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Serine 58 of 14-3-3zeta is a molecular switch regulating ASK1 and oxidant stress-induced cell death.


ABSTRACT: Oxidant stress is a ubiquitous stressor with negative impacts on multiple cell types. ASK1 is a central mediator of oxidant injury, but while mechanisms of its inhibition, such as sequestration by 14-3-3 proteins and thioredoxin, have been identified, mechanisms of activation have remained obscure and the signaling pathways regulating this are not clear. Here, we report that phosphorylation of 14-3-3zeta at serine 58 (S58) is dynamically regulated in the cell and that the phosphorylation status of S58 is a critical factor regulating oxidant stress-induced cell death. Phosphorylation of S58 releases ASK1 from 14-3-3zeta, and ASK1 then activates stress-activated protein kinases, leading to cell death. While several members of the mammalian sterile 20 (Mst) family of kinases can phosphorylate S58 when overexpressed, we identify Ste20/oxidant stress response kinase 1 (SOK-1), an Mst family member known to be activated by oxidant stress, as a central endogenous regulator of S58 phosphorylation and thereby of ASK1-mediated cell death. Our findings identify a novel pathway that regulates ASK1 activation and oxidant stress-induced cell death.

SUBMITTER: Zhou J 

PROVIDER: S-EPMC2715813 | biostudies-other | 2009 Aug

REPOSITORIES: biostudies-other

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Serine 58 of 14-3-3zeta is a molecular switch regulating ASK1 and oxidant stress-induced cell death.

Zhou Jibin J   Shao Zhili Z   Kerkela Risto R   Ichijo Hidenori H   Muslin Anthony J AJ   Pombo Celia C   Force Thomas T  

Molecular and cellular biology 20090518 15


Oxidant stress is a ubiquitous stressor with negative impacts on multiple cell types. ASK1 is a central mediator of oxidant injury, but while mechanisms of its inhibition, such as sequestration by 14-3-3 proteins and thioredoxin, have been identified, mechanisms of activation have remained obscure and the signaling pathways regulating this are not clear. Here, we report that phosphorylation of 14-3-3zeta at serine 58 (S58) is dynamically regulated in the cell and that the phosphorylation status  ...[more]

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