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.
Highlights
Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins
At axon growth cone (AGC) of mouse hippocampal neurons, we found that endogenous Plexin A1 located within fast Endophilin-mediated endocytosis (FEME) carriers in a proportion similar to that in resting HUVEC cells
Instead of looking for BAR proteins colocalizing onto the transient Endophilin clusters at the leading edge[6], we focused on those that localized onto FEME carriers produced upon fetal bovine serum (FBS) addition (Fig. 7a)
Summary
Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Using chemical and genetic inhibition, we find that Cdk[5] and GSK3β are negative regulators of FEME They antagonize the binding of Endophilin to Dynamin-1 and to CRMP4, a Plexin A1 adaptor. FEME is primed by a cascade of molecular events starting with active, GTP-loaded, Cdc[42] recruiting CIP4/FBP17 that engage the 5′-phosphatase SHIP2 and Lamellipodin (Lpd) The latter concentrates Endophilin into clusters on discrete locations of the plasma membrane[6]. The kinases inhibit at least three steps: endophilin binding and recruitment of CRMP4 and Dynamin-1 and Bin[1] binding and recruitment of Dynein This regulates cargo sorting, membrane scission, and FEME carrier transport onto microtubules. This control is required for proper growth cone formation, axon elongation, and branching
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