Abstract
The phosphatidylinositol-3-OH-kinase (PI(3)K) effector protein kinase B regulates certain insulin-responsive genes, but the transcription factors regulated by protein kinase B have yet to be identified. Genetic analysis in Caenorhabditis elegans has shown that the Forkhead transcription factor daf-16 is regulated by a pathway consisting of insulin-receptor-like daf-2 and PI(3)K-like age-1. Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf-16, both in vitro and in vivo. Inhibition of endogenous PI(3)K and protein kinase B activity prevents protein kinase B-dependent phosphorylation of AFX and reveals residual protein kinase B-independent phosphorylation that requires Ras signalling towards the Ral GTPase. In addition, phosphorylation of AFX by protein kinase B inhibits its transcriptional activity. Together, these results delineate a pathway for PI(3)K-dependent signalling to the nucleus.
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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3T3 Cells
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Animals
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Blood Proteins / antagonists & inhibitors
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Blood Proteins / genetics
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Blood Proteins / metabolism*
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Cell Cycle Proteins
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Cloning, Molecular
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Forkhead Transcription Factors
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Humans
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Insulin / metabolism
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Mice
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
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ras Proteins / metabolism
Substances
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Blood Proteins
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Cell Cycle Proteins
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FOXO4 protein, human
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Forkhead Transcription Factors
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Insulin
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Transcription Factors
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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ras Proteins