Distinct roles for Rho Versus Rac/Cdc42 GTPases downstream of Vav2 in regulating mammary epithelial acinar architecture

Lei Duan, Gengsheng Chen, Sumeet Virmani, Guo Guang Ying, Srikumar M. Raja, Byung Min Chung, Mark A. Rainey, Manjari Dimri, Cesar F. Ortega-Cava, Xiangshan Zhao, Robert J. Clubb, Chun Tu, Alagarsamy L. Reddi, Mayumi Naramura, Vimla Band, Hamid Band

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Non-malignant mammary epithelial cells (MECs) undergo acinar morphogenesis in three-dimensional Matrigel culture, a trait that is lost upon oncogenic transformation. Rho GTPases are thought to play important roles in regulating epithelial cell-cell junctions, but their contributions to acinar morphogenesis remain unclear. Here we report that the activity of Rho GTPases is down-regulated in non-malignant MECs in three-dimensional culture with particular suppression of Rac1 and Cdc42. Inducible expression of a constitutively active form of Vav2, a Rho GTPase guanine nucleotide exchange factor activated by receptor tyrosine kinases, in three-dimensional MEC culture activated Rac1 and Cdc42; Vav2 induction from early stages of culture impaired acinar morphogenesis, and induction in preformed acini disrupted the pre-established acinar architecture and led to cellular outgrowths. Knockdown studies demonstrated that Rac1 and Cdc42 mediate the constitutively active Vav2 phenotype, whereas in contrast, RhoA knockdown intensified the Vav2-induced disruption of acini, leading to more aggressive cell outgrowth and branching morphogenesis. These results indicate that RhoA plays an antagonistic role to Rac1/Cdc42 in the control of mammary epithelial acinar morphogenesis.

Original languageEnglish (US)
Pages (from-to)1555-1568
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number2
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Duan, L., Chen, G., Virmani, S., Ying, G. G., Raja, S. M., Chung, B. M., Rainey, M. A., Dimri, M., Ortega-Cava, C. F., Zhao, X., Clubb, R. J., Tu, C., Reddi, A. L., Naramura, M., Band, V., & Band, H. (2010). Distinct roles for Rho Versus Rac/Cdc42 GTPases downstream of Vav2 in regulating mammary epithelial acinar architecture. Journal of Biological Chemistry, 285(2), 1555-1568. https://doi.org/10.1074/jbc.M109.057976