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NF-κB is a target of AKT in anti-apoptotic PDGF signalling

Nature volume 401, pages 86–90 (1999)Cite this article

Abstract

The mechanisms of cell proliferation and transformation are intrinsically linked to the process of apoptosis: the default of proliferating cells is to die unless specific survival signals are provided1,2. Platelet-derived growth factor (PDGF) is a principal survival factor that inhibits apoptosis and promotes proliferation1, but the mechanisms mediating its anti-apoptotic properties are not completely understood. Here we show that the transcription factor NF-κB3,4,5 is important in PDGF signalling. NF-κB transmits two signals: one is required for the induction of proto-oncogene c-myc and proliferation, and the second, an anti-apoptotic signal, counterbalances c-Myc cytotoxicity. We have traced a putative pathway whereby PDGF activates NF-κB through Ras and phospatidylinositol-3-kinase (PI(3)K) to the PKB/Akt protein kinase and the IκB kinase (IKK); NF-κB thus appears to be a target of the anti-apoptotic Ras/PI(3)K/Akt pathway6,7. We show that, upon PDGF stimulation, Akt transiently associates in vivo with IKK and induces IKK activation. These findings establish a role for NF-κB in growth factor signalling and define an anti-apoptotic Ras/PI(3)K/Akt/IKK/NF-κB pathway, thus linking anti-apoptotic signalling with transcription machinery.

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Figure 1: The mitogenic function of NF-κB.
Figure 2: The anti-apoptotic function of NF-κB.
Figure 3: NF-κB is a target of a Ras/PI(3)K/Akt/IKK pathway.
Figure 4: Akt associates with IKK in vivo and induces IKK activation.
Figure 5: NF-κB in PDGF signalling.

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Acknowledgements

We thank P. Tsichlis, J. Woronicz, A. Manning, F. Mercurio, C. Der, T. Davis, W. Kaufmann, A. Danilkovitch and A. Baldwin for sharing reagents; A. Baldwin, C. Der and P. Cohen for stimulating discussions; C. Bradham for assistance in kinase assays; J. Watson for editorial assistance; and members of the S.M. laboratory, A. Miagkov and D. Kovalenko for technical assistance. This work was supported by grants from the National Institutes of Health and the Arthritis Foundation.

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  1. Thurston Arthritis Research Center, and Center for Inflammatory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599–7280, USA

    Julia A. Romashkova & Sergei S. Makarov

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  1. Julia A. Romashkova
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  2. Sergei S. Makarov
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Correspondence to Sergei S. Makarov.

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Romashkova, J., Makarov, S. NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401, 86–90 (1999). https://doi.org/10.1038/43474

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