Regulation of G-Protein Signaling by RKTG via Sequestration of the Gβγ Subunit to the Golgi Apparatus

Abstract

Upon ligand binding, G-protein-coupled receptors (GPCRs) impart the signal to heterotrimeric G proteins composed of ␣, ␤, and ␥ subunits, leading to dissociation of the G␣ subunit from the G␤␥ subunit. While the G␣ subunit is imperative for downstream signaling, the G␤␥ subunit, in its own right, mediates a variety of cellular responses such as GPCR desensitization via recruiting GRK to the plasma membrane and AKT stimulation. Here we report a mode of spatial regulation of the G␤␥ subunit through alteration in subcellular compartmentation. RKTG (Raf kinase trapping to Golgi apparatus) is a newly characterized membrane protein specifically localized at the Golgi apparatus. The N terminus of RKTG interacts with G␤ and tethers G␤␥ to the Golgi apparatus. Overexpression of RKTG impedes the interaction of G␤␥ with GRK2, abrogates the ligand-induced change of subcellular distribution of GRK2, reduces isoproterenol-stimulated phosphorylation of the ␤2-adrenergic receptor (␤2AR), and alters ␤2AR desensitization. In addition, RKTG inhibits G␤␥-and ligand-mediated AKT phosphorylation that is enhanced in cells with downregulation of RKTG. Silencing of RKTG also alters GRK2 internalization and compromises ligand-induced G␤ translocation to the Golgi apparatus. Taken together, our results reveal that RKTG can modulate GPCR signaling through sequestering G␤␥ to the Golgi apparatus and thereby attenuating the functions of G␤␥.

RKTG overexpression inhibits proliferation and induces apoptosis of human leukemia cells via suppression of the ERK and PI3K/AKT signaling pathways

“…The inhibitory activity of RKTG on Raf/MEK/ERK signaling has been reported in several tumor cell lines (11,12,14,15,20). Additionally, the activation of the PI3K/AKT signaling pathway induced by Gβlγ2 overexpression in monkey kidney fibroblast cells COS7 has been previously reported to be markedly abrogated by RKTG co-overexpression (28). The present study demonstrated that upregulation of RKTG significantly suppressed the activation of ERK and PI3K/AKT signaling pathways.…”

Signalling to and from the secretory pathway

“…RKTG can also regulate signalling through GPCRs by binding to the Gb subunit of heterotrimeric G proteins and by tethering Gb to the Golgi complex (Jiang et al, 2010). This recruitment impedes the interaction between Gb and b-adrenergic receptor kinase 1 (ARBK1, also known and hereafter referred to as GRK2), whose activation is crucial for the desensitisation of GPCRs, such as the b2-adrenergic receptor (ADRB2).…”

“…This recruitment impedes the interaction between Gb and b-adrenergic receptor kinase 1 (ARBK1, also known and hereafter referred to as GRK2), whose activation is crucial for the desensitisation of GPCRs, such as the b2-adrenergic receptor (ADRB2). Accordingly, overexpression of RKTG inhibits desensitisation of this receptor (Jiang et al, 2010). Gb also mediates ADRB2-induced activation of Akt, which itself is inhibited by RKTG overexpression (Jiang et al, 2010).…”

Identification of PAQR3 as a new candidate tumor suppressor in hepatocellular carcinoma

“…Progestin and adipoQ receptor family member III (PAQR3), also named RKTG, negatively regulates the Ras/Raf/MEK/ERK signaling cascade and the G protein-coupled receptor (GPCR) Gβγ subunit signaling pathway (8,9). PAQR3 is a member of the PAQR family of proteins comprising an intriguing group of recently discovered receptors and a seven transmembrane protein localized at the Golgi apparatus (8,10).…”