Journal
IMMUNITY
Volume 37, Issue 4, Pages 697-708Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2012.07.014
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Funding
- Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ)
- Israeli Ministry of Science, Culture and Sport (MOST)
- Deutsche Krebshilfe
- Wilhelm Sander Stiftung
- Tumorzentrum Heidelberg/Mannheim
- Helmholtz Alliance for Systems Biology
- Emmy-Noet her Grant of the Deutsche Forschungsgemeinschaft
- Jose Carreras Leukarnie-Stiftung
- Helmholtz Alliance for Immunotherapy of Cancer
- Max-Eder Junior Group Program of the German Cancer Aid
- [SFB 405]
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Signal transduction to nuclear factor-kappa B (NE-kappa B) 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-kappa B activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-kappa B 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-kappa B signaling in NF-kappa B-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 NE-kappa B signaling in a subgroup of T cell lymphomas.
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