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

TGF beta 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 beta 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 beta. TGF beta disrupts cell junctions and induces tropomyosin-mediated actin fibers and matrix adhesion. Smad transcription factors mediate both steps of the TGF beta-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 beta-induced EMT is not sufficient for the acquisition of the invasive potential and activated Ras alters this TGF beta response, conferring the tumorigenic and invasive potential.