EGFR controls IQGAP basolateral membrane localization and mitotic spindle orientation during epithelial morphogenesis

• Published in: The EMBO journal 2014-01, Vol.33 (2), p.129-145
• Main Authors: Bañón-Rodríguez, Inmaculada, Gálvez-Santisteban, Manuel, Vergarajauregui, Silvia, Bosch, Minerva, Borreguero-Pascual, Arantxa, Martín-Belmonte, Fernando
• Format: Article
• Language: English
• Subjects: Animals; Cell adhesion & migration; Cell cycle; Cell division; Cell Membrane - metabolism; cell polarity; Cell Polarity - physiology; Cells, Cultured; cytoskeleton; Dogs; EMBO05; EMBO06; epithelial morphogenesis; Epithelium - growth & development; Epithelium - metabolism; HEK293 Cells; Humans; Localization; lumenogenesis; Madin Darby Canine Kidney Cells; Membranes; Morphogenesis - genetics; Protein Interaction Domains and Motifs; ras GTPase-Activating Proteins - chemistry; ras GTPase-Activating Proteins - metabolism; Receptor, Epidermal Growth Factor - metabolism; Spindle Apparatus - physiology; spindle orientation; Tissue Distribution
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1002/embj.201385946

Establishing the correct orientation of the mitotic spindle is an essential step in epithelial cell division in order to ensure that epithelial tubules form correctly during organ development and regeneration. While recent findings have identified some of the molecular mechanisms that underlie spindle orientation, many aspects of this process remain poorly understood. Here, we have used the 3D‐MDCK model system to demonstrate a key role for a newly identified protein complex formed by IQGAP1 and the epithelial growth factor receptor (EGFR) in controlling the orientation of the mitotic spindle. IQGAP1 is a scaffolding protein that regulates many cellular pathways, from cell‐cell adhesion to microtubule organization, and its localization in the basolateral membrane ensures correct spindle orientation. Through its IQ motifs, IQGAP1 binds to EGFR, which is responsible for maintaining IQGAP1 in the basolateral membrane domain. Silencing IQGAP1, or disrupting the basolateral localization of either IQGAP1 or EGFR, results in a non‐polarized distribution of NuMA, mitotic spindle misorientation and defects in single lumen formation. Synopsis Inactive EGFR recruits IQGAP1 to the basolateral membrane of epithelial cells to ensure proper NuMA‐dependent mitotic spindle orientation. EGF‐EGFR signaling disrupts IQGAP1 polarization, causing spindle misorientation and affecting lumen formation in epithelial tubules IQGAP1 localizes to the basolateral membrane of epithelial cells in an EGFR‐dependent manner. IQGAP1 is required for NuMA complex localization to the basolateral membrane. IQGAP1 polarization is required for proper mitotic spindle orientation and single lumen formation. EGFR activation induces its internalization, the redistribution of IQGAP1 and therefore mitotic spindle re‐orientation. Graphical Abstract Inactive EGFR recruits IQGAP1 to the basolateral membrane of epithelial cells to ensure proper NuMA‐dependent mitotic spindle orientation. EGF‐EGFR signaling disrupts IQGAP1 polarization, causing spindle misorientation and affecting lumen formation in epithelial tubules.