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

• Published in: eLife Vol. 6
• Main Authors: Javadi, Arman, Deevi, Ravi K, Evergren, Emma, Blondel-Tepaz, Elodie, Baillie, George S, Scott, Mark Gh, Campbell, Frederick C
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 27.07.2017; eLife Sciences Publications, Ltd
• Subjects: Animals; ARHGAP21; Arrestin; beta-Arrestin 1 - antagonists & inhibitors; beta-Arrestin 1 - genetics; beta-Arrestin 1 - metabolism; Binding Sites; Caco-2 Cells; Cancer; Cancer Biology; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cdc42 protein; Cell Biology; Cell division; Cell Membrane - metabolism; Cell Membrane - ultrastructure; Defective mutant; Gene Expression Regulation; GTPase-activating protein; GTPase-Activating Proteins - antagonists & inhibitors; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Guanosine triphosphatases; HCT116 Cells; HEK293 Cells; Humans; Immunoglobulins; Kinases; Localization; Membrane proteins; Mice; Mice, Inbred C57BL; Microscopy; Molecular modelling; Morphogenesis; Organoids - cytology; Organoids - metabolism; Organoids - ultrastructure; Phosphatase; Protein Binding; Proteins; PTEN; PTEN Phosphohydrolase - antagonists & inhibitors; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Software; Spindle Apparatus - metabolism; Spindle Apparatus - ultrastructure; Tissue Culture Techniques; Cdc42 protein; Morphogenesis; ARHGAP21; cell biology; PTEN; Arrestin; cancer biology; human
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.24578

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 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.