TAO kinases mediate activation of p38 in response to DNA damage

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. Fulllength 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.

Checkpoint control and cancer

“…The contribution of p38 to the DDR was attributed to the phosphorylation of cdc25B and cdc25C by MK2 (Manke et al, 2005). Moreover, rapid and transient activation of the p38/MK2 pathway was also reported after IR, or treatment with doxorubicin or alkylating agents such as methyl methanesulfonate (MMS) (Mikhailov et al, 2004;Raman et al, 2007;Lafarga et al, 2009;Phong et al, 2010). Activation of the p38/MK2 branch of the checkpoint has been reported to involve ATM/ATR-dependent activation of Thousand and one amino acid protein kinases (TAO) that belong to the MAPKKK family.…”

MAP3Ks as central regulators of cell fate during development

“…6; Hutchison et al, 1998;Chen et al, 2003;Raman et al, 2007). The cell cycle protein, Ataxia telangiectasia mutated (ATM), is activated in response to DNA damage, and directly phosphorylates TAOk.…”

“…The cell cycle protein, Ataxia telangiectasia mutated (ATM), is activated in response to DNA damage, and directly phosphorylates TAOk. Phosphorylated TAOk then causes activation of p38 MAPK leading cells to enter the G2/M damage checkpoint for DNA repair (Raman et al, 2007). To date, three of these MAP3Ks have been characterized: TAOk1, TAOk2, and TAOk3.…”

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…Other functions of MARKK/TAO-1 involve mitosis progression and MAPK/p38 signaling upon stress induced activation. 94,95 By these mechanisms, apart from the toxic effects of S262/S356 phosphorylated tau, MARKK might contribute to neurodegeneration and cell death.…”