DUSP3/VHR: A Druggable Dual Phosphatase for Human Diseases

Abstract

Protein tyrosine kinases (PTK), discovered in the 1970s, have been considered master regulators of biological processes with high clinical significance as targets for human diseases. Their actions are countered by protein tyrosine phosphatases (PTP), enzymes yet underrepresented as drug targets because of the high homology of their catalytic domains and high charge of their catalytic pocket. This scenario is still worse for some PTP subclasses, for example, for the atypical dual-specificity phosphatases (ADUSPs), whose biological functions are not even completely known. In this sense, the present work focuses on the dual-specificity phosphatase 3 (DUSP3), also known as VH1-related phosphatase (VHR), an uncommon regulator of mitogen-activated protein kinase (MAPK) phosphorylation. DUSP3 expression and activities are suggestive of a tumor suppressor or tumor-promoting enzyme in different types of human cancers. Furthermore, DUSP3 has other biological functions involving immune response mediation, thrombosis, hemostasis, angiogenesis, and genomic stability that occur through either MAPK-dependent or MAPK-independent mechanisms. This broad spectrum of actions is likely due to the large substrate diversity and molecular mechanisms that are still under scrutiny. The growing advances in characterizing new DUSP3 substrates will allow the development of pharmacological inhibitors relevant for possible future clinical trials. This review covers all aspects of DUSP3, since its gene cloning and crystallographic structure resolution, in addition to its classical and novel substrates and the biological processes involved, followed by an update of what is currently known about the DUSP3/VHR-inhibiting compounds that might be considered potential drugs to treat human diseases.

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

“…In the cell, DUSP26 is located predominantly in the nucleus, although weak staining has been observed in the cytoplasm, whereas DUSP13A and DUSP13B and DUSP29 are cytosolic proteins [ 26 , 27 ]. DUSP3 also localises to the nucleus and cytoplasm and, unlike most other aDUSPs, both DUSP3 and DUSP26 have a broad range of MAPK and non-MAPK substrates [ 9 ]. Their sequence similarity and broad functions might suggest a role of DUSP3 and DUSP26 in overlapping physiological processes.…”

“…The absence of the MBD in the aDUSPs suggests that (i) they can dephosphorylate non-MAPK substrates and (ii) alternative regulatory mechanisms are in place to regulate their function. This is highlighted by DUSP3, the most researched aDUSP (recently reviewed by [ 9 , 23 , 24 ]). Although DUSP3 is able to dephosphorylate ERK, JNK and p38, it can also dephosphorylate tyrosine residues of non-MAPK substrates such as STAT5, EGFR and FAK [ 9 ].…”

“…This is highlighted by DUSP3, the most researched aDUSP (recently reviewed by [ 9 , 23 , 24 ]). Although DUSP3 is able to dephosphorylate ERK, JNK and p38, it can also dephosphorylate tyrosine residues of non-MAPK substrates such as STAT5, EGFR and FAK [ 9 ]. Moreover, where the MKPs are upregulated transcriptionally by MAPK signalling and translationally by MAPK binding, DUSP3 is unaffected by MAPK signalling and its catalytic activity is increased by binding to a range of non-MAPK proteins [ 9 , 25 ].…”

Dual-Specificity Phosphatases in Neuroblastoma Cell Growth and Differentiation

“…DUSP3 (VHR) is the prototype of small-size atypical DUSPs, and displays substrate specificity towards ERK1/2 and JNKs. However, some other proteins, including STAT5, FAK, growth factor receptors, and nuclear proteins regulating DNA damage repair, have been shown to be tyrosine-dephosphorylated by DUSP3 and have been proposed as DUSP3 physiological substrates [ 110 , 137 ]. As mentioned for other MKPs, DUSP3 mRNA was upregulated in SH-SY5Y cells differentiated in the presence of AgNP [ 61 ], as well as on SH-SY5Y or SMS-KCNR cells differentiated by RA ( Figure 2 B, bottom panel), but the potential role of DUSP3 in NB cell growth and differentiation remains unexplored.…”

Estudos funcionais e biológicos associados à interação de DUSP3 com a proteína HNRNPC1/C2

“…Sob condições específicas, algumas proteínas cinases (Tyr ou Ser / Thr) podem fosforilar DUSP3 aumentando sua atividade fosfatase (em azul à direita) em seus substratos. Tomado de Monteiro et al 2018. DUSP3 é uma das aDUSPs mais estudadas, devido à sua implicação em câncer.…”