Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2001, PMID: 11551902

Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398 plays distinct roles for binding GTPase-activating protein and Nck and is essential for inhibiting insulin-stimulated activation of Ras and Akt.

Wick, M J; Dong, L Q; Hu, D; Langlais, P; Liu, F

A GTPase-activating protein (GAP)-associated 60-kDa protein has been found to undergo rapid tyrosine phosphorylation in response to insulin stimulation. However, whether this protein is a direct in vivo substrate for the insulin receptor (IR) tyrosine kinase and whether the tyrosine phosphorylation plays a role in insulin signaling remain to be established. Here we show that the insulin-stimulated tyrosine phosphorylation of the GAP-associated protein, now identified as p62(dok), is inhibited by Grb10, an adaptor protein that binds directly to the kinase domain of the IR, both in vitro and in cells. Replacing Tyr(362) and Tyr(398) with phenylalanine greatly decreased the IR-catalyzed p62(dok) tyrosine phosphorylation in vitro, suggesting that these two residues are the major IR-mediated phosphorylation sites. However, mutations at Tyr(362) and Tyr(398) only partially blocked insulin-stimulated p62(dok) tyrosine phosphorylation in cells, indicating that p62(dok) is also a target for other cellular tyrosine kinase(s) in addition to the IR. Replacing Tyr(362) with phenylalanine abolished the interaction between p62(dok) and Nck. Mutations at Tyr(362/398) of p62(dok) disrupted the interaction between p62(dok) and GAP and decreased the inhibitory effect of p62(dok) on the insulin-stimulated activation of Ras and Akt, but not mitogen-activated protein kinase. Furthermore, the inhibitory effect of p62(dok) on Akt phosphorylation could be blocked by coexpression of a constitutively active Ras. Taken together, our findings indicate that p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway.

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

Text Mining Data

p62dok → Insulin receptor: " Insulin receptor mediated p62dok tyrosine phosphorylation at residues 362 and 398 plays distinct roles for binding GTPase activating protein and Nck and is essential for inhibiting insulin stimulated activation of Ras and Akt "

Akt → insulin: " Insulin receptor mediated p62dok tyrosine phosphorylation at residues 362 and 398 plays distinct roles for binding GTPase activating protein and Nck and is essential for inhibiting insulin stimulated activation of Ras and Akt "

p62(dok) → insulin: " However, mutations at Tyr ( 362 ) and Tyr ( 398 ) only partially blocked insulin stimulated p62(dok) tyrosine phosphorylation in cells, indicating that p62(dok) is also a target for other cellular tyrosine kinase ( s ) in addition to the IR "

mitogen activated protein kinase → insulin: " Mutations at Tyr ( 362/398 ) of p62(dok) disrupted the interaction between p62(dok) and GAP and decreased the inhibitory effect of p62(dok) on the insulin stimulated activation of Ras and Akt, but not mitogen activated protein kinase "

Akt → insulin: " Mutations at Tyr ( 362/398 ) of p62(dok) disrupted the interaction between p62(dok) and GAP and decreased the inhibitory effect of p62(dok) on the insulin stimulated activation of Ras and Akt , but not mitogen activated protein kinase "

Akt — p62(dok): " Furthermore, the inhibitory effect of p62(dok) on Akt phosphorylation could be blocked by coexpression of a constitutively active Ras "

Manually curated Databases

  • IRef Biogrid Interaction: DOK1 — INSR (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: NCK1 — DOK1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: DOK1 — RASA1 (physical association, affinity chromatography technology)
  • IRef Hprd Interaction: DOK1 — INSR (in vitro)
  • IRef Hprd Interaction: DOK1 — INSR (in vivo)
  • IRef Hprd Interaction: GRB10 — DOK1 (in vitro)
  • IRef Hprd Interaction: GRB10 — DOK1 (in vivo)
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/SHC/GRB2/Sos1 complex (INSR-INS-SHC1-GRB2-SOS1) → HRAS/GTP complex (HRAS) (modification, activates)
    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)
    Evidence: assay
  • NCI Pathway Database Insulin Pathway: HRAS/GTP complex (HRAS) → HRAS/GDP complex (HRAS) (modification, collaborate)
    Evidence: assay
  • NCI Pathway Database Insulin Pathway: RasGAP (RASA1) → p62DOK/RasGAP complex (DOK1-RASA1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Insulin Pathway: RasGAP (RASA1) → p62DOK (DOK1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Insulin Pathway: RasGAP (RASA1) → NCK1 (NCK1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Insulin Pathway: RasGAP (RASA1) → p62DOK/RasGAP complex (DOK1-NCK1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Insulin Pathway: p62DOK/RasGAP complex (DOK1-RASA1) → p62DOK (DOK1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Insulin Pathway: p62DOK/RasGAP complex (DOK1-RASA1) → NCK1 (NCK1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Insulin Pathway: p62DOK/RasGAP complex (DOK1-RASA1) → p62DOK/RasGAP complex (DOK1-NCK1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Insulin Pathway: p62DOK (DOK1) → NCK1 (NCK1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Insulin Pathway: p62DOK (DOK1) → p62DOK/RasGAP complex (DOK1-NCK1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Insulin Pathway: NCK1 (NCK1) → p62DOK/RasGAP complex (DOK1-NCK1) (modification, collaborate)
    Evidence: physical interaction
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/SHC/GRB10 complex (INSR-INS-SHC1-GRB10) → p62DOK (DOK1) (modification, inhibits)
    Evidence: assay
  • NCI Pathway Database Insulin Pathway: Insulin Receptor/Insulin/SHC/GRB10 complex (INSR-INS-SHC1-GRB10) → Insulin Receptor/Insulin/SHC/GRB2/Sos1 complex (INSR-INS-SHC1-GRB2-SOS1) (modification, inhibits)
    Evidence: assay
In total, 34 gene pairs are associated to this article in curated databases