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G protein βγ translocation to the Golgi apparatus activates MAPK via p110γ-p101 heterodimers

Khater, M;Wei, Z;Xu, X;Huang, W;Lokeshwar, BL;Lambert, NA;Wu, G;

The Golgi apparatus (GA) is a cellular organelle that plays a critical role in the processing of proteins for secretion. Activation of G protein-coupled receptors (GPCRs) at the plasma membrane (PM) induces the translocation of G protein βγ dimers to the GA. However, the functional significance of this translocation is largely unknown. Here, we study PM-GA translocation of all 12 Gγ subunits in response to chemokine receptor CXCR4 activation and demonstrate that Gγ9 is a unique Golgi-translocating Gγ subunit. CRISPR-Cas9-mediated knockout of Gγ9 abolishes activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), two members of the mitogen-activated protein kinase (MAPK) family, by CXCR4. We show that chemically induced recruitment to the GA of Gβγ dimers containing different Gγ subunits activates ERK1/2, whereas recruitment to the PM is ineffective. We also demonstrate that pharmacological inhibition of phosphoinositide 3-kinase γ (PI3Kγ) and depletion of its subunits p110γ and p101 abrogate ERK1/2 activation by CXCR4 and Gβγ recruitment to the GA. Knockout of either Gγ9 or PI3Kγ significantly suppresses prostate cancer PC3 cell migration, invasion and metastasis. Collectively, our data demonstrate a novel function for Gβγ translocation to the GA, via activating PI3Kγ heterodimers p110γ-p101, to spatiotemporally regulate MAPK activation by GPCRs and ultimately control tumor progression.