G(i)α proteins exhibit functional differences in the activation of ERK1/2, Akt and mTORC1 by growth factors in normal and breast cancer cells.
G(i)α proteins exhibit functional differences in the activation of ERK1/2, Akt and mTORC1 by growth factors in normal and breast cancer cells.
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DOI：
10.1186/1478-811x-12-10
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发表时间：
2014-02-13
期刊：
影响因子：
--
通讯作者：
Chu WM
中科院分区：
文献类型：
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作者：
Wang Z;Dela Cruz R;Ji F;Guo S;Zhang J;Wang Y;Feng GS;Birnbaumer L;Jiang M;Chu WM
在经典模型中，GIα蛋白包括GI1α、GI2α和GI3α，在激素和神经递质的作用下，GIα蛋白偶联受体(GIαPCRs)将信号传导到下游信号通路中起着重要作用。我们以前的研究表明，GI1α、GI2α和GI3α在表皮生长因子及其家族成员激活PI3K/Akt/mTORC 1途径中也起重要作用。然而，这些Giα蛋白在表皮生长因子激活细胞外信号调节蛋白激酶1和2(ERK1/2)中的遗传作用在很大程度上尚不清楚。此外，尚不清楚这些GIα蛋白是否也参与了其他生长因子家族成员对Akt/mTORC1和ERK1/2通路的激活。此外，这些GIα蛋白在乳腺癌中的作用仍有待阐明。我们发现，GI2ERK1/2表达水平低的GI1/3缺陷MEF表现出EGF、IGF1和胰岛素激活ERK1/2的缺陷，而EGF和FGFs激活Akt和mTORC1时，GI2ERK1/2被α激活。Gi1/2/3基因敲除的乳腺癌细胞表现出类似的激活缺陷和体外生长和侵袭缺陷。乳腺癌细胞中与RTKs、GAB1、FRS2和Shp2相关的Giα蛋白及其消融可抑制GAB1、GRS2和Shp2对表皮生长因子和胰岛素样生长因子-1的反应或与FRS2和Grb2的相互作用。Giα蛋白通过不同的生长因子家族不同地调节Akt、mTORC1ERK1/2的激活。Giα蛋白对乳腺癌细胞的生长和侵袭具有重要作用。
In a classic model, Giα proteins including Gi1α, Gi2α and Gi3α are important for transducing signals from Giα protein-coupled receptors (GiαPCRs) to their downstream cascades in response to hormones and neurotransmitters. Our previous study has suggested that Gi1α, Gi2α and Gi3α are also important for the activation of the PI3K/Akt/mTORC1 pathway by epidermal growth factor (EGF) and its family members. However, a genetic role of these Giα proteins in the activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) by EGF is largely unknown. Further, it is not clear whether these Giα proteins are also engaged in the activation of both the Akt/mTORC1 and ERK1/2 pathways by other growth factor family members. Additionally, a role of these Giα proteins in breast cancer remains to be elucidated. We found that Gi1/3 deficient MEFs with the low expression level of Gi2α showed defective ERK1/2 activation by EGFs, IGF-1 and insulin, and Akt and mTORC1 activation by EGFs and FGFs. Gi1/2/3 knockdown breast cancer cells exhibited a similar defect in the activations and a defect in in vitro growth and invasion. The Giα proteins associated with RTKs, Gab1, FRS2 and Shp2 in breast cancer cells and their ablation impaired Gab1’s interactions with Shp2 in response to EGF and IGF-1, or with FRS2 and Grb2 in response to bFGF. Giα proteins differentially regulate the activation of Akt, mTORC1 and ERK1/2 by different families of growth factors. Giα proteins are important for breast cancer cell growth and invasion.