Our research interests lie at the interface between membrane trafficking and cell signalling. Once activated, mitogenic receptors such as members of the EGF receptor (EGFR) family need to be downregulated in order to prevent overprolonged signalling. Downregulation involves the removal of the activated receptors from the cell surface and their transport to the lysosome, where they are degraded. Defects in this process are linked with disease, and receptor trafficking is influenced directly by several cancer therapeutics. A central event during receptor downregulation occurs within the early endosome, where the cytoplasmic tail of EGFR is ubiquitinated and subsequently sorted away from recycling receptors. EGFR is then incorporated into intralumenal vesicles within the multivesicular body (MVB), which moves away from the early endosome and fuses with the lysosome. The MVB pathway is also used for sorting other cargo, including other classes of signalling receptor and viruses such as HIV. Understanding the basis for MVB sorting is therefore critical for developing strategies to combat a variety of diseases and infections.
The aim of our research is to understand how ubiquitinated receptors are sorted away from recycling receptors and targeted to the MVB pathway. We are utilising a variety of biochemical and cell biology techniques to address key questions:
- How are ubiquitinated mitogenic receptors recognised by cellular machinery and segregated away from recycling cargo?
- How is this segregation of receptors coupled to endosomal signalling events to ensure that the duration of mitogenic signalling is correctly regulated?