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Gene interactions and pathways from curated databases and text-mining
Mol Endocrinol 2007, PMID: 17405905

Direct interactions with G α i and G βγ mediate nongenomic signaling by estrogen receptor α .

Kumar, Premlata; Wu, Qian; Chambliss, Ken L; Yuhanna, Ivan S; Mumby, Susanne M; Mineo, Chieko; Tall, Gregory G; Shaul, Philip W

Estrogen induces G protein-dependent nongenomic signaling in a variety of cell types via the activation of a plasma membrane-associated subpopulation of estrogen receptor alpha (ER alpha). Using pull-down experiments with purified recombinant proteins, we now demonstrate that ER alpha binds directly to G alpha i and G betagamma. Mutagenesis and the addition of blocking peptide reveals that this occurs via amino acids 251-260 and 271-595 of ER alpha, respectively. Studies of ER alpha complexed with heterotrimeric G proteins further show that estradiol causes the release of both G alpha i and G betagamma without stimulating GTP binding to G alpha i. Moreover, in COS-7 cells, the disruption of ER alpha-G alpha i interaction by deletion mutagenesis of ER alpha or expression of blocking peptide, as well as G betagamma sequestration with beta-adrenergic receptor kinase C terminus, prevents nongenomic responses to estradiol including src and erk activation. In endothelial cells, the disruption of ER alpha-G alpha i interaction prevents estradiol-induced nitric oxide synthase activation and the resulting attenuation of monocyte adhesion that contributes to estrogen-related cardiovascular protection. Thus, through direct interactions, ER alpha mediates a novel mechanism of G protein activation that provides greater diversity of function of both the steroid hormone receptor and G proteins.

Document information provided by NCBI PubMed

Text Mining Data

nitric oxide synthase → ER alpha-G: " In endothelial cells, the disruption of ER alpha-G alpha i interaction prevents estradiol induced nitric oxide synthase activation and the resulting attenuation of monocyte adhesion that contributes to estrogen related cardiovascular protection "

Manually curated Databases

  • NCI Pathway Database Plasma membrane estrogen receptor signaling: Gai/GDP complex (GNAI2_GNAI3_GNAO1_GNAO1_GNAZ_GNAI1) → G beta/gamma complex (GNB1-GNG2) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: Gai/GDP complex (GNAI2_GNAI3_GNAO1_GNAO1_GNAZ_GNAI1) → ER alpha/Gai/GDP/Gbeta gamma complex (ESR1-GNAI2_GNAI3_GNAO1_GNAO1_GNAZ_GNAI1-GNB1-GNG2) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: Gai/GDP complex (GNAI2_GNAI3_GNAO1_GNAO1_GNAZ_GNAI1) → None (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: Gai/GDP complex (GNAI2_GNAI3_GNAO1_GNAO1_GNAZ_GNAI1) → E2/ER alpha (dimer) complex (ESR1) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: G beta/gamma complex (GNB1-GNG2) → ER alpha/Gai/GDP/Gbeta gamma complex (ESR1-GNAI2_GNAI3_GNAO1_GNAO1_GNAZ_GNAI1-GNB1-GNG2) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: G beta/gamma complex (GNB1-GNG2) → None (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: G beta/gamma complex (GNB1-GNG2) → E2/ER alpha (dimer) complex (ESR1) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: ER alpha/Gai/GDP/Gbeta gamma complex (ESR1-GNAI2_GNAI3_GNAO1_GNAO1_GNAZ_GNAI1-GNB1-GNG2) → None (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: ER alpha/Gai/GDP/Gbeta gamma complex (ESR1-GNAI2_GNAI3_GNAO1_GNAO1_GNAZ_GNAI1-GNB1-GNG2) → E2/ER alpha (dimer) complex (ESR1) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: None → E2/ER alpha (dimer) complex (ESR1) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: E2/ER alpha (dimer)/PELP1/Src/p52 SHC complex (ESR1-PELP1-SRC-SHC1) → E2/ER alpha (dimer)/PELP1/Src/p52 SHC/GRB2/SOS1 complex (ESR1-PELP1-SRC-SHC1-GRB2-SOS1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: E2/ER alpha (dimer)/PELP1/Src/p52 SHC complex (ESR1-PELP1-SRC-SHC1) → GRB2/SOS1 complex (GRB2-SOS1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: E2/ER alpha (dimer)/PELP1/Src/p52 SHC/GRB2/SOS1 complex (ESR1-PELP1-SRC-SHC1-GRB2-SOS1) → GRB2/SOS1 complex (GRB2-SOS1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Plasma membrane estrogen receptor signaling: ER alpha/Gai/GDP/Gbeta gamma complex (ESR1-GNAI2_GNAI3_GNAO1_GNAO1_GNAZ_GNAI1-GNB1-GNG2) → Src (SRC) (modification, activates)
    Evidence: mutant phenotype
In total, 63 gene pairs are associated to this article in curated databases