1. Cancer Biology
  2. Cell Biology
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PTEN controls glandular morphogenesis through a juxtamembrane β-Arrestin1/ARHGAP21 scaffolding complex

  1. Arman Javadi
  2. Ravi K Deevi
  3. Emma Evergren
  4. Elodie Blondel-Tepaz
  5. George S Baillie
  6. Mark GH Scott
  7. Frederick Charles Campbell  Is a corresponding author
  1. Queen's University of Belfast, United Kingdom
  2. Institut Cochin, France
  3. University of Glasgow, United Kingdom
Research Article
  • Cited 14
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Cite this article as: eLife 2017;6:e24578 doi: 10.7554/eLife.24578

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.

Article and author information

Author details

  1. Arman Javadi

    Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Ravi K Deevi

    Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Emma Evergren

    Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Elodie Blondel-Tepaz

    Inserm, U1016, Institut Cochin, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. George S Baillie

    Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Mark GH Scott

    Inserm, U1016, Institut Cochin, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1557-1856
  7. Frederick Charles Campbell

    Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom
    For correspondence
    f.c.campbell@qub.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0363-9964

Funding

Cancer Research UK (C9136/A15342)

  • Frederick Charles Campbell

Department of Education and Learning, Northern Ireland (Studentship)

  • Arman Javadi

Fondation ARC pour la Recherche sur le Cancer

  • Mark GH Scott

Medical Research Council (MRC(MR/J007412/1))

  • George S Baillie

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Mohan K Balasubramanian, University of Warwick, United Kingdom

Publication history

  1. Received: December 23, 2016
  2. Accepted: July 24, 2017
  3. Accepted Manuscript published: July 27, 2017 (version 1)
  4. Version of Record published: August 30, 2017 (version 2)

Copyright

© 2017, Javadi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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