Europhosphatases Conference 2005
10-14 July 2005
Churchill College, Cambridge, UK

Organisers:

Denis Alexander , Babraham Institute, Cambridge, UK
Edgar Da Cruz e Silva, Universidade de Aveiro, Portugal
Joaquin Arino, Universidad Autonoma de Barcelona, Spain

Report

Summary & Evaluation

Despite the London bombings taking place two days before delegates were due to travel to Cambridge, only two registered delegates dropped out as a result, and the 170 who eventually participated in the Conference had no regrets. Sir Michael Berridge gave an excellent opening Keynote Lecture on the first evening, and it was noticeable that nearly all delegates managed to register in time for this lecture.

Overall the standard of lectures from the 34 invited Speakers was consistently excellent. Most Speakers kept in mind the theme of the Conference - 'The Biology of Phosphatases' - and took care to place their molecular findings within a biologically relevant context. The opening session entitled 'Surveying the Phosphatase Scene - the Big Picture', was particularly helpful for younger delegates new to the phosphatase field to provide a broad framework within which the more detailed findings discussed in the subsequent sessions could then be placed.

A striking aspect of this Workshop, on which several of the more senior scientists commented, was the very large proportion of younger delegates who attended and presented Posters, mainly PhD students or recent post docs, and of course the FEBS YTF grants helped greatly to achieve this goal. It is a reflection of the way in which the phosphatase field has been growing over the past 5-10 years that so many new people are being drawn into the field, which of course augurs well for the future of this research area.

Another highlight of the Conference was the way in which its focus on phosphatases as an enzyme class brought together people from such a wide range of disciplines, including neuroscientists, immunologists, plant biochemists, developmental biologists, people working in bioinformatics, cell biologists, medical scientists and people from the biotech and pharmaceutical industries. It is rare to have a Conference of this size with such a range of disciplines represented, and of course this facilitates greatly the cross-fertilisation of ideas between disciplines. The Conference was well supported by various Companies, with Company displays present throughout the Conference.

Churchill College was a good venue for this Conference because all accommodation and activities could be held on the same campus, which is a big plus in terms of encouraging interactions. Both the food and accommodation were of a high standard, and the College specialises in running Conferences of this type with an efficient Conference Office. The Poster Sessions were held in the evenings with a free bar to encourage active participation and by general consensus having posters at this time of day was considered the best use of the evenings. The only down-side was that the hall held for the posters was too cramped and too crowded, as a number of respondents have (correctly) mentioned in their questionnaires. Based on previous Europhosphatases Conferences, it was estimated that 60 poster boards would be sufficient, but in the end there were more than 90 posters, which must be a record for this Conference series, but it did mean that the hall became too crowded. Having said that, everyone agreed that the poster sessions were really well attended and an excellent aspect of the Workshop.

The next Conference in this series will be organised in 2007 by Edgar Da Cruz e Silva in Portugal.

Scientific Content

The Europhosphatases 2005 FEBS Workshop under the title 'The Biology of Phosphatases' was attended by more than 170 delegates, many of them relative newcomers to this research field, reflecting the high level of interest in protein dephosphorylation as a key regulatory step in a great variety of biological systems. Neuroscientists, immunologists, plant biochemists, developmental biologists, people working in bioinformatics, cell biologists, medical scientists and people from the biotech and pharmaceutical industries, were all drawn to this inter-disciplinary interaction by their common interest in phosphatases.

A comprehensive and exhaustive bio-informatic mining of the human and other genomes has now identified most of the phosphatases that exist. Nevertheless, novel phosphatase activities are still being described, and A. Gohla (Dusseldorf, Germany), the recipient of a FEBS Youth Travel Fellowship, described the purification of a new type of cofilin phosphatase called Chronophin (CIN), which is necessary for the regulation of cofilin-dependent actin dynamics during cell division. CIN is a novel HAD-type phosphotransferase, an unusual class of enzyme that forms an intermediate containing a mixed anhydride with an essential aspartate. Cofilin is the first phospho-serine protein substrate to be identified for a HAD phosphatase in mammals. A-C. Gingras (Seattle, WA, USA) described how proteomic approaches are being successfully employed to define the breadth of regulatory proteins capable of interacting with the limited number of PSP catalytic sub-units. Interaction networks consisting of at least 63 proteins in mammals and 43 proteins in yeast were found to surround the PP2A, PP4 and PP6 phosphoserine/threonine phosphatases. These PP2A-like catalytic subunits were found to share some common interactors but sequester into specific modules, reinforcing the idea that specificity is conferred by the precise composition of associated complexes.

The regulation of phosphatase activities and actions is a continuing topic of great interest to the phosphatase field. N.Tonks (Cold Spring Harbor, NY, USA) discussed how the controlled generation of reactive oxygen species (ROS) has the capacity for fine-tuning signalling pathways by the transient inhibition of PTP activity. The conserved cysteine within the active site of the PTPs constitutes not only the critical nucleophile of the catalytic mechanism but concurrently, because it exists as a thiolate anion at neutral pH, is exposed for potential regulation by reversible oxidation. The ready reversal of the reaction in physiological reducing agents makes certain that the oxidation of the catalytic cysteine leads to only a short-lived loss of activity. An outstanding question in this field is whether ROS such as H2O2 can be delivered in a controlled manner to tyrosine phosphatases. Evidence exists to suggest that the insulin-triggered generation of ROS may specifically affect the TCPTP and PTP1b phosphatases and J. den Hertog (Utrecht, The Netherlands) demonstrated that classical PTP domains might be differentially influenced by reversible oxidation and, furthermore, correlated sensitivity to oxidation with the specific orientation of the conserved arginine within the active-site of PTPs.

The success of the protein tyrosine kinase inhibitory drug, Gleevec, for the treatment of cancer has spurred efforts to generate equivalent inhibitors for the PTPs. Z-Y. Zhang (New York, USA), however, described how two major hurdles have held up the PTP inhibitor field. Firstly, the conserved nature of the PTP active site has thus far precluded the development of specific inhibitors and secondly the charged nature of phosphotyrosine mimetics reduces their cell membrane permeability. The current focus is hence on nonpeptidic PTP inhibitors with less negatively charged groups that can achieve inhibition by binding to less conserved sites on the PTP surface.

The neurobiology of phosphatases received extensive coverage during the Workshop. Most excitatory synapses in the mammalian brain are found on specialised membrane protrusions called dendritic spines. Neurabin (Nrb), a conserved regulator of PP1, plays important roles in spine development and maturation. S. Shenolikar (Ann Arbor, MI, USA) reported that disrupting the functions of a Nrb/PP1 complex hindered the morphological and functional maturation of dendritic spines. Nrb/PP1 was also reported to have measurable effects on the long-term potentiation and depression of excitatory synaptic transmission, indicating that Nrb-mediated targeting of PP1 is important for events underlying synaptic plasticity. I. Mansuy (Zurich, Switzerland) reported the effects of modulating PP1 activity on excitatory postsynaptic potentials at CA1-CA3 synapses in hippocampal slices under ischemic conditions. Inhibition of PP1 activity using pharmacological, genetic and physiological approaches worsened the effects of ischemia on postsynaptic potentials, whilst elevation of PP1 activity improved recovery, indicating that PP1 has a neuroprotective role.

Given the central importance of PPs to cell biology, it is not surprising that this family of enzymes has been directly implicated in a number of human disorders and offers an attractive target for pharmacological intervention in alleviating disease. B. Neel (Boston MA, USA) reported that somatic SHP-2 missense mutations have been found in 35% of cases of sporadic juvenile myelomonocytic leukaemia and a lower but significant incidence in pediatric acute myelegenous leukaemia, myelodysplastic syndrome and B cell acute lymphoblastic leukaemia. Germ-line mutations in SHP-2 have also been described in the autosomal dominant, Noonan and multiple lentigenes LEOPARD syndromes, that each share similar features including congenital heart defects and facial and skeletal abnormalities. In its basal state, SHP-2 is held in a catalytically inactive configuration by the insertion of residues from its amino-terminal SH-2 (N-SH2) domain into the PTP domain but engagement of PY-containing ligands by the SH-2 domains of SHP-2 leads to an allosteric release of this auto-inhibition. For the Noonan syndrome (NS) and leukaemia patients, gain-of-function SHP-2 mutants have been identified that primarily interfere with the N-SH2 -PTP domain inhibitory interface but some mutants also appear to increase the sensitivity of SH2 domain ligand engagement.

These highlights represent just the tip of an ice-berg of what proved to be an exciting Workshop in which the molecular details of how this fascinating class of enzymes operate in situ are steadily being elucidated. But there is still a long way to go.