| First Author | Khater M | Year | 2021 |
| Journal | J Biol Chem | Pages | 100325 |
| PubMed ID | 33493514 | Mgi Jnum | J:302166 |
| Mgi Id | MGI:6507081 | Doi | 10.1016/j.jbc.2021.100325 |
| Citation | Khater M, et al. (2021) G protein betagamma translocation to the Golgi apparatus activates MAPK via p110gamma-p101 heterodimers. J Biol Chem :100325 |
| abstractText | 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 betagamma dimers to the GA. However, the functional significance of this translocation is largely unknown. Here, we study PM-GA translocation of all 12 Ggamma subunits in response to chemokine receptor CXCR4 activation and demonstrate that Ggamma9 is a unique Golgi-translocating Ggamma subunit. CRISPR-Cas9-mediated knockout of Ggamma9 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 Gbetagamma dimers containing different Ggamma subunits activates ERK1/2, whereas recruitment to the PM is ineffective. We also demonstrate that pharmacological inhibition of phosphoinositide 3-kinase gamma (PI3Kgamma) and depletion of its subunits p110gamma and p101 abrogate ERK1/2 activation by CXCR4 and Gbetagamma recruitment to the GA. Knockout of either Ggamma9 or PI3Kgamma significantly suppresses prostate cancer PC3 cell migration, invasion and metastasis. Collectively, our data demonstrate a novel function for Gbetagamma translocation to the GA, via activating PI3Kgamma heterodimers p110gamma-p101, to spatiotemporally regulate MAPK activation by GPCRs and ultimately control tumor progression. |
