Dual-specificity phosphatases: critical regulators with diverse cellular targets.
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.
Patterson
Kate I
KI
Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst 2010, Sydney, NSW, Australia. k.patterson@garvan.org.au
Brummer
Tilman
T
O'Brien
Philippa M
PM
Daly
Roger J
RJ
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D054640:Dual Specificity Phosphatase 3 / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000145:classification / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism
D018797:Cell Cycle Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D054638:Dual Specificity Phosphatase 1; D054640:Dual Specificity Phosphatase 3; D054637:Dual-Specificity Phosphatases; D008565:Membrane Proteins; D054639:Mitogen-Activated Protein Kinase Phosphatases; D051059:PTEN Phosphohydrolase; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C498627:DUSP13B protein, human; C522887:STYXL2 protein, human; C489855:dual specificity phosphatase 12; C525231:slingshot phosphatase 2, human; C120902:CDC14A protein, human; C474200:CDC14B protein, human; C084429:CDKN3 protein, human; C114064:DUSP11 protein, human; C498843:DUSP14 protein, human; C473895:DUSP18 protein, human; C477223:DUSP19 protein, human; C442824:DUSP22 protein, human; C497817:DUSP23 protein, human; C500883:DUSP26 protein, human; C517025:DUSP3 protein, human; C490198:PTP4A1 protein, human; C487561:PTP4A2 protein, human; C114990:EPM2A protein, human