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Type-2A protein phosphatase activity is required to maintain death receptor responsiveness

Oncogene volume 22, pages 7677–7686 (2003)Cite this article

Abstract

Type-2A protein phosphatase (PP2A) is a key regulator in many different cell signaling pathways and an important determinant in tumorigenesis. One of the signaling targets of PP2A is the mitogen-activated protein kinase (MAPK/ERK) cascade. In this study, we wanted to determine whether PP2A could be involved in regulation of death receptor activity through its capacity to regulate MAPK/ERK. To this end, we studied the effects of two different routes of protein phosphatase inhibition on death receptor-mediated apoptosis. We demonstrated that the apoptosis mediated by Fas, TNF-α, and TRAIL in U937 cells is suppressed by calyculin A, an inhibitor of type-1 and type-2A protein phosphatases. The inhibition of the protein phosphatase activity was shown to subsequently increase the MAPK activity in these cells, and the level of activation corresponded to the degree of suppression of cytokine-mediated apoptosis. A more physiological inhibitor, the intracellular PP2A inhibitor protein I2PP2A, protected transfected HeLa cells in a similar way from Fas-mediated apoptosis and induced activation of MAPK in I2PP2A transfected cells. A corresponding inhibition could also be obtained by stable transfection with a constitutively active form of the MAPK kinase, MKK1 (also referred to as MEK1). The inhibitor-mediated protection was highly efficient in preventing early stages of apoptosis, as no caspase-8 cleavage occurred in these cells. The observed apoptosis suppression is likely to facilitate the tumor-promoting effect of a range of different type-2A protein phosphatase inhibitors, and could explain the reported tumor association of I2PP2A.

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Acknowledgements

We thank Helena Saarento for excellent technical assistance. Financial support from the Academy of Finland, the Finnish Cancer Foundations, the Sigrid Jusélius Foundation, the Victoria Foundation, and Åbo Akademi University are gratefully acknowledged.

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Author notes

  1. Ann-Sofi Härmälä-Braskén and Andrey Mikhailov: These two authors contributed equally to this work

Authors and Affiliations

  1. Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, POB 123, Turku, FIN-20521, Finland

    Ann-Sofi Härmälä-Braskén, Andrey Mikhailov, Thomas S Söderström, Annika Meinander, Tim H Holmström & John E Eriksson

  2. Department of Biochemistry and Pharmacy, Åbo Akademi University, POB 66, Turku, FIN-20521, Finland

    Ann-Sofi Härmälä-Braskén

  3. Department of Biology, Åbo Akademi University, Turku, FIN-20520, Finland

    Thomas S Söderström & Tim H Holmström

  4. Department of Biology, Laboratory of Animal Physiology, University of Turku, Turku, FIN-20014, Finland

    Annika Meinander & John E Eriksson

  5. Glogozymes, 6351 corte del Albeto Suite 101, Carlsbad, 92009, California, USA

    Zahi Damuni

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  1. Ann-Sofi Härmälä-Braskén
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Correspondence to John E Eriksson.

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Härmälä-Braskén, AS., Mikhailov, A., Söderström, T. et al. Type-2A protein phosphatase activity is required to maintain death receptor responsiveness. Oncogene 22, 7677–7686 (2003). https://doi.org/10.1038/sj.onc.1207077

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