期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 296, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.jbc.2021.100325
关键词
-
资金
- National Institutes of Health, United States [R35GM136397, R01GM118915, R01GM130142]
- Veterans Affairs Office of Research and Development, United States [BX003862]
The study demonstrates that G gamma 9 is a unique Golgi-translocating G gamma subunit, which regulates the activation of mitogen-activated protein kinases by activating PI3K gamma heterodimers p110 gamma-p101 in a spatiotemporal manner, ultimately controlling 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 beta gamma dimers to the GA. However, the functional significance of this translocation is largely unknown. Here, we study PM-GA translocation of all 12 G gamma subunits in response to chemokine receptor CXCR4 activation and demonstrate that G gamma 9 is a unique Golgi-translocating G gamma subunit. CRISPR-Cas9-mediated knockout of G gamma 9 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 G beta gamma dimers containing different G gamma subunits activates ERK1/2, whereas recruitment to the PM is ineffective. We also demonstrate that pharmacological inhibition of phosphoinositide 3-kinase. (PI3K gamma) and depletion of its subunits p110 gamma and p101 abrogate ERK1/2 activation by CXCR4 and G beta gamma recruitment to the GA. Knockout of either G gamma 9 or PI3K gamma significantly suppresses prostate cancer PC3 cell migration, invasion, and metastasis. Collectively, our data demonstrate a novel function for G beta gamma translocation to the GA, via activating PI3K gamma heterodimers p110 gamma-p101, to spatiotemporally regulate mitogen-activated protein kinase activation by G protein-coupled receptors and ultimately control tumor progression.
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