Abstract
Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) represses translation initiation by binding to eukaryotic initiation factor 4E (eIF4E). 4E-BP1 also binds to the eIF4E homologous protein (4EHP). We show that eIF4E-binding mutants of 4E-BP1 (Y54A and L59A) fail to form heterodimeric complexes with wild-type 4EHP. In addition, the W95A mutant of 4EHP, similar to a homologous mutation in eIF4E, inhibits its binding to wild-type 4E-BP1. Interestingly, 4EHP over-expression instigates a negative feedback loop that inhibits upstream signaling to 4E-BP1 and ribosomal protein S6 kinase 1 (S6K1) whereas the 4E-BP1-binding-deficient mutant of 4EHP(W95A) was unable to trigger this feedback loop. Thus, the interaction of 4EHP with 4E-BP1 is necessary for this observed impaired signaling to 4E-BP1 and S6K1.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Cycle Proteins
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Cell Line
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Eukaryotic Initiation Factor-4E / genetics
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Eukaryotic Initiation Factor-4E / metabolism*
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Eukaryotic Initiation Factors
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Feedback, Physiological
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Humans
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Insulin / pharmacology
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Mice
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Mutation, Missense
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Peptide Initiation Factors / genetics
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Peptide Initiation Factors / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Binding
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RNA Cap-Binding Proteins / genetics
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RNA Cap-Binding Proteins / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism
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Transfection
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cell Cycle Proteins
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EIF4E2 protein, human
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EIF4EBP1 protein, human
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Eif4ebp1 protein, mouse
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Eukaryotic Initiation Factor-4E
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Eukaryotic Initiation Factors
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Insulin
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Peptide Initiation Factors
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Phosphoproteins
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RNA Cap-Binding Proteins
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eIF4E2 protein, mouse
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RPS6KA1 protein, human
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Ribosomal Protein S6 Kinases, 90-kDa
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Rps6ka1 protein, mouse