Alissa Weaver
Faculty Member
Last active: 4/2/2019

WAVE2 regulates epithelial morphology and cadherin isoform switching through regulation of Twist and Abl.

Bryce NS, Reynolds AB, Koleske AJ, Weaver AM
PLoS One. 2013 8 (5): e64533

PMID: 23691243 · PMCID: PMC3654908 · DOI:10.1371/journal.pone.0064533

BACKGROUND - Epithelial morphogenesis is a dynamic process that involves coordination of signaling and actin cytoskeletal rearrangements.

PRINCIPAL FINDINGS - 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.

MeSH Terms (9)

Cadherins Epithelial-Mesenchymal Transition Humans Nuclear Proteins Protein Isoforms Proto-Oncogene Proteins c-abl Real-Time Polymerase Chain Reaction Twist-Related Protein 1 Wiskott-Aldrich Syndrome Protein Family

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