The article discusses the mechanism by which oncogenic Ras inhibits TGFβ/Smad signaling in epithelial cells. TGFβ typically suppresses cell proliferation in normal epithelial cells, but this effect is often lost in cells with oncogenic Ras mutations. The study shows that oncogenic Ras inhibits TGFβ signaling by negatively regulating Smad2 and Smad3, key mediators of TGFβ signaling. Specifically, Ras activates Erk MAP kinases, leading to phosphorylation of Smad2 and Smad3 at specific sites in their linker regions, which prevents their nuclear accumulation and subsequent transcriptional activity. This phosphorylation is distinct from the TGFβ receptor-mediated phosphorylation that activates Smad nuclear translocation. Mutating these MAP kinase sites in Smad3 makes it resistant to Ras inhibition, restoring TGFβ's growth-inhibitory effects in Ras-transformed cells. EGF, which activates Ras less strongly than oncogenic mutations, causes less extensive phosphorylation and cytoplasmic retention of Smads. The findings reveal a mechanism for the balance between TGFβ and Ras signals in normal cells and the silencing of TGFβ's antimetogenic effects in cancer cells with hyperactive Ras. This study provides insights into how oncogenic Ras mutations subvert TGFβ signaling, contributing to cancer progression.The article discusses the mechanism by which oncogenic Ras inhibits TGFβ/Smad signaling in epithelial cells. TGFβ typically suppresses cell proliferation in normal epithelial cells, but this effect is often lost in cells with oncogenic Ras mutations. The study shows that oncogenic Ras inhibits TGFβ signaling by negatively regulating Smad2 and Smad3, key mediators of TGFβ signaling. Specifically, Ras activates Erk MAP kinases, leading to phosphorylation of Smad2 and Smad3 at specific sites in their linker regions, which prevents their nuclear accumulation and subsequent transcriptional activity. This phosphorylation is distinct from the TGFβ receptor-mediated phosphorylation that activates Smad nuclear translocation. Mutating these MAP kinase sites in Smad3 makes it resistant to Ras inhibition, restoring TGFβ's growth-inhibitory effects in Ras-transformed cells. EGF, which activates Ras less strongly than oncogenic mutations, causes less extensive phosphorylation and cytoplasmic retention of Smads. The findings reveal a mechanism for the balance between TGFβ and Ras signals in normal cells and the silencing of TGFβ's antimetogenic effects in cancer cells with hyperactive Ras. This study provides insights into how oncogenic Ras mutations subvert TGFβ signaling, contributing to cancer progression.