TAO kinases mediate activation of p38 in response to DNA damage

Malavika Raman, Svetlana Earnest, Kai Zhang, Yingming Zhao, Melanie H. Cobb

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

Thousand and one amino acid (TAO) kinases are Ste20p-related MAP kinase kinase kinases (MAP3Ks) that activate p38 MAPK. Here we show that the TAO kinases mediate the activation of p38 in response to various genotoxic stimuli. TAO kinases are activated acutely by ionizing radiation, ultraviolet radiation, and hydroxyurea. Full-length and truncated fragments of dominant negative TAOs inhibit the activation of p38 by DNA damage. Inhibition of TAO expression by siRNA also decreases p38 activation by these agents. Cells in which TAO kinases have been knocked down are less capable of engaging the DNA damage-induced G2/M checkpoint and display increased sensitivity to IR. The DNA damage kinase ataxia telangiectasia mutated (ATM) phosphorylates TAOs in vitro; radiation induces phosphorylation of TAO on a consensus site for phosphorylation by the ATM protein kinase in cells; and TAO and p38 activation is compromised in cells from a patient with ataxia telangiectasia that lack ATM. These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM.

Original languageEnglish (US)
Pages (from-to)2005-2014
Number of pages10
JournalEMBO Journal
Volume26
Issue number8
DOIs
Publication statusPublished - Apr 18 2007

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Keywords

  • DNA damage
  • G2-M checkpoint
  • MAPKs
  • Protein kinases
  • Ste20p homolog

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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