Tyrosine phosphatase inhibition triggers sustained canonical serine-dependent NFκB activation via Src-dependent blockade of PP2A
Tyrosine phosphatase inhibition triggers sustained canonical serine-dependent NFκB activation via Src-dependent blockade of PP2A
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DOI：
10.1016/j.bcp.2010.04.028
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发表时间：
2010-08-15
影响因子：
5.8
通讯作者：
Kulms, Dagmar
中科院分区：
文献类型：
--
作者：
Barisic, Sandra;Schmidt, Claudia;Kulms, Dagmar
Activation status of Tyr-kinase Src as well as of the transcription factor NF kappa B is a decisive criterion for the onset of cancer and in conveying radio-resistance. While the activation status of Src is Tyr phosphorylation-dependent, NF kappa B activation requires Ser phosphorylation of its cytosolic inhibitor, I kappa B alpha. Since constitutive NF kappa B activation was linked to tumor maintenance, its tight regulation is mandatory.We provide evidence that inhibition of pan-Tyr phosphatase activity by orthovanadate is translated via Src to inhibition of Ser phosphatase PP2A, thereby changing the physiologic response of the cell. In particular we unravelled a new sequence of molecular interactions linking initial activating Tyr416 phosphorylation of Src not to Tyr42-dependent phosphorylation and degradation of I kappa B alpha, but to sustained Ser177/181 phosphorylation of I kappa B alpha kinase IKK beta following IL-1 stimulation. Consequently, sustained IKK beta activation provides for chronic canonical I kappa B alpha degradation, thereby eliciting constitutive NF kappa B activation. As the critical translator of Tyr to Set phosphorylation we identified Ser/Thr phosphatase PP2A. We show that the catalytic subunit PP2Ac serves as a Src substrate with Tyr307 phosphorylation leading to its catalytic inhibition. Additionally to the known survival pathways triggered by Src, Src-mediated canonical and persistent NF kappa B activation may fortify its tumorigenic effects. (C) 2010 Elsevier Inc. All rights reserved.
