Gene interactions and pathways from curated databases and text-mining
J Biol Chem 1999, PMID: 10567412

Internalized epidermal growth factor receptors participate in the activation of p21(ras) in fibroblasts.

Haugh, J M; Huang, A C; Wiley, H S; Wells, A; Lauffenburger, D A

Regulated activation of the highly conserved Ras GTPase is a central event in the stimulation of cell proliferation, motility, and differentiation elicited by receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR). In fibroblasts, this involves formation and membrane localization of Shc.Grb2.Sos complexes, which increases the rate of Ras guanine nucleotide exchange. In order to control Ras-mediated cell responses, this activity is regulated by receptor down-regulation and a feedback loop involving the dual specificity kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK). We investigated the role of EGFR endocytosis in the regulation of Ras activation. Of fundamental interest is whether activated receptors in endosomes can participate in the stimulation of Ras guanine nucleotide exchange, because the constitutive membrane localization of Ras may affect its compartmentalization. By exploiting the differences in postendocytic signaling of two EGFR ligands, epidermal growth factor and transforming growth factor-alpha, we found that activated EGFR located at the cell surface and in internal compartments contribute equally to the membrane recruitment and tyrosine phosphorylation of Shc in NR6 fibroblasts expressing wild-type EGFR. Importantly, both the rate of Ras-specific guanine nucleotide exchange and the level of Ras-GTP were depressed to near basal values on the time scale of receptor trafficking. Using the selective MEK inhibitor PD098059, we were able to block the feedback desensitization pathway and maintain activation of Ras. Under these conditions, the generation of Ras-GTP was not significantly affected by the subcellular location of activated EGFR. In conjunction with our previous analysis of the phospholipase C pathway in the same cell line, this suggests a selective continuation of specific signaling activities and cessation of others upon receptor endocytosis.

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Text Mining Data

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Manually curated Databases

  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF complex (EGFR-EGF) → GRB2/SOS1 complex (GRB2-SOS1) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF complex (EGFR-EGF) → EGFR/EGFR/EGF/EGF/GRB2/SOS1 complex (EGFR-EGF-GRB2-SOS1) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: GRB2/SOS1 complex (GRB2-SOS1) → EGFR/EGFR/EGF/EGF/GRB2/SOS1 complex (EGFR-EGF-GRB2-SOS1) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF/p46 SHC complex (EGFR-EGF-SHC1) → EGFR/EGFR/EGF/EGF complex (EGFR-EGF) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF/p46 SHC complex (EGFR-EGF-SHC1) → p46 SHC (SHC1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF complex (EGFR-EGF) → p46 SHC (SHC1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF complex (EGFR-EGF) → p52 SHC (SHC1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF complex (EGFR-EGF) → EGFR/EGFR/EGF/EGF/p52 SHC complex (EGFR-EGF-SHC1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: p52 SHC (SHC1) → EGFR/EGFR/EGF/EGF/p52 SHC complex (EGFR-EGF-SHC1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: None → RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: None → EGFR/EGFR/EGF/EGF/p46 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: None → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: None → None (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → EGFR/EGFR/EGF/EGF/p46 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → None (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF/p46 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF/p46 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) → None (modification, activates)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → None (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF/p46 SHC complex (EGFR-EGF-SHC1) → GRB2/SOS1 complex (GRB2-SOS1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF/p46 SHC complex (EGFR-EGF-SHC1) → EGFR/EGFR/EGF/EGF/p46 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: GRB2/SOS1 complex (GRB2-SOS1) → EGFR/EGFR/EGF/EGF/p46 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: None → RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: None → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: None → EGFR/EGFR/EGF/EGF/p52 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: None → None (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → EGFR/EGFR/EGF/EGF/p52 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → None (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → None (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF/p52 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) → None (modification, activates)
    Evidence: assay
  • NCI Pathway Database Internalization of ErbB1: GRB2/SOS1 complex (GRB2-SOS1) → EGFR/EGFR/EGF/EGF/p52 SHC complex (EGFR-EGF-SHC1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: GRB2/SOS1 complex (GRB2-SOS1) → EGFR/EGFR/EGF/EGF/p52 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF/p52 SHC complex (EGFR-EGF-SHC1) → EGFR/EGFR/EGF/EGF/p52 SHC/GRB2/SOS1 complex (EGFR-EGF-SHC1-GRB2-SOS1) (modification, collaborate)
    Evidence: assay, physical interaction
In total, 36 gene pairs are associated to this article in curated databases