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Article

  • The EMBO Journal (2004) 23, 4451 - 4461
  • doi:10.1038/sj.emboj.7600455

Published online: 28 October 2004

Autophosphorylation of ataxia-telangiectasia mutated is regulated by protein phosphatase 2A

Aaron A Goodarzi1,2,a, Jyoti C Jonnalagadda3,a, Pauline Douglas2, David Young3, Ruiqiong Ye2, Greg BG Moorhead1, Susan P Lees-Miller1,2 and Kum Kum Khanna3

  1. Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
  2. Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, Canada
  3. Queensland Institute of Medical Research, Brisbane, Australia

Correspondence to:

Susan P Lees-Miller, Department of Biochemistry & Molecular Biology, University of Calgary, 3330 Hospital Drive, NW, Calgary, AB, Canada T2N 4N1. Tel.: +1 403 220 7628; Fax: +1 403 210 3899; E-mail: leesmill@ucalgary.ca

Kum Kum Khanna, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD 4029, Australia. Tel.: +61 7 33620338; Fax: +61 7 33620105; E-mail: kumkumK@qimr.edu.au

aThese two authors contributed equally to this work

Received 22 July 2004; Accepted 1 October 2004

Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro. OA did not induce gamma-H2AX foci, suggesting that it induces ATM autophosphorylation by inactivation of a protein phosphatase rather than by inducing DNA double-strand breaks. In support of this, we show that ATM interacts with the scaffolding (A) subunit of protein phosphatase 2A (PP2A), that the scaffolding and catalytic (C) subunits of PP2A interact with ATM in undamaged cells and that immunoprecipitates of ATM from undamaged cells contain PP2A-like protein phosphatase activity. Moreover, we show that IR induces phosphorylation-dependent dissociation of PP2A from ATM and loss of the associated protein phosphatase activity. We propose that PP2A plays an important role in the regulation of ATM autophosphorylation and activity in vivo.

  • Keywords:

    • ATM,
    • autophosphorylation,
    • okadaic acid,
    • protein phosphatase