Abstract
AbstractTransforming growth factor-[beta] (TGF-[beta]) is a multifunctional cytokine of key importance for controlling embryogenesis and tissue homeostasis. How TGF-[beta] signals are attenuated and terminated is not well understood. Here, we show that TMEPAI, a direct target gene of TGF-[beta] signaling, antagonizes TGF-[beta] signaling by interfering with TGF-[beta] type I receptor (T[beta]RI)-induced R-Smad phosphorylation. TMEPAI can directly interact with R-Smads via a Smad interaction motif (SIM). TMEPAI competes with Smad anchor for receptor activation (SARA) for R-Smad binding, thereby sequestering R-Smads from T[beta]RI kinase activation. In mammalian cells, ectopic expression of TMEPAI inhibited TGF-[beta]-induced PAI-1 production, whereas specific siRNA-mediated knockdown of TMEPAI expression potentiated TGF-[beta]-induced Smad2 phosphorylation and cellular responsiveness by TGF-[beta]. Consistently, TMEPAI inhibits activin-mediated mesoderm formation in Xenopus embryos. Taken together, TMEPAI participates in a negative feedback loop to control the duration and intensity of TGF-[beta] signaling.
Highlights
Transforming growth factor-β (TGF-β) is a pivotal cytokine that regulates the growth and differentiation of many different cell types
Challenging C2C12 cells with BMP could not induce the expression of Transmembrane prostate androgen-induced RNA (TMEPAI) (Supplementary Fig. 1a), unlike I-Smads whose transcripts are known to be elevated by multiple TGF-β family members [13,14]
We have presented evidence demonstrating that TMEPAI, a transmembrane protein, is implicated in termination of TGF-β signaling
Summary
Transforming growth factor-β (TGF-β) is a pivotal cytokine that regulates the growth and differentiation of many different cell types. The TGF-β family signals via specific serine/threonine kinase receptors and intracellular signal transducing molecules, termed Smads [1]. TGF-β signaling is initiated by ligand binding to TGF-β type II receptor (TβRII), which induces the formation of heteromeric complexes between specific TGF-β type I receptor (TβRI) and TβRII serine/threonine kinases. TβRI ( termed activin receptor-like kinase (ALK) is phosphorylated and activated by TβRII. Active TβRI catalyzes the C-terminal serine phosphorylation of receptor-regulated (R-)Smad proteins. Among R-Smads, Smad and Smad act downstream of TGF-β, activin, and nodal type I receptors, whereas Smad, Smad, and Smad are phosphorylated by bone morphogenetic protein (BMP) type I receptors. R-Smads can form a ternary complex with a common-partner Smad and translocate to the nucleus, where they regulate the transcription of target genes [2]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
