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Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway
M Furuhashi1, K Yagi, H Yamamoto
1Department of Biochemistry, The Japanese Foundation for Cancer Research (JFCR) Cancer Institute, Toshima-ku, Tokyo 170-8455, Japan.
Abstract:
Axin acts as a negative regulator in Wnt signaling through interaction with various molecules involved in this pathway, including beta-catenin, adenomatous polyposis coli, and glycogen synthase kinase 3beta. We show here that Axin also regulates the effects of Smad3 on the transforming growth factor beta (TGF-beta) signaling pathway. In the absence of activated TGF-beta receptors. Axin physically interacted with Smad3 through its C-terminal region located between the beta-catenin binding site and Dishevelled-homologous domain. An Axin homologue, Axil (also called conductin), also interacted with Smad3. In the absence of ligand stimulation, Axin was colocalized with Smad3 in the cytoplasm in vivo. Upon receptor activation, Smad3 was strongly phosphorylated by TGF-beta type I receptor (TbetaR-I) in the presence of Axin, and dissociated from TbetaR-I and Axin. Moreover, the transcriptional activity of TGF-beta was enhanced by Axin and repressed by an Axin mutant which is able to bind to Smad3. Axin may thus function as an adapter of Smad3, facilitating its activation by TGF-beta receptors for efficient TGF-beta signaling.
Insights
Axin regulates transforming growth factor beta (TGF-beta) signaling by interacting with Smad3. This interaction enhances TGF-beta receptor-mediated Smad3 activation and promotes downstream signaling.
Area of Science:
- Molecular Biology
- Cell Signaling
Background:
- Axin is a known negative regulator of Wnt signaling, interacting with key pathway components like beta-catenin.
- The role of Axin in other signaling pathways, particularly transforming growth factor beta (TGF-beta) signaling, is less understood.
Purpose of the Study:
- To investigate the interaction between Axin and Smad3 within the TGF-beta signaling pathway.
- To elucidate the functional consequences of this interaction on TGF-beta signaling modulation.
Main Methods:
- Co-immunoprecipitation assays to demonstrate physical interaction between Axin and Smad3.
- In vivo colocalization studies using microscopy.
- Reporter gene assays to assess transcriptional activity modulation.
Main Results:
- Axin directly binds to Smad3 via its C-terminal region.
- Axin and Smad3 colocalize in the cytoplasm prior to TGF-beta receptor activation.
- Axin enhances Smad3 phosphorylation by TGF-beta type I receptor (TbetaR-I) and promotes TGF-beta transcriptional activity.
Conclusions:
- Axin functions as an adapter protein for Smad3, facilitating its activation by TGF-beta receptors.
- This interaction enhances the efficiency of TGF-beta signaling.
- Axin's role extends beyond Wnt signaling to include modulation of TGF-beta pathway.