Glucose exerts a permissive effect on the regulation of the initiation factor 4E binding protein 4E-BP1.
The eukaryotic initiation factor 4E (eIF4E) binding protein (4E-BP1) interacts directly with eIF4E and prevents it from forming initiation factor (eIF4F) complexes required for the initiation of cap-dependent mRNA translation. Insulin and other agents induce the phosphorylation of 4E-BP1 at multiple sites, resulting in its release from eIF4E, and this involves signalling through the mammalian target of rapamycin (mTOR). Here we show that D-glucose promotes the ability of insulin to bring about the phosphorylation of 4E-BP1 and the formation of eIF4F complexes. This appears to involve facilitation of the phosphorylation of at least three phosphorylation sites on 4E-BP1, i.e. Thr-36, Thr-45 and Thr-69. Non-metabolizable glucose analogues cannot substitute for D-glucose, but other hexoses can. This suggests that a product of hexose metabolism mediates the permissive effect of glucose. The effect of glucose was concentration-dependent within the range 1-5 mM. In contrast with the situation for 4E-BP1, glucose does not allow full activation of the 70 kDa ribosomal protein S6 kinase (p70 S6k; another target of mTOR signalling) or phosphorylation, in vivo, of its substrate, ribosomal protein S6. Taken together with earlier data showing that amino acids regulate 4E-BP1 and p70 S6k, the present findings show that 4E-BP1 in particular is regulated in response to the availability of both amino acids and sugars.
Patel
J
J
Division of Molecular Physiology, School of Life Sciences, MSI/WTB Complex, Dow Street, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Wang
X
X
Proud
C G
CG
D000818:Animals; D016466:CHO Cells; D050260:Carbohydrate Metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D006224:Cricetinae; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006601:Hexoses / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000502:physiology; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; D015852:Eukaryotic Initiation Factor-2; D006601:Hexoses; D007328:Insulin; D010750:Phosphoproteins; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D005947:Glucose