Research in the Division of Cell Signalling and Immunology

Research in the Division of Cell Signalling and Immunology

Head of Division Deputy Head of Division Professor Colin Watts Professor Hari Hundal Division Secretary Laboratory Manager Mrs Naomi Bolser Mrs Wendy James Welcome to the Division of Cell Signalling and Immunology (CSI). CSI is the most recently formed Division in the College of Life Sciences and hosts research groups whose work is relevant to the pathologies associated with cancer, diabetes, infectious disease, autoimmunity and allergy. A common theme that links the activities of the 10 different groups is a shared interest in the mechanisms that cells use to sense external signals such as those detected by various receptors in the immune system on the one hand and on the other, internal signals that indicate changes in cellular metabolic activity and energy status. Remarkably, the biochemical wiring underlying these diverse systems is often overlapping providing unexpected opportunities for collaboration among the different groups in CSI. CSI is planning to expand its activities and would like to hear from scientists at any career stage with overlapping or complementary interests interested in relocating to Dundee. Dr Victoria Cowling v.h.cowling@dundee.ac.uk Lecturer Biochemical and biological function of the mrna methyl cap We are investigating how mrna translation is regulated to promote cell growth and proliferation. Our current focus is a modification of the 5 end of mrna, the methyl cap, which is necessary for efficient mrna translation. We recently discovered that c-myc oncoprotein upregulates mrna cap methylation and that this mechanism is essential for c-myc to promote cell proliferation and transformation. We are investigating the mechanism of mrna cap methylation in mammalian cells and how it is regulated by oncoproteins including c-myc. We asking which genes are regulated by cap methylation, how are they regulated, and why is this mechanism necessary for cell proliferation? Programme Leaders Professor Doreen Cantrell d.a.cantrell@dundee.ac.uk Wellcome Principal Research Fellow T lymphocyte signal transduction The regulation of T lymphocyte biology is essential for the adaptive immune response. The research objective of the laboratory is the characterisation of signal transduction pathways in T lymphocytes with the aim of understanding how evolutionarily conserved signalling molecules control immune functions. One current research topic in the laboratory is the role of the Protein Kinase D family of serine/threonine kinases. PKDs are selectively activated by triggering of antigen receptors and play a key role in controlling cytokine production by T cells. Other work in the laboratory focuses on how Phospholipid kinase 1 (PDK1) controls T cell migration into secondary lymphoid tissue and how the kinases LKB1 and AMP-activated protein kinase (AMPK) regulate T cell energy metabolism. Professor Paul Crocker p.r.crocker@dundee.ac.uk Wellcome Trust Senior Fellow in Basic Biomedical Science Glycan recognition and signalling in the immune system The research in Paul Crocker s laboratory is focussed on deciphering glycocodes in the immune system. Through our discovery of the siglec family of sialic acid binding Ig-like lectins, we are studying how inflammatory and immune responses are regulated by these membrane receptors, using both in vitro and in vivo models. In humans, 13 siglecs are expressed by cells of the immune system where they mediate both adhesive and signalling functions. A variety of important human pathogens express sialic acid ligands and we are also studying the role of siglecs in host defence to infection.

Professor Grahame Hardie d.g.hardie@dundee.ac.uk Professor of Cellular Signalling AMP-Activated Protein Kinase A Drug Target in Diabetes and in Cancer Professor Hari Hundal h.s.hundal@dundee.ac.uk Reader Regulation of cell signalling and fuel metabolism in response to hormonal, nutrient and stress-inducing stimuli My laboratory discovered AMP-activated protein kinase (AMPK), which acts as a sensor of energy status in eukaryotic cells. AMPK regulates energy balance at the cellular and whole body levels, and is switched on by metabolic stress, such as deprivation for oxygen or glucose, or muscle ATP depletion caused by exercise. AMPK is the target for the drug metformin, used to treat >120 million patients with type 2 diabetes worldwide. A current focus is its role in cancer: AMPK inhibits cell growth and proliferation, but many tumour cells have undergone changes that allow them to evade surveillance by the system. The work in my lab focuses on the control of intracellular signalling processes that regulate uptake, storage and metabolism of fuels (e.g. glucose) in response to hormonal, stress and nutritional cues. We are particularly interested in defining the molecular mechanisms by which over supply of certain nutrients, such as saturated fatty acids, induce a marked reduction in insulin responsiveness in tissues such as skeletal muscle. Changes in cellular amino acid availability also exert powerful effects on signalling pathways regulating cell growth and differentiation. We are currently exploring the role of membrane amino acid transporters - not only in terms of their capacity to relay nutrients to the intracellular compartment, but as molecular sensors of amino acid availability that can regulate the activity of key intracellular molecules (e.g. mtor) involved in nutrient signalling. Dr Nick Leslie n.r.leslie@dundee.ac.uk RCUK Academic Fellow PTEN and PI 3-Kinase Signalling The PI 3-kinase/PTEN signalling pathway is a key regulator of cell growth, survival and motility in many cell types and its uncontrolled activity is a characteristic of most tumours and many other diseases. Our work aims to understand in more detail the workings of the proteins that make up the core of this pathway, and the lipid signalling molecules that they synthesise and degrade. We use a variety of approaches from enzymology, proteomics and lipid biochemistry to functional studies in cultured cells and in vivo. Dr Alan Prescott a.r.prescott@dundee.ac.uk Senior Lecturer The role of the cytoskeleton in cell specific differentiation: Macropinocytosis by dendritic cells Dendritic cells are essential for presentation of foreign antigens to T cells to illicit an immune response. They sample their peripheral tissue environment by engulfing large volumes of the surrounding mileu by macropinocytosis. Macropinosomes form from the aggregation of many actin-driven ruffles. This process is down regulated in mature dendritic cells which migrate to secondary lymphoid organs for antigen presentation to T cells. During the initial encounter with antigen there is a brief burst of enhanced macropinocytosis accompanied by a loss of podosomes-cell substrate adhesive structures that are also actin rich. The main thrust of our research is to understand how these two types of actin structures are regulated. Novel regulators of the actin cytoskeleton will be identified and localised by advanced microscopy techniques. (Collaborative project with Colin Watts).

Professor Colin Watts c.watts@dundee.ac.uk Professor of Immunobiology Antigen capture and presentation by dentritic cells We are interested in the earliest stages of the immune response when foreign antigens are taken up by antigen presenting cells, processed and presented to T cells. Our group is working on the role of proteases and their regulators in immune responses and on dendritic cells which are key antigen presenting cells as well as being sensors of microbial infection. Our aim is to understand the molecular cell biology of antigen presentation by dendritic cells with a the longer term aim of exploiting this knowledge to improve our ability to manipulate the immune response. Affiliate Members Dr Peter Taylor (School of Learning and Teaching) p.m.taylor@dundee.ac.uk Senior Lecturer The System L1 amino acid transporter:- Physiological functions and therapeutic possibilities My research interests centre on the physiological functions of membranetransport mechanisms for amino acids (AA) and thyroid hormones (TH). System L1 (formed as a CD98-LAT1 protein heterodimer) is an AA transporter of importance for control of cellular nutrient signaling (hence possibly for control of cell growth and T-lymphocyte activation) and also for control of TH action (these hormones are AAs and are recognised as System L1 substrates). System L1 is a useful vector for targeted delivery of AA-based drugs to particular tissues (e.g. CNS / tumours) and has therapeutic potential in several other areas; for example, CD98-LAT1 selective inhibitors should have immunosuppressive actions and (by blocking TH entry into certain tissue types) be beneficial in treatment of hyperthyroidism.

Professor Daan van Aalten (Primary affiliation is with Molecular Microbiology) dava@davapc1.bioch.dundee.ac.uk Wellcome Trust Senior Research Fellow and Professor of Biological Chemistry Molecular and Cellular Glycobiology The Molecular & Cellular Glycobiology group of Daan van Aalten has two research themes. Using Aspergillus fumigatus as a model system, we are trying to understand the molecular mechanisms of the enzymes involved in fungal cell wall assembly and aim to exploit this model to generate leads for the next generation of antifungals. The second theme is centered on understanding the molecular mechanisms and functional implications of the O-GlcNAc posttranslation modification, and how this modification competes with protein phosphorylation in signal transduction networks. Sir James Black Centre College of Life Sciences University of Dundee Dundee DD1 5EH Tel: 00 44 (0)1382 384238