G protein βγ translocation to the Golgi apparatus activates MAPK via p110γ-p101 heterodimers.
G protein βγ translocation to the Golgi apparatus activates MAPK via p110γ-p101 heterodimers.
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DOI：
10.1016/j.jbc.2021.100325
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Wu G
中科院分区：
文献类型：
--
作者：
Khater M;Wei Z;Xu X;Huang W;Lokeshwar BL;Lambert NA;Wu G
高尔基体（GA）是一种细胞器，在蛋白质分泌过程中起着关键作用。质膜（PM）上G蛋白偶联受体的激活诱导G蛋白βγ二聚体易位至GA。然而，这种易位的功能意义在很大程度上是未知的。在这里，我们研究了所有12个Gγ亚基对趋化因子受体CXCR 4活化的PM-GA易位，并证明Gγ9是一个独特的高尔基体易位Gγ亚基。CRISPR-Cas9介导的Gγ9敲除消除了CXCR 4对细胞外信号调节激酶1和2（ERK 1/2）（促分裂原活化蛋白激酶家族的两个成员）的激活。我们发现，化学诱导的含有不同Gγ亚基的Gβγ二聚体向GA的募集激活ERK 1/2，而向PM的募集是无效的。我们还证明，药理学抑制磷脂酰肌醇3-激酶γ（PI 3 K γ）及其亚基p110γ和p101的耗竭通过CXCR 4和Gβγ募集到GA而消除ERK 1/2活化。Gγ9或PI 3 K γ的敲除显著抑制前列腺癌PC 3细胞的迁移、侵袭和转移。总的来说，我们的数据证明了Gβγ易位到GA的新功能，通过激活PI 3 K γ异源二聚体p110γ-p101，时空调节G蛋白偶联受体激活的丝裂原活化蛋白激酶，并最终控制肿瘤进展。
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.
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