Dual-specificity phosphatases: critical regulators with diverse cellular targets

Abstract

DUSPs (dual-specificity phosphatases) are a heterogeneous group of protein phosphatases that can dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within the one substrate. DUSPs have been implicated as major modulators of critical signalling pathways that are dysregulated in various diseases. DUSPs can be divided into six subgroups on the basis of sequence similarity that include slingshots, PRLs (phosphatases of regenerating liver), Cdc14 phosphatases (Cdc is cell division cycle), PTENs (phosphatase and tensin homologues deleted on chromosome 10), myotubularins, MKPs (mitogen-activated protein kinase phosphatases) and atypical DUSPs. Of these subgroups, a great deal of research has focused on the characterization of the MKPs. As their name suggests, MKPs dephosphorylate MAPK (mitogen-activated protein kinase) proteins ERK (extracellular-signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 with specificity distinct from that of individual MKP proteins. Atypical DUSPs are mostly of low-molecular-mass and lack the N-terminal CH2 (Cdc25 homology 2) domain common to MKPs. The discovery of most atypical DUSPs has occurred in the last 6 years, which has initiated a large amount of interest in their role and regulation. In the past, atypical DUSPs have generally been grouped together with the MKPs and characterized for their role in MAPK signalling cascades. Indeed, some have been shown to dephosphorylate MAPKs. The current literature hints at the potential of the atypical DUSPs as important signalling regulators, but is crowded with conflicting reports. The present review provides an overview of the DUSP family before focusing on atypical DUSPs, emerging as a group of proteins with vastly diverse substrate specificity and function.

Activation of the mitogen-activated protein kinase (MAPK) signalling pathway in the liver of mice is related to plasma glucose levels after acute exercise

“…Microarray expression analysis indicated upregulation of dual-specificity phosphatase (DUSP) isoforms, which dephosphorylate MAPK. We studied the mRNA transcripts of Dusp1, which is expressed in high amounts in the liver, and Dusp6, the protein product of which shows high substrate specificity for ERK [29], and found a transient upregulation of mRNA levels of both phosphatase genes in the liver (Fig. 2i,j).…”

MAPK signaling in inflammation-associated cancer development

“…MAPKs can be negatively regulated by a group of DUSPs, all of which harbor an HCxxxxxR protein tyrosine phosphatase (PTP) motif (Patterson et al, 2009). DUSPs inactivate MAPK signaling by removing the phosphate group from the threonine and tyrosine residues.…”

Prevention of JNK Phosphorylation as a Mechanism for Rosiglitazone in Neuroprotection after Transient Cerebral Ischemia: Activation of Dual Specificity Phosphatase

“…Mitogen-activated protein kinase phosphatases, also known as dual-specificity phosphatases (DUSPs), can inactivate MAPKs via dephosphorylation. 8 Dual-specificity phosphatase 8 is abundantly expressed in the brain, heart, and lungs. 9 DUSP8 is reported to act specifically via JNK and p38 MAPK, unlike extracellular signal-regulated kinase.…”

“…9 DUSP8 is reported to act specifically via JNK and p38 MAPK, unlike extracellular signal-regulated kinase. 8 Recent reports show that TZDs modulate JNK expression and activity in cardiac ischemia reperfusion injury 10 and in insulinresistant brains, which results in reduction of tau phosphorylation. 11 Hence, we examined JNK and DUSP8 as possible mechanisms for the neuroprotective effect observed after treatment with rosiglitazone after cerebral ischemia.…”