Genes and Immunity (2013) 14, 1–6 & 2013 Macmillan Publishers Limited All rights reserved 1466-4879/13 www.nature.com/gene REVIEW Dual-specificity phosphatases 2: surprising positive effect at the molecular level and a potential biomarker of diseases WWei1,2, Y Jiao2,3, A Postlethwaite4,5, JM Stuart4,5, Y Wang6, D Sun1 and W Gu2 Dual-specificity phosphatases (DUSPs) is an emerging subclass of the protein tyrosine phosphatase gene superfamily, a heterogeneous group of protein phosphatases that can dephosphorylate both phosphotyrosine and phosphoserine/ phosphothreonine residues within the one substrate. Recently, a series of investigations of DUSPs defined their essential roles in cell proliferation, cancer and the immune response. This review will focus on DUSP2, its involvement in different diseases and its potential as a therapeutic target. Genes and Immunity (2013) 14, 1–6; doi:10.1038/gene.2012.54; published online 29 November 2012 Keywords: dual-specificity phosphatases; disease; mitogen-activated protein kinase; immune INTRODUCTION extracellular stimuli. Inducible nucleuses MKPs include DUSP1, Mitogen-activated protein kinase (MAPK) activation cascades DUSP2, DUSP4 and DUSP5, which originated from a common mediate various physiological processes, such as cell proliferation, ancestral gene. They were shown to dephosphorylate Erks, Jnk differentiation, stress responses, inflammation, apoptosis and and p38 MAPKs to the same extent and to be induced by growth immune defense.1–4 Dysregulation of MAPK activation cascades or stress signals. DUSP6, DUSP7 and DUSP9 are cytoplasmic Erk- has been implicated in various diseases and has been the focus of specific MPKs, which can preferentially recognize Erk1 and Erk2 extensive research.5–7 MAPKs are grouped into three major classes in vitro. DUSP8, DUSP16 and DUSP10 are cytoplasmic and nuclear. based on their preferential activation by extracellular stimuli: They recognize Jnk and p38 and can inactivate p38 and Jnk 15,16 classic Erk1 and Erk2 and p38 proteins (p38a, p38b, p38g and p38 MAPKs. They negatively regulate members of the MAPK d) and Jun N-terminal kinases (Jnk1, Jnk2 and Jnk3). These are all superfamily (MAPK/Erk, SAPK/Jnk and p38), which are associated activated by dual phosphorylation of the threonine and tyrosine with cellular proliferation and differentiation. As major residues in a conserved ‘TXY’ (Thr-Xaa-Tyr) motif (where X is E for regulators of MAPK signaling, DUSPs have been implicated as Erk, G for p38 or P for Jnk). major modulators of the critical signaling pathways that are Dual-specificity phosphatases (DUSPs) are an emerging dysregulated in various diseases. subclass of the protein tyrosine phosphatase gene superfamily, Recently, a series of investigation in DUSPs defined essential 17–23 a heterogeneous group of protein phosphatases that can roles in cell proliferation and cancer and their immune 4,24 dephosphorylate both phosphotyrosine and phosphoserine/ response. Although there are at least 11 MKPs (many of them phosphothreonine residues within the one substrate.8 They can were thought to have a similar role to regulate MAPK cascades), regulate activity of MAPK through TXY motif dephosphorylation it is obvious that each of them has different substrate specificities as well as represent particularly important negative regulators.8,9 and physiological roles. This review will focus on one of the In addition to their dephosphorylating capacity, DUSPs serve DUSPs: DUSP2. We will present what is currently known about to anchor or shuttle MAPKs and control their subcellular its involvement in different diseases and potential as a therapeutic localization.10,11 target. The human genome contains 30 putative DUSP genes, 11 of which are specific for the MAPKs Erk, Jnk and p38.12,13 Those genes have been referred to as MAP kinase phosphatases HISTORY AND BASIC FUNCTIONS OF DUSP2 13 (MKPs). Another subgroup of DUSPs contains 19 DUSPs, which DUSP2 has also been referred to as the phosphatase of activated 13 have been referred to as ‘atypical’ DUSPs. Some of them have cells 1. It is a 32-kDa protein, originally cloned in 1993 from human been shown to regulate MAPKs as they share some characteristic T cells as an immediate-early gene.25 DUSP2 localizes in the of the MKPs. They contain the DUSP catalytic domain but lack the nucleus and is predominantly expressed in hematopoietic tissues 14 N-terminal CH2 domain found in MKPs. with high T-cell content, such as thymus, spleen, lymph nodes, Different members of the family of MKPs show distinct peripheral blood and other organs (brain and liver).25–28 Its substrate, different tissue distribution and subcellular localization, expression is induced rapidly in mitogen-stimulated T and B cells and different modes of inducibility of their expression by after stimulation.25,29 As a member of the dual-specificity protein 1Institute of Endemic Fluorosis Disease, Center for Endemic Disease Control, Center for Disease Control and Prevention, Harbin Medical University, Harbin, PRC; 2Departments of Orthopaedic Surgery and BME, Campbell Clinic, University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA; 3Mudanjiang Medical College, Mudanjiang, PRC; 4Division of connective Tissue Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA; 5Department of Veterans Affairs Medical Center, Memphis, TN, USA and 6Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. Correspondence: Professor D Sun, Institute of Endemic Fluorosis Disease, Center for Endemic Disease Control, Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, PRC. or Professor W Gu, Department of Orthopaedic Surgery–Campbell Clinic, University of Tennessee Health Science Center, 956 Court Ave, Memphis, TN 38163, USA. E-mail: [email protected] or [email protected] Received 16 August 2012; revised 8 October 2012; accepted 10 October 2012; published online 29 November 2012 Dual-specificity phosphatases 2 effect in diseases W Wei et al 2 Figure 1. The DUSP2 phosphorylation signaling pathways in immune cells. MAPKs are activated by stresses and phosphorylated on Tyr and Thr residues. The three-tiered kinase dynamic cascade leads to downregulation of MAPKs (Jnk, Erk1/2 and p38) activation and in the nucleus to transcription factor activation for cellular responses, such as cytokine production, apoptosis, proliferation, differentiation and inflammatory. Simultaneously, the same signal transduction pathways are triggered in macrophages and mast cells by TLR ligands and FceRI ligation, respectively. They induce the expression of the DUSP2 gene in the nucleus, resulting in the accumulation of DUSP2. DUSP2 may control Jun- Erk negative cross-talk in cells, inactivate and anchor Erk2, and it could dephosphorylate p38 in vivo and co-associates with another protein. Arrows indicate stimulation and red lines indicate inhibition within the pathway. phosphatase subfamily, DUSP2 inactivates its target kinases by with DUSP243 that includes the amino-terminal domain.44 DUSP2 dephosphorylating both the phosphoserine/threonine and has two conserved, positively charged amino-acid residues phosphotyrosine residues.8 It is a member of MKPs with protein (Arg294 and Arg295), which are important for binding to the tyrosine phosphatase and CH2 domains.13,30 Similar to the other phosphothreonine of Erk2.44 Mutation of either residue alone or in members of DUSP family, the function of DUSP2 has been combination lead to a nearly complete loss of Erk2-induced described as a typically negative regulator of MAPK signaling. catalytic activation of DUSP2 and its ability to dephosphorylate DUSP2 can preferentially dephosphorylate Erk1/2 and p38 but not Erk2.43 DUSP2 contributes to the dephosphorylation of protein Jnk in vitro.31,32 Although there have been reports of low kinase C-activated Erk2 in the nucleus, inactivating and anchoring phosphatase activity of DUSP2 for Jnk in vitro,31 DUSP2 it. DUSP2, together with DUSP1 and DUSP4, regulates Erk2 deficiency has led to increased activity of Jnk and unexpected dephosphorylation and compartmentalization in response to impairment of the activity of extracellular Erk and p38.4 The sustained protein kinase C-mediated signaling. Overexpression DUSP2 signaling pathways are shown in Figure 1. of DUSP2 prevents Erk2 activation and causes Erk2 nuclear Erk1/2 is phosphorylated on Tyr and Thr residues and activated accumulation or immunoprecipitation with Erk2.45 by growth factors such as platelet-derived growth factor,33,34 Similarly, p38 MAPK is phosphorylated on Tyr and Thr residues epidermal growth factor,33 nerve growth factor,35 and in response and, generally, is more responsive to stress stimuli.46 The p38 can to insulin.36,37 Activation of Erk1/2 has a central role in many be strongly activated by various environmental stresses, such as cellular responses, such as cell motility, proliferation, diffe- oxidative stress, ultraviolet irradiation, hypoxia and ischemia.47 rentiation and survival.38,39 Activation of the Erk pathway can P38 MAPKs have also been shown to have roles in cell protect pancreatic tumor cells from apoptosis and regulate their proliferation and survival. The a-subtype of p38 can negatively progression in the cell cycle.40 As the convergence point of most regulate cell-cycle progression and apoptosis.48,49 P38 also has an mitogenic signaling pathways, Erk is becoming an ideal target for important role in normal immune and inflammatory responses47