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Transforming Growth Factor-β (TGF-β) and TGF-β–Associated Kinase 1 Are Required for R-Ras–Mediated Transformation of Mammary Epithelial Cells

Departments of ¹ Cancer Biology, ² Medicine (Division of Nephrology), ³ Cell and Developmental Biology, and ⁴ Urologic Surgery, Vanderbilt University Medical Center; and ⁵ Department of Medicine, Veterans Affairs Hospital, Nashville, Tennessee

Requests for reprints: Roy Zent, Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Room C3210, MCN, Nashville, TN 37232. Phone: 615-322-4632; Fax: 615-322-4690; E-mail: roy.zent{at}vanderbilt.edu.

Key Words: Ras • cancer • mTOR • p38 MAPK • PI3 Kinase • EpH4 cells

Transforming growth factor-β (TGF-β) cooperates with oncogenic members of the Ras superfamily to promote cellular transformation and tumor progression. Apart from the classic (H-, K-, and N-) Ras GTPases, only the R-Ras subfamily (R-Ras, R-Ras2/TC21, and R-Ras3/M-Ras) has significant oncogenic potential. In this study, we show that oncogenic R-Ras transformation of EpH4 cells requires TGF-β signaling. When murine EpH4 cells were stably transfected with a constitutively active R-Ras(G38V) mutant, they were no longer sensitive to TGF-β–mediated growth inhibition and showed increased proliferation and transformation in response to exogenous TGF-β. R-Ras/EpH4 cells require TGF-β signaling for transformation to occur and they produce significantly elevated levels of endogenous TGF-β, which signals in an autocrine fashion. The effects of TGF-β are independent of Smad2/3 activity and require activation of TGF-β–associated kinase 1 (TAK1) and its downstream effectors c-Jun NH₂-terminal kinase and p38 mitogen-activated protein kinase as well as the phosphoinositide 3-kinase/Akt and mammalian target of rapamycin pathways. Thus, TAK1 is a novel link between TGF-β signaling and oncogenic R-Ras in the promotion of tumorigenesis. [Cancer Res 2008;68(15):6224–31]