Epidermal growth factor signaling via Ras controls the Smad transcriptional co-repressor TGIF

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Abstract
Smad transcription factors mediate the actions of transforming growth factor‐β (TGF‐β) cytokines during development and tissue homeostasis. TGF‐β receptor‐activated Smad2 regulates gene expression by associating with transcriptional co‐activators or co‐repressors. The Smad co‐repressor TGIF competes with the co‐activator p300 for Smad2 association, such that TGIF abundance helps determine the outcome of a TGF‐β response. Small alterations in the physiological levels of TGIF can have profound effects on human development, as shown by the devastating brain and craniofacial developmental defects in heterozygotes carrying a hypomorphic TGIF mutant allele. Here we show that TGIF levels modulate sensitivity to TGF‐β‐mediated growth inhibition, that TGIF is a short‐lived protein and that epidermal growth factor (EGF) signaling via the Ras–Mek pathway causes the phosphorylation of TGIF at two Erk MAP kinase sites, leading to TGIF stabilization and favoring the formation of Smad2–TGIF co‐repressor complexes in response to TGF‐β. These results identify the first mechanism for regulating TGIF levels and suggest a potential link for Smad and Ras pathway convergence at the transcriptional level.