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

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. 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. G protein–coupled receptors (GPCRs) modulate a wide variety of cell functions through activating cognate heterotrimeric G proteins, arrestins, and other signaling molecules (1Weis W.I. Kobilka B.K. The molecular basis of G protein-coupled receptor activation.Annu. Rev. Biochem. 2018; 87: 897-919Crossref PubMed Scopus (266) Google Scholar). In the classical GPCR signaling system, GPCRs at the plasma membrane (PM), once activated by hormones or neurotransmitters, function as guanine nucleotide exchange factors to enhance the exchange of GDP for GTP from Gα subunits, leading to the dissociation of active GTP-bound Gα and free Gβγ dimers, which can separately activate downstream effectors, such as adenylyl cyclases, phospholipases, mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinases (PI3Ks), and ion channels (2Smrcka A.V. Fisher I. G-protein betagamma subunits as multi-functional scaffolds and transducers in G-protein-coupled receptor signaling.Cell. Mol. Life Sci. 2019; 76: 4447-4459Crossref PubMed Scopus (22) Google Scholar, 3Khan S.M. Sleno R. Gora S. Zylbergold P. Laverdure J.P. Labbe J.C. Miller G.J. Hebert T.E. The expanding roles of Gbetagamma subunits in G protein-coupled receptor signaling and drug action.Pharmacol. Rev. 2013; 65: 545-577Crossref PubMed Scopus (140) Google Scholar, 4Campbell A.P. Smrcka A.V. Targeting G protein-coupled receptor signalling by blocking G proteins.Nat. Rev. Drug Discov. 2018; 17: 789-803Crossref PubMed Scopus (45) Google Scholar). In recent years, several studies have demonstrated that, after activation by GPCRs at the PM, some Gβγ dimers can translocate from the PM to intracellular organelles, including the Golgi apparatus (GA), likely via passive diffusion, and that the efficiency of translocation is determined by Gγ anchoring to the PM, as well as Gγ interaction with the receptors (5Akgoz M. Kalyanaraman V. Gautam N. Receptor-mediated reversible translocation of the G protein betagamma complex from the plasma membrane to the Golgi complex.J. Biol. Chem. 2004; 279: 51541-51544Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 6Akgoz M. Kalyanaraman V. Gautam N. G protein betagamma complex translocation from plasma membrane to Golgi complex is influenced by receptor gamma subunit interaction.Cell. Signal. 2006; 18: 1758-1768Crossref PubMed Scopus (33) Google Scholar, 7Saini D.K. Kalyanaraman V. Chisari M. Gautam N. A family of G protein betagamma subunits translocate reversibly from the plasma membrane to endomembranes on receptor activation.J. Biol. Chem. 2007; 282: 24099-24108Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 8Chisari M. Saini D.K. Cho J.H. Kalyanaraman V. Gautam N. G protein subunit dissociation and translocation regulate cellular response to receptor stimulation.PLoS One. 2009; 4e7797Crossref PubMed Scopus (24) Google Scholar, 9O'Neill P.R. Karunarathne W.K. Kalyanaraman V. Silvius J.R. Gautam N. G-protein signaling leverages subunit-dependent membrane affinity to differentially control betagamma translocation to intracellular membranes.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: E3568-E3577Crossref PubMed Scopus (24) Google Scholar, 10Senarath K. Payton J.L. Kankanamge D. Siripurapu P. Tennakoon M. Karunarathne A. Ggamma identity dictates efficacy of Gbetagamma signaling and macrophage migration.J. Biol. Chem. 2018; 293: 2974-2989Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Although the Golgi-localized Gβγ complex can activate phospholipase C (11Malik S. deRubio M. R. Smrcka A.V. G protein betagamma subunits regulate through a Golgi Biol. PubMed Scopus Google Scholar, J.C. Smrcka A.V. G protein betagamma subunits with and activate phospholipase Biol. Chem. 2018; 293: Full Text Full Text PDF PubMed Scopus Google and protein kinase N. J.R. V. of Golgi is through the activation of protein kinase Full Text Full Text PDF PubMed Scopus Google Scholar, R. of from the to plasma membrane by Golgi-localized G protein betagamma Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and regulate R. of from the to plasma membrane by Golgi-localized G protein betagamma Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, P. M. M. kinase and Gbetagamma subunits translocation of from the Golgi apparatus to the plasma Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, inhibition of Gbetagamma functions at the plasma membrane and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Golgi N. J.R. V. of Golgi is through the activation of protein kinase Full Text Full Text PDF PubMed Scopus Google Scholar, inhibition of Gbetagamma functions at the plasma membrane and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D.K. Karunarathne W.K. N. Saini D. Cho J.H. Kalyanaraman V. Gautam N. of Golgi and by G protein betagamma complex Natl. Acad. Sci. U. S. A. PubMed Scopus Google D.K. Karunarathne W.K. N. Saini D. Cho J.H. Kalyanaraman V. Gautam N. of Golgi and by G protein betagamma complex Natl. Acad. Sci. U. S. A. PubMed Scopus Google and (11Malik S. deRubio M. R. Smrcka A.V. G protein betagamma subunits regulate through a Golgi Biol. PubMed Scopus Google the and functions of Gβγ translocation from the PM to the GA largely The extracellular signal-regulated kinases 1 and 2 and in cellular and with the of is that all GPCRs can activate the However, ERK1/2 activation by different GPCRs or the GPCR in different cell through different signaling such as Gβγ subunits, arrestins, receptor kinases and protein kinases P. N. activation of kinase by G-protein gamma PubMed Scopus Google Scholar, that receptor of mitogen-activated protein kinase is by G gamma activation of Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, M. P. R. of G protein-coupled receptors to the signaling through 3-kinase PubMed Scopus Google Scholar, M. K. S. K. K. R. A. M. that for the of receptor signaling to Signal. PubMed Scopus Google Scholar, Miller S. G.J. K. D.K. of protein kinase PubMed Scopus Google Scholar, Miller Activation and of extracellular signal-regulated kinases by Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, S. S. S. M. roles of in GPCR signaling with and Signal. 2018; PubMed Scopus Google Scholar, K. The and function of mitogen-activated protein kinase activation by Signal. PubMed Scopus Google Scholar, of extracellular signal-regulated kinase activation by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. and of and G activation by the Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, A. of the receptor Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. D. M. kinase signalling from after GPCR Biol. 18: PubMed Scopus Google Scholar). Although complex activation have and have to function as scaffolds in ERK1/2 activation on the the of ERK1/2 activation by GPCRs and by G proteins is to at the PM Miller Activation and of extracellular signal-regulated kinases by Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, S. and of and G activation by the Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, A. of the receptor Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. of GPCR Sci. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). a family of kinases that the of at the and can on and and which heterodimers of a subunit and a and the PI3Kγ subunit p110γ can a complex with the subunit p101 or that the cell GPCRs can activate and and Gβγ dimers activate and γ PI3Kγ activation by Gβγ and studies have that Gβγ can with p110γ and p101 with on cell Rev. 2013; PubMed Scopus Google Scholar, in cell signalling and Rev. Mol. Biol. 2019; PubMed Scopus Google Scholar, in roles of of activation and Rev. PubMed Scopus Google Scholar). the signaling have to to prostate the ERK1/2 and in prostate cancer and activation of ERK1/2 and is with and in roles of of activation and Rev. PubMed Scopus Google Scholar, D. Activation of mitogen-activated protein kinase with prostate cancer Google Scholar, Targeting the mitogen-activated protein kinase for the of 2007; PubMed Scopus Google Scholar, S. The in Full Text Full Text PDF PubMed Scopus Google Scholar). However, the molecular for the of the ERK1/2 and in prostate cancer we study the function of Gβγ translocation to the GA in ERK1/2 activation by the chemokine receptor CXCR4 in prostate cancer and and CXCR4 is a in of prostate cancer and CXCR4 prostate cancer and S. S. The role of CXCR4 in PubMed Scopus Google Scholar, of the in prostate cancer to Google Scholar). We demonstrate that Gβγ translocation to the GA activates the ERK1/2 through the PI3Kγ We also show that knockout of the Gγ9 subunit and p110γ prostate cancer cell migration, invasion, and metastasis. data a novel function of Gβγ translocation to the GA to spatiotemporally regulate activation by GPCRs and control tumor progression. Gγ subunits with a and the Golgi in and Gβγ translocation to the GA in response to CXCR4 activation by with by the in at the GA by in 12 Gγ subunits at the PM in and induced Gγ translocation from the PM to intracellular at different and However, translocation of Gγ9 to the GA that of other Gγ subunit and The Gγ9 at the GA by The of of Gγ9 at the PM, and GA that Gγ9 at the PM and Gγ9 at the GA of Gγ9 from the PM to the GA with a of The Gγ subunit to Gγ9 which GA translocation by In the translocation Gγ subunits, the and of translocation in and and data that Gγ9 is a unique Golgi-translocating Gγ subunit. study the function of Gβγ we on ERK1/2 activated ERK1/2 in a and the and in and A and ERK1/2 activation by by with the Gβγ Smrcka A.V. of G protein gamma subunit signaling and PubMed Scopus Google and the CXCR4 of which free Gβγ dimers at the GA, ERK1/2 activation by In of the which on activation and data role of Golgi-localized Gβγ in ERK1/2 activation by CXCR4. In to the roles of and Gγ subunits in we the to Gγ9 or in and Gγ9 and knockout by Gγ9 knockout and Gγ9 and knockout also by the depletion of and Gγ9 knockout in all ERK1/2 activation by whereas knockout have a Gγ9 knockout ERK1/2 activation after at all in PC3 and of Gγ9 ERK1/2 activation by in Gγ9 knockout and data that the of Gγ9 is for ERK1/2 activation by CXCR4. the role of Gβγ translocation to the GA in ERK1/2 a translocation to Gβγ dimers to either the GA or the In this system, the for GA and of for PM to protein Gγ subunits to the to Gβγ to the GA and the PM in and (11Malik S. deRubio M. R. Smrcka A.V. G protein betagamma subunits regulate through a Golgi Biol. PubMed Scopus Google Scholar, R. of from the to plasma membrane by Golgi-localized G protein betagamma Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The by and Gγ9 recruitment of or Gγ9 to the GA in complex with to activate ERK1/2 in and whereas recruitment to the PM to Gγ9 translocation to the GA activated ERK1/2 in a and data that different Gβγ dimers can activate ERK1/2 at the GA. activation of ERK1/2 at the GA, we the of Golgi including A and which Golgi via A. Biol. 109: PubMed Scopus Google Scholar). with of Golgi Golgi as by a and ERK1/2 activation induced by ERK1/2 activation by and the and in and and data demonstrate that the of the Golgi is for ERK1/2 activation by to the GA CXCR4 at the PM, likely by its from the to the cell P. factors modulate the cell of G protein-coupled PubMed Scopus Google we the of Golgi on ERK1/2 activation by We determined the of different Gα subunits on ERK1/2 activation by Gβγ translocation to the GA. of or subunits ERK1/2 activation by in and PC3 In the of subunits, Gβγ to the GA. to also to the GA and with Gβγ that of Gα subunits ERK1/2 activation by the on the GA. to ERK1/2 ERK1/2 activation by of of Gγ9 of to activate ERK1/2 a functional of Gβγ Gγ subunit in ERK1/2 the molecular the function of Golgi-localized Gβγ in ERK1/2 we the of pharmacological inhibition of Gβγ downstream on ERK1/2 activation by with and two ERK1/2 activation by The PI3Kγ and the ERK1/2 the the the phospholipase C of the protein kinase and the protein kinases C of ERK1/2 activation by in a and the and in and and ERK1/2 activation induced by recruitment of Gγ9 to the GA also by with or or the ERK1/2 activation by that ERK1/2 activation by Golgi-localized Gβγ is through with two and and the ERK1/2 activation by the role of PI3Kγ in ERK1/2 we p110γ knockout and the to the from Gγ9 knockout to activate ERK1/2 in p110γ knockout translocation of Gγ9 to the GA to activate ERK1/2 in p110γ knockout data demonstrate that ERK1/2 activation by and Gβγ translocation to the GA on the role of subunits of PI3Kγ in ERK1/2 activation by we determined the of of p101 and to p110γ knockout by p101 by ERK1/2 activation by and in PC3 whereas and study p110γ and p101 at the GA, p110γ and p101 with or with the Golgi in PC3 p110γ and p101 in the and p110γ and p101 with the Golgi data that ERK1/2 activation by Gβγ on the GA. Gβγ and PI3Kγ also for ERK1/2 activation by other GPCRs in and we receptors with activated ERK1/2, which by with and the ERK1/2 activation also by with or or to on ERK1/2 activation by knockout of Gγ9 and ERK1/2 activation by In Gγ9 and p110γ knockout ERK1/2 activation by and 1 and data that Gβγ translocation to the GA a through which GPCRs to activate via We PC3 to the of Gγ9 and PI3Kγ knockout on cancer cell and in In the of PC3 Gγ9 and p110γ in response to as with control In knockout PC3 PC3 cell significantly after in The by the ERK1/2 and as well as the PI3Kγ to migration, PC3 cell in response to in Gγ9 and p110γ knockout in knockout as with control recruitment of Gγ9 to the GA also PC3 cell invasion, which by and PI3Kγ we determined the of Gγ9 and PI3Kγ knockout on PC3 in Gγ9 and p110γ knockout PC3 the of to the to to and for and that the tumor in the of with Gγ9 and p110γ knockout after as with in the with control and data demonstrate a role by Gγ9 and PI3Kγ in prostate tumor metastasis. In this we demonstrate that Gβγ translocation from the PM to the GA is for ERK1/2 activation by CXCR4 in different We have that Gβγ dimers that Gγ9 with to translocation to the GA, in of translocation and translocation in and to in other cell (5Akgoz M. Kalyanaraman V. Gautam N. Receptor-mediated reversible translocation of the G protein betagamma complex from the plasma membrane to the Golgi complex.J. Biol. Chem. 2004; 279: 51541-51544Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 7Saini D.K. Kalyanaraman V. Chisari M. Gautam N. A family of G protein betagamma subunits translocate reversibly from the plasma membrane to endomembranes on receptor activation.J. Biol. Chem. 2007; 282: 24099-24108Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 9O'Neill P.R. Karunarathne W.K. Kalyanaraman V. Silvius J.R. Gautam N. G-protein signaling leverages subunit-dependent membrane affinity to differentially control betagamma translocation to intracellular membranes.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: E3568-E3577Crossref PubMed Scopus (24) Google Scholar, 10Senarath K. Payton J.L. Kankanamge D. Siripurapu P. Tennakoon M. Karunarathne A. Ggamma identity dictates efficacy of Gbetagamma signaling and macrophage migration.J. Biol. Chem. 2018; 293: 2974-2989Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, D.K. Karunarathne W.K. N. Saini D. Cho J.H. Kalyanaraman V. Gautam N. of Golgi and by G protein betagamma complex Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The function of Gβγ translocation to the GA in activating ERK1/2 is by of that demonstrate that knockout of Gγ9 abolishes ERK1/2 activation by chemically induced translocation of Gγ9 to the GA activates ERK1/2, and ERK1/2 activation by translocation of is by Golgi-localized and Golgi is that, as with recruitment of and on the GA also ERK1/2 that different Gβγ to activate ERK1/2 at the GA. However, studies Gγ9 in GA translocation and the ERK1/2 activation at the GA the of Gβγ translocation in ERK1/2 several GPCRs have to Gβγ translocation to the GA in different (5Akgoz M. Kalyanaraman V. Gautam N. Receptor-mediated reversible translocation of the G protein betagamma complex from the plasma membrane to the Golgi complex.J. Biol. Chem. 2004; 279: 51541-51544Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 6Akgoz M. Kalyanaraman V. Gautam N. G protein betagamma complex translocation from plasma membrane to Golgi complex is influenced by receptor gamma subunit interaction.Cell. Signal. 2006; 18: 1758-1768Crossref PubMed Scopus (33) Google Scholar, 7Saini D.K. Kalyanaraman V. Chisari M. Gautam N. A family of G protein betagamma subunits translocate reversibly from the plasma membrane to endomembranes on receptor activation.J. Biol. Chem. 2007; 282: 24099-24108Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 8Chisari M. Saini D.K. Cho J.H. Kalyanaraman V. Gautam N. G protein subunit dissociation and translocation regulate cellular response to receptor stimulation.PLoS One. 2009; 4e7797Crossref PubMed Scopus (24) Google Scholar, 9O'Neill P.R. Karunarathne W.K. Kalyanaraman V. Silvius J.R. Gautam N. G-protein signaling leverages subunit-dependent membrane affinity to differentially control betagamma translocation to intracellular membranes.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: E3568-E3577Crossref PubMed Scopus (24) Google Scholar, 10Senarath K. Payton J.L. Kankanamge D. Siripurapu P. Tennakoon M. Karunarathne A. Ggamma identity dictates efficacy of Gbetagamma signaling and macrophage migration.J. Biol. Chem. 2018; 293: 2974-2989Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, I. M. Kalyanaraman V. Gautam N. G protein complex translocation is induced by and receptors and is by the subunit Signal. 2006; 18: PubMed Scopus Google and our data have that, in to ERK1/2 activation is also by Gγ9 the we by GPCRs to activate the ERK1/2 Gβγ is of activating downstream signaling molecules (2Smrcka A.V. Fisher I. G-protein betagamma subunits as multi-functional scaffolds and transducers in G-protein-coupled receptor signaling.Cell. Mol. Life Sci. 2019; 76: 4447-4459Crossref PubMed Scopus (22) Google Scholar, 3Khan S.M. Sleno R. Gora S. Zylbergold P. Laverdure J.P. Labbe J.C. Miller G.J. Hebert T.E. The expanding roles of Gbetagamma subunits in G protein-coupled receptor signaling and drug action.Pharmacol. Rev. 2013; 65: 545-577Crossref PubMed Scopus (140) Google Scholar). We have demonstrated that ERK1/2 activation by Golgi-localized Gβγ is through its as pharmacological inhibition of CRISPR-Cas9–mediated knockout of subunit and of subunit p101 ERK1/2 activation by GPCR and translocation of is also by our data that p110γ and p101 at the GA and a study that at the GA S. K. M. S. A novel phosphoinositide 3-kinase in the and its Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). also a role in ERK1/2 its inhibition ERK1/2 PI3Kγ and can activated by GPCRs and PI3Kγ can activated by Gβγ with on cell Rev. 2013; PubMed Scopus Google Scholar, in cell signalling and Rev. Mol. Biol. 2019; PubMed Scopus Google Scholar, in roles of of activation and Rev. PubMed Scopus Google Scholar). Although a of studies have the function of Gβγ and PI3Kγ in ERK1/2 studies that the interaction at the PM P. N. activation of kinase by G-protein gamma PubMed Scopus Google Scholar, that receptor of mitogen-activated protein kinase is by G gamma activation of Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, M. P. R. of G protein-coupled receptors to the signaling through 3-kinase PubMed Scopus Google Scholar). PI3Kγ to for and activation of ERK1/2, likely via a PM M. P. R. of G protein-coupled receptors to the signaling through 3-kinase PubMed Scopus Google Scholar). In macrophage via activating PI3Kγ at the PM, whereas Gγ9 K. Payton J.L. Kankanamge D. Siripurapu P. Tennakoon M. Karunarathne A. Ggamma identity dictates efficacy of Gbetagamma signaling and macrophage migration.J. Biol. Chem. 2018; 293: 2974-2989Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). data that different Gβγ dimers activate PI3Kγ in to control different cellular to the of signaling and functional our data demonstrate a in which GPCR activation at the PM induces Gβγ translocation to the GA activates the PI3Kγ p110γ-p101, leading to the activation of the data also a novel function of the GA as a signaling in activation by in which the GA a to the translocation of activation of and activation of ERK1/2 of the study is the function of Gβγ translocation to the GA and ERK1/2 activation in prostate tumor progression. the studies have demonstrated that, to GPCRs at the PM in the and of different cancer and to and G for cancer V. N. A. P. the G protein-coupled and for cancer Biol. Chem. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar, A.V. of and Gbetagamma A for cancer Sci. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). the of the ERK1/2 in the of prostate the molecules in of this to for prostate cancer D. Activation of mitogen-activated protein kinase with prostate cancer Google Scholar, Targeting the mitogen-activated protein kinase for the of 2007; PubMed Scopus Google Scholar). Although in and activation of the ERK1/2 and of A. A. I. N. to 2006; PubMed Scopus Google Scholar, S.M. S. D. D. R. of activation of the signaling by of 2004; Full Text Full Text PDF PubMed Scopus Google with prostate cancer have on the of that control ERK1/2 activation in prostate cancer J.L. function in of prostate Natl. Acad. Sci. U. S. A. 2012; 109: PubMed Scopus Google Scholar). We have that Gγ9 is a of ERK1/2 at the GA. In Gγ9 P. R. P. S. G protein subunit by prostate cancer and interaction with 2013; PubMed Scopus Google and CXCR4 of the in prostate cancer to Google in prostate cancer and activation of GPCRs and G proteins CXCR4 and for the activation of the ERK1/2 in prostate we have demonstrated that knockout of Gγ9 and PI3Kγ suppresses prostate cancer cell migration, invasion, and with studies the roles of Gβγ in prostate cancer P. S. G protein betagamma signaling prostate cancer and the efficacy of PubMed Google Scholar, R. K. Targeting Gbetagamma signaling to prostate tumor and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google that Golgi-localized as well as for prostate cancer from and from control to PI3Kγ subunits p101 and and and and the PI3Kγ subunits p101 and from and from and from and from and from Fisher and from and from from and from from and ERK1/2 from from other as M. M. M. proteins control the membrane of 2019; Full Text Full Text PDF PubMed Scopus Google Scholar, S. prostate via PubMed Scopus Google Scholar). The Gγ Gγ9 and p110γ and p101 from from Gautam as D.K. Kalyanaraman V. Chisari M. Gautam N. A family of G protein betagamma subunits translocate reversibly from the plasma membrane to endomembranes on receptor activation.J. Biol. Chem. 2007; 282: 24099-24108Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). The and by V. Smrcka and as (11Malik S. deRubio M. R. Smrcka A.V. G protein betagamma subunits regulate through a Golgi Biol. PubMed Scopus Google Scholar, R. of from the to plasma membrane by Golgi-localized G protein betagamma Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The and as N. A. R. G protein for active G protein-coupled receptors (GPCRs) in Biol. Chem. 2018; 293: Full Text Full Text PDF PubMed Scopus Google Scholar, K. P.R. and of containing G protein-coupled receptors and G PubMed Scopus Google Scholar). and p110γ and by and The and by in the of and Gγ9 which with The by the two and in the Gγ9 as a and C at the and in the nucleotide of the Gγ9 to and to the and from and PC3 in with 2 and in with The Fisher and which the by as and for PubMed Scopus Google Scholar). with as control or containing for and in at a of for Knockout of the proteins determined by of p101 and as for the of and receptors from the to the cell of a G protein-coupled Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The on with at a of for 12 study the of p101 and on ERK1/2 activation by with with and The at a of and for and with or Gβγ on for and with subunits, and the for and with at 1 The for the and protein a The translocation of Gβγ to the GA in response to by the of at the GA. with and its for and with translocation of Gβγ to the PM and the GA, with and with either or for and for with at 1 for the of Gα subunits on Gβγ translocation to the GA, with and study Golgi with the Golgi and with different Golgi for study p110γ and p101 at the GA, with or p110γ and with the Golgi for In with for with for and with for The with and The a with a in for and for with or as in the the and the with the by the of of ERK1/2 activation determined by ERK1/2 by as M. M. M. proteins control the membrane of 2019; Full Text Full Text PDF PubMed Scopus Google Scholar, for the of and receptors from the to the cell of a G protein-coupled Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of PC3 the PC3 in and 2 to at for at the in in the with The and by and as D. N. and PubMed Scopus (24) Google Scholar). studies by the and of CRISPR-Cas9–mediated knockout PC3 and control and with the The with and by for and PC3 in via the The tumor by of after of The data by and as and as as the data from The that have of with the of this We V. and for in this We also for with M. N. A. and the study and M. and migration, and and the M. K. and N. A. G protein translocation and the M. K. and and the M. N. A. and the by from the of and to and to N. A. and of and to The is the of the and the of the of

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