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

Geert J. P. L. Kops, Nancy D. de Ruiter, Alida M. M. De Vries-Smits, David R. Powell, Johannes L. Bos and Boudewijn M. Th. Burgering ()
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Geert J. P. L. Kops: Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, University of Utrecht
Nancy D. de Ruiter: Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, University of Utrecht
Alida M. M. De Vries-Smits: Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, University of Utrecht
David R. Powell: Baylor College of Medicine
Johannes L. Bos: Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, University of Utrecht
Boudewijn M. Th. Burgering: Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, University of Utrecht

Nature, 1999, vol. 398, issue 6728, 630-634

Abstract: Abstract The phosphatidylinositol-3-OH-kinase (PI(3)K) effector protein kinase B (refs 1, 2) regulates certain insulin-responsive genes3,4, 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 (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.

Date: 1999
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DOI: 10.1038/19328

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