Distinct Roles for Rho Versus Rac/Cdc42 GTPases Downstream of Vav2 in Regulating Mammary Epithelial Acinar Architecture

被引：23

作者：

Duan, Lei ^{[1
,5
]}

Chen, Gengsheng ^{[5
]}

Virmani, Sumeet ^{[5
]}

Ying, GuoGuang ^{[5
]}

Raja, Srikumar M. ^{[1
,5
]}

Chung, Byung Min ^{[1
,5
]}

Rainey, Mark A. ^{[1
,5
]}

Dimri, Manjari ^{[5
]}

Ortega-Cava, Cesar F. ^{[1
,5
]}

Zhao, Xiangshan ^{[2
,5
]}

Clubb, Robert J. ^{[1
,5
]}

Tu, Chun ^{[1
,5
]}

Reddi, Alagarsamy L. ^{[5
]}

Naramura, Mayumi ^{[1
,3
,5
]}

Band, Vimla ^{[1
,2
,4
,5
]}

Band, Hamid ^{[1
,2
,3
,4
,5
]}

机构：

[1] Univ Nebraska, Med Ctr, Eppley Inst Canc & Allied Dis, Omaha, NE 68198 USA

[2] Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE 68198 USA

[3] Univ Nebraska, Med Ctr, Dept Biochem & Mol Biol, Coll Med, Omaha, NE 68198 USA

[4] Univ Nebraska, Med Ctr, Eppley Canc Ctr, Omaha, NE 68198 USA

[5] Northwestern Univ, Feinberg Sch Med, Dept Med, NorthShore Univ HealthSyst, Evanston, IL 60201 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2010年 / 285卷 / 02期

基金：

美国国家卫生研究院;

关键词：

CELL-CELL ADHESION; GROWTH-FACTOR RECEPTORS; BASEMENT-MEMBRANE CULTURES; GTP-BINDING PROTEIN; HUMAN BREAST-CANCER; RAC1 SMALL GTPASES; MDCK CELLS; BRANCHING MORPHOGENESIS; NUCLEAR-ORGANIZATION; SIGNALING PATHWAYS;

D O I：

10.1074/jbc.M109.057976

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1555 / 1568

页数：14

共 64 条

[1]

Vav2 is an activator of Cdc42, Rac1, and RhoA [J].