The Ups and Downs of Kinases

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Science  10 Mar 2006:
Vol. 311, Issue 5766, pp. 1349
DOI: 10.1126/science.311.5766.1349c

Jeffrey et al. explored the role of the nuclear-localized dual specificity phosphatase (DUSP) isoform known as phosphatase of activated cells 1 (PAC-1, which is encoded by the DUSP2 gene) in the regulation of leukocyte activity and in a mouse model of autoimmune arthritis. Surprisingly, cells from Dusp2−/− mice showed decreased induction of inflammatory arthritis (delayed onset of symptoms and diminished histological and clinical features). Stimulated macrophages and bone marrow-derived mast cells from these mice exhibited reduced gene expression and secretion of inflammatory mediators; in addition, cultured mast cells exhibited greater apoptosis and decreased cell survival. Despite in vitro evidence that the mitogen-activated protein kinases (MAPKs) p38 and ERK are substrates of PAC-1, their activities decreased in the Dusp2−/− mast cells and macrophages. In contrast, phosphorylation of the MAPK c-Jun N-terminal kinase (JNK) increased. PAC-1 deficiency reduced gene expression by the transcriptional regulator Elk1, and inhibition of JNK in PAC-1 deficient cells rescued ERK phosphorylation and Elk1-mediated transcription, suggesting that the JNK pathway regulates the ERK pathway so that when JNK activity goes up, ERK activity goes down. These results point to therapeutic targeting of PAC-1 as a modulator of MAPK signaling in immune cells, especially for treatment of autoimmune disease. — NRG

Nat. Immunol. 7, 274 (2006).

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