrosine residues Tyr 90, Try 344, and Try 485. This effect is likely involved in regulating neuronal activity and/or tumor growth. © 2011 Elsevier B.V.
 
ISSN0167-4889
2013 Impact Factor: 5.297
2013 SCImago Journal Rankings: 2.999
 
DOIhttp://dx.doi.org/10.1016/j.bbamcr.2011.10.010
 
ISI Accession Number IDWOS:000301155700010
Funding AgencyGrant Number
University of Hong Kong201007176213
Sun Chieh Yeh Heart Foundation of Hong Kong
Funding Information:

The study was supported in part by a Small Project Fund (201007176213) of the University of Hong Kong and by Sun Chieh Yeh Heart Foundation of Hong Kong. Wei Wu is supported by a postgraduate studentship from the University of Hong Kong. Ming-Qing Dong is supported by a postdoctoral fellowship of the University of Hong Kong. The authors thank Dr. L Pardo, Max Planck Institute of Experimental Medicine, Gottingen, Germany, for generously providing us with the hEAG1/pTracer CMV plasmid.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorWu, W
 
dc.contributor.authorDong, MQ
 
dc.contributor.authorWu, XG
 
dc.contributor.authorSun, HY
 
dc.contributor.authorTse, HF
 
dc.contributor.authorLau, CP
 
dc.contributor.authorLi, GR
 
dc.date.accessioned2011-11-24T10:04:13Z
 
dc.date.available2011-11-24T10:04:13Z
 
dc.date.issued2012
 
dc.description.abstractHuman ether á-go-go gene potassium channels (hEAG1 or Kv10.1) are expressed in brain and various human cancers and play a role in neuronal excitement and tumor progression. However, the functional regulation of hEAG channels by signal transduction is not fully understood. The present study was therefore designed to investigate whether hEAG1 channels are regulated by protein tyrosine kinases (PTKs) in HEK 293 cells stably expressing hEAG1 gene using whole-cell patch voltage-clamp, immunoprecipitation, Western blot, and mutagenesis approaches. We found that the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556 (10μM), but not the platelet growth factor receptor (PDGFR) kinase inhibitor AG1295 (10μM) or the Src-family inhibitor PP2 (10μM), can inhibit hEAG1 current, and the inhibitory effect can be reversed by the protein tyrosine phosphatase (PTP) inhibitor orthovanadate. Immunoprecipitation and Western blot analysis revealed that tyrosine phosphorylation level of hEAG1 channels was reduced by AG556, and the reduction was significantly countered by orthovanadate. The hEAG1 mutants Y90A, Y344A and Y485A, but not Y376A and Y479A, exhibited reduced response to AG556. Interestingly, the inhibition effect of AG556 was lost in triple mutant hEAG1 channels at Y90, Y344, and Y485 with alanine. These results demonstrate for the first time that hEAG1 channel activity is regulated by EGFR kinase at the tyrosine residues Tyr 90, Try 344, and Try 485. This effect is likely involved in regulating neuronal activity and/or tumor growth. © 2011 Elsevier B.V.
 
dc.description.naturepostprint
 
dc.identifier.citationBiochimica Et Biophysica Acta - Molecular Cell Research, 2012, v. 1823 n. 2, p. 282-289 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.bbamcr.2011.10.010
 
dc.identifier.citeulike9967806
 
dc.identifier.doihttp://dx.doi.org/10.1016/j.bbamcr.2011.10.010
 
dc.identifier.epage289
 
dc.identifier.hkuros197775
 
dc.identifier.hkuros199747
 
dc.identifier.isiWOS:000301155700010
Funding AgencyGrant Number
University of Hong Kong201007176213
Sun Chieh Yeh Heart Foundation of Hong Kong
Funding Information:

The study was supported in part by a Small Project Fund (201007176213) of the University of Hong Kong and by Sun Chieh Yeh Heart Foundation of Hong Kong. Wei Wu is supported by a postgraduate studentship from the University of Hong Kong. Ming-Qing Dong is supported by a postdoctoral fellowship of the University of Hong Kong. The authors thank Dr. L Pardo, Max Planck Institute of Experimental Medicine, Gottingen, Germany, for generously providing us with the hEAG1/pTracer CMV plasmid.

 
dc.identifier.issn0167-4889
2013 Impact Factor: 5.297
2013 SCImago Journal Rankings: 2.999
 
dc.identifier.issue2
 
dc.identifier.openurl
 
dc.identifier.pmid22061963
 
dc.identifier.scopuseid_2-s2.0-84862802638
 
dc.identifier.spage282
 
dc.identifier.urihttp://hdl.handle.net/10722/143374
 
dc.identifier.volume1823
 
dc.languageeng
 
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/bbamcr
 
dc.publisher.placeNetherlands
 
dc.relation.ispartofBiochimica et Biophysica Acta - Molecular Cell Research
 
dc.relation.referencesReferences in Scopus
 
dc.rightsNOTICE: this is the author’s version of a work that was accepted for publication in Biochimica et Biophysica Acta. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochimica et Biophysica Acta, 2012, v. 1823 n. 2, p. 282-289. DOI: 10.1016/j.bbamcr.2011.10.010
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subjectEGFR kinase
 
dc.subjectIon channel modulation
 
dc.subjectProtein tyrosine kinase
 
dc.subjectProtein tyrosine phosphorylation
 
dc.subjectSignal transduction
 
dc.titleHuman ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinase
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine