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 α, β, and γ subunits, leading to dissociation of the Gα subunit from the Gβγ subunit. While the Gα subunit is imperative for downstream signaling, the Gβγ 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 Gβγ 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 Gβ and tethers Gβγ to the Golgi apparatus. Overexpression of RKTG impedes the interaction of Gβγ with GRK2, abrogates the ligand-induced change of subcellular distribution of GRK2, reduces isoproterenol-stimulated phosphorylation of the β2-adrenergic receptor (β2AR), and alters β2AR desensitization. In addition, RKTG inhibits Gβγ- 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 Gβ translocation to the Golgi apparatus. Taken together, our results reveal that RKTG can modulate GPCR signaling through sequestering Gβγ to the Golgi apparatus and thereby attenuating the functions of Gβγ.

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

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Articles of Significant Interest Selected from This Issue by the Editors

We thank Marc G. Caron at Duke University Medical Center for providing the plasmid.

This work was supported by research grants from the Chinese Academy of Sciences (Knowledge Innovation Program KSCX1-YW-02), the National Natural Science Foundation of China (30588002 and 30830037), the Science & Technology Commission of Shanghai Municipality (75407001), and the Ministry of Science and Technology of China (2007CB947100 and 2006CB943900) to Y.C.