Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1

KL Jeffrey, T Brummer, MS Rolph, SM Liu… - Nature …, 2006 - nature.com
KL Jeffrey, T Brummer, MS Rolph, SM Liu, NA Callejas, RJ Grumont, C Gillieron, F Mackay
Nature immunology, 2006nature.com
Mitogen-activated protein kinases facilitate many cellular processes and are essential for
immune cell function. Their activity is controlled by kinases and dual-specificity
phosphatases. A comprehensive microarray analysis of human leukocytes identified DUSP2
(encoding the phosphatase PAC-1) as one of the most highly induced transcripts in
activated immune cells. We generated Dusp2−/− mice and found considerably reduced
inflammatory responses in the'K/BxN'model of rheumatoid arthritis. PAC-1 deficiency led to …
Abstract
Mitogen-activated protein kinases facilitate many cellular processes and are essential for immune cell function. Their activity is controlled by kinases and dual-specificity phosphatases. A comprehensive microarray analysis of human leukocytes identified DUSP2 (encoding the phosphatase PAC-1) as one of the most highly induced transcripts in activated immune cells. We generated Dusp2−/− mice and found considerably reduced inflammatory responses in the 'K/BxN' model of rheumatoid arthritis. PAC-1 deficiency led to increased activity of Jun kinase (Jnk) but unexpected impairment of the activity of extracellular signal–regulated kinase (Erk) and the kinase p38, reduced activity of the transcription factor Elk1 and a complex of mobilized transcription factor NFAT and the AP-1 transcription factor and decreased effector immune cell function. Thus, PAC-1 is a key positive regulator of inflammatory cell signaling and effector functions, mediated through Jnk and Erk mitogen-activated protein kinase crosstalk.
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