Abstract
The endosomal system provides rich signal processing capabilities for responses elicited by growth factor receptors and their ligands. At the single cell level, endosomal trafficking becomes a critical component of signal processing, as exemplified by the epidermal growth factor (EGF) receptors. Activated EGFRs are trafficked to the phosphatase-enriched peri-nuclear region (PNR), where they are dephosphorylated and degraded. The details of the mechanisms that govern the movements of stimulated EGFRs towards the PNR, are not completely known. Here, exploiting the advantages of lattice light-sheet microscopy, we show that EGFR activation by EGF triggers a transient calcium increase causing a whole-cell level redistribution of Adaptor Protein, Phosphotyrosine Interacting with PH Domain And Leucine Zipper 1 (APPL1) from pre-existing endosomes within one minute, the rebinding of liberated APPL1 directly to EGFR, and the dynein-dependent translocation of APPL1-EGF-bearing endosomes to the PNR within ten minutes. The cell spanning, fast acting network that we reveal integrates a cascade of events dedicated to the cohort movement of activated EGF receptors. Our findings support the intriguing proposal that certain endosomal pathways have shed some of the stochastic strategies of traditional trafficking and have evolved processes that provide the temporal predictability that typify canonical signaling.
Highlights
The endosomal system provides rich signal processing capabilities for responses elicited by growth factor receptors and their ligands
Based on the aforementioned experiments that provide evidence of endosomal dynamics and protein redistributions, in Fig. 6 we present a model of the proposed events involving epidermal growth factor (EGF), EGFR, Ca2+, APPL1, ER-associated phosphatase, and dynein from before, and up to 5 min after, EGF stimulation
Before exposure to EGF, EGFR predominantly exists in its monomeric state[41], APPL1 is bound to pre-existing endosomes, and Ca2+ levels are low
Summary
The endosomal system provides rich signal processing capabilities for responses elicited by growth factor receptors and their ligands. At the single cell level, endosomal trafficking becomes a critical component of signal processing, as exemplified by the epidermal growth factor (EGF) receptors. The intracellular itineraries of the two receptors are distinct with stimulated EGFRs localizing to late endosomes and transferrin receptors recycled back through the early endosomes marked by Rab[58,12,13,14,15,16]. APPL1 binding to EGFR results in a cohort, dynein-mediated movement of EGFR towards the perinuclear region of the cell where the endosomal maturation and signal quenching of EGFRs occur
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