Abstract
Protein tyrosine phosphatases have long been considered key regulators of biological processes and are therefore implicated in the origins of various human diseases. Heterozygosity, mutations, deletions, and the complete loss of some of these enzymes have been reported to cause neurodegenerative diseases, autoimmune syndromes, genetic disorders, metabolic diseases, cancers, and many other physiological imbalances. Vaccinia H1-related phosphatase, also known as dual-specificity phosphatase 3, is a protein tyrosine phosphatase enzyme that regulates the phosphorylation of the mitogen-activated protein kinase signaling pathway, a central mediator of a diversity of biological responses. It has been suggested that vaccinia H1-related phosphatase can act as a tumor suppressor or tumor-promoting phosphatase in different cancers. Furthermore, emerging evidence suggests that this enzyme has many other biological functions, such as roles in immune responses, thrombosis, hemostasis, angiogenesis, and genomic stability, and this broad spectrum of vaccinia H1-related phosphatase activity is likely the result of its diversity of substrates. Hence, fully identifying and characterizing these substrate-phosphatase interactions will facilitate the identification of pharmacological inhibitors of vaccinia H1-related phosphatase that can be evaluated in clinical trials. In this review, we describe the biological processes mediated by vaccinia H1-related phosphatase, especially those related to genomic stability. We also focus on validated substrates and signaling circuitry with clinical relevance in human diseases, particularly oncogenesis.
Highlights
Protein tyrosine phosphatases (PTPs) are highly catalytically active enzymes that counteract the actions of protein tyrosine kinases (PTKs)
atypical dual-specificity phosphatases (ADUSPs) possess the consensus catalytic domain of PTPs and typical dual-specificity tyrosine phosphatases (DUSPs), and this domain is responsible for their phosphatase activity
ADUSPs do not have the CH2 (Cdc25 homology 2) domain that is normally associated with typical DUSPs [5,8] and is responsible for their specificity for mitogen-activated protein kinases (MAPKs) [8,11,12]
Summary
Lilian Cristina Russo, Jessica Oliveira Farias, Pault Yeison Minaya Ferruzo, Lucas Falcao Monteiro, Fabio Luıs Forti*. Based on the presence of phosphorylatable tyrosine residues and what is known of the biological processes they regulate, experimental validation studies performed using cellular and biochemical assays suggested that nucleophosmin (NPM), nucleolin (NCL), and heterogeneous ribonucleoprotein isoforms C1/C2 (hnRNP C1/C2) are very likely to be VHR substrates [27] These proteins are tyrosine-phosphorylated in vivo and in vitro and could be potential targets of dephosphorylation by VHR, especially because they are involved in cell cycle regulation and genomic instability (DNA damage response and repair) processes [53,54,55,56]. This is the first evidence to show that natural compounds obtained from natural sources can have potential regulatory effects on PTPs/DUSPs during different cell biology and tissue developmental processes and suggest the possibility that they could be used to treat human pathologies [73]
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