Protein Tyrosine Phosphatases: Structure, regulation and biological function
Nevertheless, several PTP genes have recently been linked to diseases including cancer, diabetes, osteoporosis, hypertension, demyelinating disease and ulcers. Since PTPs now represent an exciting class of enzymes for drug targeting, it is urgent that we obtain a deeper understanding o f the molecular, cellular and tissue functions of these enzymes, under normal and pathologic conditions. The proposed network has scientific, technological and training objectives. We aim to rapidly define PTP structures, substrates and ligands, and define the signalling output of PTPs. We will then aim to relate this to the involvement of PTPs in human disease etiology and progression.
This knowledge can then be exploited ultimately in the development of therapeutics targeted at PTPs enzymes. The PTP field is relatively small and geographically fragmented and a key objective is to bring together groups in Europe and Associate States, to deliver a highly interactive network that is interdisciplinary and intersectorial. This Network will be founded on the principal of effective training for the EU-funded researchers and will offer a unique training platform that will increase critical mass, collaboration and best practice in this field.
UNIVERSITY COLLEGE LONDON
Andrew STOKER (Dr)
FUNDACION DE LA COMUNIDAD VALENCIANA CENTRO DE INVESTIGACION PRINCIPE FELIPE
INSTITUTE OF BIOCHEMISTRY OF THE ROMANIAN ACADEMY
KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
STICHTING KATHOLIEKE UNIVERSITEIT
MERCK SERONO S.A. - GENEVA
THE UNIVERSITY OF MANCHESTER
WEIZMANN INSTITUTE OF SCIENCE
The Chancellor, Masters and Scholars of the University of Oxford
UNIVERSITY COLLEGE LONDON
Final Activity Report Summary - PTPNET (Protein Tyrosine Phosphatases: Structure, Regulation and Biological Function)
Under the scientific umbrella of four main Research Tasks, our objective was to advance the field at a multidisciplinary level, while also training young researchers in this fast-moving area. We recruited 9 ESRs and 5 ERs and delivered a comprehensive training programme at Network meetings and 5 workshops focussing on microscopy, structural biology, biochemistry of cancer cells, the biotechnology industry and intellectual property. This unique package of training was embraced by all of the researchers and they acquired research skills and "key skills" that will help them in their careers. Eight PhD degrees have been awarded to ESRs and one ER has already obtained an independent research post. PTPNET contained one industrial partner and 11 academic partners. Our goal was to bring these closer together in a collaborative, long-lasting structure, reducing fragmentation and maximising transfer of knowledge and technologies. We succeeded on all counts, with many material exchanges, new and sustainable collaborations and joint papers. The scientific output of PTPNET therefore came at several levels.
We have so far published 40 peer-reviewed papers, 15 of which involved at least 2 partners. These papers spanned several key disciplines and while some highlights of the work will be given below, there are many further successful projects that cannot be covered here. Our Oxford team produced a seminal paper in Science, using structural biology to describe a novel mechanism whereby PTP enzymes are controlled in neurons. This has relevance to the failure of nerve repair in the brain and spine and provides critical insight into the role of PTPs in nerve regeneration. It is hoped that therapeutic approaches for enhancing nerve repair will be developed on the back of these studies.
Teams in Sweden and Germany studied how chemicals known as reactive oxygen species (ROS) can control PTPs. ROS are produced under many disease conditions including cancer and neurodegeneration. Our teams showed how ROS control the activities of PTPs in different tissue models. It may now be possible to design ways to reduce ROS damage to PTPs and thus ameliorate disease severity. Our French team discovered the role for a PTP in cells that make myelin - the "insulator" of nerve fibres. Myelin is damaged in multiple sclerosis and there is great interest in developing ways to repair it. Our Swiss industrial team also researched multiple sclerosis and documented several new PTPs as potential therapeutic targets. This work thus provided important new knowledge with translational potential. Other teams discovered new roles for PTPs in both brain tumours and leukaemia, and a Dutch team completed the first ever screen of PTP gene function in zebrafish.
Finally, our Manchester team successfully delivered the web resource PhosphaBase, a publically accessible database and research platform for studying PTPs across hundreds of organisms. This is a major success for the Network, leaving a positive and lasting legacy.
Deliverables not available
Publications not available