Abstract
BackgroundEpithelial morphogenesis is a dynamic process that involves coordination of signaling and actin cytoskeletal rearrangements.Principal FindingsWe analyzed the contribution of the branched actin regulator WAVE2 in the development of 3-dimensional (3D) epithelial structures. WAVE2-knockdown (WAVE2-KD) cells formed large multi-lobular acini that continued to proliferate at an abnormally late stage compared to control acini. Immunostaining of the cell-cell junctions of WAVE2-KD acini revealed weak and heterogeneous E-cadherin staining despite little change in actin filament localization to the same junctions. Analysis of cadherin expression demonstrated a decrease in E-cadherin and an increase in N-cadherin protein and mRNA abundance in total cell lysates. In addition, WAVE2-KD cells exhibited an increase in the mRNA levels of the epithelial-mesenchymal transition (EMT)-associated transcription factor Twist1. KD of Twist1 expression in WAVE2-KD cells reversed the cadherin switching and completely rescued the aberrant 3D morphological phenotype. Activity of the WAVE2 complex binding partner Abl kinase was also increased in WAVE2-KD cells, as assessed by tyrosine phosphorylation of the Abl substrate CrkL. Inhibition of Abl with STI571 rescued the multi-lobular WAVE2-KD 3D phenotype whereas overexpression of Abl kinase phenocopied the WAVE2-KD phenotype.ConclusionsThe WAVE2 complex regulates breast epithelial morphology by a complex mechanism involving repression of Twist1 expression and Abl kinase activity. These data reveal a critical role for WAVE2 complex in regulation of cellular signaling and epithelial morphogenesis.
Highlights
Epithelial morphogenesis is a complex process that involves coordination of cellular proliferation, apoptosis, and motility through cell-cell interactions [1,2,3,4]
The WAVE2 complex regulates breast epithelial morphology by a complex mechanism involving repression of Twist1 expression and Abl kinase activity. These data reveal a critical role for WAVE2 complex in regulation of cellular signaling and epithelial morphogenesis
To understand how dynamic membrane protrusions such as lamellipodia contribute to epithelial morphogenesis in 3D, we expressed shRNA against WAVE2 in MCF10A mammary epithelial cells
Summary
Epithelial morphogenesis is a complex process that involves coordination of cellular proliferation, apoptosis, and motility through cell-cell interactions [1,2,3,4]. A concerted adhesive switch that frequently occurs in aggressive cancers is known as epithelial-mesenchymal transition (EMT). EMT is best understood as a developmental process that contributes to mesoderm formation and neural crest delamination [6,7]. A central feature of canonical EMT is cadherin switching from E-cadherin to a mesenchymal family member, usually Ncadherin, to accommodate the more dynamic adhesive activity associated with elevated cell motility. Epithelial morphogenesis is a dynamic process that involves coordination of signaling and actin cytoskeletal rearrangements
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