Daria Martin, Schering Stiftung Projektraum

 

Sparking signals: kinases as molecular signal transducers and pharmacological drug targets in inflammation

Dr. Arne von Bonin, Dr. Ulrich Zügel, CRBA Inflammation, Bayer Schering Pharma AG, Berlin, Germany
Prof. Dr. Gottfried Baier, Human Genetics Department, Medical University of Innsbruck
Prof. Dr. Burkhart Schraven, Institute for Immunology, University of Magdeburg

Potsdam-Hermannswerder, June 20-22, 2007

Around 50 internationally renowned scientists in the field of kinase research met at a scientific symposium organized by the Ernst Schering Foundation. The symposium was held in Potsdam-Hermannswerder near Berlin, Germany, from the 20th to the 22nd of June 2007. For three days many experts from academic and industrial research groups discussed the latest findings on this enzymatic group of key regulators involved in a multitude of signalling reactions.

Protein kinases regulate the majority of signalling events in the body. They do this by chemically transferring a phosphate group from ATP, the bodies universally available form of energy, to a target structure. They are, thus, able to change, depending on their particular target, the proteins enzymatic activity, its intracellular localization or its interactions with other proteins or enzymes. The human genome contains 518 different kinases that modify a so far unknown number of substrates, possibly several thousand. Kinases are often found in complex protein structures. These protein complexes can be found on the cytosolic side of membrane receptors, where they are responsible for signal transduction to the inside of the cell. Furthermore, kinases regulate various processes in the cells organelles i.e. at the Golgi- apparatus. Inside the nucleus, kinases control the transcriptional activity of certain genes. Amongst the genes regulated by kinases are inflammation mediators. Inflammatory processes, in particular chronic inflammation, play a key role in certain types of diseases like rheumatoid arthritis, asthma, multiple sclerosis, psoriasis, or inflammatory bowel disease. Additionally metabolic diseases like type-2 diabetes and certain cardiovascular illnesses (i.e. arteriosclerosis) can, according to latest research, be caused by inflammatory processes.

What are the mechanisms of signal transduction during inflammatory processes? Which pathways are disturbed in diseases like cancer or chronic inflammation? What are the roles of kinases during the course of the inflammatory process? And last but not least, how can their activity be controlled and modified by new therapeutics? These were just some of the questions asked by scientists from Germany, Austria, Switzerland, the UK and the US during the workshop in Potsdam.

In his opening lecture professor Arthur Weiss, from Howard Hughes Medical Institute of the University of California, San Francisco, USA, gave an insight into his latest research on the kinase ZAP-70, which has been found to be associated with the T-cell receptor (TCR). Weiss was able to demonstrate the fundamental role of ZAP-70 for the correct function of the TCR. A single point mutation in the ZAP-70 gene results, in the mouse model, in a phenotype with a severe autoimmune disease, very similar to rheumatoid arthritis. Interestingly however ZAP-70 seems to play a very different part in a common form of leukaemia – chronic lymphatic leukaemia (CLL). Here the loss of ZAP-70 seems to be associated with a positive prognosis for patients suffering from CLL – they might live with the disease for 20 – 30 years. On the contrary, patients with the ZAP-70 protein have a much shorter prognostic outcome. "When I started studying intracellular signalling at the beginning of the 1980s, there was little known about these processes", recalls Arthur Weiss, who is one of the pioneers in the field of kinase research. "All we knew at the time was that there was something that induced cells on the outside and then something happened on the inside, but we had no idea how. It was like a black box. Today we know what most of the components are, now we have to understand how they regulate each other." Only then will one be able to understand how enzymes, like ZAP-70, can on the one hand be crucial for correct functioning of (here) T-cells and on the other hand be detrimental to a patient (as demonstrated for CLL), believes the professor from California.

A prime example for the dual functions that many kinases fulfil was the work presented by Magdalena Koziczak-Holbro, scientist at Novartis Pharma AG, Basel, Switzerland. Her research group works on the role of IRAK-4, a kinase which is part of the Toll-like-receptor (TLR) protein complex. The group has been investigating whether knocking out IRAK-4 could be used to treat certain chronic inflammatory diseases like rheumatoid arthritis. "Knocking out IRAK-4 seems to suppress inflammation in murine as well as in human cells. We were no longer able to detect inflammation signalling", explains Koziczak-Holbro. "Therefore we think that specifically targeting IRAK-4 and the TLR could be a useful treatment for chronic inflammatory diseases like rheumatoid arthritis."

Professor Kevan Shokat from the University of Berkeley, California, USA presented a completely new strategy to study the functions of enzymes, which he termed "chemical genetics". It combines protein engineering of certain enzymes and organic synthesis of respective target molecules. "So far people relied on two conventional methods to study signal transduction pathways. On the one hand, knock out models completely prevent the protein expression, and thereby destroy potential scaffolding functions as well. On the other hand, using chemical inhibitors bears the risk – and this is particularly true for kinases as their ATP binding pockets are highly homologous – of observing reactions that are not exclusively caused by the kinase under investigation", explained Shokat. The advantage of chemical genetics is that it relies on genetics to select the target of a small molecule, ensuring that only the intended protein is targeted by the small molecule synthesized. "This method is a powerful tool to investigate all the functions of a kinase without having to do much guesswork. One can use it to understand the various substrates of the enzyme. Potential drug candidates can thus be evaluated and studied without the risk of targeting also other kinases", says Professor Shokat.

While scientists in academia are still trying to understand kinases and the signalling networks controlled by them, researchers in the industry are looking for compounds that can be used in drug design. Their focus is on inflammation and cancer. Dr. Gerard Drewes from the Heidelberg, Germany, based biotech company Cellzome introduced "quantitative chemical proteomics" as a novel tool to test a large number of kinases against a library of chemical compounds. This type of protein screening involves the immobilization of the chemical compounds on so called Kinobeads. The treated beads are then added to a cell lysate where they will bind all kinases that interact with the compounds on the beads. Pulling down those kinases will thus allow for further investigations, including compound profiles of individual kinases, which can then be used to identify potential suitable drug candidates.

Dr. Ulrich Zügel and Dr. Arne von Bonin, both from the Therapeutic Research Group Inflammation and Immunology of Bayer Schering Pharma and co-organizers of the Potsdam symposium, were satisfied upon its conclusion. "Everyone seemed to have had a good time here. All participants were highly motivated and an open discussion between researchers from applied and academic research took place. We think we will all take home a lot of new ideas", they said. Professor Weiss agrees. "Interacting with people here and exchanging ideas with people from the industry is good for academics like me. We both have very different scientific approaches. Academics are more creative and tend to ask more fundamental questions, while people from the industry are very focussed on a goal and can get results much quicker. I think interacting periodically is very useful and all that remains is for us to see how this interaction comes to fruition."

The results of the symposium will be published by the Springer publishing house and will be available in bookstores. The series "Scientific Symposia" by the Schering Foundation will be continued from the 14th to the 16th of November 2007 with a workshop on "Oncogenes meet metabolism – from deregulated genes to a broader understanding of tumor physiology " in Berlin, Germany.

The Ernst Schering Foundation was founded by Schering AG in 2002, primarily to promote science and culture. The goal of the Ernst Schering Foundation is to promote projects, people, or institutions, both in science and culture, which are distinguished by excellence and innovation. By initiating and promoting projects or work on experimental subjects that transcend traditional disciplinary boundaries, the foundation aims to promote interdisciplinary thinking and work, by artists and scientists alike. It intends to promote and encourage talented young people working in science and culture and to help them along on parts of their journey. To achieve these goals, the Ernst Schering Foundation grants fellowships, awards prizes, initiates and supports projects, invites renowned scientists and artists and organizes symposia and workshops on an international level. By introducing young children and teenagers to scientific and cultural projects, it wishes to encourage the young to get involved in science and art.

Glossary:

Antigen (short for antibody generating): substances that can be recognized by the adaptive immune system. This includes viruses as well as bacteria.

B-cells: The principal function of B cells is to make antibodies against soluble antigens. B cells are an essential component of the adaptive immune system.

Chronische lymphatische Leukämie (CLL): a type of adult leukaemia caused by an abnormal accumulation of B lymphocytes. CLL is the most common form of leukaemia in adults. The key risk factor is age.

Humoral immunity: the aspect of immunity that is mediated by secreted antibodies, produced in the cells of the B lymphocyte lineage (B cell). As such it is part of the acquired adaptive immune system, not the more "primitive" innate immune system.

Knock-out-Model: a model animal that has had one or more of its genes made inoperable through a gene knockout. By inactivating the gene and studying the animal for any resulting differences, researchers can infer the probable function of that gene.

Makrophages und neutrophiles: cell that ingests and destroy foreign matter such as microorganisms or debris via a process known as phagocytosis. They are part of the innate immunity.

Proteomics: the large-scale study of proteins, particularly their structures and functions. The term "proteomics" was coined to make an analogy with genomics, the study of the genes.

Toll-like-receptor (TLR): a type of pattern recognition receptors (PRRs). TLRs recognize molecules that are broadly shared by pathogens but distinguishable from host molecules.

T-cells: a group of white blood cells known as lymphocytes. T-cells play a central role in cell-mediated immunity. Together with B-cells they represent the major part of the adaptive immune system.

T-cell-receptor (TCR): a molecule found on the surface of T-cells that is responsible for recognizing antigens.

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