Epidermal growth factor signaling via Ras controls the Smad transcriptional co-repressor TGIF Journal Article
| Authors: | Lo, R. S.; Wotton, D.; Massagué, J. |
| Article Title: | Epidermal growth factor signaling via Ras controls the Smad transcriptional co-repressor TGIF |
| 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. |
| Keywords: | signal transduction; epidermal growth factor; mitogen activated protein kinase; controlled study; protein phosphorylation; unclassified drug; human cell; dna-binding proteins; nonhuman; animal cell; animals; cell division; smad protein; smad2 protein; transforming growth factor beta; cell line; homeodomain proteins; transfection; cercopithecus aethiops; cos cells; phosphorylation; gene expression regulation; transcription regulation; kinetics; recombinant proteins; cell strain cos1; ras protein; trans-activators; ras proteins; repressor protein; repressor proteins; phosphates; ras; egf; protein p300; smad; tgf-β; humans; human; priority journal; article; tgif; protein tgif |
| Journal Title: | EMBO Journal |
| Volume: | 20 |
| Issue: | 1-2 |
| ISSN: | 0261-4189 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2001-01-15 |
| Start Page: | 128 |
| End Page: | 136 |
| Language: | English |
| DOI: | 10.1093/emboj/20.1.128 |
| PUBMED: | 11226163 |
| PROVIDER: | scopus |
| PMCID: | PMC140192 |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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