Ras alters epithelial-mesenchymal transition in response to TGFbeta 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.
Safina
Alfiya F
AF
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
Varga
Andrea E
AE
Bianchi
Anna
A
Zheng
Qiao
Q
Kunnev
Dimiter
D
Liang
Ping
P
Bakin
Andrei V
AV
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016764:Cell Polarity; D021982:Cell-Matrix Junctions / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D016023:Integrins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D014335:Tropomyosin; D018631:ras Proteins