%0 Journal Article %1 Barisic2010 %A Barisic, Sandra %A Schmidt, Claudia %A Walczak, Henning %A Kulms, Dagmar %D 2010 %J Biochemical Pharmacology %K 2010 izi kulms %N 4 %P 439--447 %R 10.1016/j.bcp.2010.04.028 %T Tyrosine phosphatase inhibition triggers sustained canonical serine-dependent NFκB activation via Src-dependent blockade of PP2A %U https://www.ncbi.nlm.nih.gov/pubmed/20450893 %V 80 %X 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 Ser 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. © 2010 Elsevier Inc. %Z Barisic, SandraSchmidt, ClaudiaWalczak, HenningKulms, DagmarengResearch Support, Non-U.S. Gov'tEnglandBiochem Pharmacol. 2010 Aug 15;80(4):439-47. doi: 10.1016/j.bcp.2010.04.028. Epub 2010 May 5. %7 2010/05/11 %@ 1873-2968 (Electronic)$\backslash$r0006-2952 (Linking)

@article{Barisic2010, abstract = {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 Ser 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. {\textcopyright} 2010 Elsevier Inc.}, added-at = {2018-02-01T15:26:24.000+0100}, annote = {Barisic, SandraSchmidt, ClaudiaWalczak, HenningKulms, DagmarengResearch Support, Non-U.S. Gov'tEnglandBiochem Pharmacol. 2010 Aug 15;80(4):439-47. doi: 10.1016/j.bcp.2010.04.028. Epub 2010 May 5.}, author = {Barisic, Sandra and Schmidt, Claudia and Walczak, Henning and Kulms, Dagmar}, biburl = {https://puma.ub.uni-stuttgart.de/bibtex/23070f4d61cda49c269078237e5b93eb6/cristiano}, doi = {10.1016/j.bcp.2010.04.028}, edition = {2010/05/11}, interhash = {33b08d2191f9f1c7efd6fb7265329ec7}, intrahash = {3070f4d61cda49c269078237e5b93eb6}, isbn = {1873-2968 (Electronic)$\backslash$r0006-2952 (Linking)}, issn = {00062952}, journal = {Biochemical Pharmacology}, keywords = {2010 izi kulms}, number = 4, pages = {439--447}, pmid = {20450893}, timestamp = {2019-01-17T13:42:57.000+0100}, title = {{Tyrosine phosphatase inhibition triggers sustained canonical serine-dependent NFκB activation via Src-dependent blockade of PP2A}}, url = {https://www.ncbi.nlm.nih.gov/pubmed/20450893}, volume = 80, year = 2010 }