Exploiting rhomboid-like proteins to control signalling

Integral membrane proteins, which include receptors, channels and other cell surface proteins, mediate communication between cells, regulate physiology and pathology, and are the target of about half of all therapeutic drugs. My lab discovered that rhomboids are an evolutionarily widespread family of intramembrane proteases, and that they define a broader superfamily of rhomboid-like proteins (RLPs). The hallmark function of the RLPs is to bind with high specificity (and, in the case of rhomboids, cleave) the TMDs of other membrane proteins. I now plan to focus our attention towards exploiting what we have learned: the overarching goal of this proposal is to take advantage of RLPs to manipulate membrane proteins and thereby reengineer cell signalling. This will allow us to control the generation of, and response to, signals generated by integral membrane proteins (for example, TNF production in inflammation, T cell activation by CARs, or EGFR signalling in cancer). To do this, we will capitalise on our previous insights, but we will also solve open fundamental mechanistic questions, thereby further extending our ability to manipulate signalling outputs. In the future, we hope that the toolkit that we build can be used in a diverse range of therapeutic and research contexts.