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Phosphorylation
and dephosphorylation together represent a vital molecular mechanism for the
regulation of protein function. In fact it has been estimated that about 30%
of all eukaryotic proteins are controlled by the reversible phosphorylation
of specific serine, threonine and tyrosine residues. Effectively this implies
that all cellular processes without exception are regulated by this key post-translational
protein modification. The phosphorylation of proteins is catalysed by enzymes
known as protein kinases, and results in a wide range of changes in protein
function, including alterations in enzyme activity, targeting of proteins to
different cellular locations, changes in protein conformation, modification
of binding properties and changes in the binding of transcription factors to
DNA leading to altered gene expression. The dephosphorylation of proteins is
catalysed by a group of enzymes known as phosphatases, and it is these enzymes
which are the focus of this proposed Conference. It is the finely tuned balance
between the actions of kinases and phosphatases which determines the phosphorylation
status of each protein, thereby controlling its functional status.
The completion of the sequencing of the human genome has revealed that there
are around 100 different tyrosine phosphatases in the genome, that is, phosphatases
that are selective for the dephosphorylation of phosphotyrosine residues. In
addition the genes encoding about 15 different catalytic sub-units selective
for phosphoserine and phosphothreonine residues have been identified. In practice
each catalytic sub-unit of this class of phosphatases combines with a diverse
array of regulatory sub-units, generating a large collection of enzymes with
quite different locations and substrates. For example, the type 2A phosphatase
alone can exist in more than 70 different forms generated by this combinatorial
mechanism. Laboratories active in the phosphatase research arena have used bioinformatics
to classify the wide array of phosphatases identified in the human genome, as
well as the genomes of other species, and their results may be viewed at www.science.novonordisk.com/ptp
. The two people who have collaborated to generate this web-site, Nick Tonks
(Cold Spring Harbor, USA) and Niels Moller (NovoNordisk, Denmark), will both
be speakers in the Mini-Symposium.
The sheer number and complexity of phosphoproteins entails proteomic and bioinformatics
approaches for their analysis. It is the intention of this Mini-Symposium to
give an overview of the latest technologies involved in these approaches and
then to show how functional genomics is being applied in various contexts to
the elucidation of phosphatase biology. This will involve talks on structural
and proteomic approaches to the investigation of phosphatases, and several leaders
in this field have already accepted to speak in this session.
Sufficient work
has already been carried out in this field to know that the roles of phosphatases
in situ are critical to all cellular processes and therefore to the health and
well-being of both humans and animals. The specific roles that mutant phosphatases
play in human disease are increasingly being recognized and these enzymes are
providing novel sites for pharmaceutical intervention of active interest to
the drug industry. A few recent discoveries, several as yet unpublished, highlight
the biological importance of the phosphatases:
• The PTP1B and TCPTP tyrosine phosphatases have been shown to dephosphorylate
the insulin receptor, thereby providing potentially important pharmaceutical
targets for type 2 diabetes.
• The gene encoding the SHP-2 tyrosine tyrosine phosphatase has been found
to exist in multiple mutant forms that cause hyper-activation of the enzyme,
leading to Noonan Syndrome, Juvenile Myelomyelogenous Leukaemia and Actute Lymphoblastic
Leukaemia.
• Protein phosphatase 1 (a serine/threonine phosphatase) has been shown
to regulate HIV-1 transcription. This same phosphatase has also been shown to
be involved in the recovery of the brain from ischaemia, an important finding
in understanding the biological impact of strokes.
• The LAR transmembrane phosphatase has been shown to regulate synapse
morphogenesis in the brain.
• Alterations in type 2A phosphatase expression and carboxyl methylation
have been found to be associated with Alzheimer's Disease pathology.
• The complex roles played by several different phosphatases in the regulation
of the cell cycle have recently been elucidated.
• The PT-PEST tyrosine phosphatase has been shown to regulate cell motility
by coordinating the linkage between the forward cellular protrusion and tail
retraction that is essential for this process.
• The PTP-epsilon phosphatase has been found to be critical in osteoclasts,
the cells that degrade bone.
• Disruption of the PP1R3A gene, encoding the targeting subunit of the
muscle-specific glycogen-associated phosphatase, has led to key insights into
the regulation of glycogen metabolism.
• STEP, a tyrosine phosphatase expressed in the striatum in the brain,
has been found to be involved in 'fear conditioning' in mice, of relevance to
human conditions such as anxiety stress disorder and Tourette's Syndrome.
This list could of course be extended over many pages, but gives some indication
of the breadth of biological systems in which phosphatases have recently been
shown to be important. Yet despite these significant advances, our knowledge
of phosphatase biology remains very rudimentary, and functional genomics will
be essential in order to handle effectively the immense volume of data that
are currently being generated by genomic analyses.
Venue:
Churchill College, Cambridge, UK
10 - 14 July, 2005
Nick Tonks (Cold
Spring Harbor, USA): 'Phosphatases - an Overview'
Matthias Mann (Odense, Denmark): 'Functional Genomics - an Overview'
Anne-Claud Gingras (TBC) (Canada by 2005): 'The Functional Genomics of Phosphatases'
Marc Mumby
(Dallas, USA): 'From Proteomics to Phosphatase Function'
David Barford
(London, UK): 'Structural motifs in phosphatase genomics'
Niels Moller
(NovoNordisk, Denmark): 'Phosphatases as drug targets'
Conference
Speakers:
Denis Alexander,
The Babraham Institute, UK
Luke Alphey, University of Oxford, UK
Joaquin Arino, University of Barcelona, Spain
David Barford, Institute of Cancer Research, UK
Matthieu Bollen, University of Leuven, Belgium
Patricia Cohen, University of Dundee, UK
Edgar Da Cruz e Silva, Universidade de Aveiro, Portugal
Anna De Paoli-Roach, University of Indiana, USA
Jeroen den Hertog, Netherlands Institute for Developmental Biology, The Netherlands
Ari Elson, The Weizmann Institute, Israel
Anne-Claud Gingras, Institute for Systems Biology, Seattle, USA
Jozef Goris, University of Leuven, Belgium
Jurgen Gotz, University of Zürich, Switzerland
Brian Hemmings, Friedrich Miescher Institute, Switzerland
Susanne Klumpp, University of Munster, Germany
Sally Kornbluth, Duke University, USA
Matthias Man,n University of Southern Denmark
Isabelle Mansuy, University of Zürich, Switzerland
James Matthews, University of Wales College of Medicine, UK
Niels Moller, Novo Nordisk, Denmark
Marc Mumby, University of Texas, USA
Angus Nairn, Yale University USA
Benjamin Neel, Harvard University, USA
Masaharu Noda, National Institute for Basic Biology, Okazaki, Japan
Egan Ogris, Medical University of Vienna, Austria
Catherine Pallen, University of British Columbia, Canada
Rafael Pulido, University of Valencia, Spain
Michael Reth, Max-Planck-Institute for Immunobiology, Germany
Shirish Shenolikar, Duke University, USA
Alistair Sim, University of Newcastle, Australia
Nick Tonks, Cold Spring Harbor Laboratory, USA
Michel Tremblay, McGill University, Canada
David Virshup, University of Utah, USA
Melanie Welham, University of Bath, UK
Registration is now closed.