文摘
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Summary
Signal transduction to nuclear factor-kappa B (NF-¦ÊB) 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-¦ÊB activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-¦ÊB 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-¦ÊB signaling in NF-¦ÊB-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-¦ÊB signaling in a subgroup of T?cell lymphomas.
