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ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signaling
1Laboratory of Molecular Genetics, Tsukuba Life Science Center, RIKEN, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
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.
Insights
Activating transcription factor 2 (ATF-2) acts as a key link between the Smad and TAK1 pathways in transforming growth factor-beta (TGF-beta) signaling. This interaction synergistically enhances ATF-2
Area of Science:
- Molecular Biology
- Cell Signaling
- Genetics
Background:
- Transforming growth factor-beta (TGF-beta) signaling is crucial for cellular processes.
- TGF-beta signaling involves both Smad and TGF-beta-activated kinase-1 (TAK1) pathways.
- The interplay between these pathways for signal amplification remains unclear.
Purpose of the Study:
- To investigate how Smad and TAK1 pathways cooperate in TGF-beta signaling.
- To identify the nuclear targets mediating synergistic TGF-beta signal amplification.
- To elucidate the role of Activating Transcription Factor-2 (ATF-2) in this process.
Main Methods:
- Investigated the interaction between Smad3/Smad4 and ATF-2 using biochemical assays.
- Analyzed the role of TAK1 and p38 in ATF-2 phosphorylation.
- Assessed the impact of Smad binding and ATF-2 phosphorylation on ATF-2 trans-activating capacity.
Main Results:
- TGF-beta stimulation leads to Smad3/Smad4 binding to ATF-2 via specific protein domains.
- TGF-beta signaling induces ATF-2 phosphorylation through the TAK1 and p38 kinases.
- Both Smad binding and phosphorylation synergistically enhance ATF-2's transcriptional activity.
Conclusions:
- ATF-2 serves as a central nuclear target integrating Smad and TAK1 pathways in TGF-beta signaling.
- The coordinated action of Smad and TAK1 pathways on ATF-2 is essential for synergistic signal amplification.
- This study reveals a novel mechanism for amplifying TGF-beta responses.