Direct control of the Forkhead transcription factor AFX by protein kinase B

• Published in: Nature (London) Vol. 398; no. 6728; pp. 630 - 634
• Main Authors: Burgering, Boudewijn M. Th, Kops, Geert J. P. L, Ruiter, Nancy D. de, De Vries-Smits, Alida M. M, Powell, David R, Bos, Johannes L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 15.04.1999; Nature Publishing Group
• Subjects: 3T3 Cells; Animals; Biological and medical sciences; Blood Proteins - antagonists & inhibitors; Blood Proteins - genetics; Blood Proteins - metabolism; Caenorhabditis elegans; Cell physiology; Cellular biology; Cloning, Molecular; Fundamental and applied biological sciences. Psychology; Genetics; Humans; Insulin; Insulin - metabolism; Mice; Molecular and cellular biology; Phosphorylation; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; ras Proteins - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Signal transduction; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Cells, Cultured; Human; Protein hormone; Signal transduction; Pancreatic hormone; Phosphorylation; Cell line; Enzyme; Protein kinase; Transferases; Transcription factor; Insulin; 1-Phosphatidylinositol 3-kinase
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/19328

The phosphatidylinositol-3-OH-kinase (PI(3)K) effector protein kinase B (refs 1, 2) 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 (refs 5-8). Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), 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.