Arl15 upregulates the TGFβ family signaling by promoting the assembly of the Smad-complex

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Arl15 upregulates the TGFβ family signaling by promoting the assembly of the Smad-complex
Title:
Arl15 upregulates the TGFβ family signaling by promoting the assembly of the Smad-complex
Journal Title:
eLife
Publication Date:
14 July 2022
Citation:
Shi, M., Tie, H. C., Divyanshu, M., Sun, X., Zhou, Y., Boh, B. K., Vardy, L. A., & Lu, L. (2022). Arl15 upregulates the TGFβ family signaling by promoting the assembly of the Smad-complex. ELife, 11. CLOCKSS. https://doi.org/10.7554/elife.76146
Abstract:
The hallmark event of the canonical transforming growth factor β (TGFβ) family signaling is the assembly of the Smad-complex, consisting of the common Smad, Smad4, and phosphorylated receptor-regulated Smads. How the Smad-complex is assembled and regulated is still unclear. Here, we report that active Arl15, an Arf-like small G protein, specifically binds to the MH2 domain of Smad4 and colocalizes with Smad4 at the endolysosome. The binding relieves the autoinhibition of Smad4, which is imposed by the intramolecular interaction between its MH1 and MH2 domains. Activated Smad4 subsequently interacts with phosphorylated receptor-regulated Smads, forming the Smad-complex. Our observations suggest that Smad4 functions as an effector and a GTPase activating protein (GAP) of Arl15. Assembly of the Smad-complex enhances the GAP activity of Smad4 toward Arl15, therefore dissociating Arl15 before the nuclear translocation of the Smad-complex. Our data further demonstrate that Arl15 positively regulates the TGFβ family signaling.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research / project is supported by the Ministry of Education - AcRF Tier1
Grant Reference no. : RG35/17

This research / project is supported by the Ministry of Education - Tier 2
Grant Reference no. : MOE2015-T2-2-073

This research / project is supported by the Ministry of Education - Tier 2
Grant Reference no. : MOE2018-T2-2-026
Description:
ISSN:
2050-084X
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