TY - JOUR
T1 - Cdk5 and GSK3β inhibit fast endophilin-mediated endocytosis
AU - Ferreira, Antonio P.A.
AU - Casamento, Alessandra
AU - Carrillo Roas, Sara
AU - Halff, Els F.
AU - Panambalana, James
AU - Subramaniam, Shaan
AU - Schützenhofer, Kira
AU - Chan Wah Hak, Laura
AU - McGourty, Kieran
AU - Thalassinos, Konstantinos
AU - Kittler, Josef T.
AU - Martinvalet, Denis
AU - Boucrot, Emmanuel
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85103976394&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-22603-4
DO - 10.1038/s41467-021-22603-4
M3 - Article
C2 - 33893293
AN - SCOPUS:85103976394
SN - 2041-1723
VL - 12
SP - 2424
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2424
ER -