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

J Biol Chem. Jan-Jun 2021;296:100325. doi: 10.1016/j.jbc.2021.100325. Epub 2021 Jan 23.

Abstract

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 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 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 mitogen-activated protein kinase activation by G protein-coupled receptors and ultimately control tumor progression.

Keywords: CXCR4; ERK1/2; G protein; G protein–coupled receptor; Golgi; Gβγ; MAPK; PI3Kγ; signaling; translocation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Membrane / genetics
  • Class Ib Phosphatidylinositol 3-Kinase / genetics*
  • Dimerization
  • GTP-Binding Protein beta Subunits / genetics*
  • GTP-Binding Protein gamma Subunits / genetics*
  • Golgi Apparatus / genetics*
  • HEK293 Cells
  • Humans
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Protein Transport / genetics
  • Receptors, CXCR4 / genetics*
  • Receptors, G-Protein-Coupled / genetics
  • Signal Transduction / genetics

Substances

  • CXCR4 protein, human
  • G-protein Beta gamma
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Receptors, CXCR4
  • Receptors, G-Protein-Coupled
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Mitogen-Activated Protein Kinase Kinases