Membrane Traffic

We are interested in how secretory trafficking coordinates cellular signalling during normal physiology, and its contribution to inflammatory disease and cancer. 60% of all current drugs target membrane proteins, illustrating the medical importance of this pathway. However the complex biogenesis and trafficking of many signalling proteins is poorly understood, providing an incentive to understand the secretory pathway better. In eukaryotes, one third of translated proteins are secretory proteins. These fold in the endoplasmic reticulum (ER) and traffic to the plasma membrane, where signalling occurs. Until recently, it was believed that secretory traffic was accomplished by a default mechanism called ‘bulk flow’ whereby newly synthesized proteins are packaged into trafficking vesicles at the rate that they are produced. However, it is now clear that trafficking, especially of membrane proteins, is controlled by additional influences, including trafficking partners, post-translational modifications or regulation of protein stability. We elaborate this theme of trafficking control over signalling in the projects indicated below, using a combination of mouse genetics, disease models, cell biology and biochemistry. 1. Genetic screens to identify novel trafficking factors for the major inflammatory cytokine receptors. 2. Role of quality control in the secretory pathway during development and disease. 3. How membrane trafficking regulates signalling controlled by metalloproteases.