Endophilin, Lamellipodin, and Mena cooperate to regulate F-actin-dependent EGF-receptor endocytosis
Open Access
- 27 September 2013
- journal article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 32 (20), 2722-2734
- https://doi.org/10.1038/emboj.2013.212
Abstract
The epidermal growth factor receptor (EGFR) plays an essential role during development and diseases including cancer. Lamellipodin (Lpd) is known to control lamellipodia protrusion by regulating actin filament elongation via Ena/VASP proteins. However, it is unknown whether this mechanism supports endocytosis of the EGFR. Here, we have identified a novel role for Lpd and Mena in clathrin‐mediated endocytosis (CME) of the EGFR. We have discovered that endogenous Lpd is in a complex with the EGFR and Lpd and Mena knockdown impairs EGFR endocytosis. Conversely, overexpressing Lpd substantially increases the EGFR uptake in an F‐actin‐dependent manner, suggesting that F‐actin polymerization is limiting for EGFR uptake. Furthermore, we found that Lpd directly interacts with endophilin, a BAR domain containing protein implicated in vesicle fission. We identified a role for endophilin in EGFR endocytosis, which is mediated by Lpd. Consistently, Lpd localizes to clathrin‐coated pits (CCPs) just before vesicle scission and regulates vesicle scission. Our findings suggest a novel mechanism in which Lpd mediates EGFR endocytosis via Mena downstream of endophilin.Keywords
This publication has 57 references indexed in Scilit:
- Structural Basis of Membrane Bending by the N-BAR Protein EndophilinCell, 2012
- Membrane Fission Is Promoted by Insertion of Amphipathic Helices and Is Restricted by Crescent BAR DomainsCell, 2012
- Structural Organization of the Actin Cytoskeleton at Sites of Clathrin-Mediated EndocytosisCurrent Biology, 2011
- Synaptojanin 1-Mediated PI(4,5)P2 Hydrolysis Is Modulated by Membrane Curvature and Facilitates Membrane FissionDevelopmental Cell, 2011
- c-Abl, Lamellipodin, and Ena/VASP Proteins Cooperate in Dorsal Ruffling of Fibroblasts and Axonal MorphogenesisCurrent Biology, 2010
- Coordinated Actions of Actin and BAR Proteins Upstream of Dynamin at Endocytic Clathrin-Coated PitsDevelopmental Cell, 2009
- Actin nucleation and elongation factors: mechanisms and interplayCurrent Opinion in Cell Biology, 2009
- Actin and endocytosis: mechanisms and phylogenyCurrent Opinion in Cell Biology, 2009
- A Mena Invasion Isoform Potentiates EGF-Induced Carcinoma Cell Invasion and MetastasisDevelopmental Cell, 2008
- Clathrin-Mediated Internalization Is Essential for Sustained EGFR Signaling but Dispensable for DegradationDevelopmental Cell, 2008