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

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.