Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-22603-4
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Funding
- Fundacao para a Ciencia e Tecnologia
- Biotechnology and Biological Sciences Research Council (BBSRC) LIDo PhD scholarship
- Medical Research Council
- Lister Institute of Preventive Medicine
- Marie Skodowska-Curie grant [661733]
- ERC [282430]
- MRC [MR/N025644/1]
- Wellcome Trust [104913/Z/14/ZBM]
- BBSRC [BB/R01552X]
- Lister Institute Research Fellow
- BBSRC Pathfinder grant [BB/R01552X]
- Birkbeck/Wellcome Trust Institutional Strategic Support Fund (ISSF2) Career Development Award
- European Research Council (ERC) [282430] Funding Source: European Research Council (ERC)
- Marie Curie Actions (MSCA) [661733] Funding Source: Marie Curie Actions (MSCA)
- Medical Research Council [MR/N025644/1] Funding Source: researchfish
- MRC [MR/N025644/1] Funding Source: UKRI
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The authors demonstrate that Cdk5 and GSK3 beta act as negative regulators of fast Endophilin-mediated endocytosis (FEME), playing critical roles in axon elongation, branching, and growth cone formation in hippocampal neurons.
Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Fast Endophilin-mediated endocytosis, FEME, is not constitutively active but triggered upon receptor activation. High levels of growth factors induce spontaneous FEME, which can be suppressed upon serum starvation. This suggested a role for protein kinases in this growth factor receptor-mediated regulation. Using chemical and genetic inhibition, we find that Cdk5 and GSK3 beta are negative regulators of FEME. They antagonize the binding of Endophilin to Dynamin-1 and to CRMP4, a Plexin A1 adaptor. This control is required for proper axon elongation, branching and growth cone formation in hippocampal neurons. The kinases also block the recruitment of Dynein onto FEME carriers by Bin1. As GSK3 beta binds to Endophilin, it imposes a local regulation of FEME. Thus, Cdk5 and GSK3 beta are key regulators of FEME, licensing cells for rapid uptake by the pathway only when their activity is low. Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Here, the authors show that Cdk5 and GSK3 beta are negative regulators of fast Endophilin-mediated endocytosis (FEME).
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