title: WAVE2 regulates epithelial morphology and cadherin isoform switching through regulation of Twist and Abl.
abstract: BACKGROUND
  Epithelial morphogenesis is a dynamic process that involves coordination of signaling and actin cytoskeletal rearrangements.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Bryce
authors.forename: Albert B
authors.initials: AB
authors.lastname: Reynolds
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koleske
authors.forename: Alissa M
authors.initials: AM
authors.lastname: Weaver
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000502:physiology*
chemical_list: D015820:Cadherins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D016315:Proto-Oncogene Proteins c-abl