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PLoS One. 2013 May 15;8(5):e64533. doi: 10.1371/journal.pone.0064533. Print 2013.

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

Author information

1
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Abstract

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.

PMID:
23691243
PMCID:
PMC3654908
DOI:
10.1371/journal.pone.0064533
[Indexed for MEDLINE]
Free PMC Article

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