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Rac1-PAK1 regulation of Rab11 cycling promotes junction destabilization
File(s)
Author(s)
Erasmus, JC
Smolarczyk, K
Brezovjakova, H
Mohd-Naim, NF
Lozano, E
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.
Date Issued
2021-06-01
Date Acceptance
2021-02-04
Citation
The Journal of Cell Biology, 2021, 220 (6), pp.1-19+
URI
URL
DOI
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/).
License URL
Sponsor
Medical Research Council (MRC)
Brunei Darussalam High Commission
Cancer Research UK
Biotechnology and Biological Sciences Research Council (BBSRC)
Identifier
https://rupress.org/jcb/article/220/6/e202002114/212034/Rac1-PAK1-regulation-of-Rab11-cycling-promotes
Grant Number
G0600791
CID00466624
11980
BB/M022617/1
Subjects
06 Biological Sciences
11 Medical and Health Sciences
Developmental Biology
Publication Status
Published online
Article Number
e202002114
Date Publish Online
2021-04-29