Gene interactions and pathways from curated databases and text-mining
Blood 2004, PMID: 12920017

The phosphoserine-585-dependent pathway of the GM-CSF/IL-3/IL-5 receptors mediates hematopoietic cell survival through activation of NF-kappaB and induction of bcl-2.

Guthridge, Mark A; Barry, Emma F; Felquer, Fernando A; McClure, Barbara J; Stomski, Frank C; Ramshaw, Hayley; Lopez, Angel F

We have recently identified a novel mechanism of hematopoietic cell survival that involves site-specific serine phosphorylation of the common beta subunit (beta(c)) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors. However, the downstream components of this pathway are not known, nor is its relationship to survival signals triggered by tyrosine phosphorylation of the receptor clear. We have now found that phosphorylation of Ser585 of beta(c) in response to GM-CSF recruited 14-3-3 and phosphatidyl inositol 3-OH kinase (PI 3-kinase) to the receptor, while phosphorylation of the neighboring Tyr577 within this "viability domain" promoted the activation of both Src homology and collagen (Shc) and Ras. These are independent processes as demonstrated by the intact reactivity of phosphospecific anti-Ser585 and anti-Tyr577 antibodies on the cytotoxic T-lymphocyte-ecotrophic retroviral receptor neomycin (CTL-EN) mutants beta(c)Tyr577Phe and beta(c)Ser585Gly, respectively. Importantly, while mutants in which either Ser585 (beta(c)Ser585Gly) or all tyrosines (beta(c)F8) were substituted showed a defect in Akt phosphorylation, nuclear factor kappaB (NF-kappaB) activation, bcl-2 induction, and cell survival, the mutant beta(c)Tyr577Phe was defective in Shc, Ras, and extracellular signal-related kinase (ERK) activation, but supported CTL-EN cell survival in response to GM-CSF. These results demonstrate that both serine and tyrosine phosphorylation pathways play a role in hematopoietic cell survival, are initially independent of each other, and converge on NF-kappaB to promote bcl-2 expression.

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Text Mining Data

Src homology and collagen (Shc) → Tyr577: " We have now found that phosphorylation of Ser585 of beta ( c ) in response to GM-CSF recruited 14-3-3 and phosphatidyl inositol 3-OH kinase ( PI 3-kinase ) to the receptor, while phosphorylation of the neighboring Tyr577 within this `` viability domain '' promoted the activation of both Src homology and collagen (Shc) and Ras "

Manually curated Databases

  • NCI Pathway Database GMCSF-mediated signaling events: GMCSF/GMR alpha/CSF2RB/JAK2 (dimer) complex (CSF2RB-JAK2-CSF2-CSF2RA) → YWHAZ (YWHAZ) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database GMCSF-mediated signaling events: GMCSF/GMR alpha/CSF2RB/JAK2 (dimer) complex (CSF2RB-JAK2-CSF2-CSF2RA) → GMCSF/GMR alpha/CSF2RB/JAK2 (dimer)/YWHAZ complex (CSF2RB-JAK2-YWHAZ-CSF2-CSF2RA) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database GMCSF-mediated signaling events: YWHAZ (YWHAZ) → GMCSF/GMR alpha/CSF2RB/JAK2 (dimer)/YWHAZ complex (CSF2RB-JAK2-YWHAZ-CSF2-CSF2RA) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database GMCSF-mediated signaling events: GMCSF/GMR alpha/CSF2RB/JAK2 (dimer)/YWHAZ/SHC/PI3K complex (CSF2RB-JAK2-YWHAZ-SHC1-PIK3CA-PIK3R1-CSF2-CSF2RA) → GMCSF/GMR alpha/CSF2RB/JAK2 (dimer)/YWHAZ/SHC complex (CSF2RB-JAK2-YWHAZ-SHC1-CSF2-CSF2RA) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database GMCSF-mediated signaling events: GMCSF/GMR alpha/CSF2RB/JAK2 (dimer)/YWHAZ/SHC/PI3K complex (CSF2RB-JAK2-YWHAZ-SHC1-PIK3CA-PIK3R1-CSF2-CSF2RA) → PI3K complex (PIK3CA-PIK3R1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database GMCSF-mediated signaling events: GMCSF/GMR alpha/CSF2RB/JAK2 (dimer)/YWHAZ/SHC complex (CSF2RB-JAK2-YWHAZ-SHC1-CSF2-CSF2RA) → PI3K complex (PIK3CA-PIK3R1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database GMCSF-mediated signaling events: GMCSF/GMR alpha/CSF2RB/JAK2 (dodecamer)/SHC/GRB2/SOS1 complex (CSF2RB-JAK2-SHC1-CSF2-CSF2RA-GRB2-SOS1) → None (modification, activates)
    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/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, activates)
    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)
    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) → None (modification, activates)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database GMCSF-mediated signaling events: None → RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database GMCSF-mediated signaling events: None → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database GMCSF-mediated signaling events: None → None (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database GMCSF-mediated signaling events: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database GMCSF-mediated signaling events: RAS family/GDP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → None (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database GMCSF-mediated signaling events: RAS family/GTP complex (HRAS_KRAS_HRAS_KRAS_NRAS) → None (modification, collaborate)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database GMCSF-mediated signaling events: MEK1-2-active (MAP2K1/MAP2K2) → MEK1-2 (MAP2K1/MAP2K2) (modification, collaborate)
  • NCI Pathway Database GMCSF-mediated signaling events: MEK1-2 (MAP2K1/MAP2K2) → RAF1 (RAF1) (modification, collaborate)
  • NCI Pathway Database GMCSF-mediated signaling events: Erk1-2 (MAPK3/MAPK1) → MEK1-2-active (MAP2K1/MAP2K2) (modification, collaborate)
    Evidence: genetic interaction
  • NCI Pathway Database GMCSF-mediated signaling events: Erk1-2 (MAPK3/MAPK1) → Erk1-2-active (MAPK3/MAPK1) (modification, collaborate)
    Evidence: genetic interaction
  • NCI Pathway Database GMCSF-mediated signaling events: MEK1-2-active (MAP2K1/MAP2K2) → Erk1-2-active (MAPK3/MAPK1) (modification, activates)
    Evidence: genetic interaction
In total, 86 gene pairs are associated to this article in curated databases