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First published online November 8, 2006
doi: 10.1242/10.1242/jcs.03266

Journal of Cell Science 119, 4607-4615 (2006)
Published by The Company of Biologists 2006
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Diverse physiological functions for dual-specificity MAP kinase phosphatases

Robin J. Dickinson and Stephen M. Keyse*

Cancer Research UK Stress Response Laboratory, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK


Figure 1
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  		Fig. 1. Classification, domain structure and phylogenetic analysis of the dual-specificity MAPK phosphatases. (A) Domain structures of the ten catalytically active DUSP proteins and MK-STYX. In addition to the N-terminal non-catalytic domain containing the Cdc25/rhodanese-homology region and the catalytic site, the positions of the conserved kinase-interaction motif (KIM), nuclear localisation signals (NLS), nuclear export signals (NES) and PEST sequences are indicated. The three subgroups revealed by the phylogenetic analysis are indicated by the background colour. (B) DUSP sequence analysis. Human DUSP amino acid sequences were aligned using CLUSTALW (http://align.genome.jp/) and a phylogenetic tree was generated. The three subgroups of DUSP proteins together with defining properties are indicated by the coloured ovals.

 

Figure 2
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  		Fig. 2. Physiological roles of DUSP1/MKP-1 in immunity and metabolic regulation. (A) In macrophages, LPS signals through Toll-like receptor (TLR), which engages the adaptor proteins MyD88 and TRIF. This leads to an early response, in which p38 MAPK and JNK are activated and contribute to the expression of TNF, and is followed by induction of MKP-1 expression, which serves to downregulate p38/JNK activities and TNF production. At later times, as MKP-1 expression declines, the levels of p38 MAPK and JNK activity remain higher than in unstimulated cells and promote IL10 expression. (B) In insulin-responsive tissues, MKP-1 regulates multiple MAPK pathways in the nucleus, and thus controls the expression of genes involved in fatty acid metabolism and energy expenditure. The activities of MAPKs in the cytosol are not subject to regulation by MKP-1. Therefore, negative feedback controls, such as the phosphorylation of IRS by JNK, are unaffected.

 




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