PMID- 28749339
OWN - NLM
STAT- MEDLINE
DCOM- 20180515
LR  - 20240210
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 6
DP  - 2017 Jul 27
TI  - PTEN controls glandular morphogenesis through a juxtamembrane 
      beta-Arrestin1/ARHGAP21 scaffolding complex.
LID - 10.7554/eLife.24578 [doi]
LID - e24578
AB  - PTEN controls three-dimensional (3D) glandular morphogenesis by coupling 
      juxtamembrane signaling to mitotic spindle machinery. While molecular mechanisms 
      remain unclear, PTEN interacts through its C2 membrane-binding domain with the 
      scaffold protein beta-Arrestin1. Because beta-Arrestin1 binds and suppresses the Cdc42 
      GTPase-activating protein ARHGAP21, we hypothesize that PTEN controls Cdc42 
      -dependent morphogenic processes through a beta-Arrestin1-ARHGAP21 complex. Here, we 
      show that PTEN knockdown (KD) impairs beta-Arrestin1 membrane localization, 
      beta-Arrestin1-ARHGAP21 interactions, Cdc42 activation, mitotic spindle orientation 
      and 3D glandular morphogenesis. Effects of PTEN deficiency were phenocopied by 
      beta-Arrestin1 KD or inhibition of beta-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 beta-Arrestin1, ARHGAP21 and Cdc42.
FAU - Javadi, Arman
AU  - Javadi A
AD  - Centre for Cancer Research and Cell Biology, Queen's University of Belfast, 
      Belfast, United Kingdom.
FAU - Deevi, Ravi K
AU  - Deevi RK
AD  - Centre for Cancer Research and Cell Biology, Queen's University of Belfast, 
      Belfast, United Kingdom.
FAU - Evergren, Emma
AU  - Evergren E
AD  - Centre for Cancer Research and Cell Biology, Queen's University of Belfast, 
      Belfast, United Kingdom.
FAU - Blondel-Tepaz, Elodie
AU  - Blondel-Tepaz E
AD  - Inserm, U1016, Institut Cochin, Paris, France.
AD  - CNRS, UMR8104, Paris, France.
AD  - Univ. Paris Descartes, Sorbonne Paris Cite, Paris, France.
FAU - Baillie, George S
AU  - Baillie GS
AD  - Institute of Cardiovascular and Medical Science, College of Medical, Veterinary 
      and Life Sciences, University of Glasgow, Glasgow, Scotland.
FAU - Scott, Mark Gh
AU  - Scott MG
AUID- ORCID: 0000-0002-1557-1856
AD  - Inserm, U1016, Institut Cochin, Paris, France.
AD  - CNRS, UMR8104, Paris, France.
AD  - Univ. Paris Descartes, Sorbonne Paris Cite, Paris, France.
FAU - Campbell, Frederick C
AU  - Campbell FC
AUID- ORCID: 0000-0002-0363-9964
AD  - Centre for Cancer Research and Cell Biology, Queen's University of Belfast, 
      Belfast, United Kingdom.
LA  - eng
GR  - 15342/CRUK_/Cancer Research UK/United Kingdom
GR  - MC_PC_15039/MRC_/Medical Research Council/United Kingdom
GR  - MR/J007412/1/MRC_/Medical Research Council/United Kingdom
GR  - C9136/A15342/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170727
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (ARHGAP21 protein, human)
RN  - 0 (ARRB1 protein, human)
RN  - 0 (GTPase-Activating Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (beta-Arrestin 1)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - EC 3.6.5.2 (CDC42 protein, human)
RN  - EC 3.6.5.2 (cdc42 GTP-Binding Protein)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Caco-2 Cells
MH  - Cell Membrane/*metabolism/ultrastructure
MH  - GTPase-Activating Proteins/antagonists & inhibitors/*genetics/metabolism
MH  - Gene Expression Regulation
MH  - HCT116 Cells
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Organoids/cytology/*metabolism/ultrastructure
MH  - PTEN Phosphohydrolase/antagonists & inhibitors/*genetics/metabolism
MH  - Protein Binding
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Signal Transduction
MH  - Spindle Apparatus/*metabolism/ultrastructure
MH  - Tissue Culture Techniques
MH  - beta-Arrestin 1/antagonists & inhibitors/*genetics/metabolism
MH  - cdc42 GTP-Binding Protein/genetics/metabolism
PMC - PMC5576923
OTO - NOTNLM
OT  - ARHGAP21
OT  - Arrestin
OT  - Cdc42 protein
OT  - Morphogenesis
OT  - PTEN
OT  - cancer biology
OT  - cell biology
OT  - human
COIS- No competing interests declared.
EDAT- 2017/07/28 06:00
MHDA- 2018/05/16 06:00
PMCR- 2017/07/27
CRDT- 2017/07/28 06:00
PHST- 2016/12/23 00:00 [received]
PHST- 2017/07/24 00:00 [accepted]
PHST- 2017/07/28 06:00 [pubmed]
PHST- 2018/05/16 06:00 [medline]
PHST- 2017/07/28 06:00 [entrez]
PHST- 2017/07/27 00:00 [pmc-release]
AID - 24578 [pii]
AID - 10.7554/eLife.24578 [doi]
PST - epublish
SO  - Elife. 2017 Jul 27;6:e24578. doi: 10.7554/eLife.24578.