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

Abstract

SummaryThe 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.

Golgi localized Arl15 regulates cargo transport, cell adhesion and motility

“…Epitope-tagged Arl15 primarily localizes majorly to the Golgi and a cohort to the cell surface (Rocha et al, 2017; Shi et al, 2022; Wu et al, 2021; Zhao et al, 2017; Zolotarov et al, 2021). Here, we evaluated the reported Arl15 intracellular localization in various mammalian cell types.…”

“…Epitope-tagged Arl15 primarily localizes majorly to the Golgi and a cohort to the cell surface (Rocha et al, 2017;Shi et al, 2022;Wu et al, 2021;Zhao et al, 2017;Zolotarov et al, (which was not certified by peer review) is the author/funder. All rights reserved.…”

“…Shen and co-workers showed that high glucose-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs) was attenuated by the enhanced expression of Arl15 (Shen et al, 2019). More recent studies show that Arl15 interacts with CNNM (cyclin M) proteins to inhibit the magnesium transport activity through enhancing their N-glycosylation (Zolotarov et al, 2021), and binding of Arl15 to Smad4 promote the Smad-complex formation and regulates TGFβ signaling (Shi et al, 2022). Overall, these studies place Arl15 as a signaling molecule in several genetic and metabolic traits in addition to magnesium homeostasis.…”