title: Direct control of the Forkhead transcription factor AFX by protein kinase B.
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.
authors.affiliation: Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, University of Utrecht, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Kops
authors.forename: N D
authors.initials: ND
authors.lastname: de Ruiter
authors.forename: A M
authors.initials: AM
authors.lastname: De Vries-Smits
authors.forename: D R
authors.initials: DR
authors.lastname: Powell
authors.forename: J L
authors.initials: JL
authors.lastname: Bos
authors.forename: B M
authors.initials: BM
authors.lastname: Burgering
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001798:Blood Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D003001:Cloning, Molecular; D051858:Forkhead Transcription Factors; D006801:Humans; D007328:Insulin / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism
chemical_list: D001798:Blood Proteins; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D007328:Insulin; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins