Direct control of the forkhead transcription faotor 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; Boudewijn M.Th Burgering

doi:10.1038/19328

Direct control of the forkhead transcription faotor 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, Boudewijn M.Th Burgering^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

The phosphatidylinositol-3-OH-kinase (PI(3)K) effector protein kinase B (refs 1, 2) regulates certain insulin-responsive genes^3,4, 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 (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 vive. 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 Ra1 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.

Original language	English
Pages (from-to)	630-634
Number of pages	5
Journal	Nature
Volume	398
Issue number	6728
DOIs	https://doi.org/10.1038/19328
Publication status	Published - 15 Apr 1999

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@article{f23e60fabe38405598bf2c9fe5795661,

title = "Direct control of the forkhead transcription faotor AFX by protein kinase B",

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 (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 vive. 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 Ra1 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.",

author = "Kops, {Geert J.P.L.} and {De Ruiter}, {Nancy D.} and {De Vries-Smits}, {Alida M.M.} and Powell, {David R.} and Bos, {Johannes L.} and Burgering, {Boudewijn M.Th}",

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AU - Kops, Geert J.P.L.

AU - De Ruiter, Nancy D.

AU - De Vries-Smits, Alida M.M.

AU - Powell, David R.

AU - Bos, Johannes L.

AU - Burgering, Boudewijn M.Th

PY - 1999/4/15

Y1 - 1999/4/15

N2 - 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 (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 vive. 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 Ra1 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.

AB - 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 (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 vive. 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 Ra1 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.

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Direct control of the forkhead transcription faotor AFX by protein kinase B

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