Abstract
Endosomal trafficking of receptors and associated proteins plays a critical role in signal processing. Until recently, it was thought that trafficking was shut down during cell division. Thus, remarkably, the regulation of trafficking during division remains poorly characterized. Here we delineate the role of mitotic kinases in receptor trafficking during asymmetric division. Targeted perturbations reveal that Cyclin-dependent Kinase 1 (CDK1) and Aurora Kinase promote storage of Fibroblast Growth Factor Receptors (FGFRs) by suppressing endosomal degradation and recycling pathways. As cells progress through metaphase, loss of CDK1 activity permits differential degradation and targeted recycling of stored receptors, leading to asymmetric induction. Mitotic receptor storage, as delineated in this study, may facilitate rapid reestablishment of signaling competence in nascent daughter cells. However, mutations that limit or enhance the release of stored signaling components could alter daughter cell fate or behavior thereby promoting oncogenesis.
Highlights
Dividing cells undergo dynamic shifts in membrane trafficking
Transgenic Mesp>Fibroblast Growth Factor Receptor (FGFR)::Venus embryos were fixed at 15-min intervals spanning founder cell mitosis and costained with an anti-green fluorescent protein (GFP) antibody to visualize FGFR::VENUS and a chromatin marker (DRAQ5) to facilitate precise mitotic staging [20,22]
We propose a new model for mitotic regulation of FGFR trafficking (Fig 6)
Summary
Dividing cells undergo dynamic shifts in membrane trafficking. During mitotic entry, internalization of plasma membrane promotes cell rounding [1]. Membrane and associated integral membrane proteins are trafficked through a well-delineated system of endosomal compartments [1,4]. In this endosomal trafficking network, Rab GTPases dictate compartment-specific functions (Fig 1A). Endocytosed vesicles fuse to form early endosomes distinguished by RAB4 and RAB5. These early endosomes can either recycle back to the plasma membrane through RAB4-dependent fast recycling or mature into late endosomes through a RAB7-dependent pathway. Late endosomes eventually fuse with lysosomes leading to degradation of integral membrane proteins and other cargo [5].
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