The role of RGS12 in tissue repair and human diseases

Abstract

Regulator of G protein signaling 12 (RGS12) belongs to the superfamily of RGS proteins defined by a conserved RGS domain that canonically binds and deactivates heterotrimeric G-proteins. As the largest family member, RGS12 is widely expressed in many cells and tissues. In the past few decades, it has been found that RGS12 affects the activity of various cells in the human body, participates in many physiological and pathological processes, and plays an important role in the pathogenesis of many diseases. Here, we set out to comprehensively review the role of RGS12 in human diseases and its mechanisms, highlighting the possibility of RGS12 as a therapeutic target for the treatment of human diseases.

Keywords: Cancer; Nervous disorders; Osteoporosis; RGS12; Tissue repair.

Figure 1

Regulation of GPCR signaling by RGS12. The Gβγ heterodimer serves to couple Gα to the receptor and to inhibit its spontaneous release of GDP. Ligand-occupied, GPCRs stimulate signal onset for Gα subunits, facilitating GDP release, subsequent binding of GTP, and release of the Gβγ dimer. Both the GTP-bound Gα and liberated Gβγ moieties are then able to modulate the activity of downstream molecules. RGS proteins stimulate signal termination by acting as GAPs for Gα, dramatically enhancing their intrinsic rate of GTP hydrolysis. GPCR, G-protein-coupled receptor; RGS, regulator of G-protein signaling; RGS12, regulator of G protein signaling 12; Gβγ, βγ subunit complex of G protein; Gα, alpha subunit of G protein; GDP, guanosine diphosphate; GTP, guanosine triphosphate; GAPs, GTPase-accelerating proteins. This figure was drawn using Figdraw.

Figure 2

Overview of RGS12 expression in various human diseases. Arrows indicate the regulation of the respective diseases. The main concern is the regulation of RGS in the diseases described in this review (brain, oral cavity, ear, prostate gland, bone, and joint). RGS, regulator of G-protein signaling; RGS12, regulator of G protein signaling 12. This figure was drawn using Figdraw.

Figure 3

The relevant signaling pathways of RGS12 in bone homeostasis. In OCs, RGS12 regulates the RANKL/Ca²⁺/NFAT2 signaling pathway to promote the terminal differentiation of OCs. Meanwhile, in OBs, RGS12 promotes the activity of GTPase against the Gαi subunit, enhancing the inhibition of Gαi mediated signaling and resulting in osteolytic phenotype. RGS12, regulator of G protein signaling 12; OCs, osteoclasts; RANKL, receptor activator of NF-κB ligand; NFAT2, activated T nuclear factor 2; OBs, osteoblasts. This figure was drawn using Figdraw.

Figure 4

The relevant signaling pathways of RGS12 in arthritis. RGS12 promotes the degradation of IκB by enhancing the ubiquitination. Due to the degradation of IκB, NF-κB translocates into the nucleus and further promotes the gene expression of cytokines such as IL-1β, IL-6, and TNF-α during inflammation. RGS12, regulator of G protein signaling 12; IκB, inhibitory kappa B; NF-κB, nuclear factor κB; IL, interleukin; TNF-α, tumor necrosis factor-alpha. This figure was drawn using Figdraw.

Figure 5

The signaling pathways of RGS12 in tumor. (i) RGS12 negatively regulates the level and activity of AKT protein to inhibit the expression of MNX1. (ii) RGS12 interacts with PTEN through the PDZ domain, up-regulating phosphorylation and sumoylation of PTEN, thereby inactivating the AKT/mTOR signaling pathway and suppressing OSCC growth. (iii) RGS12 enhances the phosphorylation of MYCBP2 to degrade the ciliary protein KIF2A. (iv) RGS12 binds to YAP and inhibits the nuclear translocation of YAP and the expression of Ezrin. RGS12, regulator of G protein signaling 12; AKT, protein kinase B; MNX1, motor neuron and pancreas homeobox 1; PTEN, phosphatase and tension homolog; PDZ, PSD-95/Discs large/ZO-1 homology; mTOR, mammalian target of rapamycin; OSCC, oral squamous cell carcinoma; MYCBP2, Myc-binding protein 2; KIF2A, kinase family member 2A; YAP, Yes-associated protein. This figure was drawn using Figdraw.