Transforming growth factor-beta (TGF-beta) and TGF-beta-associated kinase 1 are required for R-Ras-mediated transformation of mammary epithelial cells.

Erdogan M, Pozzi A, Bhowmick N, Moses HL, Zent R
Cancer Res. 2008 68 (15): 6224-31

PMID: 18676846 · DOI:10.1158/0008-5472.CAN-08-0513

Transforming growth factor-beta (TGF-beta) 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-beta signaling. When murine EpH4 cells were stably transfected with a constitutively active R-Ras(G38V) mutant, they were no longer sensitive to TGF-beta-mediated growth inhibition and showed increased proliferation and transformation in response to exogenous TGF-beta. R-Ras/EpH4 cells require TGF-beta signaling for transformation to occur and they produce significantly elevated levels of endogenous TGF-beta, which signals in an autocrine fashion. The effects of TGF-beta are independent of Smad2/3 activity and require activation of TGF-beta-associated kinase 1 (TAK1) and its downstream effectors c-Jun NH(2)-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-beta signaling and oncogenic R-Ras in the promotion of tumorigenesis.

MeSH Terms (10)

Blotting, Western Cell Line Cell Proliferation Cell Transformation, Neoplastic Humans Mammary Glands, Human MAP Kinase Kinase Kinases Oncogene Protein p21(ras) Signal Transduction Transforming Growth Factor beta

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