Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Dual-Specificity Protein Phosphatases

  • Sheila Prabhakar
  • Swapna Asuthkar
  • Andrew J. Tsung
  • Kiran K. Velpula
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101694

Synonyms

Historical Background

In the 1980s, the regulatory role of protein phosphorylation in influencing cell growth, differentiation, and division was found to be mediated by the coordinated action of protein kinases and phosphatases. One particular family of protein ser/thr kinases, known as MAPKs, play key mitogen-activated protein kinases (MAPKs) play key regulatory roles by responding to various extracellular and intracellular stimuli and changes. By phosphorylating downstream targets including protein kinases and transcription factors, activated MAPKs regulate the transcription of MAPK-regulated genes, translation of proteins, and protein activity. The basic physiological processes of the cell growth and survival including cell division, differentiation, metabolism, motility, immunological processes and responses rely on MAPK pathways and cascades. Disruptions of MAPK signaling have been implicated in many diseases especially cancer. Protein kinases and their role in signal transduction and cell cycle regulation were discovered almost 10 years prior to phosphatases and began to be targeted as drug targets. So, what are dual specificity what are dual specificity protein phosphatases (DUSPs) and what is their association with kinases? While kinases attach a phosphate group to a protein, phosphatases remove the phosphate group. In other words, DUSPs appear to serve as negative regulators of MAPKs. DUSPs comprise a family of phosphatases with the unique ability to dephosphorylate both the threonine/serine and tyrosine residues of their substrate. The first phosphatase VH-1 was identified in the Vaccinia virus (Guan et al. 1991). Although the function of the protein was unknown, the researchers suggested that the open reading frame of the purified protein expressed in bacteria hydrolyzed substrates containing both phosphotyrosine and phosphoserine. The mechanism of hydrolysis by the vaccinia phosphatase suggested the role of an essential cysteine in the catalytic activity of both substrates. In 1993, a group investigating dual specificity phosphatases analogous to VH-I found highly conserved sequence homology in smallpox variola virus, orthopox virus, and baculovirus Autographa californica (Hakes et al. 1993). The role of DUSPs as a key cell cycle regulator was discovered by a study exploring the regulatory mechanism of human cyclin-dependent kinases (CDKs) in CDK/cyclin complexes. The S-phase progression of the cell cycle was regulated by CDK2 via phosphorylation on Thr-14 and Tyr-15, while CDC2/cyclin B1 was activated through treatment with phosphatases. They confirmed that Cdc25 family members comprise a class of dual-specificity phosphatases and that the phosphorylation-dephosphorylation play roles in the cell cycle by serving as check points (Sebastian et al. 1993). In the same year, MKP-1 (3CH134) was identified as a dual specificity phosphatase that dephosphorylates and inactivates p42 MAP kinase both in vitro and in vivo (Sun et al. 1993). Kinase-associated phosphatase (KAP), representing an additional class of DUSPs, which was able to bind multiple CDKs, was studied in yeast and in mammalian cells (Hannon et al. 1993). The role of DUSP in transcriptional regulation was established when the first human PTPase gene belonging to VH-1 like PTPase subfamily, CL100, was isolated and its promoter characterized. CL 100 gene expression was found to be inducible by mitogen stimulation and oxidative stress (Kwak et al. 1994). The PTPase motif in the catalytic region aligned with the catalytic domain of the aforementioned Cdc25. However, this study showed a second region of sequence homology to cdc25, the CH2 domain of the CL100 gene. The feature of dual-specificity phosphatases, a subfamily of PTPases, was identified as the ability to dephosphorylate phosphotyrosine and phosphoserine/threonine residues. The role of dual-specificity phosphatases in the downregulation of MAP kinase pathways was elucidated (Kortenjann and Shaw 1995) in a study investigating the molecular role of the family of MAP kinases. The enzymes encoded by the DUSPs were related to the PTPs by their possession of the conserved PTP motif, similarities of catalytic mechanism, and similarities in tertiary structure (Barford et al. 1998). In yeast and mammalian cells, KAP interacted with cdc2 and CDK2 however showed a preference for cdc2 in mammalian cells. A proposed model for MAP kinase inactivation by DUSPs showed that rapid transcription of one or more DUSPs were triggered by various factors including growth factors, cytokines and other cellular stresses (Camps et al. 2000). By 2000, nine mammalian DSP gene family members were identified all of which were implicated in inactivating MAP kinases: CL100/MKP-1 (adult rat brain), PAC1 (hematopoietic cells), hVH-2/MKP-2, hVH3/B23(adult rat brain), hVH-5 (brain, heart and skeletal muscle), MKP-3/PYST1 (adult rat brain) (same as rVH-6), B-59, MKP-4 (placenta, kidney, and embryonic liver), and MKP-5 (liver and skeletal muscle). Further, some of these were localized in the nucleus, while others were exclusively cytosolic. In the 1990s protein kinases were the focus of research, and by 2002, they were seen as major drug targets of the twenty-first century (Cohen 2002). In the first decade of the millennium, the role of protein phosphatases as key regulators in biological processes and therefore as drug targets was increasingly recognized.

Structure, Role, and Classification of DUSPs

Classification of DUSPs

The HUGO Gene Nomenclature Committee (HGNC) currently reports the DUSP gene family comprises 44 genes grouped into any one of the following six classes. There are approximately 18 atypical DUSPs, 4 CDC14 phosphatases, 11 MKPs, 3 PTPs, 5 PTENs, and 3 slingshot protein phosphatases within the DUSP family.

The six classes that DUSPs have been divided into include slingshots, PRLs (phosphatases of regenerating liver), Cdc14 phosphatases, PTENs, myotubularins, MKPs, and atypical DUSPs (Patterson et al. 2009).
  • Slingshot phosphatases are encoded by three genes and appear to play a role in actin polymerization. They have been found to contain the conserved PTP catalytic domain as well as the 14–3-3 binding motifs, a C-terminal F-actin (filamentous actin)-binding site, and a SH3 (Src homology 3) binding motif.

  • Phosphatase of regenerating liver (PRL): There are three PRLs shown to be overexpressed in cancer cells especially in metastasis. They are being explored as targets for cancer therapy.

  • Cdc14 phosphatases: There are four Cdc14 phosphatases which play major roles in the phases of cell cycle including regulation of initiation of mitosis, DNA damage checkpoint control, centrosome maturation, spindle stability, cytokineses with a role in inhibition of cell cycle progression.

  • Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylate D3-phosphorylated inositol phospholipids. There are 16 myotubularin phosphatases whose role is not yet fully known and five PTEN-like phosphatases implicated in cancers with effects in proliferative and survival signaling.

  • Mitogen-activated protein kinase phosphatases (MKPs) are named after the MAPKs. They dephosphorylate MKPs and dephosphorylate MAPKs at both phosphothreonine and phosphotyrosine residues simultaneously. Ten proteins have been identified in this best studied group of DUSPs. Even in resting or unstressed cells, MKPs are known to be expressed at low levels and upon stimulation can increase expression very rapidly. The same MKP can have different effects and levels of effects depending on the type of cell and context. They play key roles as regulators in signaling pathways. MKPs are subject to posttranslational modification, sensitive to reversible oxidation and inactivation, can be phosphorylated directly by their substrates and implicated in many diseases. MKPs have been found to play double roles based on the cancer type. They work as tumor promoters in some and as tumor suppressors in others and are used as biomarkers in specific cancers.

  • Atypical DUSPs: There are 16 atypical DUSPs characterized by being smaller and lacking the CH2 domain in the N-terminus that is common with typical DUSPs. Atypical DUSPs targeting protein substrates play roles in the MAPK pathway and other pathways. There are others that target nonprotein substrates and some act as scaffold proteins. Atypical DUSPs have been implicated in normal cell functions including cellular proliferation, metabolism, and differentiation and play roles in inflammation, diabetes, and cancer.

A former method of classification used to classify 25 human DUSP genes was based on amino acid alignment. DUSPs have been divided into two groups based on the presence or absence of the MKB/KIM domain into typical DUSPs (or MKPs) and atypical DUSPs, respectively (Huang and Tan 2012). Based on subcellular localization, typical DUSPs have been further grouped into nuclear, cytoplasmic, and dually located DUSPs (Huang and Tan 2012).

Structure

A recent study explored the structure and function of several DUSP family proteins using homology modeling and experimental structure determination. The specificity of the substrate with various DUSPs was found to be a function of the active site loop to strand switch. Further, it was shown that cysteine residues help protect enzyme activity (Jeong et al. 2014).

Catalytic Mechanism

All DUSPs contain a common phosphatase domain with conserved aspartic acid, cysteine, and arginine residues in the catalytic site. The catalytic mechanism of DUSP was first investigated in a study that used VHR as a model enzyme for the DUSP family (Zhou et al. 1994). Experimental evidence suggested that the putative active site cysteine, Cys 124, is required for forming a thiol-phosphate-enzyme intermediate during catalysis. A recent review of DUSP structure presents a clear mechanism of catalytic activity (Rios et al. 2014). In the first step of dephosphorylation, a thiol-phosphate covalent transient intermediate is formed using the catalytic cysteine. In the second step, the conserved Asp acts a general base activating a water molecule which hydrolyzes the intermediate complex, releasing the phosphate. Amino acid sequence alignment of 10 catalytically active MKPs, 13 atypical DUSPs, and 3 PRLs reveal three structural loops: the P-loop (which includes the conserved catalytic Cys), the WPD-loop which includes the catalytic Asp, and the TI/Q-loop which includes the residues that interact with the structural water molecule (Rios et al. 2014). However, there is variability in the length and amino acid composition of the WPD and the TI/Q-loop. For example, in PTENs and PRL-3, the WPD-loop Asp residue does not interact/participate with nonproteinaceous substrates. As noted above, understanding the structural similarities and differences in DUSP structure is critical in designing DUSP-catalytic inhibition strategies.

Regulation of DUSPs

The DUSPs that play a role in the three major MAPK pathways are depicted below (Fig. 1). As observed from the diagram, MKPs play pivotal roles as coordinators of MAPK signaling and crosstalk. They are not simple feedback regulators, as previously thought. Some of the areas still unclear include how MKPs maintain spatial control of MAPK signaling, the interplay between delayed transcriptional feedback by MKPs in the nucleus and posttranslational feedback loops like ERK phosphorylation of RAF in the cytoplasm (Caunt and Keyse 2013). DUSPs have also been implicated as regulators of non-MAPK protein targets including STAT, histone, and FAK. Atypical DUSPs are known to have the most varied substrate specificity and as such have other protein and nonprotein (RNA) substrates. Some atypical DUSPs such as DUSP 19, 22, and 23 do not directly effect their targets through catalytic activity but are scaffold proteins affecting interaction of signaling proteins (Patterson et al. 2009) (Fig. 1).
Dual-Specificity Protein Phosphatases, Fig. 1

Various DUSPs and their roles in the major MAPK pathways and non-MAP kinase targets in mammalian cells. The direction of the arrows indicate the pathway the DUSP is implicated in and the color of the arrows suggest the role as a transcriptional activator/upregulation (green) or downregulation (red)

The three main mechanisms of DUSP regulation include (Patterson et al. 2009; Huang and Tan 2012)
  • Regulation at the transcriptional level – DUSPs are often regulated through a negative feedback mechanism, which is directly dependent on MAPK activation. One of the most important regulators of nuclear DUSPs is p53, which regulates the transcription of all four nuclear DUSPs. Epigenetic modifications and microRNA-medicated gene silencing also serve to regulate DUSPs.

  • Regulation at the post-translational level via chemical modification – Myristoylation and/or phosphorylation are examples of the post-translational modifications that serve to stabilize DUSP expression levels. When MAP kinases phosphorylate DUSPs, they are protected from degradation by the proteasomes and half-life can be prolonged.

  • Regulation of protein activity via catalytic activation/inhibition – The catalytic activity of DUSPs can be enhanced or inhibited as an additional form of regulation. Activity of some DUSPs is enhanced upon binding to the MAPK substrate. DUSPs can compete with MAP kinase substrates for binding with MAP kinases. The cysteine residue in the catalytic site, which is subject/sensitive to reversible oxidation of the DUSP, often renders it inactive. During this process, there is the production of reactive oxygen species (ROS).

One of the interesting features of DUSP regulation is a dramatic transcriptional induction by growth factors or factors that induce cellular stress, seen especially in leucocytes. DUSPs respond to various stimuli differently depending upon the type of cell and context. Another level of regulation occurs through the control of protein expression. Activation of some DUSPs occurs following binding to their substrates. Reversible oxidation provides a mode for activation or deactivation of some DUSPs. Some DUSPs can control the subcellular localization of MAPKs. DUSPs appear to show substrate specificity although this may depend upon the cell type and type of stimulus. The efficacies of any two DUSPs in dephosphorylating a given MAPK may differ.

Role of DUSPs in Human Health and Disease

As observed earlier, MAPKs are implicated in physiological processes of cell growth and function including embryogenesis, immunity, cardiac function, neuronal plasticity, and metabolism. By dephosphorylating and therefore inactivating MAPKs, DUSPs (MKPs) play a critical role in the MAPK pathways, which in turn affects the cell’s response to external and internal stimuli. When the expression and/or function of DUSPs is pathologically altered, or when DUSPs are mutated, it leads to disease. Although it may seem simple to target a specific DUSP implicated in a specific disease, the growing body of knowledge on DUSPs suggests a complex web of stringent regulation, which affects multiple signal transduction partners and feedback control mechanisms, making their validation as drug targets difficult. Understanding the full extent of DUSPs implicated in human health and disease has led to the proposal/development of drugs that target DUSPs. The disorders that DUSPs have been implicated in include tumor-related, neurological, and muscle disorders, and cardiovascular and inflammatory diseases (Table 1).
Dual-Specificity Protein Phosphatases, Table 1

Role of DUSPs in Human Health and Disease

DUSP/s

General category of disease

Details of DUSP implicated in specific diseases

Reference

DUSP1

Allergies

Allergies to house dust mite

Golebski et al. 2015

DUSP1, DUSP 5

Bone-related disorders

DUSP1 (osteolytic lesions in arthritis), DUSP 5 (rheumatoid arthritis)

Vattakuzhi et al. 2012;

Moon et al. 2014

DUSP1, DUSP4, DUSP6, DUSP26

Cancers

Brain cancers

Prabhakar et al. 2014

DUSP1, DUSP2, DUSP6, DUSP7, DUSP26

DUSP1 (breast, prostate, ovarian) DUSP2 (ovarian cancer and leukemia), DUSP6 (pancreatic cancer, DUSP7 (AML), DUSP26 (certain cancers)

Jeffrey et al. 2007

DUSP28

human hepatocellular carcinoma

Wang et al. 2014

DUSP 6

Stomach cancer

Liu et al. 2013

DUSP4 and DUSP10

Colorectal cancer

DeVriendt et al. 2013; Zhang et al. 2014

DUSP2

Various cancers

Wei et al. 2013

DUSP5 and 6

Endocrine/hormonal function

severe hyperparathyroidism

Roman-Garcia et al. 2012

DUSP1 (MKP1), DUSP6 (MKP2), PTEN, PTP4A1 (PRL-1), MTM1, MTMR2, MTMR3, MTMR7, MTMR9, MTMR13, MTMR14

Hereditary disorders

DUSP1 (MKP1), DUSP6 (MKP2), PTEN, PTP4A1 (PRL-1), MTM1, MTMR2 (Charcot-Marie-Tooth Disease), MTMR3 (lung and gastric cancer and early onset inflammatory bowel disease), MTMR7 (risk to variant Creutzfeudlt-Jakob disease), MTMR9 (susceptibility to metabolic syndrome and obesity), SBF2 or MTMR 13 (Charcot-Marie Tooth Disease 4B2), MTMR14 (Autosomal centronuclear myopathy), EPM2A (laforin) – myoclonic epilepsy of Lafora

Hendriks and Pulido 2013

Cdc25A and B

MKP-1

Neurodegenerative

Alzheimer’s Disease and cancers

Huntington’s Disease

Ducruet et el. 2005; Taylor et al. 2013

DUSP 5

Vascular development and disease

infantile hemangioma

Pramanik et al. 2009

Inhibitors of DUSPs – Targets for Therapy

As the knowledge of DUSPs grew, the potential use of DUSP inhibitors became a viable option for treating diseases caused by overexpression. Therefore, MAPK-dephosphorylating DUSPs are emerging as targets in treating diseases implicated by DUSP regulation. Sodium orthovanadate was the first DUSP inhibitor used in the 1990s. By 2002, several natural product inhibitors, synthetic derivatives of natural products, and synthetic inhibitors were identified as potent inhibitors of DUSPs (Lyon et al. 2002). The initial challenge of the geometrically shallow and hydrophilic nature of the catalytic domain of DUSPs was overcome by targeting the KIM-MAPK interactions using small-molecule inhibitors. Other approaches proposed for DUSP inhibition have included RNA interference and antisense approaches (Jeffrey et al. 2007). The first study to assess individual DUSP-knockout to test the effects on ERK2 regulation revealed a surprisingly large number of DUSPs responsible for the independent regulation of the ERK2 signaling pathway. Because many MKP-DUSPs are bivalent (i.e., having oncogenic or tumor-suppressing functions depending on cell type and signaling context), direct inhibition of DUSPs in cancer seems challenging. A list of MKP-DUSP expression by cancer type, specific inhibitors used in therapy, and their sensitivity to therapy was compiled by Nunes-Xavier et al. (2011). In an extensive review on DUSPs published in 2012, the authors highlighted reasons why DUSPs make novel targets in medical research and treatment of conditions implicated by DUSPs: their small size and simple domain structure makes pharmacological inhibition of DUSPs successful and effects are likely to be safer, milder, and less dramatic, due to compensatory effects from other DUSPs (Huang and Tan 2012).

Kinases from three major MAPK pathways, including MAPK ERK1/2, p38s, and JNKs, are rendered inactive through the dephosphorylation by DUSPs. Therefore, DUSP enzyme inhibitors seem to be promising targets for use in diseases such as cancer, which involves the overexpression or hyperactivity of a DUSP. Rios et al. (2014) listed the active MKPs and small-sized atypical DUSPs, their substrates, and their representative inhibitors projected to have therapeutic benefits in human disease. This review also discusses the emerging alternative strategies used for DUSP inhibition. Oxidation, differential redox regulation, reversible oxidation, antibody and gene therapies, farnesylation inhibition, and PRL-inhibitory strategies all exist to inhibit DUSP. These inhibition strategies can be used singly or as combination therapies. A recent review provides an updated list of inhibitors of DUSPs that belong to MAPK phosphatases, which can be used to prevent or mitigate human disease. However, several challenges are yet to be overcome before DUSP-inhibitor-based treatments can be clinically validated. Knockout mice, structure-affinity studies, and chemical library screening were used to identify small-molecule inhibitors of Vaccinia H1-related (VHR) phosphatase, also known as dual-specificity phosphatase (DUSP) 3. Examples of small-molecule inhibitors include SA3, RK-682, GATPT, and MLS 0437605 (Pavic et al. 2015). Korotchenko et al. (2014) explored the inhibition of DUSP by a specific inhibitor via structure-activity relationship. They were able to synthesize a series of 26 analogs with modifications in four functional groups of the pharmacophore. In vivo studies using transgenic zebrafish were confirmed by in vitro studies. Salubrinal acts as a DUSP2 inhibitor and suppresses inhibition in anticollagen, antibody-induced arthritis (Hamamura et al. 2015). The crystal structure of DUSP7, a potential drug target for certain types of cancers, has been been determined (Lountos et al. 2015). A further understanding of the challenges arising from specific structural features associated with the active site is needed to develop DUSP7 inhibitors (Lountos et al. 2015). This class of enzymes was considered “undruggable” due to the highly conserved structure and charged and reactive catalytic site but has now become a focus of drug targets (Hoekstra et al. 2016).

Summary

Protein kinases, including the MAPKs have long been implicated in cellular growth, differentiation, division, and metabolism. It was only in the early 1990s that the critical role of new group of enzymes, protein phosphatases, and more specifically, DUSPs, was discovered as playing regulatory roles by dephosphorylating kinases part of MAPK pathways. The human genome encodes about 44 DUSPs named for their ability to dephosphorylate both tyrosine and serine/threonine residues within one substrate. DUSPs are subdivided into six subgroups based on sequence similarity, substrate specificity, and physiological role. The six groups are as follows: Slingshots, PRLs, CDC14s, PTENs and Myotubularins, MKPs, and atypical DUSPs. Some DUSPs are known to occur in the nucleus, others in the cytoplasm, while some are dually located. In cells that are at rest, they are known to be expressed at low levels, but upon stimulation, can be very rapidly transcribed. The mechanisms of DUSP regulation suggest that DUSPs are regulated at the transcriptional level, post-translational level, and protein activity level. The phosphatase domain of a DUSP contains a conserved aspartic acid, cysteine, and arginine residues in the catalytic site. Dephosphorylation occurs when the catalytic cysteine participates in the formation a thiol-phosphate covalent transient intermediate. Ever since the role of DUSPs as key regulators of MAPKs began to emerge, researchers explored the role of DUSPs in diseases. Research of DUSPs implicated in diseases till date has revealed that specific DUSPs serve as tumor promoters or tumor suppressors in various cancers depending on the type of cell or signaling context. This feature makes it difficult to target DUSPs in cancer treatment by direct inhibition. DUSPs have also been implicated in neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, various brain cancers, hereditary disorders, and endocrine disorders and even in allergic responses. Although DUSPs began to be targeted in treating diseases associated with MAPK-phosphatase regulation a decade later than when kinases were prominent, they seem to be more desirable for targeting because of features including their diversity in structure, specificity, and function and small-size and safe application with fewer side effects. It must be noted that DUSPs not only target MAPKs but other regulators including STATs, histones, etc., and their complexity in signal regulation is likened to that of a neuron network. Many strides have been made in the field of development of DUSP-inhibitors so far, and current work continues to focus on in vivo efforts to validate the in vitro results. Knock-out studies, structure-affinity, and chemical screening methods are used in identifying inhibitors. Understanding the catalytic activity of DUSPs helps exploit them as drug targets through oxidation, differential redox regulation, reversible oxidation, antibody and gene therapies, farnesylation inhibition, and PRL-inhibitory strategies. Some of these inhibition strategies can be used singly or as combination therapies. In conclusion, this review provides a general overview of the classification, structure, function, and the regulatory role of DUSPs in human health and disease and presents a short update on how DUSPs are being explored as targets in cancer treatment and therapy.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Sheila Prabhakar
    • 1
  • Swapna Asuthkar
    • 2
  • Andrew J. Tsung
    • 2
    • 3
  • Kiran K. Velpula
    • 2
    • 3
  1. 1.College of Natural and Health SciencesSoutheastern UniversityLakelandUSA
  2. 2.Department of Cancer Biology and PharmacologyUniversity of Illinois College of Medicine at PeoriaPeoriaUSA
  3. 3.Department of NeurosurgeryUniversity of Illinois College of Medicine at PeoriaPeoriaUSA