Document Detail

D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a.
MedLine Citation:
PMID:  14710188     Owner:  NLM     Status:  MEDLINE    
The protein kinase CK1 phosphorylates serine residues that are located close to another phosphoserine in the consensus pSer-Xaa-Xaa-Ser. This specificity generates regions in its target proteins containing two or more neighbouring phosphoserine residues, termed here multisite phosphorylation domains (MPDs). In this paper, we demonstrate that D4476 is a potent and rather selective inhibitor of CK1 in vitro and in cells. In H4IIE hepatoma cells, D4476 specifically inhibits the phosphorylation of endogenous forkhead box transcription factor O1a (FOXO1a) on Ser322 and Ser325 within its MPD, without affecting the phosphorylation of other sites. Our results indicate that these residues are targeted by CK1 in vivo and that the CK1-mediated phosphorylation of the MPD is required for accelerated nuclear exclusion of FOXO1a in response to IGF-1 and insulin. D4476 is much more potent and specific than IC261 or CKI-7, and is therefore the most useful CK1 inhibitor currently available for identifying physiological substrates of CK1.
Graham Rena; Jenny Bain; Matthew Elliott; Philip Cohen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  EMBO reports     Volume:  5     ISSN:  1469-221X     ISO Abbreviation:  EMBO Rep.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2004-01-07     Completed Date:  2004-11-22     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100963049     Medline TA:  EMBO Rep     Country:  England    
Other Details:
Languages:  eng     Pagination:  60-5     Citation Subset:  IM    
MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
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MeSH Terms
Benzamides / metabolism,  pharmacology*
Casein Kinase I / metabolism*
Cells, Cultured
Culture Media, Serum-Free
DNA-Binding Proteins / metabolism*
Forkhead Transcription Factors
Imidazoles / metabolism,  pharmacology*
Serine / chemistry
Substrate Specificity
Transcription Factors / metabolism*
Tumor Cells, Cultured
Reg. No./Substance:
0/4-(4-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide; 0/Benzamides; 0/Culture Media, Serum-Free; 0/DNA-Binding Proteins; 0/FOXO1 protein, human; 0/Forkhead Transcription Factors; 0/Imidazoles; 0/Transcription Factors; 56-45-1/Serine; EC Kinase I

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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