Giα proteins exhibit functional differences in the activation of ERK1/2, Akt and mTORC1 by growth factors in normal and breast cancer cells

摘要

Background In a classic model, G_iα proteins including G_i1α, G_i2α and G_i3α are important for transducing signals from G_iα protein-coupled receptors (G_iαPCRs) to their downstream cascades in response to hormones and neurotransmitters. Our previous study has suggested that G_i1α, G_i2α and G_i3α 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 G_iα 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 G_iα 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 G_iα proteins in breast cancer remains to be elucidated. Results We found that Gi1/3 deficient MEFs with the low expression level of G_i2α 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 G_iα 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. Conclusions G_iα proteins differentially regulate the activation of Akt, mTORC1 and ERK1/2 by different families of growth factors. G_iα proteins are important for breast cancer cell growth and invasion.