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GRB2 — HRAS

Pathways - manually collected, often from reviews:

• OpenBEL Selventa BEL large corpus: HRAS → Complex of GRB2-SHC1 (increases, GRB2/SHC1 Activity)
  Evidence: Phosphorylation of Shc produces its binding to the adaptor protein Grb2, causing activation of the protooncogene ras, which is also upstream of the MAP kinase pathway.
• NCI Pathway Database PDGFR-beta signaling pathway: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → PDGF-BB/PDGFRB (dimer)/GRB2/SOS1/SHP2 complex (PDGFRB-GRB2-SOS1-PTPN11-PDGFB) (modification, collaborate)
  Rönnstrand et al., Oncogene 1999, Gibbs et al., J Biol Chem 1990, Kundra et al., J Cell Biol 1995, Li et al., Mol Cell Biol 1994
  Evidence: mutant phenotype
• NCI Pathway Database TCR signaling in naïve CD8+ T cells: GRB2/SOS1/SHC complex (GRB2-SOS1-SHC1) → RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Reynolds et al., J Biol Chem 2004
  Evidence: assay, other species
• NCI Pathway Database TCR signaling in naïve CD8+ T cells: GRB2/SOS1/SHC complex (GRB2-SOS1-SHC1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Reynolds et al., J Biol Chem 2004
  Evidence: assay, other species
• NCI Pathway Database Neurotrophic factor-mediated Trk receptor signaling: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → FRS2 family/SHP2/GRB2/SOS1 complex (FRS3_FRS2-PTPN11-GRB2-SOS1) (modification, collaborate)
  Wright et al., Mol Biol Cell 1997
  Evidence: other species
• NCI Pathway Database Neurotrophic factor-mediated Trk receptor signaling: FRS2 family/SHP2/GRB2/SOS1 complex (FRS3_FRS2-PTPN11-GRB2-SOS1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Wright et al., Mol Biol Cell 1997
  Evidence: other species
• NCI Pathway Database IL2-mediated signaling events: IL2/IL2R alpha/beta/gamma/JAK1/LCK/JAK3/SHC/GRB2/SOS1/GAB2 complex (IL2RA-IL2RB-IL2RG-IL2-JAK1-LCK-JAK3-SHC1-GRB2-SOS1-GAB2) → RAS family/GDP/Aiolos complex (HRAS_KRAS_HRAS_KRAS_NRAS-IKZF3) (modification, activates)
  Romero et al., EMBO J 1999, Cacalano et al., Nat Cell Biol 2001, Satoh et al., J Biol Chem 1992, Graves et al., J Immunol 1992, Nelms et al., Immunity 1998
  Evidence: mutant phenotype, physical interaction, other species
• NCI Pathway Database IL2-mediated signaling events: IL2/IL2R alpha/beta/gamma/JAK1/LCK/JAK3/SHC/GRB2/SOS1/GAB2 complex (IL2RA-IL2RB-IL2RG-IL2-JAK1-LCK-JAK3-SHC1-GRB2-SOS1-GAB2) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Romero et al., EMBO J 1999, Cacalano et al., Nat Cell Biol 2001, Satoh et al., J Biol Chem 1992, Graves et al., J Immunol 1992, Nelms et al., Immunity 1998
  Evidence: mutant phenotype, physical interaction, other species
• NCI Pathway Database PDGFR-beta signaling pathway: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → PDGF-BB/PDGFRB (dimer)/p52 SHC/GRB2/SOS1 complex (PDGFRB-SHC1-GRB2-SOS1-PDGFB) (modification, collaborate)
  Gibbs et al., J Biol Chem 1990, Benjamin et al., J Biol Chem 1994, Salcini et al., Oncogene 1994, Yokote et al., J Biol Chem 1994
  Evidence: mutant phenotype
• NCI Pathway Database PDGFR-beta signaling pathway: PDGF-BB/PDGFRB (dimer)/p52 SHC/GRB2/SOS1 complex (PDGFRB-SHC1-GRB2-SOS1-PDGFB) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Gibbs et al., J Biol Chem 1990, Benjamin et al., J Biol Chem 1994, Salcini et al., Oncogene 1994, Yokote et al., J Biol Chem 1994
  Evidence: mutant phenotype
• NCI Pathway Database IGF1 pathway: IGF-1R heterotetramer/IGF1/GRB2/Sos/Shc complex (IGF1R-IGF1-GRB2-SHC1-SOS1) → HRAS/GTP complex (HRAS) (modification, activates)
• NCI Pathway Database IGF1 pathway: IGF-1R heterotetramer/IGF1/GRB2/Sos/Shc complex (IGF1R-IGF1-GRB2-SHC1-SOS1) → HRAS/GDP complex (HRAS) (modification, activates)
• NCI Pathway Database Neurotrophic factor-mediated Trk receptor signaling: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → SHC/GRB2/SOS1 complex (SHC1-GRB2-SOS1) (modification, collaborate)
  Li et al., Science 1992
  Evidence: assay, other species
• NCI Pathway Database Neurotrophic factor-mediated Trk receptor signaling: SHC/GRB2/SOS1 complex (SHC1-GRB2-SOS1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Li et al., Science 1992
  Evidence: assay, other species
• NCI Pathway Database TCR signaling in naïve CD4+ T cells: GRB2/SOS1/SHC complex (GRB2-SOS1-SHC1) → RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Parry et al., J Immunol 2006, Egan et al., Nature 1993
  Evidence: expresssion pattern, assay, other species
• NCI Pathway Database TCR signaling in naïve CD4+ T cells: GRB2/SOS1/SHC complex (GRB2-SOS1-SHC1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Parry et al., J Immunol 2006, Egan et al., Nature 1993
  Evidence: expresssion pattern, assay, other species
• NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met): HRAS/GDP complex (HRAS) → HGF(dimer)/MET(dimer)/GRB2/SOS1 complex (MET-GRB2-SOS1-HGF) (modification, collaborate)
  Schaeper et al., J Cell Biol 2000, Ponzetto et al., Cell 1994, Graziani et al., J Biol Chem 1993
  Evidence: assay
• NCI Pathway Database ErbB2/ErbB3 signaling events: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → ErbB2/ErbB3/neuregulin 1 beta/SHC/GRB2/SOS1 complex (ERBB2-ERBB3-NRG1-SHC1-GRB2-SOS1) (modification, collaborate)
  Goodearl et al., Dev Neurosci 2001
  Evidence: mutant phenotype, assay
• NCI Pathway Database ErbB2/ErbB3 signaling events: ErbB2/ErbB3/neuregulin 1 beta/SHC/GRB2/SOS1 complex (ERBB2-ERBB3-NRG1-SHC1-GRB2-SOS1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Goodearl et al., Dev Neurosci 2001
  Evidence: mutant phenotype, assay
• NCI Pathway Database SHP2 signaling: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → PDGF-BB/PDGFRB (dimer)/GRB2/SOS1/SHP2 complex (PDGFRB-GRB2-SOS1-PTPN11-PDGFB) (modification, collaborate)
  Rönnstrand et al., Oncogene 1999, Gibbs et al., J Biol Chem 1990, Kundra et al., J Cell Biol 1995, Li et al., Mol Cell Biol 1994
  Evidence: mutant phenotype
• NCI Pathway Database Fc-epsilon receptor I signaling in mast cells: SHC/GRB2/SOS1 complex (SOS1-GRB2-SHC1) → HRAS/GTP complex (HRAS) (modification, activates)
• NCI Pathway Database Fc-epsilon receptor I signaling in mast cells: SHC/GRB2/SOS1 complex (SOS1-GRB2-SHC1) → HRAS/GDP complex (HRAS) (modification, activates)
• NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met): HRAS/GDP complex (HRAS) → HGF(dimer)/MET(dimer)/p52 SHC/GRB2/SOS1 complex (MET-SHC1-GRB2-SOS1-HGF) (modification, collaborate)
  Pelicci et al., Oncogene 1995
  Evidence: assay
• NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met): FAK/GRB2/SOS1 complex (GRB2-SOS1-PTK2) → HRAS/GTP complex (HRAS) (modification, activates) Chen et al., J Biol Chem 1998
  Evidence: assay, physical interaction
• NCI Pathway Database Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met): FAK/GRB2/SOS1 complex (GRB2-SOS1-PTK2) → HRAS/GDP complex (HRAS) (modification, activates) Chen et al., J Biol Chem 1998
  Evidence: assay, physical interaction
• NCI Pathway Database EGFR-dependent Endothelin signaling events: HRAS/GDP complex (HRAS) → EGF/EGFR dimer/SHC/GRB2/SOS1 complex (EGF-EGFR-SHC1-GRB2-SOS1) (modification, collaborate)
  Iwasaki et al., Endocrinology 1999, Daub et al., Nature 1996
  Evidence: mutant phenotype, other species
• NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/SHC/GRB2/Sos1 complex (INSR-INS-SHC1-GRB2-SOS1) → HRAS/GTP complex (HRAS) (modification, activates) Wick et al., J Biol Chem 2001, Ouwens et al., J Biol Chem 1994, Yamauchi et al., J Biol Chem 1994, Pronk et al., Mol Cell Biol 1994, Sasaoka et al., J Biol Chem 1994
  Evidence: assay
• NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/SHC/GRB2/Sos1 complex (INSR-INS-SHC1-GRB2-SOS1) → HRAS/GDP complex (HRAS) (modification, activates) Wick et al., J Biol Chem 2001, Ouwens et al., J Biol Chem 1994, Yamauchi et al., J Biol Chem 1994, Pronk et al., Mol Cell Biol 1994, Sasaoka et al., J Biol Chem 1994
  Evidence: assay
• NCI Pathway Database Internalization of ErbB1: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → EGFR/EGFR/EGF/EGF/GRB2/SOS1 complex (EGFR-EGF-GRB2-SOS1) (modification, collaborate)
  Haugh et al., J Biol Chem 1999, Pennock et al., Mol Cell Biol 2003, Wiley et al., J Biol Chem 1991, Di Guglielmo et al., EMBO J 1994, Herbst et al., J Biol Chem 1994
  Evidence: assay
• NCI Pathway Database Internalization of ErbB1: EGFR/EGFR/EGF/EGF/GRB2/SOS1 complex (EGFR-EGF-GRB2-SOS1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Haugh et al., J Biol Chem 1999, Pennock et al., Mol Cell Biol 2003, Wiley et al., J Biol Chem 1991, Di Guglielmo et al., EMBO J 1994, Herbst et al., J Biol Chem 1994
  Evidence: assay
• NCI Pathway Database GMCSF-mediated signaling events: GMCSF/GMR alpha/CSF2RB/JAK2 (dodecamer)/SHC/GRB2/SOS1 complex (CSF2RB-JAK2-SHC1-CSF2-CSF2RA-GRB2-SOS1) → RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Piu et al., Oncogene 2002, Guthridge et al., Blood 2004, Lanfrancone et al., Oncogene 1995, Sato et al., EMBO J 1993
  Evidence: mutant phenotype, assay
• NCI Pathway Database GMCSF-mediated signaling events: GMCSF/GMR alpha/CSF2RB/JAK2 (dodecamer)/SHC/GRB2/SOS1 complex (CSF2RB-JAK2-SHC1-CSF2-CSF2RA-GRB2-SOS1) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Piu et al., Oncogene 2002, Guthridge et al., Blood 2004, Lanfrancone et al., Oncogene 1995, Sato et al., EMBO J 1993
  Evidence: mutant phenotype, 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)
  Haugh et al., J Biol Chem 1999
  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)
  Haugh et al., J Biol Chem 1999
  Evidence: assay
• NCI Pathway Database Regulation of Ras family activation: GRB2/SOS1 complex (GRB2-SOS1) → HRAS/GDP complex (HRAS) (modification, activates) Freedman et al., Proc Natl Acad Sci U S A 2006*, Gureasko et al., Nature structural & molecular biology 2008, McDonald et al., Arch Biochem Biophys 2008*, Li et al., Nature 1993*, Buday et al., Cell 1993*, Chardin et al., Science 1993
  Evidence: assay, physical interaction
• NCI Pathway Database Regulation of Ras family activation: HRAS/GDP complex (HRAS) → GRB2/SOS2 complex (GRB2-SOS2) (modification, collaborate)
  Gureasko et al., Nature structural & molecular biology 2008, Yang et al., J Biol Chem 1995*, Nielsen et al., Mol Cell Biol 1997*
  Evidence: assay
• NCI Pathway Database IGF1 pathway: IGF-1R heterotetramer/IGF1/IRS1/GRB2/Sos complex (IGF1R-IGF1-IRS1-GRB2-SOS1) → HRAS/GDP complex (HRAS) (modification, activates)
• NCI Pathway Database Neurotrophic factor-mediated Trk receptor signaling: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → FRS2 family/GRB2/SOS1 complex (GRB2-SOS1-FRS3_FRS2) (modification, collaborate)
  Kouhara et al., Cell 1997
  Evidence: mutant phenotype
• NCI Pathway Database Neurotrophic factor-mediated Trk receptor signaling: FRS2 family/GRB2/SOS1 complex (GRB2-SOS1-FRS3_FRS2) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
  Kouhara et al., Cell 1997
  Evidence: mutant phenotype
• 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)
  Haugh et al., J Biol Chem 1999
  Evidence: assay
• NCI Pathway Database Neurotrophic factor-mediated Trk receptor signaling: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → SH2B family/GRB2/SOS1 complex (GRB2-SOS1) (modification, collaborate)
  Qian et al., Neuron 1998
  Evidence: mutant phenotype, assay, other species
• NCI Pathway Database Insulin Pathway: Insulin Receptor/Insuli/IRS1/GRB2/SHC/Sos complex (INSR-INS-SHC1-SOS1-GRB2-IRS1) → HRAS/GTP complex (HRAS) (modification, activates) Wada et al., Endocrinology 1999, Sharma et al., Mol Endocrinol 2005, Pronk et al., Mol Cell Biol 1994, Sasaoka et al., J Biol Chem 1994, Myers et al., Mol Cell Biol 1994
  Evidence: assay
• NCI Pathway Database Insulin Pathway: Insulin Receptor/Insuli/IRS1/GRB2/SHC/Sos complex (INSR-INS-SHC1-SOS1-GRB2-IRS1) → HRAS/GDP complex (HRAS) (modification, activates) Wada et al., Endocrinology 1999, Sharma et al., Mol Endocrinol 2005, Pronk et al., Mol Cell Biol 1994, Sasaoka et al., J Biol Chem 1994, Myers et al., Mol Cell Biol 1994
  Evidence: assay
• Reactome Reaction: GRB2 → HRAS (reaction) Kainulainen et al., J Biol Chem 2000, Chesi et al., Blood 2001, Ronchetti et al., Oncogene 2001, Duronio et al., Proc Natl Acad Sci U S A 1992, Paez et al., Science 2004, Sordella et al., Science 2004, Shimamura et al., Cancer Res 2005, Roskoski et al., Biochem Biophys Res Commun 2005, Reber et al., Eur J Pharmacol 2006, Miyazawa et al., Exp Hematol 1991, Kunii et al., Cancer Res 2008, Byron et al., Cancer Res 2008, Cha et al., J Biol Chem 2009, Roidl et al., Oncogene 2010, Turner et al., Cancer Res 2010, Weiss et al., Sci Transl Med 2010, Dutt et al., PloS one 2011, Wesche et al., Biochem J 2011, Janes et al., Oncogene 1994, Satoh et al., Mol Cell Biol 1993, Chardin et al., Science 1993, Xie et al., J Biol Chem 1995, Sepp-Lorenzino et al., Oncogene 1996, Boriack-Sjodin et al., Nature 1998, Heldin et al., Biochim Biophys Acta 1998, Raffioni et al., J Biol Chem 1998
• WikiPathways Angiopoietin Like Protein 8 Regulatory Pathway: SOS1/SOS2/GRB2 → HRAS (activation)
• WikiPathways Interleukin-11 Signaling Pathway: GRB2 → HRAS (activation)
• WikiPathways Signaling Pathways in Glioblastoma: GRB2 → NRAS/KRAS/HRAS (mim-stimulation)
• WikiPathways p38 MAPK Signaling Pathway: SHC1/GRB2/RASGRF1 → HRAS (unknown)
• WikiPathways BDNF-TrkB Signaling: Complex of SHC1-GRB2-SOS1-GAB1-GAB2 → NRAS/KRAS/HRAS (activation)
• WikiPathways DNA Damage Response (only ATM dependent): Complex of GRB2-SOS1-SOS2 → HRAS/KRAS/NRAS (activation)

Protein-Protein interactions - manually collected from original source literature:

Studies that report less than 10 interactions are marked with *

• IRef Bind Interaction: Complex of GRB2-SOS1-HRAS Chardin et al., Science 1993
• IRef Hprd Interaction: HRAS — GRB2 (in vivo) Jeon et al., Biochem Biophys Res Commun 2001*
• IRef Ophid Interaction: GRB2 — HRAS (aggregation, interologs mapping) Brown et al., Bioinformatics 2005

Text-mined interactions from Literome

Schneider et al., Eur J Immunol 1995 (Second Messenger Systems) : T cell antigen CD28 binds to the GRB-2/SOS complex, regulators of p21ras
de Vries-Smits et al., Oncogene 1995 : This phosphorylation is delayed with respect to Shc-Grb2-mSOS complex formation and activation of p21ras
Byrne et al., Oncogene 1996 (Pheochromocytoma) : p21Ras activation by the guanine nucleotide exchange factor Sos, requires the Sos/Grb2 interaction and a second ligand dependent signal involving the Sos N-terminus ... To clarify the role of the Sos/Grb2 interaction in ligand stimulated p21Ras activation, we have utilised the observation that overexpression of the Sos C-terminal domain can effectively inhibit p21Ras dependent signalling in three different mammalian systems