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Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A

Oncogene volume 24, pages 7830–7838 (2005)Cite this article

Abstract

Protein kinase B (PKB) or Akt is one of several second messenger kinases that are activated by cell attachment and growth factor signaling, and that transmit signals to the cell nucleus to inhibit apoptosis and thereby increase cell survival during proliferation. Other viral proteins target this pathway by increasing PKB/Akt phosphorylation, and this pathway has been implicated in the transformation of human keratinocytes by HPV E6 and E7, together with activated notch 1. Here, we examine how HPV E7 expression affects the phosphorylation of PKB. We show that HPV-16 E7 increases the level of phosphorylation of PKB in response to serum stimulation, by a mechanism independent of downregulation of PTEN phosphatase, a known inhibitor of the PI3K (PI3 kinase) pathway. The use of specific antibodies shows that some proportion of PKB/Akt that is phosphorylated both on threonine 308 and serine 473 is maintained in the presence of E7 in a PI3 kinase-independent manner, and is activated for phosphorylation of BAD, a known downstream target of PKB/Akt. Use of E7 mutants has ruled out both an inhibition of IGFBP-3, a known E7 target and PKB/Akt modulator, and the interaction of E7 with cellular pocket proteins, as being the mechanism for the PKB/Akt stimulation. PKB binds PP2A and is a known substrate of PP2A. Here, we show that HPV E7 also binds to both the 35 kDa catalytic and 65 kDa structural subunits of PP2A, an interaction that sequesters these subunits and inhibits their interaction with PKB, thereby maintaining PKB/Akt signaling by inhibiting its dephosphorylation.

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Acknowledgements

We thank David Evans for the kind gift of plasmid pcDNA3 PP2A Cα. This work was supported, in part, by a research grant from the Associazione Italiana per la Ricerca sul Cancro.

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Authors and Affiliations

  1. International Centre for Genetic Engineering and Biotechnology, Area Science Park, Padriciano-99, Trieste, 34012, Italy

    David Pim, Paola Massimi & Lawrence Banks

  2. Department of Metabolic Medicine, Imperial College, DuCane Road, London, W12 ONN, UK

    Stephen M Dilworth

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  1. David Pim
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  2. Paola Massimi
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  3. Stephen M Dilworth
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  4. Lawrence Banks
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Correspondence to David Pim.

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Pim, D., Massimi, P., Dilworth, S. et al. Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A. Oncogene 24, 7830–7838 (2005). https://doi.org/10.1038/sj.onc.1208935

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