Oncogenic Ras inhibits TGFβ/Smad signaling by negatively regulating Smad2 and Smad3. In normal epithelial cells, TGFβ inhibits proliferation, but oncogenic Ras mutations often lead to loss of TGFβ responses. This study shows that oncogenic Ras inhibits TGFβ signaling by preventing the nuclear accumulation of Smad2 and Smad3. Ras activates Erk MAP kinases, which phosphorylate Smad2 and Smad3 at specific sites in the linker region, distinct from TGFβ receptor phosphorylation sites. Mutation of these sites in Smad3 rescues TGFβ growth inhibitory responses in Ras-transformed cells. EGF, which is weaker than oncogenic Ras in activating Ras, causes less phosphorylation and cytoplasmic retention of Smad2 and Smad3. These findings suggest a mechanism for the counterbalanced regulation of Smad2/Smad3 by TGFβ and Ras signals in normal cells, and for the silencing of antitumorigenic TGFβ functions by hyperactive Ras in cancer cells. The results reconcile observations on the interaction between TGFβ and Ras pathways and provide insights into the subversion of TGFβ signaling by oncogenic Ras mutations in cancer. The study also shows that oncogenic Ras inhibits Smad nuclear accumulation by phosphorylation of specific sites in the linker region, which is distinct from TGFβ receptor phosphorylation sites. EGF induces less phosphorylation and cytoplasmic retention of Smad2 and Smad3 compared to oncogenic Ras. The results suggest that oncogenic Ras, acting through Mek1 and Erk kinases, induces the phosphorylation of Smad2 and Smad3 at a cluster of Ser/Thr-Pro sites in the linker region. These findings highlight the role of Ras in inhibiting TGFβ signaling and the implications for cancer development. The study also discusses the implications for cancer, showing that TGFβ signaling is often lost in cancer due to mutations in components of the TGFβ/Smad pathway. Oncogenic Ras mutations can disrupt TGFβ signaling, leading to loss of growth inhibition and promoting tumor progression. The study provides insights into the molecular mechanisms underlying the interaction between TGFβ and Ras pathways in normal and cancer cells.Oncogenic Ras inhibits TGFβ/Smad signaling by negatively regulating Smad2 and Smad3. In normal epithelial cells, TGFβ inhibits proliferation, but oncogenic Ras mutations often lead to loss of TGFβ responses. This study shows that oncogenic Ras inhibits TGFβ signaling by preventing the nuclear accumulation of Smad2 and Smad3. Ras activates Erk MAP kinases, which phosphorylate Smad2 and Smad3 at specific sites in the linker region, distinct from TGFβ receptor phosphorylation sites. Mutation of these sites in Smad3 rescues TGFβ growth inhibitory responses in Ras-transformed cells. EGF, which is weaker than oncogenic Ras in activating Ras, causes less phosphorylation and cytoplasmic retention of Smad2 and Smad3. These findings suggest a mechanism for the counterbalanced regulation of Smad2/Smad3 by TGFβ and Ras signals in normal cells, and for the silencing of antitumorigenic TGFβ functions by hyperactive Ras in cancer cells. The results reconcile observations on the interaction between TGFβ and Ras pathways and provide insights into the subversion of TGFβ signaling by oncogenic Ras mutations in cancer. The study also shows that oncogenic Ras inhibits Smad nuclear accumulation by phosphorylation of specific sites in the linker region, which is distinct from TGFβ receptor phosphorylation sites. EGF induces less phosphorylation and cytoplasmic retention of Smad2 and Smad3 compared to oncogenic Ras. The results suggest that oncogenic Ras, acting through Mek1 and Erk kinases, induces the phosphorylation of Smad2 and Smad3 at a cluster of Ser/Thr-Pro sites in the linker region. These findings highlight the role of Ras in inhibiting TGFβ signaling and the implications for cancer development. The study also discusses the implications for cancer, showing that TGFβ signaling is often lost in cancer due to mutations in components of the TGFβ/Smad pathway. Oncogenic Ras mutations can disrupt TGFβ signaling, leading to loss of growth inhibition and promoting tumor progression. The study provides insights into the molecular mechanisms underlying the interaction between TGFβ and Ras pathways in normal and cancer cells.