Critical Roles of Dual-Specificity Phosphatases in Neuronal Proteostasis and Neurological Diseases

Abstract

Protein homeostasis or proteostasis is a fundamental cellular property that encompasses the dynamic balancing of processes in the proteostasis network (PN). Such processes include protein synthesis, folding, and degradation in both non-stressed and stressful conditions. The role of the PN in neurodegenerative disease is well-documented, where it is known to respond to changes in protein folding states or toxic gain-of-function protein aggregation. Dual-specificity phosphatases have recently emerged as important participants in maintaining balance within the PN, acting through modulation of cellular signaling pathways that are involved in neurodegeneration. In this review, we will summarize recent findings describing the roles of dual-specificity phosphatases in neurodegeneration and offer perspectives on future therapeutic directions.

Keywords: ER stress; autophagy; dual-specificity phosphatases; heat shock response; neuron; oxidative stress; protein aggregates; protein homeostasis.

Figure 1

The schematic classifications of human dual-specificity phosphatases. Phosphatases are classified into seven gene families, of which Protein Phosphatases are one. They are further categorized into five groups, which includes Class I classical Cys-based Phosphatases. This group is then subdivided into dual-specificity phosphatases, Receptor-type Protein Tyrosine Phosphatases, and Non-receptor-type Protein Tyrosine Phosphatases. Dual-specificity Phosphatases are categorized by six subfamilies: (i) Mitogen-activated Protein Kinase Phosphatases (MKP); (ii) Atypical DUSPs; (iii) Slingshot Protein Phosphatases; (iv) Protein Tyrosine Phosphatases type IVA; (v) CDC14 Phosphatases and (vi) PTEN Protein Phosphatases. Members of each subfamily are as listed in the figure. Data are adapted from the HUGO Gene Nomenclature Committee at the European Bioinformatics Institute, http://www.genenames.org/.

Figure 2

Structural features of typical members from each DUSP subfamily. (a–f) Molecular representations of typical member from each DUSP subfamily using data available from Protein Data Bank (PDB) and redrawn using Avogadro: an open-source molecular builder and visualization tool, version 1.XX, http://avogadro.cc/. Cyan color on the structure indicates helix, yellow color indicates sheet, and brown color represents loop structures; (a) Image of 1M3G represents DUSP2 structure [20] of the MKP subfamily; (b) Image of 3F81 represents DUSP3 structure [21] of the atypical-DUSP subfamily; (c) Image of 2NT2 represents SSH2 structure [22] of the slingshot phosphatase subfamily; (d) Image of 1XM2 represents PTP4A1 structure [23] of the PTP4A phosphatase subfamily; (e) Image of 1OHC represents CDC14A structure [24] of the CDC14 phosphatase subfamily; (f) Image of 1D5R represents PTEN structure [25] of the PTEN phosphatase subfamily; (g) Domain representation of typical member of each DUSP subfamily: DUSP2, DUSP3, SSH2, PTP4A1, CDC14A and PTEN created from data available on InterPro [26] (not drawn-to-scale). Abbreviations of domains listed in the figure include, PTP-like: Protein tyrosine phosphatase-like; DSPc: Dual-specificity phosphatase, catalytic; DSP-N: Dual-specificity phosphatase, N-terminal. Numbers on the right side indicate amino acid length. It should be noted that variations exist in individual members from each subfamily in presence/absence of protein domains and taken into consideration. For further information on protein domains of an individual DUSP, please refer to Table 1 and [27]; (h) Multiple sequence alignment of typical members of each DUSP subfamily: DUSP2, DUSP3, SSH2, PTP4A1, CDC14A and PTEN. Amino acid sequences were obtained from UniProt [28], and aligned using Clustal Omega at EMBL-EBI [29,30]. Blue box indicates the conserved catalytic DUSP motif (V)-HC-XX-X-XX-R-(S/T), where X represents any amino acid; (:) indicates conservation between groups of strongly similar properties; (*) indicates a conserved residue; (.) indicates conservation between groups of weakly similar properties.

Figure 2

Structural features of typical members from each DUSP subfamily. (a–f) Molecular representations of typical member from each DUSP subfamily using data available from Protein Data Bank (PDB) and redrawn using Avogadro: an open-source molecular builder and visualization tool, version 1.XX, http://avogadro.cc/. Cyan color on the structure indicates helix, yellow color indicates sheet, and brown color represents loop structures; (a) Image of 1M3G represents DUSP2 structure [20] of the MKP subfamily; (b) Image of 3F81 represents DUSP3 structure [21] of the atypical-DUSP subfamily; (c) Image of 2NT2 represents SSH2 structure [22] of the slingshot phosphatase subfamily; (d) Image of 1XM2 represents PTP4A1 structure [23] of the PTP4A phosphatase subfamily; (e) Image of 1OHC represents CDC14A structure [24] of the CDC14 phosphatase subfamily; (f) Image of 1D5R represents PTEN structure [25] of the PTEN phosphatase subfamily; (g) Domain representation of typical member of each DUSP subfamily: DUSP2, DUSP3, SSH2, PTP4A1, CDC14A and PTEN created from data available on InterPro [26] (not drawn-to-scale). Abbreviations of domains listed in the figure include, PTP-like: Protein tyrosine phosphatase-like; DSPc: Dual-specificity phosphatase, catalytic; DSP-N: Dual-specificity phosphatase, N-terminal. Numbers on the right side indicate amino acid length. It should be noted that variations exist in individual members from each subfamily in presence/absence of protein domains and taken into consideration. For further information on protein domains of an individual DUSP, please refer to Table 1 and [27]; (h) Multiple sequence alignment of typical members of each DUSP subfamily: DUSP2, DUSP3, SSH2, PTP4A1, CDC14A and PTEN. Amino acid sequences were obtained from UniProt [28], and aligned using Clustal Omega at EMBL-EBI [29,30]. Blue box indicates the conserved catalytic DUSP motif (V)-HC-XX-X-XX-R-(S/T), where X represents any amino acid; (:) indicates conservation between groups of strongly similar properties; (*) indicates a conserved residue; (.) indicates conservation between groups of weakly similar properties.

Figure 3

A proposed working model showing the involvement of DUSPs in pathways of proteostasis that contribute to neurodegeneration. A simplified version of proteostasis is represented under three central themes—protein biogenesis, protein quality control processes, and protein degradation. In this article, we highlight the role of DUSPs in protein quality control and breakdown, with respect to neurological disorders. Protein translation, folding, and transport occur largely within the endoplasmic reticulum (ER). An increased load of misfolded proteins in the ER evokes the ER stress response, and several DUSPs have been shown to participate in this pathway of proteostasis. Next, protein aggregates are the by-products of accumulated misfolded proteins and represent the hallmarks of many neurodegenerative diseases. DUSPs participate in phosphorylation-dependent modulation of protein aggregation mostly by regulating MAPK and related signaling pathways. Reactive oxygen species (ROS) production is often triggered in response to protein aggregates and results in oxidative stress. DUSPs participate in the oxidative stress response (OxR), and may have protective or aggravating roles, depending on the phosphatase. Further, DUSPs have a confirmed involvement in the heat shock response (HSR) pathway by either self-modulation or by direct interaction with the heat shock proteins/molecular chaperones. Heat shock proteins assist misfolded and aggregated proteins to refold and attain their native conformation. Proteins which fail to refold even after assistance from the heat shock response pathway, may then be degraded (indicated by dotted arrow). Finally, autophagy is the major degradation route for toxic-protein aggregates, and is known to be influenced by some DUSPs. When individual cells become overwhelmed by proteotoxic stress, they may enter apoptosis. The initiation of the apoptotic cascade is also known to be influenced by certain DUSPs.