Role of Ras and Mapks in TGFβ signaling

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Abstract

Normal signaling by TGFβ, in the absence of serum or exogenous factors, involves a rapid activation of Ras, Erks, and Sapks in proliferating cultures of TGFβ-sensitive untransformed epithelial cells and human carcinoma cells. Expression of either RasN17 or dominant-negative (DN) MKK4, or addition of the MEK1 inhibitor PD98059, can block the ability of TGFβ to induce AP-1 complex formation at the TGFβ1 promoter and to autoinduce its own production. The primary components present in this TGFβ-stimulated AP-1 complex are JunD and Fra-2, although c-Jun, and possibly Fos B, may also be present. While there are two potential Smad binding elements (SBE's) in the TGFβ1 promoter, supershift assays suggest that at least one of these does not bind Smad4, and the other is unable to bind factors activated by TGFβ. In contrast, TGFβ autoinduction is Smad3-dependent, as DN Smad3 inhibits the ability of TGFβ to stimulate TGFβ1 promoter activity. Our results indicate that TGFβ can activate both the MKK4/Sapk and MEK/Erk pathways, through Ras and TGFβ R1 and R11, to induce TGFβ1 production; Smad4 does not appear to be involved, and Smad3 appears to function independently of this Smad4. We also demonstrate that activation of the Ras/Mapk pathway by TGFβ positively modulates Smad1-signaling-pathway activation by TGFβ. In addition, Smad1 could enhance TGFβ activation of the SBE reporter SBE-luc and this effect could be blocked by co-expression of a DN TGFβ R1 receptor or by the MEK1 inhibitor PD98059. This cross-talk between the MEK/Erk and Smad1 pathways was mediated through the four Erk consensus phosphorylation sites in the linker region of Smad1. Mutation of these sites resulted in a loss of the ligand- dependence of both Smad1-Smad4 interactions and nuclear accumulation of Smad1, as well as a loss of the ability of Smad1 to enhance TGFβ-mediated SBE activation. Our results provide evidence that Erk-mediated phosphorylation of Smad1 in response to TGFβ is critical for regulating Smad1 subcellular localization; this may be a key determinant in maintaining TGFβ-dependent transcriptional activation. (C) 2000 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)23-35
Number of pages13
JournalCytokine and Growth Factor Reviews
Volume11
Issue number1-2
DOIs
StatePublished - Apr 2000

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Immunology and Allergy
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

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