A mechanism of repression of TGFfβ/Smad signaling by oncogenic Ras Journal Article
| Authors: | Kretzschmar, M.; Doody, J.; Timokhina, I.; Massagué, J. |
| Article Title: | A mechanism of repression of TGFfβ/Smad signaling by oncogenic Ras |
| Abstract: | TGFβ can override the proliferative effects of EGF and other Ras- activating mitogens in normal epithelial cells. However, epithelial cells harboring oncogenic Ras mutations often show a loss of TGFβ antimitogenic responses. Here we report that oncogenic Ras inhibits TGFβ signaling in mammary and lung epithelial cells by negatively regulating the TGFβ mediators Smad2 and Smad3. Oncogenically activated Ras inhibits the TGFβ- induced nuclear accumulation of Smad2 and Smad3 and Smad-dependent transcription. Ras acting via Erk MAP kinases causes phosphorylation of Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain. These sites are separate from the TGFβ receptor phosphorylation sites that activate Smad nuclear translocation. Mutation of these MAP kinase sites in Smad3 yields a Ras- resistant form that can rescue the growth inhibitory response to TGFβ in Ras-transformed cells. EGF, which is weaker than oncogenic mutations at activating Ras, induces a less extensive phosphorylation and cytoplasmic retention of Smad2 and Smad3. Our results suggest a mechanism for the counterbalanced regulation of Smad2/Smad3 by TGFβ and Ras signals in normal cells, and for the silencing of antimitogenic TGFβ functions by hyperactive Ras in cancer cells. |
| Keywords: | signal transduction; protein expression; dna binding protein; dna-binding proteins; dose response; nonhuman; cell proliferation; animal cell; animal; metabolism; animals; complex formation; biological model; mitogen activated protein kinase kinase 1; smad2 protein; smad3 protein; transforming growth factor beta; cell line; luciferase; colonic neoplasms; dose-response relationship, drug; tumor cells, cultured; transfection; protein serine threonine kinase; protein tyrosine kinase; cos cells; phosphorylation; time; time factors; cell transformation, neoplastic; drug antagonism; enzyme phosphorylation; transcription regulation; genetic transfection; cell culture; cell transformation; protein-serine-threonine kinases; colon tumor; transactivator protein; gene repression; smad3 protein, human; cell strain cos1; epithelium cell; models, genetic; ras protein; protein-tyrosine kinases; trans-activators; cell nucleus; ras proteins; dna binding; luciferases; oncogene ras; mitogen activated protein kinase kinase; mitogen-activated protein kinase kinases; ras; map kinase kinase 1; growth inhibition; map kinase; smad; tgfΒ; map2k1 protein, human; humans; human; priority journal; article; smad2 protein, human |
| Journal Title: | Genes and Development |
| Volume: | 13 |
| Issue: | 7 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 1999-04-01 |
| Start Page: | 804 |
| End Page: | 816 |
| Language: | English |
| PUBMED: | 10197981 |
| PROVIDER: | scopus |
| PMCID: | PMC316599 |
| DOI: | 10.1101/gad.13.7.804 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 16 August 2016 -- Source: Scopus |
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