A Review of DUSP26: Structure, Regulation and Relevance in Human Disease

Abstract

Dual specificity phosphatases (DUSPs) play a crucial role in the regulation of intracellular signalling pathways, which in turn influence a broad range of physiological processes. DUSP malfunction is increasingly observed in a broad range of human diseases due to deregulation of key pathways, most notably the MAP kinase (MAPK) cascades. Dual specificity phosphatase 26 (DUSP26) is an atypical DUSP with a range of physiological substrates including the MAPKs. The residues that govern DUSP26 substrate specificity are yet to be determined; however, recent evidence suggests that interactions with a binding partner may be required for DUSP26 catalytic activity. DUSP26 is heavily implicated in cancer where, akin to other DUSPs, it displays both tumour-suppressive and -promoting properties, depending on the context. Here we review DUSP26 by evaluating its transcriptional patterns, protein crystallographic structure and substrate binding, as well as its physiological role(s) and binding partners, its role in human disease and the development of DUSP26 inhibitors.

Tubular IKKβ Deletion Alleviates Acute Ischemic Kidney Injury and Facilitates Tissue Regeneration

“…These time differences in cell proliferation are in line with transient cell cycle arrest, which was shown to be protective in acute kidney injury [ 31 ]. Furthermore, in agreement with the observation of diminished fibrosis and collagen 3 expression, we observed higher Dusp26 mRNA level at 14 days after I/R injury in IKKβ ∆Tub compared to control, which was presented earlier to reduce ROS formation and fibrosis [ 32 ]. In addition, mRNA of fibrosis promoting factors such as Adam19 [ 23 ], P2rx7 [ 33 ] and fibrinogen subunits Fga, Fgb and Fgg [ 34 , 35 ] were significantly reduced in IKKβ ∆Tub compared to control at 14 days after I/R injury supporting the important role of IKKβ in ameliorating the renal outcome in the long-term after I/R injury.…”

An Unconventional Ligand for Scribble PDZ-4 Domain Mediates Its Interaction with Dusp26

“…Despite the fact that Dusp26, as many other phosphatases, has been considered an "undruggable" target, three chemical inhibitors of Dusp26 have been reported in literature. However, it is unlikely that they will be used clinically, mainly due to their off-target effects [32]. Our findings might be of particular interest in the development of novel and selective Dusp26 inhibitors for therapeutic applications.…”

“…Dusp26 is an atypical dual-specificity phosphatase with numerous MAPK and non-MAPK substrates [32]. Several lines of evidence suggest that Dusp26 targets are recruited through adaptor proteins that connect the phosphatase to the substrates [17,[33][34][35]].…”

“…Atypical dual-specificity phosphatases are becoming more and more relevant as their complex network is further elucidated, and they seem to be promising drug targets to reprogram MAPK-dependent pathways altered in diseases [32,48]. However, the molecular mechanism that determines the target specificity of these enzymes is far from being elucidated, and too often the exact dephosphorylated residue is unknown, as is the phosphatase region that allows for the recognition.…”

Mouse hybrid genome mediates diverse brain phenotypes with the specificity of reciprocal crosses

“…Our findings demonstrated the impact of cell‐type on the status of genomic imprinting in the brain. Regarding the functions and functional consequences of the genes: DUSP26 regulates intracellular signaling pathways and is heavily implicated in cancer 67 ; ENPP1 hydrolyses ATP and is mainly implicated in mineralization disorders and soft‐tissue calcification 68 ; NDUFS7 mediates mitochondrial electron transport and is involved in cancer 69 ; and PLCG1 regulates the dynamics of the actin cytoskeleton and is involved in kidney and brain development 70 . Moreover, knockout mice for all four genes are available in the International Mouse Strain Resource (http://www.findmice.org/index).…”