The behaviour of cells within a tissue is controlled by the cell’s environment. Amongst the most important signals that cells receive are in the form of circulating small proteins called growth factors. These bind to specific proteins, called receptors, which are found on the surface of cells. Binding of growth factors causes the receptors to alter their pattern of interactions with many molecules inside the cell that control cell growth. In this way growth factor receptors relay information between the cell exterior and interior to stimulate so-called mitogenic responses, which enable cells to grow and divide. In order to prevent these responses continuing endlessly, which leads to uncontrolled cell division and eventually to cancer, the growth factor receptor must be hidden inside the cell and eventually destroyed. The aim of our work is to understand how activated mitogenic receptors follow the pathway from the cell surface to their site of degradation, and how the cell makes sure this transit occurs only when it has received sufficient stimulus from circulating growth factors.

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:

1. How are ubiquitinated mitogenic receptors recognised by cellular machinery and segregated away from recycling cargo?
2. How is this segregation of receptors coupled to endosomal signalling events to ensure that the duration of mitogenic signalling is correctly regulated?

Self-funded PhD studentship: A moving account of degradation: receptor signalling, endosomes and motor proteins 

Endosomes are hubs for regulating multiple signaling pathways, because endosomal sorting determines the fate of cell surface signalling receptors. Activated receptors are internalised into endosomes. Some return to the surface from the endosome and continue to signal, some remain active within a ‘signalling endosome’, whilst others are sorted towards lysosomal degradation. This choice is crucial for determining the impact of receptor signalling on cell fate. Epidermal growth factor receptor (EGFR) serves as an exemplary model of a signaling receptor whose trafficking is linked to the signaling output. The decision of whether EGFR remains active or is degraded is determined by several membrane trafficking switches, but also is set against a highly motile backdrop: progression of cargo towards the lysosome is accompanied by the inward movement of endosomes from the periphery towards the cell centre, whilst recycling pathways are also spatially controlled. In all, this creates a spatiotemporal pattern of signaling that is instrumental in controlling cell fate. Whilst endosome motility is governed over short ranges by actin, microtubule-based movement is critical for moving endosomes between the cell periphery and cell centre, and requires the minus-end microtubule motor protein dynein. This project seeks to establish how EGFR-dependent signalling, and specifically MAP kinase family signaling, controls dynein-dependent motility of endosomes, including those containing EGFR. The overall objective of the PhD project is to identify how endocytic membrane trafficking steps are coordinated with endosome motility, and how such coupling is linked to EGFR-dependent signalling.

References

[1] Reck-Peterson SL et al. Nat Rev Mol Cell Biol. 19, 382-398 (2018).

[2] Bonifacino JS, Neefjes J. Curr Opin Cell Biol. 47, 1-8 (2017).

[3] Granger E et al. Semin Cell Dev Biol. 31, 20-9 (2014).