ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signaling

J Biol Chem. 1999 Mar 26;274(13):8949-57. doi: 10.1074/jbc.274.13.8949.

Abstract

Upon transforming growth factor-beta (TGF-beta) binding to its cognate receptor, Smad3 and Smad4 form heterodimers and transduce the TGF-beta signal to the nucleus. In addition to the Smad pathway, another pathway involving a member of the mitogen-activated protein kinase kinase kinase family of kinases, TGF-beta-activated kinase-1 (TAK1), is required for TGF-beta signaling. However, it is unknown how these pathways function together to synergistically amplify TGF-beta signaling. Here we report that the transcription factor ATF-2 (also called CRE-BP1) is bound by a hetero-oligomer of Smad3 and Smad4 upon TGF-beta stimulation. ATF-2 is one member of the ATF/CREB family that binds to the cAMP response element, and its activity is enhanced after phosphorylation by stress-activated protein kinases such as c-Jun N-terminal kinase and p38. The binding between ATF-2 and Smad3/4 is mediated via the MH1 region of the Smad proteins and the basic leucine zipper region of ATF-2. TGF-beta signaling also induces the phosphorylation of ATF-2 via TAK1 and p38. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity. These results indicate that ATF-2 plays a central role in TGF-beta signaling by acting as a common nuclear target of both Smad and TAK1 pathways.

MeSH terms

  • Activating Transcription Factor 2
  • Animals
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Leucine Zippers
  • MAP Kinase Kinase Kinases*
  • Mammals
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Smad3 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Recombinant Fusion Proteins
  • Smad3 Protein
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7