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Article: Human ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinase

TitleHuman ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinase
Authors
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
Citation
Biochimica Et Biophysica Acta - Molecular Cell Research, 2012, v. 1823 n. 2, p. 282-289 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/143374
ISSN
2014 Impact Factor: 5.019
2013 SCImago Journal Rankings: 2.999
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorWu, Wen_HK
dc.contributor.authorDong, MQen_HK
dc.contributor.authorWu, XGen_HK
dc.contributor.authorSun, HYen_HK
dc.contributor.authorTse, HFen_HK
dc.contributor.authorLau, CPen_HK
dc.contributor.authorLi, GRen_HK
dc.date.accessioned2011-11-24T10:04:13Z-
dc.date.available2011-11-24T10:04:13Z-
dc.date.issued2012en_HK
dc.identifier.citationBiochimica Et Biophysica Acta - Molecular Cell Research, 2012, v. 1823 n. 2, p. 282-289en_HK
dc.identifier.issn0167-4889en_HK
dc.identifier.urihttp://hdl.handle.net/10722/143374-
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.en_HK
dc.languageengen_US
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/bbamcren_HK
dc.relation.ispartofBiochimica et Biophysica Acta - Molecular Cell Researchen_HK
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 kinaseen_HK
dc.subjectIon channel modulationen_HK
dc.subjectProtein tyrosine kinaseen_HK
dc.subjectProtein tyrosine phosphorylationen_HK
dc.subjectSignal transductionen_HK
dc.titleHuman ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinaseen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0006-3002&volume=&spage=&epage=&date=2011&atitle=Human+ether-à-go-go+gene+potassium+channels+are+regulated+by+EGFR+tyrosine+kinaseen_US
dc.identifier.emailLi, GR:grli@hkucc.hku.hken_HK
dc.identifier.authorityLi, GR=rp00476en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1016/j.bbamcr.2011.10.010en_HK
dc.identifier.pmid22061963en_HK
dc.identifier.scopuseid_2-s2.0-84862802638en_HK
dc.identifier.hkuros197775en_US
dc.identifier.hkuros199747-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84862802638&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume1823en_HK
dc.identifier.issue2en_HK
dc.identifier.spage282en_HK
dc.identifier.epage289en_HK
dc.identifier.isiWOS:000301155700010-
dc.publisher.placeNetherlandsen_HK
dc.identifier.scopusauthoridWu, W=43161580300en_HK
dc.identifier.scopusauthoridDong, MQ=7202127303en_HK
dc.identifier.scopusauthoridWu, XG=55261110800en_HK
dc.identifier.scopusauthoridSun, HY=35723049200en_HK
dc.identifier.scopusauthoridTse, HF=54886126900en_HK
dc.identifier.scopusauthoridLau, CP=35275317200en_HK
dc.identifier.scopusauthoridLi, GR=7408462932en_HK
dc.identifier.citeulike9967806-

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