Tyrosine dephosphorylation is required for Bak activation in apoptosis

Joanna L. Fox, Ferina Ismail, Abul Azad, Nicola Ternette, Sabrina Leverrier, Mariola J. Edelmann, Benedikt M. Kessler, Irene M. Leigh, Sarah Jackson, Alan Storey

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    32 Citations (Scopus)

    Abstract

    Activation of the cell-death mediator Bak commits a cell to mitochondrial apoptosis. The initial steps that govern Bak activation are poorly understood. To further clarify these pivotal events, we have investigated whether post-translational modifications of Bak impinge on its activation potential. In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multi-merisation. RNA interference (RNAi) screening identified non-receptor tyrosine phosphatases (PTPNs) required for Bak dephosphorylation and apoptotic induction through chemotherapeutic agents. Specifically, modulation of PTPN5 protein expression by siRNA and overexpression directly affected both Bak-Y108 phosphorylation and the initiation of Bak activation. We further show that MEK/ERK signalling directly affects Bak phosphorylation through inhibition of PTPN5 to promote cell survival. We propose a model of Bak activation in which the regulation of Bak dephosphorylation constitutes the initial step in the activation process, which reveals a previously unsuspected mechanism controlling the initiation of mitochondrial apoptosis.

    Original languageEnglish
    Pages (from-to)3853-3868
    Number of pages16
    JournalEMBO Journal
    Volume29
    Issue number22
    DOIs
    Publication statusPublished - 17 Nov 2010

    Keywords

    • apoptosis
    • Bak
    • mitochondria
    • phosphatase
    • SIGNAL-REGULATED KINASE
    • CYTOCHROME-C RELEASE
    • MITOCHONDRIAL APOPTOSIS
    • MASS-SPECTROMETRY
    • OLIGOMERIZES BAK
    • CELL-DEATH
    • PROTEIN
    • BCL-2
    • PATHWAY
    • INHIBITION

    Cite this

    Fox, J. L., Ismail, F., Azad, A., Ternette, N., Leverrier, S., Edelmann, M. J., Kessler, B. M., Leigh, I. M., Jackson, S., & Storey, A. (2010). Tyrosine dephosphorylation is required for Bak activation in apoptosis. EMBO Journal, 29(22), 3853-3868. https://doi.org/10.1038/emboj.2010.244