Role of Ras Signaling in the Induction of Snail by Transforming Growth Factor-β

• Published in: The Journal of biological chemistry 2009-01, Vol.284 (1), p.245-253
• Main Authors: Horiguchi, Kana, Shirakihara, Takuya, Nakano, Ayako, Imamura, Takeshi, Miyazono, Kohei, Saitoh, Masao
• Format: Article
• Language: English
• Subjects: cats; Enzyme Induction - drug effects; Gene Expression Regulation, Neoplastic - drug effects; HeLa Cells; hematologic tests; Humans; lipid metabolism disorders; Mutation; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Phosphorylation; Proto-Oncogene Proteins p21(ras) - biosynthesis; Proto-Oncogene Proteins p21(ras) - genetics; Signal Transduction - drug effects; Smad Proteins - genetics; Smad Proteins - metabolism; Snail Family Transcription Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; triacylglycerols
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M804777200

The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during the progression of epithelial tumors. EMT can be induced by transforming growth factor (TGF)-β in some tumor cells. Here, we demonstrate the molecular mechanism whereby Snail, a key regulator of EMT, is induced by TGF-β in tumor cells. Snail induction by TGF-β was highly dependent on cooperation with active Ras signals, and silencing of Ras abolished Snail induction by TGF-β in pancreatic cancer Panc-1 cells. Transfection of constitutively active Ras into HeLa cells led to induction of Snail by TGF-β, while representative direct targets of TGF-β, including Smad7 and PAI-1, were not affected by Ras signaling. Using mitogen-activated protein kinase inhibitors or Smad3 or Smad2 mutants, we found that phosphorylation at the linker region of Smad2/3 was not required for the induction of Snail by TGF-β. Taken together, these findings indicate that Ras and TGF-β-Smad signaling selectively cooperate in the induction of Snail, which occurs in a Smad-dependent manner, but independently of phosphorylation at the linker region of R-Smads by Ras signaling.