Cdk5 and GSK3β inhibit fast endophilin-mediated endocytosis

Antonio P. A. Ferreira, Alessandra Casamento, Sara Carrillo Roas, Els F. Halff, James Panambalana, Shaan Subramaniam, Kira Schützenhofer, Laura Chan Wah Hak, Kieran McGourty, Konstantinos Thalassinos, Josef T. Kittler, Denis Martinvalet and Emmanuel Boucrot ()
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Antonio P. A. Ferreira: University College London
Alessandra Casamento: University College London
Sara Carrillo Roas: University College London
Els F. Halff: University College London
James Panambalana: University College London
Shaan Subramaniam: University College London
Kira Schützenhofer: University College London
Laura Chan Wah Hak: University College London
Kieran McGourty: University College London
Konstantinos Thalassinos: University College London
Josef T. Kittler: University College London
Denis Martinvalet: University of Padova
Emmanuel Boucrot: University College London

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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 GSK3β 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 GSK3β binds to Endophilin, it imposes a local regulation of FEME. Thus, Cdk5 and GSK3β are key regulators of FEME, licensing cells for rapid uptake by the pathway only when their activity is low.

Date: 2021
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DOI: 10.1038/s41467-021-22603-4

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