Article

Targeting dual-specificity phosphatases: Manipulating MAP kinase signalling and immune responses

Immunology and Inflammation Research Program, The Garvan Institute, Darlinghurst, Sydney, NSW 2010, Australia.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 06/2007; 6(5):391-403. DOI: 10.1038/nrd2289
Source: PubMed

ABSTRACT

Dual-specificity phosphatases (DUSPs) are a subset of protein tyrosine phosphatases, many of which dephosphorylate threonine and tyrosine residues on mitogen-activated protein kinases (MAPKs), and hence are also referred to as MAPK phosphatases (MKPs). The regulated expression and activity of DUSP family members in different cells and tissues controls MAPK intensity and duration to determine the type of physiological response. For immune cells, DUSPs regulate responses in both positive and negative ways, and DUSP-deficient mice have been used to identify individual DUSPs as key regulators of immune responses. From a drug discovery perspective, DUSP family members are promising drug targets for manipulating MAPK-dependent immune responses in a cell-type and disease-context-dependent manner, to either boost or subdue immune responses in cancers, infectious diseases or inflammatory disorders.

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Available from: Kate L Jeffrey, Apr 27, 2015
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    • "The intensity and duration of the MAPK activation are controlled by the dual-specificity phosphatases (DUSPs), many of which dephosphorylate threonine and tyrosine residues on MAPK, and hence are also referred to as MAPK phosphatases (MKPs). Consequently , the controlled expression of DUSP family members in different cells and tissues regulates MAPK activation intensity and duration to determine the type of physiological response (Jeffrey et al., 2007; Patterson et al., 2009). MKP-1 is a nuclear DUSP (also known as DUSP1) with higher p38 and JNK substrate specificity. "
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    • "These MAPK-specific DUSPs are further classified based on gene structure, substrate specificity, and subcellular localization into three groups composed of nuclear DUSPs, cytosolic ERK-specific DUSPs, and DUSPs that selectively inactivate JNK and p38 MAPKs (Table 1). Lastly, DUSPs are highly inducible at the level of gene expression in a cell-type and stimulus-dependent manner (Dickinson and Keyse, 2006; Jeffrey et al., 2007; Keyse, 2008). For adipocytes, these stimuli include insulin and the synthetic glucocorticoid dexamethasone (Kusari et al., 1997; Kassel et al., 2001). "
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