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Rac1-PAK1 regulation of Rab11 cycling promotes junction destabilization

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Title: Rac1-PAK1 regulation of Rab11 cycling promotes junction destabilization
Authors: Erasmus, JC
Smolarczyk, K
Brezovjakova, H
Mohd-Naim, NF
Lozano, E
Matter, K
Braga, V
Item Type: Journal Article
Abstract: Rac1 GTPase is hyper-activated in tumours and contributes to malignancy.Rac1 disruption of junctions requires its effector PAK1, but the precise mechanisms are unknown. Here we identify that E-cadherinis internalized via micropinocytosis in a PAK1–dependent manner, without catenin dissociation and degradation. In addition to internalization, PAK1 regulates E-cadherin transport by fine-tuning Rab small GTPase function. PAK1 phosphorylates RabGDI(a core Rab regulator), but not RabGDI. Phosphorylated RabGDIpreferentiallyassociateswith Rab5 and Rab11, which is predicted to promote Rab retrieval from membranes. Consistent with this hypothesis, Rab11is activated by hyper-activeRac1andinhibition of Rab11 function partially rescues E-cadherin destabilization. Thus, Rac1 activation reduces surface cadherin levels as a net result of higher bulk flow of membrane uptake that counteractsRab11-dependentE-cadherin delivery to junctions (recycling and/or exocytosis). This unique small GTPase crosstalk has impact onRac1 and PAK1regulation of membrane remodelling during epithelial de-differentiation, adhesion and motility.
Issue Date: 1-Jun-2021
Date of Acceptance: 4-Feb-2021
URI: http://hdl.handle.net/10044/1/86050
DOI: 10.1083/jcb.202002114
ISSN: 0021-9525
Publisher: Rockefeller University Press
Start Page: 1
End Page: 19+
Journal / Book Title: The Journal of Cell Biology
Volume: 220
Issue: 6
Copyright Statement: © 2021 Erasmus et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Medical Research Council (MRC)
Brunei Darussalam High Commission
Cancer Research UK
Biotechnology and Biological Sciences Research Council (BBSRC)
Funder's Grant Number: G0600791
Keywords: 06 Biological Sciences
11 Medical and Health Sciences
Developmental Biology
Publication Status: Published online
Article Number: e202002114
Online Publication Date: 2021-04-29
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine

This item is licensed under a Creative Commons License Creative Commons