MINIREVIEW SERIES Protein tyrosine phosphatases: sequences and beyond Wiljan J. A. J. Hendriks 1 and Andrew W. Stoker 2 1 Radboud University Nijmegen Medical Centre, the Netherlands 2 UCL Institute of Child Health, London, UK The 21st century is bringing a flood of genomic sequence data from diverse species and although this information is highly accessible, we are far from understanding its content. Recent discoveries, for example on novel RNA types, clearly show that there is still much to learn. In addition, the many, often reversible, post-translational modifications imposed upon RNAs and proteins are difficult to extract from these primary sequence data. Powers to predict such modification-prone sites are currently very modest, but at least we are now able to list the modifying enzymes involved. The future challenge is to elucidate the struc- ture–function relationships, the imposed regulatory mechanisms and the contributions to health and dis- ease for these post-translational modifiers. Phosphorylation on tyrosine residues is one key post-translational modification that cells use to control protein function, especially in cellular signalling path- ways. The extent of tyrosine phosphorylation is dic- tated by the balance of activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Since purification of the first PTP in 1988, a wide vari- ety of PTPs has been discovered by exploiting their well-conserved PTP signature motif (HCX5R; encom- passing the catalytic site cysteine). The human PTP family contains 107 members, of which 38 belong to the phosphotyrosine-specific (‘classical’) PTP subfamily and 61 to the so-called ‘dual-specific phosphatases’ (DUSPs). The latter can also dephosphorylate serine and threonine residues and even phospholipids. The exceptionally high enzyme activity and notorious sub- strate promiscuity displayed by PTPs in vitro, have often confounded research concerning their signalling roles. Recent use of animal models and state-of-the-art molecular techniques, however, has enabled the eluci- dation of important and diverse roles for PTPs in cellu- lar signalling pathways and development. Furthermore, increasing knowledge about the 3D structures of PTPs and the regulatory principles governing PTP activity, further adds to this. Recent examples of aberrant PTP actions underlying human diseases further corroborate the importance of these enzymes and put them in the limelight as novel therapeutic drug targets. In this issue of FEBS Journal such recent advance- ments are brought to you in a series of four reviews. Together with Ari Elson and Sheila Harroch we pro- vide an overview of the known functions of mamma- lian classical PTPs as it has been extracted by studying transgenic animal models and human disease states. Je- roen den Hertog, Arne O ¨ stman and Frank Bo ¨ hmer discuss the variety of regulation mechanisms exploited by the cell to make PTP activity both controllable and specific. In the third review, Rafael Pulido and Rob Hooft van Huijsduijnen highlight the role of ‘non- canonical’ DUSPs in various disease states. Finally, Lydia Tabernero, Radu Aricescu, Yvonne Jones and Stefan Szedlacsek focus on the PTP structure–function relationships that now emerge from the growing list of structural and enzymatic studies. Bearing in mind that further, advanced technologies are now being developed to study the impact of PTP action, even more exciting times lay ahead. Wiljan Hendriks (sixth from left in the photograph above, taken at the October 2007 PTPNET meeting in Jena, Germany) received his PhD in biochemistry from the Radboud University of Nijmegen, the Netherlands, for his work on molecular evolution of eye lens proteins. As an EMBO post-doctoral fellow he moved to the University of Zu ¨ rich, Switzerland, in 1989 and received training in the generation of knockout mouse models. In 1991, he began his studies at the Cell Biology Department of Radboud University Nijmegen Medical Centre, on mouse protein tyrosine phosphatase signalling. Andrew Stoker (fifth from left in the photograph above) received his PhD in virology and biochemistry from London University in 1986 and pursued post-doctoral training at UC Berkeley, California until 1991. From 1991 to 1998, he was a Royal Society University Research Fellow at Oxford University. He is now a Reader at the UCL Institute of Child Health, London. His research is focused on the developmental function of receptor type protein tyrosine phosphatases in the spinal cord and eye of avian and mammalian species. Dr Stoker is coordinating the EU-sponsored Training Network PTPNET, in which all contributing authors of this minireview series participate (accompanying photograph). doi: 10.1111/j.1742-4658.2008.06248.x FEBS Journal 275 (2008) 815 ª 2008 The Authors Journal compilation ª 2008 FEBS 815 . MINIREVIEW SERIES Protein tyrosine phosphatases: sequences and beyond Wiljan J. A. J. Hendriks 1 and Andrew W. Stoker 2 1 Radboud University Nijmegen Medical Centre, the Netherlands 2 UCL Institute. cellular signalling path- ways. The extent of tyrosine phosphorylation is dic- tated by the balance of activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Since purification. on mouse protein tyrosine phosphatase signalling. Andrew Stoker (fifth from left in the photograph above) received his PhD in virology and biochemistry from London University in 1986 and pursued