Membrane Trafficking and Cell Division
My laboratory is interested in the cell biology underlying two fundamental cellular processes - receptor downregulation and cell division. These processes are linked by the functions of a membrane trafficking apparatus – the Endosomal Sorting Complex Required for Transport (ESCRT) machinery. In both cases, the ESCRT machinery performs a topologically unique membrane fission (Figure 1).
After stimulation, growth factor receptors such as the EGF-receptor (EGFR) are ubiquitinated, internalised and trafficked to the lysosome for degradation, attenuating their signaling output and thus controlling cellular excitability. At the late-endosome, the ubiquitin is recognized and these receptors are sorted onto intra-endosomal vesicles that are severed from the limiting endosomal membrane through the actions of the ESCRT-machinery to form an endosomal multivesicular body (MVB formation - Figure 1). When the MVB fuses with the lysosome, receptors are efficiently degraded in the proteolytic lysosomal interior.
At late stages of cell division, this same ESCRT machinery is re-routed to the midbody, a membranous stalk connecting the daughter cells. In a manner topologically equivalent to the severing of endosomal vesicles during MVB formation, the ESCRT-machinery acts to sever this membranous stalk, allowing cell separation and the completion of cell division (Cytokinesis - Figure 1). This machinery also performs an analogous role in the severing of membranous stalks tethering retroviruses such as HIV-1 to allow viral release.
Defects in ESCRT-function are thought to produce failures in the termination of growth factor receptor signaling or to produce defects in cell division. We are using molecular biology, advanced imaging (fixed and live) and biochemical techniques to understand how this machinery functions and to explore the consequences of its deregulation in cancer.
Dr Jeremy Carlton (PI)
Dr Yolanda Olmos (Post-Doc)