Matthew Freeman

Membrane proteins control a wide range of fundamental biological processes and are the targets of more than half of current drugs. Our research focuses on the interface between membrane proteins, the cell biology of signalling, and mechanisms of human disease.

Using genetics to investigate the mechanisms of signalling between cells, we discovered that rhomboids were novel proteases, conserved across evolution, which regulate the production of extracellular signals. Rhomboids are intramembrane proteases, unrelated to more classical enzymes, and were found to catalyse the cleavage of transmembrane domains. The rhomboids are now known to be involved in a very wide range of biologically and medically important processes.

We subsequently discovered that the rhomboid proteases were the tip of an iceberg: the majority of the superfamily of rhomboid-like proteins have lost their protease activity during evolution. We have studied a few examples of these ‘pseudoproteases’ and have uncovered roles in controlling the fate of a wide range of membrane proteins. Our working hypothesis is that the fundamental role of the rhomboid-like domain is specific recognition of transmembrane domains. Among other functions, we have discovered roles for pseudoprotease rhomboid-like proteins in controlling inflammation, cancer and signalling.

The overall theme of our research is to understand, and learn how to manipulate, the regulatory processes that control signalling, and that shape the membrane proteome more widely. Using cell biology and genetics, as well as molecular and structural techniques, we seek to understand both the molecular mechanisms, but also the significance of these processes in fundamental biology and human disease. For example, we have revealed central roles for rhomboid-like proteins in inflammatory diseases and cancer.