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DUSP3/VHR: A Druggable Dual Phosphatase for Human Diseases

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Reviews of Physiology, Biochemistry and Pharmacology 176

Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 176))

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.

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Acknowledgments

This project was supported by FAPESP (Grants # 2008/58264-5 and # 2015/03983-0) and CNPq (Grant # 402230/2016-7) to FLF, head of the Laboratory of Signaling in Biomolecular Systems (LSBS). LCR is a senior postdoctoral fellow from the CAPES-PNPD program at the Institute of Chemistry, University of Sao Paulo. JOF is a PhD student fellow of Fapesp (# 2017/16491-4), and PYFM is a master’s fellow of CNPq, both enrolled at the postgraduation program in Biochemistry and Molecular Biology, Institute of Chemistry, University of Sao Paulo. LFM is a master’s fellow of CAPES at the Biotechnology program, also in University of Sao Paulo. All authors thank BO and JRD for technical assistance in the LSBS laboratory.

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Authors and Affiliations

  1. Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil

    Lucas Falcão Monteiro, Pault Yeison Minaya Ferruzo, Lilian Cristina Russo, Jessica Oliveira Farias & Fábio Luís Forti

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  1. Lucas Falcão Monteiro
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  2. Pault Yeison Minaya Ferruzo
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  3. Lilian Cristina Russo
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  4. Jessica Oliveira Farias
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  5. Fábio Luís Forti
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Correspondence to Fábio Luís Forti .

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  1. Heart Science Centre, The Magdi Yacoub Institute, Harefield, UK

    Pieter de Tombe

  2. Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians University of Munich, Munich, Germany

    Thomas Gudermann

  3. Department of Neurobiology , Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

    Reinhard Jahn

  4. Department of Cytobiology, University of Marburg, Marburg, Germany

    Roland Lill

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Monteiro, L.F., Ferruzo, P.Y.M., Russo, L.C., Farias, J.O., Forti, F.L. (2018). DUSP3/VHR: A Druggable Dual Phosphatase for Human Diseases. In: de Tombe, P., Gudermann, T., Jahn, R., Lill, R. (eds) Reviews of Physiology, Biochemistry and Pharmacology 176. Reviews of Physiology, Biochemistry and Pharmacology, vol 176. Springer, Cham. https://doi.org/10.1007/112_2018_12

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