Epidermal growth factor signaling via Ras controls the Smad transcriptional co-repressor TGIF.
Smad transcription factors mediate the actions of transforming growth factor-beta (TGF-beta) cytokines during development and tissue homeostasis. TGF-beta 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-beta 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-beta-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-beta. 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.
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Cell Biology Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Wotton
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Massagué
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D000818:Animals; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D010710:Phosphates; D011994:Recombinant Proteins; D012097:Repressor Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C097504:TGIF1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D018631:ras Proteins