Targeting dual-specificity phosphatases: manipulating MAP kinase signaling and immune responses

Immunology and Inflammation Research Program, The Garvan Institute, Darlinghurst, Sydney, NSW 2010, Australia.
dressNature Reviews Drug Discovery (Impact Factor: 37.23). 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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    • "DSPs dephosphorylate phosphotyrosine, phosphoserine, and phosphothreonine residues on substrates (Alonso et al. 2004; Tonks 2006). DSPs can be further classified on the basis of the presence (typical) or absence (atypical) of a MAPK-interacting domain, (Huang and Tan 2012; Jeffrey et al. 2007). For example, in Ustilago maydis, the DSP Rok1 is known to regulate mating and virulence by controlling the phosphorylation of Erk MAPKs Kpp2 and Kpp6 (Di Stasio et al. 2009). "
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    • "Second, like the NFkB pathway, stress response signals and stimuli engaged by TLRs or NLRs also induce the MAP kinase pathway (Huang et al., 2009; Ting et al., 2010). Regulation of MAPK signalling is mainly achieved by negative feedback loops via members of the dual specificity phosphatases (DUSPs) (Jeffrey et al., 2007). Analogous to the control of IkB expression by NFkB, transcription of DUSPs is directly regulated by MAPK signalling. "
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    • "The JNK subfamily contains a Thr-Pro-Tyr motif, and potently phosphorylates c-Jun, a component of AP-1 transcription factor. The p38 subfamily contains general reviews on MKPs/DUSPs have been published recently, including those focusing on cell proliferation and cancer (Boutros et al. 2008; Keyse 2008) and the immune response (Jeffrey et al. 2007; Lang et al. 2006; Li et al. 2009; Liu et al. 2007; Salojin and Oravecz 2007; Wang and Liu 2007). "
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