GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species

Abstract

The discovery and extension of G-protein-coupled receptor (GPCR) transactivation-dependent signalling has enormously broadened the GPCR signalling paradigm. GPCRs can transactivate protein tyrosine kinase receptors (PTKRs) and serine/threonine kinase receptors (S/TKRs), notably the epidermal growth factor receptor (EGFR) and transforming growth factor-β type 1 receptor (TGFBR1), respectively. Initial comprehensive mechanistic studies suggest that these two transactivation pathways are distinct. Currently, there is a focus on GPCR inhibitors as drug targets, and they have proven to be efficacious in vascular diseases. With the broadening of GPCR transactivation signalling, it is therefore important from a therapeutic perspective to find a common transactivation pathway of EGFR and TGFBR1 that can be targeted to inhibit complex pathologies activated by the combined action of these receptors. Reactive oxygen species (ROS) are highly reactive molecules and they act as second messengers, thus modulating cellular signal transduction pathways. ROS are involved in different mechanisms of GPCR transactivation of EGFR. However, the role of ROS in GPCR transactivation of TGFBR1 has not yet been studied. In this review, we will discuss the involvement of ROS in GPCR transactivation-dependent signalling.

Keywords: G protein; GPCR; TGF-beta; epidermal growth factor; transactivation.

Figure 1

Schematic representation of known and speculated roles of NADPH oxidase (Nox) and ROS in G-protein-coupled receptor (GPCR) transactivation of epidermal growth factor receptor (EGFR). GPCR transactivation of EGFR occurs via an increase in intracellular reactive oxygen species (ROS) which in turn (1) activate matrix metalloproteinase (MMP) that cleaves heparin-binding EGF-like growth factor (pro-HB-EGF) and release the EGF ligand leading to EGFR activation and subsequently phosphorylation of downstream intermediate extracellular signal-regulated kinase1/2 (ERK1/2). GPCR stimulation of ROS activates the EGFR (2) via Src-dependent pathway and (3) through inhibition of protein tyrosine phosphatases (PTPs).

Figure 2

Schematic representation of the mechanism of G-protein-coupled receptor (GPCR) transactivation of transforming growth factor-β type 1 receptor (TGFBR1). GPCR transactivation of TGFBR1 occurs via cytoskeletal rearrangement which activates Rho-associated protein kinase (RhoA/ROCK) signalling and cell-surface integrin. Activated integrin binds to and activates the large latent TGF-β complex (LLC), leading to the subsequent phosphorylation of the downstream intermediate Smad2 in the carboxy terminal.