G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

Abstract

G protein-coupled receptor kinase 2 (GRK2), an important subtype of GRKs, specifically phosphorylates agonist-activated G protein-coupled receptors (GPCRs). Besides, current research confirms that it participates in multiple regulation of diverse cells via a non-phosphorylated pathway, including interacting with various non-receptor substrates and binding partners. Fibrosis is a common pathophysiological phenomenon in the repair process of many tissues due to various pathogenic factors such as inflammation, injury, drugs, etc. The characteristics of fibrosis are the activation of fibroblasts leading to myofibroblast proliferation and differentiation, subsequent aggerate excessive deposition of extracellular matrix (ECM). Then, a positive feedback loop is occurred between tissue stiffness caused by ECM and fibroblasts, ultimately resulting in distortion of organ architecture and function. At present, GRK2, which has been described as a multifunctional protein, regulates copious signaling pathways under pathophysiological conditions correlated with fibrotic diseases. Along with GRK2-mediated regulation, there are diverse effects on the growth and apoptosis of different cells, inflammatory response and deposition of ECM, which are essential in organ fibrosis progression. This review is to highlight the relationship between GRK2 and fibrotic diseases based on recent research. It is becoming more convincing that GRK2 could be considered as a potential therapeutic target in many fibrotic diseases.

Keywords: ECM - extracellular matrix; G protein-coupled receptor kinase 2 (GRK2); G protein-coupled receptors; fibrosis; phosphorylation.

Figure 1

Functional domains and regulatory sites of GRK2. GRK2 contains multiple phosphorylation and non-phosphorylation sites. Phosphorylation sites of GRK2 by c-Src are Tyr-13 (N-terminal helix), Tyr-86 and Tyr-92 (RH domain). Protein kinase C (PKC) and protein kinase A (PKA) respectively phosphorylate GRK2 at Ser-29 and at Ser-685. GRK2 is phosphorylated on Ser-670 by extracellular-signal-regulated kinase 1/2 (ERK1/2) or cyclin-dependent protein kinase 2 (CDK2) down-regulates its activity. There is an interaction between caveolin and GRK2, which located in the PH domain (residues 567–584) and the N-terminal domain (residues 63–71).

Figure 2

GRK2 plays a diverse role in fibrosis-associated pathways. The phosphorylation of GRK2 by different kinases (PKA) also modifies kinase activity and substrate selection. GRK2 can regulate many downstream molecules and participates in the multiple signaling pathways. It not only activates PI3K/Akt, but also inhibits Akt/eNOS pathway to lower NO production. Activation of ERK1/2 pathway contributes to apoptosis. GRK2 promotes ERK1/2 phosphorylation, while ERK1/2 inhibits GRK2 phosphorylation. GRK2 and NF-κB can advance their activation through each other. Meanwhile, GRK2 inhibits Epac1/Rap1 pathway and inhibits the release of inflammatory cytokines. However, GRK2 promotes the phosphorylation of STAT1/3, which promotes the accumulation of inflammatory cytokines and contributes to the occurrence and development of fibrotic diseases.

Figure 3

Similar pathological features of organ fibrosis. Fibrosis is a wound-healing process that leads to disruption of tissue architecture, organ dysfunction and eventually organ failure, which involves liver, heart, kidneys and lungs. Under continuous injuries or stimulation, the normal tissue repair response evolves into a diverse fibrotic process, including activation of fibroblasts, production of inflammatory cytokines and exaggerated accumulation of extracellular matrix (ECM).

Figure 4

The relationship between GRK2 and fibrotic diseases. Various factors contribute to fibrosis progression in different tissues such as liver, kidney, lung, cardiac. When occurring the continuous pathological stimulus, the activated inflammatory cells and myofibroblasts will lead to extracellular matrix (ECM) production, resulting in fibrosis. Macrophages and endothelial cells can secrete cytokines. The immune cells including monocytes and neutrophils will secrete pro-inflammation factors, leading to the reactive oxygen species (ROS) and inflammation, and assist in the activation of myofibroblast. Important features of fibrous processes that are common in these organs include overproduction of cytokines, such as IL-1β, etc. Many injuries and stimulation will lead to the change of GRK2, GRK2 is involved in the pathological mechanism leading to the occurrence of organ fibrosis via multiple ways.