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

Arman Javadi1, Ravi K Deevi1, Emma Evergren1

  • 1Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom.

Elife
|July 28, 2017
PubMed

Insights

PTEN protein regulates 3D glandular development by controlling the beta-Arrestin1-ARHGAP21 complex, which impacts Cdc42 activity and cell assembly. This finding reveals a novel mechanism for PTEN in multicellular organization.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Background:

  • PTEN (Phosphatase and tensin homolog) is crucial for regulating cell growth and survival.
  • PTEN's role in three-dimensional (3D) glandular morphogenesis is linked to its interaction with beta-Arrestin1.
  • The precise molecular mechanisms by which PTEN influences morphogenic processes remain incompletely understood.

Purpose of the Study:

  • To investigate the role of PTEN in 3D glandular morphogenesis.
  • To elucidate the molecular pathway involving PTEN, beta-Arrestin1, ARHGAP21, and Cdc42 in controlling cell assembly.
  • To determine how PTEN's C2 domain mediates these effects.

Main Methods:

  • PTEN knockdown (KD) and beta-Arrestin1 knockdown (KD) were performed.
  • Interactions between beta-Arrestin1 and ARHGAP21 were analyzed.
  • Cdc42 activation, mitotic spindle orientation, and 3D glandular morphogenesis were assessed.
  • The function of the PTEN C2 domain and its membrane-binding mutant was evaluated.

Main Results:

  • PTEN KD disrupted beta-Arrestin1 membrane localization, beta-Arrestin1-ARHGAP21 interactions, Cdc42 activation, spindle orientation, and 3D morphogenesis.
  • Beta-arrestin1 KD or inhibition of beta-Arrestin1-ARHGAP21 interactions phenocopied PTEN deficiency effects.
  • ARHGAP21 silencing rescued PTEN-deficient phenotypes by enhancing Cdc42 activation.
  • The PTEN C2 domain's membrane-binding capability was essential for its morphogenic functions.

Conclusions:

  • PTEN controls 3D glandular morphogenesis by regulating a beta-Arrestin1-ARHGAP21-Cdc42 complex at the membrane.
  • This pathway is critical for proper multicellular assembly and spindle orientation.
  • The PTEN C2 domain acts as a key mediator in this regulatory network.
Keywords:
ARHGAP21ArrestinCdc42 proteinMorphogenesisPTENcancer biologycell biologyhuman

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