A PP4 holoenzyme balances physiological and oncogenic nuclear factor-kappa B signaling in T lymphocytes
Summary: Signal transduction to nuclear factor-kappa B (NF-κB) involves multiple kinases and phosphorylated target proteins, but little is known about signal termination by dephosphorylation. By RNAi screening, we have identified protein phosphatase 4 regulatory subunit 1 (PP4R1) as a negative regul...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2012
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| In: |
Immunity
Year: 2012, Volume: 37, Issue: 4, Pages: 697-708 |
| ISSN: | 1097-4180 |
| DOI: | 10.1016/j.immuni.2012.07.014 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1016/j.immuni.2012.07.014 Verlag, kostenfrei, Volltext: http://www.sciencedirect.com/science/article/pii/S1074761312004268 
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| Author Notes: | Markus Brechmann, Thomas Mock, Dorothee Nickles, Michael Kiessling, Nicole Weit, Rebecca Breuer, Wolfgang Müller, Guido Wabnitz, Felice Frey, Jan P. Nicolay, Nina Booken, Yvonne Samstag, Claus-Detlev Klemke, Marco Herling, Michael Boutros, Peter H. Krammer, and Rüdiger Arnold |
MARC
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| 245 | 1 | 2 | |a A PP4 holoenzyme balances physiological and oncogenic nuclear factor-kappa B signaling in T lymphocytes |c Markus Brechmann, Thomas Mock, Dorothee Nickles, Michael Kiessling, Nicole Weit, Rebecca Breuer, Wolfgang Müller, Guido Wabnitz, Felice Frey, Jan P. Nicolay, Nina Booken, Yvonne Samstag, Claus-Detlev Klemke, Marco Herling, Michael Boutros, Peter H. Krammer, and Rüdiger Arnold |
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| 520 | |a Summary: Signal transduction to nuclear factor-kappa B (NF-κB) involves multiple kinases and phosphorylated target proteins, but little is known about signal termination by dephosphorylation. By RNAi screening, we have identified protein phosphatase 4 regulatory subunit 1 (PP4R1) as a negative regulator of NF-κB activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-κB kinase (IKK) complex and the phosphatase PP4c, thereby directing PP4c activity to dephosphorylate and inactivate the IKK complex. PP4R1 expression was triggered upon activation and proliferation of primary human T lymphocytes and deficiency for PP4R1 caused sustained and increased IKK activity, T cell hyperactivation, and aberrant NF-κB signaling in NF-κB-addicted T cell lymphomas. Collectively, our results unravel PP4R1 as a previously unknown activation-associated negative regulator of IKK activity in lymphocytes whose downregulation promotes oncogenic NF-κB signaling in a subgroup of T cell lymphomas. | ||
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