Protein interactions and compartmentalisation in cell signalling

At the molecular level diseases are caused by failures of cellular control systems. These control systems are organised in protein networks that generate specific biological responses through combinatorial interactions between the components. In order to understand the function of these control networks we need to identify their components and how they interact with each other. This is now possible through modern technologies such as proteomics for protein identification at high speed and sensitivity, and the microscopic imaging of protein interactions. Having successfully established these technologies we want to use them in this research project to analyse the interaction network formed by three important cellular control systems (GPCR, cAMP, ERK). These three control systems are subverted in a great variety of diseases including inflammation, cancer, infection, cardiovascular and neurological disorders. Elucidating how these control systems interact will further our understanding of the molecular changes that cause disease and is expected to lead to the identification of novel molecular targets for drugs and therapeutic intervention. Ultimately, this will lead to better therapies.

Signalling pathways are important drug targets. However, the design of selective intervention strategies is hampered by the pleiotropic functions of signalling proteins and by a lack of understanding how they integrate signals to achieve biological specificity. Here we want to investigate the role of protein interactions and compartmentalisation for the function of three important and functionally interrelated signalling systems: GPCRs, cAMP PDEs and the ERK pathways. These pathways govern fundamental biological processes that are relevant for human health, including metabolic control, differentiation, malignant transformation and inflammation. Rather than simple linear pathways these signalling systems form networks whose function and behaviour is in great part determined through the assemblies of specific protein complexes in different cellular compartments. The three signalling systems to be studied provide important drug targets and known to interact at multiple levels. We want to apply our expertise in proteomics to dissect and identify the components of the multiprotein signalling complexes that connect and distinguish aspects of these signalling systems. The overall aim is to elucidate the functional connectivities between these key signalling systems with a view to understand how protein assemblies can generate networks that define biological specificity.