Document Detail


The insulin-induced signalling pathway leading to S6 and initiation factor 4E binding protein 1 phosphorylation bifurcates at a rapamycin-sensitive point immediately upstream of p70s6k.
MedLine Citation:
PMID:  9271419     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Employing specific inhibitors and docking-site mutants of growth factor receptors, recent studies have indicated that the insulin-induced increase in 40S ribosomal protein S6 and initiation factor 4E binding protein 1 (4E-BP1) phosphorylation is mediated by the mTOR/FRAP-p70s6k signal transduction pathway. However, it has not been resolved whether the phosphorylation of both proteins is mediated by p70s6k or whether they reside on parallel pathways which bifurcate upstream of p70s6k. Here we have used either rapamycin-resistant, kinase-dead, or wild-type p70s6k variants to distinguish between these possibilities. The rapamycin-resistant p70s6k, which has high constitutive activity, was able to signal to S6 in the absence of insulin and to prevent the rapamycin-induced block of S6 phosphorylation. This same construct did not increase the basal state of 4E-BP1 phosphorylation or protect it from the rapamycin-induced block in phosphorylation. Unexpectedly, the rapamycin-resistant p70s6k inhibited insulin-induced 4E-BP1 phosphorylation in a dose-dependent manner. This effect was mimicked by the kinase-dead and wild-type p70s6k constructs, which also blocked insulin-induced dissociation of 4E-BP1 from initiation factor 4E. Both the kinase-dead and wild-type constructs also blocked reporter p70s6k activation, although only the kinase-dead p70s6k had a dominant-interfering effect on S6 phosphorylation. Analysis of phosphopeptides from reporter 4E-BP1 and p70s6k revealed that the kinase-dead p70s6k affected the same subset of sites as rapamycin in both proteins. The results demonstrate, for the first time, that activated p70s6k mediates increased S6 phosphorylation in vivo. Furthermore, they show that increased 4E-BP1 phosphorylation is controlled by a parallel signalling pathway that bifurcates immediately upstream of p70s6k, with the two pathways sharing a common rapamycin-sensitive activator.
Authors:
S R von Manteuffel; P B Dennis; N Pullen; A C Gingras; N Sonenberg; G Thomas
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  17     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  1997 Sep 
Date Detail:
Created Date:  1997-09-22     Completed Date:  1997-09-22     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  5426-36     Citation Subset:  IM    
Affiliation:
Department of Growth Control, Friedrich Miescher Institut, Basel, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Carrier Proteins / metabolism*
Cells, Cultured
Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors*
Humans
Insulin / pharmacology*
Kinetics
Mutation
Peptide Initiation Factors / metabolism
Phosphorylation / drug effects
Polyenes / pharmacology*
Protein-Serine-Threonine Kinases / metabolism
Ribosomal Protein S6
Ribosomal Protein S6 Kinases
Ribosomal Proteins / metabolism*
Signal Transduction* / drug effects
Sirolimus
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/EIF4EBP2 protein, human; 0/Eukaryotic Initiation Factor-4E; 0/Eukaryotic Initiation Factors; 0/Peptide Initiation Factors; 0/Polyenes; 0/Ribosomal Protein S6; 0/Ribosomal Proteins; 11061-68-0/Insulin; 53123-88-9/Sirolimus; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Ribosomal Protein S6 Kinases
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