I am part of the Oncology, Membrane Traffic and Signaling grouping in the Department of Cellular and Molecular Physiology.
Our research is funded by the Wellcome Trust, BBSRC, Cancer Research Uk and North West Cancer Research..
Our key interests lie in understanding the regulation of growth factor receptor trafficking and signalling in mammalian cells, with a particular focus on pathways germane to cancer and neurodegenerative disease.
* Cell surface levels of growth factor receptors are tightly regulated in order to control proliferative signals. Downregulation of activated receptors involves their internalization into endosomes and subsequent sorting to lysosomes. Key to this sorting process is the reversible attachment of ubiquitin moieties to the cytoplasmic receptor tail, which are recognized by multiple components of the ensosomal sorting machinery, including Hrs and STAM, two proteins with ubiquitin interacting motifs (UIM) that have been under investigation in our lab.
* We have been focussing on the regulation of growth factor receptor dynamics by de-ubiquitination enzymes (DUBs) and have characterized two endosomal deubiquitinating enzymes, AMSH and USP8/UBPY which share a binding site on STAM. AMSH is a JAMM-domain metalloprotease AMSH, which acts preferentially on K63-linked ubiquitin chains, and its depletion from mammalian cells results in enhanced downregulation of EGF receptor (EGFR). In contrast, cells depleted of USP8/UBPY show severely decreased levels of Hrs and STAM, an increase in multivesicular endosomes that accumulate ubiquitinated proteins and failure to degrade multiple receptor tyrosine kinases. Both AMSH and UBPY undergo multiple interactions with a subset of CHMP proteins that are key components of the ESCRT (Endosomal Sorting Complex Required for Transport) machinery.
Our most recent work on USP8 shows that this protein is also required for the trafficking of lysosomal enzymes via the Mannose-6-Phosphate receptor.
* We have extended our efforts to the other members of the DUB superfamily (79 active members in the human genome) taking a multi-pronged approach involving cell biological, microscopical, biochemical and proteomic approaches to further our understanding of these enzymes.
* We have a specific interest in the role of reversible ubiquitination in endocytic trafficking and signalling of growth factor receptors and mitochondrial function.
* We are investigating the temporal and spatial regulation of the ESCRT-0 complex and its interactome using quantitative mass spectrometry.