Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1.
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.
Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
Kate L
KL
Jeffrey
Tilman
T
Brummer
Michael S
MS
Rolph
Sue M
SM
Liu
Nuria A
NA
Callejas
Raelene J
RJ
Grumont
Corine
C
Gillieron
Fabienne
F
Mackay
Shane
S
Grey
Montserrat
M
Camps
Christian
C
Rommel
Steve D
SD
Gerondakis
Charles R
CR
Mackay
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology; D054641:Dual Specificity Phosphatase 2; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000276:immunology
D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D054648:Protein Phosphatase 2; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2; C517033:Dusp2 protein, mouse; D017027:Protein Tyrosine Phosphatases