ABSTRACT
G protein-coupled receptor kinase 2 (GRK2), as a key Ser/Thr protein kinase, belong to the member of the G protein-coupled receptor kinase (GRK) family. The C-terminus of GRK2 including a plekstrin homology domain and the N-terminus of GRK2 including the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors (GPCRs), G protein, phospholipase C, phosphatidylinositol 4,5-bisphosphate, extracellular signal-regulated kinase, protein kinase A and Gβγ, which can regulate the activity of GRK2. GRK2 can regulate GPCR desensitization and internalization by phosphorylating the GPCR, promoting the affinity of binding to arrestins, and uncoupling the receptors from G proteins, which play an important role in maintaining the balance between the receptors and signal transduction. Previous studies have indicated that cardiac GRK2 overexpression can promote the phosphorylation of β-adrenergic receptor (βAR) leading to βAR desen?sitization and internalization, which play a pivotal role in inducing heart failure (HF)-related dysfunction and myocyte death. GRK2, as a regulator of cell function, is overexpression in hypertension. Overex?pression GRK2 can inhibit Akt/eNOS signaling pathway and decreased the production and activation of eNOS leading to endothelial dysfunction. Collagen-induced arthritis induces the upregulation of GRK2 expression in fibroblast- like synoviocytes. In this review, we mainly discussed the evidence for the association between GRK2 overexpression and various diseases, which suggests that GRK2 may be an effective drug target for preventing and treating heart failure, hypertension and inflammatory disease.
ABSTRACT
OBJECTIVE Basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) produced by hepatocellular carcinoma (HCC) cells are responsible for the cell growth. Accumu?lating evidence shows that insulin-like growth factor-binding protein-3 (IGFBP-3) suppresses HCC cell proliferation in both IGF- dependent and independent manners. The present study is to investigate whether treatment with exogenous IGFBP-3 inhibits bFGF and PDGF production and the cell proliferation of HCC cells. METHODS Cell Counting Kit 8 assay were designed to detect HCC cell proliferation, transcription factor early growth response- 1 (EGR1) involving in IGFBP- 3 regulation of bFGF and PDGF were detected by RT-PCR and Western blot assays. Western blot assay was adopted to detect the IGFBP- 3 regulating insulin- like growth factor 1 receptor (IGF- 1R) signaling pathway. RESULTS The present study demonstrates that IGFBP-3 suppressed IGF-1-induced bFGF and PDGF expression while it does not affect their expression in the absence of IGF-1. To delineate the underlying mechanism, Western-blot and RT-PCR assays confirmed that the transcription factor early growth response protein 1 (EGR1) is involved in IGFBP-3 regulation of bFGF and PDGF. IGFBP-3 inhibition of type 1 insulin-like growth factor receptor (IGF1R), ERK and AKT activation is IGF- 1- dependent. Furthermore, transient transfection with constitutively activated AKT or MEK partially blocks the IGFBP-3 inhibition of EGR1, bFGF and PDGF expression. CONCLUSION In conclusion, these findings suggest that IGFBP- 3 suppresses transcription of EGR1 and its target genes bFGF and PDGF through inhibiting IGF- 1-dependent ERK and AKT activation. It demonstrates the importance of IGFBP-3 in the regulation of HCC cell proliferation, suggesting that IGFBP-3 could be a target for the treatment of HCC.