Smad transcription factors as mediators of 7 transmembrane G protein-coupled receptor signalling

Abstract

The Smad transcription factors are well known for their role at the core of transforming growth factor-β (TGF-β) signalling. However, recent evidence shows that the Smad transcription factors play a vital role downstream of other classes of receptors including G protein-coupled receptors (GPCR). The versatility of Smad transcription factors originated from the two regions that can be differently activated by the TGF-β receptor superfamily or through the recruitment of intracellular kinases stimulated by other receptors classes such as GPCRs. The classic GPCR signalling cascade is further expanded to conditional adoption of the Smad transcription factor under the stimulation of Akt, demonstrating the unique involvement of the Smad transcription factor in GPCR signalling pathways in disease environments. In this review, we provide a summary of the signalling pathways of the Smad transcription factors as an important downstream mediator of GPCRs, presenting exciting opportunities for discovering new therapeutic targets for diseases.

Keywords: Akt; GPCR signalling; Smad; phospho-Smad; transactivation dependent; transforming growth factor-beta receptor.

Fig. 1. GPCR dependent and independent Smad signalling.

a The activation of the TGF-β superfamily receptor leads to the phosphorylation of R-Smads in the carboxyl terminal (Phospho-R-Smad-C) which can travel to the nucleus to regulate gene expression. The activation of TGF-β superfamily receptors also results in the recruitment of serine/threonine kinases (S/T kinases) to phosphorylate the linker region of R-Smads (Phospho-R-Smad-L), phosphorylated R-Smad-C/L can also travel to the nucleus to regulate gene expression. b GPCR via transactivation of the TGF-β superfamily receptors phosphorylate R-Smad-C which travels to the nucleus to regulate cellular responses by modulating gene expressions. The activation of TGF-β superfamily receptor also result in the recruitment of S/T kinases to phosphorylate the linker region of R-Smads which have carboxyl-terminal phosphorylated. c R-Smads are activated by GPCRs through the recruitment of S/T kinases, which phosphorylates the linker region of R-Smads. The R-Smads with only linker region phosphorylated then translocate to the nucleus to regulate transcription and cellular responses. Figure created in biorender.com.

Fig. 2. Akt acts as a switch for translocation of cytosol TGF-β receptors (TGFBR) to the membrane and GPCR transactivation dependent signalling.

Activation of Akt pathways leads to the phosphorylation of AS160, which promotes the translocation of intracellular TGFBR receptors to the cell membrane. When GPCRs are activated, the transactivation of TGFBR is observed, leading to the phosphorylation of Smad2 in the carboxyl-terminal (Phospho-Smad2C). Figure created in biorender.com.