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Article: Human ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinase
Title | Human ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinase | ||||||
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Authors | |||||||
Keywords | EGFR kinase Ion channel modulation Protein tyrosine kinase Protein tyrosine phosphorylation Signal transduction | ||||||
Issue Date | 2012 | ||||||
Publisher | Elsevier 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? | ||||||
Abstract | Human 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 Identifier | http://hdl.handle.net/10722/143374 | ||||||
ISSN | 2023 Impact Factor: 4.6 2023 SCImago Journal Rankings: 1.500 | ||||||
ISI Accession Number ID |
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 | |||||||
Grants |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Wu, W | en_HK |
dc.contributor.author | Dong, MQ | en_HK |
dc.contributor.author | Wu, XG | en_HK |
dc.contributor.author | Sun, HY | en_HK |
dc.contributor.author | Tse, HF | en_HK |
dc.contributor.author | Lau, CP | en_HK |
dc.contributor.author | Li, GR | en_HK |
dc.date.accessioned | 2011-11-24T10:04:13Z | - |
dc.date.available | 2011-11-24T10:04:13Z | - |
dc.date.issued | 2012 | en_HK |
dc.identifier.citation | Biochimica Et Biophysica Acta - Molecular Cell Research, 2012, v. 1823 n. 2, p. 282-289 | en_HK |
dc.identifier.issn | 0167-4889 | en_HK |
dc.identifier.uri | http://hdl.handle.net/10722/143374 | - |
dc.description.abstract | Human 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.language | eng | en_US |
dc.publisher | Elsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/bbamcr | en_HK |
dc.relation.ispartof | Biochimica et Biophysica Acta - Molecular Cell Research | en_HK |
dc.rights | NOTICE: 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.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | EGFR kinase | en_HK |
dc.subject | Ion channel modulation | en_HK |
dc.subject | Protein tyrosine kinase | en_HK |
dc.subject | Protein tyrosine phosphorylation | en_HK |
dc.subject | Signal transduction | en_HK |
dc.title | Human ether-à-go-go gene potassium channels are regulated by EGFR tyrosine kinase | en_HK |
dc.type | Article | en_HK |
dc.identifier.openurl | http://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+kinase | en_US |
dc.identifier.email | Li, GR:grli@hkucc.hku.hk | en_HK |
dc.identifier.authority | Li, GR=rp00476 | en_HK |
dc.description.nature | postprint | - |
dc.identifier.doi | 10.1016/j.bbamcr.2011.10.010 | en_HK |
dc.identifier.pmid | 22061963 | - |
dc.identifier.scopus | eid_2-s2.0-84862802638 | en_HK |
dc.identifier.hkuros | 197775 | en_US |
dc.identifier.hkuros | 199747 | - |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-84862802638&selection=ref&src=s&origin=recordpage | en_HK |
dc.identifier.volume | 1823 | en_HK |
dc.identifier.issue | 2 | en_HK |
dc.identifier.spage | 282 | en_HK |
dc.identifier.epage | 289 | en_HK |
dc.identifier.isi | WOS:000301155700010 | - |
dc.publisher.place | Netherlands | en_HK |
dc.relation.project | Regulation of human ether-à-go-go gene K+ channels by EGFR kinase | - |
dc.identifier.scopusauthorid | Wu, W=43161580300 | en_HK |
dc.identifier.scopusauthorid | Dong, MQ=7202127303 | en_HK |
dc.identifier.scopusauthorid | Wu, XG=55261110800 | en_HK |
dc.identifier.scopusauthorid | Sun, HY=35723049200 | en_HK |
dc.identifier.scopusauthorid | Tse, HF=54886126900 | en_HK |
dc.identifier.scopusauthorid | Lau, CP=35275317200 | en_HK |
dc.identifier.scopusauthorid | Li, GR=7408462932 | en_HK |
dc.identifier.citeulike | 9967806 | - |
dc.identifier.issnl | 0167-4889 | - |