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Fig. 10. Model depicting the proposed role of PIKfyve in regulating endosome-to-TGN retrograde transport. Our model is adapted from the model proposed by Rink and colleagues, describing the process of early to late endosomal progression (Rink et al., 2005). In their model, early endosomes are viewed as forming a temporally dynamic network of compartments that through fusion and fission events are constantly generated and renewed in the cell periphery. Progression to late endosomes occurs through repeated fusion events that enrich degradative cargo (e.g. the EGF receptor shown in red) in increasingly fewer and larger endosomes that are localised in the centre of the cell. During this progression, early and late endosomes maintain their identity through the loss of early markers, such as transferrin receptor (depicted in green), and the acquisition of late markers shown in blue (Rink et al., 2005). Our data support a model whereby PIKfyve modulates endosome-to-TGN retrograde transport primarily, but perhaps not solely, from an early endosomal compartment. A loss of, or reduction in, the activity of PIKfyve leads to a decrease in this membrane flux, which in turn induces a progressive swelling of the endosomal compartments.
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