G protein translocation to the Golgi apparatus activates MAPK via p110?-p101 heterodimers

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 at the plasma membrane (PM) induces the translocation of G protein dimers to the GA. However, the functional significance of this translocation is largely unknown. Here, we study PM-GA translocation of all 12 G? subunits in response to chemokine receptor CXCR4 activation and demonstrate that G?9 is a unique Golgitranslocating G? subunit. CRISPR-Cas9 mediated knockout of G?9 abolishes activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), two members of the mitogenactivated protein kinase family, by CXCR4. We show that chemically induced recruitment to the GA of Gdimers containing different G? subunits activates ERK1/2, whereas recruitment to the PM is ineffective. We also demonstrate that pharmacological inhibition of phosphoinositide 3-kinase ? (PI3K?) and depletion of its subunits p110? and p101 abrogate ERK1/2 activation by CXCR4 and Grecruitment to the GA. Knockout of either G?9 or PI3K? significantly suppresses prostate cancer PC3 cell migration, invasion, and metastasis. Collectively, our data demonstrate a novel function for Gtranslocation to the GA, via activating PI3K? heterodimers p110?-p101, to spatiotemporally regulate mitogen-Activated protein kinase activation by G protein coupled receptors and ultimately control tumor progression.