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Gene interactions and pathways from curated databases and text-mining
Blood 2005, PMID: 15705783

Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways.

Tong, Wei; Zhang, Jing; Lodish, Harvey F

Erythropoietin (Epo), along with its receptor EpoR, is the principal regulator of red cell development. Upon Epo addition, the EpoR signaling through the Janus kinase 2 (JAK2) activates multiple pathways including Stat5, phosphoinositide-3 kinase (PI-3K)/Akt, and p42/44 mitogen-activated protein kinase (MAPK). The adaptor protein Lnk is implicated in cytokine receptor signaling. Here, we showed that Lnk-deficient mice have elevated numbers of erythroid progenitors, and that splenic erythroid colony-forming unit (CFU-e) progenitors are hypersensitive to Epo. Lnk(-/-) mice also exhibit superior recovery after erythropoietic stress. In addition, Lnk deficiency resulted in enhanced Epo-induced signaling pathways in splenic erythroid progenitors. Conversely, Lnk overexpression inhibits Epo-induced cell growth in 32D/EpoR cells. In primary culture of fetal liver cells, Lnk overexpression inhibits Epo-dependent erythroblast differentiation and induces apoptosis. Lnk blocks 3 major signaling pathways, Stat5, Akt, and MAPK, induced by Epo in primary erythroblasts. In addition, the Lnk Src homology 2 (SH2) domain is essential for its inhibitory function, whereas the conserved tyrosine near the C-terminus and the pleckstrin homology (PH) domain of Lnk are not critical. Furthermore, wild-type Lnk, but not the Lnk SH2 mutant, becomes tyrosine-phosphorylated following Epo administration and inhibits EpoR phosphorylation and JAK2 activation. Hence, Lnk, through its SH2 domain, negatively modulates EpoR signaling by attenuating JAK2 activation, and regulates Epo-mediated erythropoiesis.

Diseases/Pathways annotated by Medline MESH: MAP Kinase Signaling System
Document information provided by NCBI PubMed

Text Mining Data

JAK2 → Epo: " Lnk inhibits erythropoiesis and Epo dependent JAK2 activation and downstream signaling pathways "

Manually curated Databases

  • NCI Pathway Database EPO signaling pathway: SHP1 (PTPN6) → EPO/EPOR (dimer) complex (EPO-EPOR) (modification, inhibits)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: SHP1 (PTPN6) → LNK (SH2B3) (modification, inhibits)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: SHP1 (PTPN6) → EPO/EPOR (dimer)/JAK2/SOCS3 complex (EPO-EPOR-JAK2-SOCS3) (modification, inhibits)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: SHP1 (PTPN6) → EPO/EPOR (dimer)/JAK2 complex (EPO-EPOR-JAK2) (modification, inhibits)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: SHP1 (PTPN6) → JAK2 (JAK2) (modification, inhibits)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: SHP1 (PTPN6) → SOCS3 (SOCS3) (modification, inhibits)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: EPO/EPOR (dimer) complex (EPO-EPOR) → LNK (SH2B3) (modification, collaborate)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: EPO/EPOR (dimer) complex (EPO-EPOR) → EPO/EPOR (dimer)/JAK2/SOCS3 complex (EPO-EPOR-JAK2-SOCS3) (modification, collaborate)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: EPO/EPOR (dimer) complex (EPO-EPOR) → EPO/EPOR (dimer)/JAK2 complex (EPO-EPOR-JAK2) (modification, collaborate)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: EPO/EPOR (dimer) complex (EPO-EPOR) → JAK2 (JAK2) (modification, collaborate)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: EPO/EPOR (dimer) complex (EPO-EPOR) → SOCS3 (SOCS3) (modification, collaborate)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: LNK (SH2B3) → EPO/EPOR (dimer)/JAK2/SOCS3 complex (EPO-EPOR-JAK2-SOCS3) (modification, inhibits)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: LNK (SH2B3) → EPO/EPOR (dimer)/JAK2 complex (EPO-EPOR-JAK2) (modification, inhibits)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: LNK (SH2B3) → JAK2 (JAK2) (modification, inhibits)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: LNK (SH2B3) → SOCS3 (SOCS3) (modification, inhibits)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: EPO/EPOR (dimer)/JAK2/SOCS3 complex (EPO-EPOR-JAK2-SOCS3) → EPO/EPOR (dimer)/JAK2 complex (EPO-EPOR-JAK2) (modification, collaborate)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: EPO/EPOR (dimer)/JAK2/SOCS3 complex (EPO-EPOR-JAK2-SOCS3) → JAK2 (JAK2) (modification, collaborate)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: EPO/EPOR (dimer)/JAK2/SOCS3 complex (EPO-EPOR-JAK2-SOCS3) → SOCS3 (SOCS3) (modification, collaborate)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: EPO/EPOR (dimer)/JAK2 complex (EPO-EPOR-JAK2) → JAK2 (JAK2) (modification, collaborate)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: EPO/EPOR (dimer)/JAK2 complex (EPO-EPOR-JAK2) → SOCS3 (SOCS3) (modification, collaborate)
    Evidence: assay, other species
  • NCI Pathway Database EPO signaling pathway: JAK2 (JAK2) → SOCS3 (SOCS3) (modification, collaborate)
    Evidence: assay, other species
In total, 19 gene pairs are associated to this article in curated databases