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Arl15 通过促进 Smad 复合物的组装来上调 TGFβ 家族信号。

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

机构信息

School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.

A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research, Singapore, Singapore.

出版信息

Elife. 2022 Jul 14;11:e76146. doi: 10.7554/eLife.76146.

DOI:10.7554/eLife.76146
PMID:35834310
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9352346/
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.

摘要

经典转化生长因子 β（TGFβ）家族信号转导的标志性事件是 Smad 复合物的组装，该复合物由共同 Smad、Smad4 和磷酸化的受体调节型 Smads 组成。Smad 复合物如何组装和调节仍不清楚。在这里，我们报告说，活性 Arl15（一种 Arf 样小 G 蛋白）特异性地与 Smad4 的 MH2 结构域结合，并与 Smad4 一起在内溶酶体中共定位。这种结合解除了 Smad4 自身抑制，这种抑制是由其 MH1 和 MH2 结构域之间的分子内相互作用引起的。激活的 Smad4 随后与磷酸化的受体调节型 Smads 相互作用，形成 Smad 复合物。我们的观察结果表明，Smad4 作为 Arl15 的效应物和 GTPase 激活蛋白（GAP）发挥作用。Smad 复合物的组装增强了 Smad4 对 Arl15 的 GAP 活性，从而在 Smad 复合物的核转位之前将 Arl15 解离。我们的数据还进一步表明，Arl15 正向调节 TGFβ 家族信号转导。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/959859eb7475/elife-76146-fig7-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/0a4ed0f7e54a/elife-76146-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/313725a56d88/elife-76146-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/959859eb7475/elife-76146-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/6a010461fc91/elife-76146-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/f1f00e579785/elife-76146-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/a1c9c40e84a1/elife-76146-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/b1517814efbd/elife-76146-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/e4562e3b1401/elife-76146-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/1da35322472f/elife-76146-fig3-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/56561e86c02b/elife-76146-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/a37f28bdacfc/elife-76146-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/0a4ed0f7e54a/elife-76146-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30d5/9352346/313725a56d88/elife-76146-fig7.jpg
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