The Urban Lab studies the function and evolution of highly-conserved signalling pathways in diverse organisms. We are particularly interested in how signalling is activated by the cell sending the signal. By initially focusing on EGF receptor signalling during Drosophila development, we discovered that rhomboid, a seven transmembrane protein, is responsible for initiating signalling by catalyzing cleavage of membrane-anchored EGF growth factors. Unexpectedly, our analysis revealed that the rhomboid active site is embedded within the membrane, providing the first description of intra-membrane proteolysis of a growth factor. Similar intramembrane proteolysis has been discovered recently, and is involved in such diverse processes as Alzheimer’s disease and regulating cholesterol biosynthesis.
Rhomboid proteins are conserved in all branches of life, suggesting that they are ancestral control factors that are now widespread signalling regulators. In fact, rhomboid proteins are the most widely-conserved membrane proteins known, but their functions have been studied in remarkably few contexts. My group is using a multidisciplinary approach combining membrane biochemistry, chemical genetics, and cell biology to study this ancient and conserved form of cell signalling and its evolution. We have recently reconstituted activity in vitro with pure recombinant components, and have discovered a role for rhomboid proteins in cell invasion by human pathogens Toxoplasma and the malaria parasite.