Ras alters epithelial-mesenchymal transition in response to TGF-β by reducing actin fibers and cell-matrix adhesion

• Published in: Cell cycle (Georgetown, Tex.) Vol. 8; no. 2; pp. 284 - 298
• Main Authors: Safina, Alfiya F., Varga, Andrea E., Bianchi, Anna, Zheng, Qiao, Kunnev, Dimiter, Liang, Ping, Bakin, Andrei
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 15.01.2009
• Subjects: Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cycle; Landes; Organogenesis; Proteins
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.8.2.7590

TGF-β and Ras regulate epithelial-mesenchymal transition (EMT), a process that contributes to tumor invasion and metastasis. The interaction of these pathways in EMT is still poorly understood. Here, we show that TGF-β induces EMT but limits cell invasion whereas hyperactivated Ras (H-RasV12) does not cause EMT but enhances cell invasion, alleviating the inhibitory effect of TGF-β. TGF-β disrupts cell junctions and induces tropomyosin-mediated actin fibers and matrix adhesion. Smad transcription factors mediate both steps of the TGF-β-induced EMT whereas RasV12 inhibits the second step by blocking the induction of tropomyosins (TPM1) and reducing cell-matrix adhesion and integrin signaling. RasV12 prevents binding of Smads to the TPM1 promoter by forcing CRM1-dependent nuclear export of Smad4. Soft agar and animal studies demonstrate that RasV12 confers the metastatic potential in epithelial cells, whereas tropomyosin suppresses tumor growth and metastases. Thus, TGF-β-induced EMT is not sufficient for the acquisition of the invasive potential and activated Ras alters this TGF-β response, conferring the tumorigenic and invasive potential.