RT Journal Article
SR Electronic
T1 Arl15 upregulates the TGFβ family signaling by promoting the assembly of the Smad-complex
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.14.472727
DO 10.1101/2021.12.14.472727
A1 Meng Shi
A1 Hieng Chiong Tie
A1 Divyanshu Mahajan
A1 Xiuping Sun
A1 Yan Zhou
A1 Boon Kim Boh
A1 Leah A. Vardy
A1 Lei Lu
YR 2021
UL http://biorxiv.org/content/early/2021/12/15/2021.12.14.472727.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.