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.
Highlights
G protein-coupled receptor kinase 2 (GRK2) is a ubiquitous member of G protein-coupled receptors (GPCRs) kinase family, which contains a group of seven serine/threonine protein kinases that is capable of specific recognition and phosphorylation of GPCRs [1]
We have found that the expression of GRK2 in liver tissue shows a downward trend with the extension of the modeling time, which is consistent with the expression tendency in rat hepatic stellate cells (HSCs)
Accumulated evidence has focused on the essential role of GRK2 subtype in fibrotic diseases
Summary
G protein-coupled receptor kinase 2 (GRK2) is a ubiquitous member of G protein-coupled receptors (GPCRs) kinase family, which contains a group of seven serine/threonine protein kinases that is capable of specific recognition and phosphorylation of GPCRs [1]. Increasing evidence suggests that GRK2, which exhibits the abnormal expression or activity, participates in the regulation of fibrosis-associated pathways, may as an essential role engages in the development of fibrotic diseases (Figure 2). Recent study suggests inhibiting GRK2 in the cardiac fibroblasts (CF) could decrease fibrosis and fibrotic gene expression [48] These findings emphasize that a complex interaction exists among GRK2 and the AC/cAMP/PKA signaling pathway during the progression of fibrosis. Whereas other studies have demonstrated that the proliferation of CFs stimulated with arginine vasopressin (AVP) is obviously increased, which through V1AR-mediated GRK2/b-arrestin/ ERK1/2 signaling [66] Another results suggest that silencing GRK2 could inhibit the continuous production of p-ERK1/2 induced by AVP decreased caspase-3/7 activity and H9c2 cell survival [67, 68]. Accumulating evidence suggests the GRK2 signaling hub can influence different cells activation [85] and tissue fibrosis process, eventually leading to organic structure destruction and dysfunction (Table 1)
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