PTEN controls glandular morphogenesis through a juxtamembrane β-Arrestin1/ARHGAP21 scaffolding complex

Javadi, A., Deevi, R. K., Evergren, E., Blondel-Tepaz, E., Baillie, G. S. , Scott, M. G.H. and Campbell, F. C. (2017) PTEN controls glandular morphogenesis through a juxtamembrane β-Arrestin1/ARHGAP21 scaffolding complex. eLife, 6, e24578. (doi:10.7554/eLife.24578) (PMID:28749339) (PMCID:PMC5576923)

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Abstract

PTEN controls three-dimensional (3D) glandular morphogenesis by coupling juxtamembrane signalling to mitotic spindle machinery. While molecular mechanisms remain unclear, PTEN interacts through its C2 membrane-binding domain with the scaffold protein β-Arrestin1. Because β-Arrestin1 binds and suppresses the Cdc42 GTPase-activating protein ARHGAP21, we hypothesize that PTEN controls Cdc42-dependent morphogenic processes through a β-Arrestin1-ARHGAP21 complex. Here we show that PTEN knockdown (KD) impairs β-Arrestin1 membrane localization, β-Arrestin1-ARHGAP21 interactions, Cdc42 activation, mitotic spindle orientation and 3D glandular morphogenesis. Effects of PTEN-deficiency were phenocopied by β-Arrestin1 KD or inhibition of β-Arrestin1-ARHGAP21 interactions. Conversely, silencing of ARHGAP21 enhanced Cdc42 activation and rescued aberrant morphogenic processes of PTEN-deficient cultures. Expression of the PTEN C2 domain mimicked effects of full-length PTEN but a membrane-binding defective mutant of the C2 domain abrogated these properties. Our results show that PTEN controls multicellular assembly through a membrane-associated regulatory protein complex composed of β-Arrestin1, ARHGAP21 and Cdc42.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George
Authors: Javadi, A., Deevi, R. K., Evergren, E., Blondel-Tepaz, E., Baillie, G. S., Scott, M. G.H., and Campbell, F. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN:2050-084X
ISSN (Online):2050-084X
Published Online:27 July 2017
Copyright Holders:Copyright © 2017 Javadi et al.
First Published:First published in eLife 6:e24578
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
588611cAMP phosphodiesterase-4: signalling complexes, regulation and potential therapeutic targets.George BaillieMedical Research Council (MRC)MR/J007412/1RI CARDIOVASCULAR & MEDICAL SCIENCES