title: 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.
abstract: BACKGROUND
  In a classic model, G(i)α proteins including G(i1)α, G(i2)α and G(i3)α are important for transducing signals from G(i)α protein-coupled receptors (G(i)αPCRs) to their downstream cascades in response to hormones and neurotransmitters. Our previous study has suggested that G(i1)α, G(i2)α and G(i3)α 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(i)α 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(i)α 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(i)α proteins in breast cancer remains to be elucidated.
  
  
  RESULTS
  We found that Gi1/3 deficient MEFs with the low expression level of G(i2)α 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(i)α 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(i)α proteins differentially regulate the activation of Akt, mTORC1 and ERK1/2 by different families of growth factors. G(i)α proteins are important for breast cancer cell growth and invasion.
authors: Zhanwei
authors: Z
authors: Wang
authors: Rica
authors: R
authors: Dela Cruz
authors: Fang
authors: F
authors: Ji
authors: Sheng
authors: S
authors: Guo
authors: Jianhua
authors: J
authors: Zhang
authors: Ying
authors: Y
authors: Wang
authors: Gen-Sheng
authors: GS
authors: Feng
authors: Lutz
authors: L
authors: Birnbaumer
authors: Cancer Biology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813, USA. jm@ucla.edu.
authors: Meisheng
authors: M
authors: Jiang
authors: Wen-Ming
authors: WM
authors: Chu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go