TY - JOUR
T1 - Distinct roles for Rho Versus Rac/Cdc42 GTPases downstream of Vav2 in regulating mammary epithelial acinar architecture
AU - Duan, Lei
AU - Chen, Gengsheng
AU - Virmani, Sumeet
AU - Ying, Guo Guang
AU - Raja, Srikumar M.
AU - Chung, Byung Min
AU - Rainey, Mark A.
AU - Dimri, Manjari
AU - Ortega-Cava, Cesar F.
AU - Zhao, Xiangshan
AU - Clubb, Robert J.
AU - Tu, Chun
AU - Reddi, Alagarsamy L.
AU - Naramura, Mayumi
AU - Band, Vimla
AU - Band, Hamid
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M109.057976
DO - 10.1074/jbc.M109.057976
M3 - Article
C2 - 19826000
AN - SCOPUS:74049112708
SN - 0021-9258
VL - 285
SP - 1555
EP - 1568
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 2
ER -