During development and tissue homeostasis, cells must integrate different signals. We investigated how cell behavior is controlled by the combined activity of transforming growth factor-β (TGF-β) and receptor tyrosine kinase (RTK) signaling, whose integration mechanism is unknown. We find that RTK/Ras/MAPK (mitogen-activated protein kinase) activity induces p53 N-terminal phosphorylation, enabling the interaction of p53 with the TGF-β-activated Smads. This mechanism confines mesoderm specification in Xenopus embryos and promotes TGF-β cytostasis in human cells. These data indicate a mechanism to allow extracellular cues to specify the TGF-β gene-expression program.