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PDK1 controls upstream PI3K expression and PIP3 generation

Oncogene volume 33, pages 3043–3053 (2014)Cite this article

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Abstract

The PI3K/PDK1/Akt signaling axis is centrally involved in cellular homeostasis and controls cell growth and proliferation. Due to its key function as regulator of cell survival and metabolism, the dysregulation of this pathway is manifested in several human pathologies including cancers and immunological diseases. Thus, current therapeutic strategies target the components of this signaling cascade. In recent years, numerous feedback loops have been identified that attenuate PI3K/PDK1/Akt-dependent signaling. Here, we report the identification of an additional level of feedback regulation that depends on the negative transcriptional control of phosphatidylinositol 3-kinase (PI3K) class IA subunits. Genetic deletion of 3-phosphoinositide-dependent protein kinase 1 (PDK1) or the pharmacological inhibition of its downstream effectors, that is, Akt and mammalian target of rapamycin (mTOR), relieves this suppression and leads to the upregulation of PI3K subunits, resulting in enhanced generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3). Apparently, this transcriptional induction is mediated by the concerted action of different transcription factor families, including the transcription factors cAMP-responsive element-binding protein and forkhead box O. Collectively, we propose that PDK1 functions as a cellular sensor that balances basal PIP3 generation at levels sufficient for survival but below a threshold being harmful to the cell. Our study suggests that the efficiency of therapies targeting the aberrantly activated PI3K/PDK1/Akt pathway might be increased by the parallel blockade of feedback circuits.

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Acknowledgements

We thank Dario Alessi for providing Akti-1/2/3 (MK-2206) and for helpful discussions. This study was supported by grants from the Deutsche Forschungsgemeinschaft SFB 773 and GRK 1302 (to SW and BS) and from the Interdisciplinary Center of Clinical Research, Faculty of Medicine, Tübingen (Nachwuchsgruppe 1866-0-0, to BS).

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Author notes

  1. S Pietkiewicz

    Present address: 7Current address: Department of Translational Inflammation Research, Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany.,

  2. N R Leslie

    Present address: 8Current address: Institute of Biological Chemistry, Biophysics and Bioengineering, EPS, Nasmyth Building, Heriot Watt University, Edinburgh, UK.,

  3. A M Dieterle and P Böhler: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany

    A M Dieterle, H Keppeler & S Alers

  2. Institute of Molecular Medicine, University Hospital Düsseldorf, Düsseldorf, Germany

    P Böhler, N Berleth, S Drießen, N Hieke, S Pietkiewicz, A S Löffler, C Peter, S Wesselborg & B Stork

  3. Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dundee, UK

    A Gray & N R Leslie

  4. Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

    H Shinohara & T Kurosaki

  5. Institute of Cellular and Molecular Immunology, University Hospital Göttingen, Göttingen, Germany

    M Engelke & J Wienands

  6. Department of Medical Genetics, MFT Services, University Hospital Tübingen, Tübingen, Germany

    M Bonin

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  1. A M Dieterle
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Correspondence to B Stork.

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Dieterle, A., Böhler, P., Keppeler, H. et al. PDK1 controls upstream PI3K expression and PIP3 generation. Oncogene 33, 3043–3053 (2014). https://doi.org/10.1038/onc.2013.266

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