Protein Reviews - Book chapter Title: Protein Phosphatases in the brain: regulation, function and disease Authors: Ry Y. Tweedie-Cullen#, C. Sehwan Park#, Isabelle M. Mansuy* Brain Research Institute, Medical Faculty of the University Zurich and Department of Biology of the ETH Zurich, CH-8057 Zurich, Switzerland #Equal contribution *Corresponding author: IMM mansuy@hifo.uzh.ch, Brain Research Institute, University of Zurich/Swiss Federal Institute of Technology Zurich, Winterthurerstrasse 190, CH- 8057 Zurich, Tel. +41 44 635-3360, Fax +41 44 635-3303 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