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.