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Protein Phosphatases in the Brain: Regulation, Function and Disease

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Post-Translational Modifications in Health and Disease

Part of the book series: Protein Reviews ((PRON,volume 13))

Abstract

Protein phosphorylation is a critical cellular process regulated by the competing actions of protein kinases (PKs) and phosphatases (PPs). While several hundred PKs exist in mammalian cells, there are only a few dozen PPs. PPs typically target Ser/Thr or Tyr residues but each has different characteristics and specificities and fall into three separate classes. PPs on their own have poor substrate specificity, however, when bound to regulatory proteins their activity and specificity is tightly controlled. Mechanisms of PP regulation range from targeting to subcellular compartments by scaffolding proteins and/or protein complexes which restrict the action of PPs to specific substrates, to the inhibition of PPs by specific inhibitory molecules or inhibitor peptides. In the adult brain, PPs are essential for synaptic functions and are involved in the negative regulation of higher-order brain functions such as learning and memory. Dysregulation of their activity has been linked to several disorders including cognitive ageing and neurodegeneration, but also cancer, diabetes and obesity. Because they are critical for multiple biological functions and could constitute a new class of drug targets, they deserve to be studied in greater detail. The complexity of their modes of action and of the systems they function in, however, requires the analysis of whole systems rather than of individual proteins in isolation, as has been the case for decades using classical molecular biology. In this review, we discuss PPs in the context of the central nervous system, their role in neuronal functions, and their regulation and dysfunction in disease. Current techniques to investigate PP signalling and associated functional networks, future directions for the development of system-wide proteomic and genomic methods of analysis, and the potential for therapeutic applications are also covered.

Ry Y. Tweedie-Cullen and C.S. Park contributed equally for this chapter

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Abbreviations

CaM:

Calmodulin

CaMKII:

Ca2+/calmodulin-dependent kinase II

CDK:

Cyclin-dependent kinase

ChIP:

Chromatin immunoprecipitation

ChIP-Seq:

Chromatin immunoprecipitation followed by sequencing

CNS:

Central nervous system

DSP/DUSP:

Dual-specificity phosphatases

HAD:

haloacid dehydrogenase

HDAC:

Histone deacetylase

I1:

Inhibitor 1

KIM:

kinase interaction motif

LMPTP/LMWPTP:

18 kDa low MW phosphatase

LTP:

Long-term potentiation

MKP:

MAPK phosphatase

MS:

Mass spectrometry

MTM:

Myotubularin

MTMR:

MTM1-related

NIPP1:

Nuclear inhibitor of protein phosphatase 1

NRPTP:

Non-receptor PTP

PKA:

Protein kinase A

PK:

Protein kinase

PP:

Protein phosphatase

PP1:

Protein phosphatase 1

PP2B:

Calcineurin

PPM:

Protein phosphatase Mg2+- or Mn2+-dependent

PPP:

Phosphoprotein phosphatase

PTEN:

Phosphatase and tensin homolog deleted in chromosome 10

PTK:

Protein tyrosine kinase

PTM:

Posttranslational modification

PTP:

Protein tyrosine phosphatases

PTP-SL:

Protein tyrosine phosphatase STEP-like

pSer/pThr/pTyr:

Phosphorylated-serine/-threonine/-tyrosine

RLPTP:

Receptor-like PTP

ROS:

Reactive oxygen species

RPTP:

Receptor PTP

Ser/Thr/Tyr:

Serine/threonine/tyrosine

SHP:

Src-homology domain containing phosphatase

STEP:

Striatal-enriched phosphatase

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  1. Brain Research Institute, Medical Faculty University Zurich/Swiss Federal Institute of Technology Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland

    Isabelle M. Mansuy

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    Cecilio J. Vidal

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Tweedie-Cullen, R.Y., Park, C.S., Mansuy, I.M. (2011). Protein Phosphatases in the Brain: Regulation, Function and Disease. In: Vidal, C. (eds) Post-Translational Modifications in Health and Disease. Protein Reviews, vol 13. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6382-6_10

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