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Article: Inhibition of protein kinase CK2 closes the CFTR Cl channel, but has no effect on the cystic fibrosis mutant Δf508-CFTR

TitleInhibition of protein kinase CK2 closes the CFTR Cl channel, but has no effect on the cystic fibrosis mutant Δf508-CFTR
Authors
KeywordsATP-binding cassette transporter
CFTR
Channel regulation
Chloride ion channel
Cystic fibrosis
Protein kinase CK2
Issue Date2009
PublisherS Karger AG. The Journal's web site is located at http://www.karger.com/CPB
Citation
Cellular Physiology And Biochemistry, 2009, v. 24 n. 5-6, p. 347-360 How to Cite?
AbstractBackground: Deletion of phenylalanine-508 (ΔF508) from the first nucleotide-binding domain (NBD1) in the wild-type cystic fibrosis (CF) transmembrane-conductance regulator (wtCFTR) causes CF. However, the mechanistic relationship between ΔF508-CFTR and the diversity of CF disease is unexplained. The surface location of F508 on NBD1 creates the potential for protein-protein interactions and nearby, lies a consensus sequence (SYDE) reported to control the pleiotropic protein kinase CK2. Methods: Electrophysiology, immunofluorescence and biochemistry applied to CFTR-expressing cells, Xenopus oocytes, pancreatic ducts and patient biopsies. Results: Irrespective of PKA activation, CK2 inhibition (ducts, oocytes, cells) attenuates CFTR-dependent Cl- transport, closing wtCFTR in cell-attached membrane patches. CK2 and wtCFTR co-precipitate and CK2 co-localized with wtCFTR (but not ΔF508-CFTR) in apical membranes of human airway biopsies. Comparing wild-type and ΔF508CFTR expressing oocytes, only ΔF508-CFTR Cl- currents were insensitive to two CK2 inhibitors. Furthermore, wtCFTR was inhibited by injecting a peptide mimicking the F508 region, whereas the ΔF508-equivalent peptide had no effect. Conclusions: CK2 controls wtCFTR, but not ΔF508-CFTR. Others find that peptides from the F508 region of NBD1 allosterically control CK2, acting through F508. Hence, disruption of CK2-CFTR interaction by ΔF508-CFTR might disrupt multiple, membrane-associated, CK2-dependent pathways, creating a new molecular disease paradigm for deleted F508 in CFTR. Copyright © 2009 S. Karger AG, Basel.
Persistent Identifierhttp://hdl.handle.net/10722/137015
ISSN
2015 Impact Factor: 4.652
2015 SCImago Journal Rankings: 1.139
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
DFGSFB A6
Wellcome Trust069150/z/02/z
Cystic Fibrosis Trust
Russell Trust
University of Bristol
ORS award
OTKAK060242
Funding Information:

We thank L. A. Pinna, D. Litchfield, A. C. Boyd, W. Skach, J. R. Riordan, C. R. O'Riordan and M. D. Amaral for gifts of reagents, vectors, antibodies and cells. We thank our laboratory colleagues, especially Z. Cai for advice and assistance and R. E. Olver and D. Meek for critical review. Supported by DFG SFB A6 to DFG SFB699 A6/A7, the Wellcome Trust (069150/z/02/z), Cystic Fibrosis Trust and Russell Trust. ZX was supported by the University of Bristol and an ORS award. PH was supported by OTKA (K060242).

References

 

DC FieldValueLanguage
dc.contributor.authorTreharne, KJen_HK
dc.contributor.authorXu, Zen_HK
dc.contributor.authorChen, JHen_HK
dc.contributor.authorBest, OGen_HK
dc.contributor.authorCassidy, DMen_HK
dc.contributor.authorGruenert, DCen_HK
dc.contributor.authorHegyi, Pen_HK
dc.contributor.authorGray, MAen_HK
dc.contributor.authorSheppard, DNen_HK
dc.contributor.authorKunzelmann, Ken_HK
dc.contributor.authorMehta, Aen_HK
dc.date.accessioned2011-07-29T02:14:19Z-
dc.date.available2011-07-29T02:14:19Z-
dc.date.issued2009en_HK
dc.identifier.citationCellular Physiology And Biochemistry, 2009, v. 24 n. 5-6, p. 347-360en_HK
dc.identifier.issn1015-8987en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137015-
dc.description.abstractBackground: Deletion of phenylalanine-508 (ΔF508) from the first nucleotide-binding domain (NBD1) in the wild-type cystic fibrosis (CF) transmembrane-conductance regulator (wtCFTR) causes CF. However, the mechanistic relationship between ΔF508-CFTR and the diversity of CF disease is unexplained. The surface location of F508 on NBD1 creates the potential for protein-protein interactions and nearby, lies a consensus sequence (SYDE) reported to control the pleiotropic protein kinase CK2. Methods: Electrophysiology, immunofluorescence and biochemistry applied to CFTR-expressing cells, Xenopus oocytes, pancreatic ducts and patient biopsies. Results: Irrespective of PKA activation, CK2 inhibition (ducts, oocytes, cells) attenuates CFTR-dependent Cl- transport, closing wtCFTR in cell-attached membrane patches. CK2 and wtCFTR co-precipitate and CK2 co-localized with wtCFTR (but not ΔF508-CFTR) in apical membranes of human airway biopsies. Comparing wild-type and ΔF508CFTR expressing oocytes, only ΔF508-CFTR Cl- currents were insensitive to two CK2 inhibitors. Furthermore, wtCFTR was inhibited by injecting a peptide mimicking the F508 region, whereas the ΔF508-equivalent peptide had no effect. Conclusions: CK2 controls wtCFTR, but not ΔF508-CFTR. Others find that peptides from the F508 region of NBD1 allosterically control CK2, acting through F508. Hence, disruption of CK2-CFTR interaction by ΔF508-CFTR might disrupt multiple, membrane-associated, CK2-dependent pathways, creating a new molecular disease paradigm for deleted F508 in CFTR. Copyright © 2009 S. Karger AG, Basel.en_HK
dc.languageengen_US
dc.publisherS Karger AG. The Journal's web site is located at http://www.karger.com/CPBen_HK
dc.relation.ispartofCellular Physiology and Biochemistryen_HK
dc.subjectATP-binding cassette transporteren_HK
dc.subjectCFTRen_HK
dc.subjectChannel regulationen_HK
dc.subjectChloride ion channelen_HK
dc.subjectCystic fibrosisen_HK
dc.subjectProtein kinase CK2en_HK
dc.titleInhibition of protein kinase CK2 closes the CFTR Cl channel, but has no effect on the cystic fibrosis mutant Δf508-CFTRen_HK
dc.typeArticleen_HK
dc.identifier.emailChen, JH: jhlchen@hku.hken_HK
dc.identifier.authorityChen, JH=rp01518en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1159/000257427en_HK
dc.identifier.pmid19910675-
dc.identifier.pmcidPMC2795324-
dc.identifier.scopuseid_2-s2.0-70450230597en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-70450230597&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume24en_HK
dc.identifier.issue5-6en_HK
dc.identifier.spage347en_HK
dc.identifier.epage360en_HK
dc.identifier.isiWOS:000271535900003-
dc.publisher.placeSwitzerlanden_HK
dc.identifier.scopusauthoridTreharne, KJ=6602620652en_HK
dc.identifier.scopusauthoridXu, Z=14055096400en_HK
dc.identifier.scopusauthoridChen, JH=7501878156en_HK
dc.identifier.scopusauthoridBest, OG=6505763839en_HK
dc.identifier.scopusauthoridCassidy, DM=26535582500en_HK
dc.identifier.scopusauthoridGruenert, DC=7005195617en_HK
dc.identifier.scopusauthoridHegyi, P=6701740152en_HK
dc.identifier.scopusauthoridGray, MA=7401585136en_HK
dc.identifier.scopusauthoridSheppard, DN=7201812458en_HK
dc.identifier.scopusauthoridKunzelmann, K=7005750781en_HK
dc.identifier.scopusauthoridMehta, A=7402756457en_HK
dc.identifier.citeulike6875039-

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