Abstract
Dual-specificity protein phosphatases comprise a protein phosphatase subfamily with selectivity towards mitogen-activated protein (MAP) kinases, also named MKPs, or mitogen-activated protein kinase (MAPK) phosphatases. As powerful regulators of the intensity and duration of MAPK signaling, a relevant role is envisioned for dual-specificity protein phosphatases (DUSPs) in the regulation of biological processes in the nervous system, such as differentiation, synaptic plasticity, and survival. Important neural mediators include nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) that contribute to DUSP transcriptional induction and post-translational mechanisms of DUSP protein stabilization to maintain neuronal survival and differentiation. Potent DUSP gene inducers also include cannabinoids, which preserve DUSP activity in inflammatory conditions. Additionally, nucleotides activating P2X7 and P2Y13 nucleotide receptors behave as novel players in the regulation of DUSP function. They increase cell survival in stressful conditions, regulating DUSP protein turnover and inducing DUSP gene expression. In general terms, in the context of neural cells exposed to damaging conditions, the recovery of DUSP activity is neuroprotective and counteracts pro-apoptotic over-activation of p38 and JNK. In addition, remarkable changes in DUSP function take place during the onset of neuropathologies. The restoration of proper DUSP levels and recovery of MAPK homeostasis underlie the therapeutic effect, indicating that DUSPs can be relevant targets for brain diseases.
Highlights
Dual-specificity phosphatases (DUSPs) comprise a family of protein tyrosine phosphatases (PTPs) with wide substrate selectivity and are known as powerful regulators of biological processes
In studies performed in primary cultures of neurons and astrocytes, neuroprotection is achieved by restoring accurate DUSP expression levels and activity to counteract the pro-apoptotic activation of p38- and Jun N-terminal kinase (JNK)-mediated signaling
It is not surprising to find striking changes in the expression levels and activity of these phosphatases in neurodegenerative diseases, as occurs with the downregulation of DUSP1 and DUSP6 in Alzheimer s disease (AD) and Huntington’s disease (HD). In these conditions, sustained changes in mitogen-activated protein kinase (MAPK) accumulate over time and are responsible for several of the toxic events related to neurodegeneration, such as apoptosis, protein aggregation, and changes in cytoskeletal dynamics
Summary
Dual-specificity phosphatases (DUSPs) comprise a family of protein tyrosine phosphatases (PTPs) with wide substrate selectivity and are known as powerful regulators of biological processes. It is interesting to point out that extracellular nucleotides, ATP, and analogues become novel players of DUSP function in neural models They activate nucleotide receptors and share the intracellular coupling to MAPK mechanisms of activation and deactivation with trophic factors [10,11]. The physiological meaning of DUSP regulation in neural systems is further analyzed concerning processes of neuroprotection against different cytotoxic insults and in pathological situations, neurodegenerative diseases, neurological disorders, and brain tumors. From this point of view, DUSPs represent new targets for extracellular mediators whose modulation seems to be essential for the maintenance and homeostasis of the nervous system
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