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

Abstract

SummaryAPPL1- 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.

The MYO6 interactome reveals adaptor complexes coordinating early endosome and cytoskeletal dynamics

“…These results support, and may provide the molecular mechanism for, our recent finding that MYO6 mediates association of APPL1 endosomes with cortical actin filaments 34, 30. Depletion of MYO6 or expression of the reverse MYO6 + affects endosome localisation in the cell cortex.…”

“…Quantitation revealed a modest non-significant increase in actin filaments and APPL1 signal intensity as well as colocalisation of APPL1 with actin upon LPA ▸ Taken together, these data suggest that the LIFT complex is an actin regulatory module, which may function downstream of GPCRs such as LPAR1 to drive RHO-mediated actin reorganisation to regulate endosome positioning and motility. These results support, and may provide the molecular mechanism for, our recent finding that MYO6 mediates association of APPL1 endosomes with cortical actin filaments [30,34]. Depletion of MYO6 or expression of the reverse MYO6 + affects endosome localisation in the cell cortex.…”

“…As such, this ability to modulate vesicle motility is likely to mediate not only receptor traffic and degradation but also the duration of signal transduction. Indeed, we have recently shown a role for MYO6 and GIPC1 in regulating Akt signalling on this compartment 34 and it will be interesting to further address the role of the LIFT complex in this pathway.…”

“…can promote actin remodelling via its activity towards RAC1 and CDC42 GTPases. recently shown a role for MYO6 and GIPC1 in regulating Akt signalling on this compartment [34] and it will be interesting to further address the role of the LIFT complex in this pathway. The second RhoGEF, DOCK7, is a GEF for both RAC1 and CDC42 [41] and has previously been associated with MYO6 [35,36].…”

TheMYO6 interactome: selective motor‐cargo complexes for diverse cellular processes

“…The GIPC‐MYO6 complex has been suggested to translocate early endosomes away from the plasma membrane through the cortical actin network, since expression of a nonfunctional MYO6 rigor mutant inhibits endosome movement . A crucial role for MYO6 in the spatial organization of the APPL1‐signalling endosomes is also supported by the findings that the depletion of MYO6 leads to the premature maturation and displacement of APPL1 endosomes from the cell cortex in the perinuclear region of the cell and expression of a mutant MYO6 that moves towards the plus end of actin filaments causes extreme cortical clustering of endosomes . Finally, recent in situ proximity labelling experiments identified a tripartite complex of GIPC1, MYO6 and LARG, which is a GEF for RHO GTPases.…”