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MYO6 Regulates Spatial Organization of Signaling Endosomes Driving AKT Activation and Actin Dynamics

Published version
Peer-reviewed

Type

Article

Change log

Authors

Masters, TA 
Tumbarello, DA 
Chibalina, MV 

Abstract

APPL1- and RAB5-positive signaling endosomes play a crucial role in the activation of AKT in response to extracellular stimuli. Myosin VI (MYO6) and two of its cargo adaptor proteins, GIPC and TOM1/TOM1L2, localize to these peripheral endosomes and mediate endosome association with cortical actin filaments. Loss of MYO6 leads to the displacement of these endosomes from the cell cortex and accumulation in the perinuclear space. Depletion of this myosin not only affects endosome positioning, but also induces actin and lipid remodeling consistent with endosome maturation, including accumulation of F-actin and the endosomal lipid PI(3)P. These processes acutely perturb endosome function, as both AKT phosphorylation and RAC-dependent membrane ruffling were markedly reduced by depletion of either APPL1 or MYO6. These results place MYO6 and its binding partners at a central nexus in cellular signaling linking actin dynamics at the cell surface and endosomal signaling in the cell cortex.

Description

Keywords

AKT activation, APPL1 endosomes, cortical actin, membrane ruffling, myosin VI, unconventional myosins, Actins, Adaptor Proteins, Signal Transducing, Animals, Cell Line, Endosomes, Enzyme Activation, Mice, Myosin Heavy Chains, Proto-Oncogene Proteins c-akt, Signal Transduction

Journal Title

Cell reports

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

19

Publisher

Elsevier
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/K001981/1)
Medical Research Council (MR/K000888/1)
British Heart Foundation (PG/15/12/31280)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (086743/Z/08/Z)
Wellcome Trust (093026/Z/10/Z)