Gene interactions and pathways from curated databases and text-mining
Mol Biol Cell 2006, PMID: 16760434

Phosphorylation of focal adhesion kinase (FAK) on Ser732 is induced by rho-dependent kinase and is essential for proline-rich tyrosine kinase-2-mediated phosphorylation of FAK on Tyr407 in response to vascular endothelial growth factor.

Le Boeuf, Fabrice; Houle, François; Sussman, Mark; Huot, Jacques

Focal adhesion kinase (FAK) is phosphorylated on tyrosine and serine residues after cell activation. In the present work, we investigated the relationship between tyrosine and serine phosphorylation of FAK in promoting endothelial cell migration in response to vascular endothelial growth factor (VEGF). We found that VEGF induces the activation of the Rho-dependent kinase (ROCK) downstream from vascular endothelial growth factor receptor (VEGFR) 2. In turn, activated ROCK directly phosphorylates FAK on Ser732. Proline-rich tyrosine kinase-2 (Pyk2) is also activated in response to VEGF. Its activation requires the clustering of integrin alphavbeta3 and triggers directly the phosphorylation of Tyr407 within FAK, an event necessary for cell migration. Interestingly, ROCK-mediated phosphorylation of Ser732 is essential for Pyk2-dependent phosphorylation of Tyr407, because the latter is abrogated in cells expressing a FAK mutant that is nonphosphorylatable on Ser732. We suggest that VEGF elicits the activation of the VEGFR2-ROCK pathway, leading to phosphorylation of Ser732 within FAK. In turn, phosphorylation of Ser732 would change the conformation of FAK, making it accessible to Pyk2 activated in response to its association with integrin beta3. Then, activated Pyk2 triggers the phosphorylation of FAK on Tyr407, promoting cell migration.

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Text Mining Data

ROCK → Rho: " We found that VEGF induces the activation of the Rho dependent kinase ( ROCK ) downstream from vascular endothelial growth factor receptor ( VEGFR) 2 "

ROCK → VEGF: " We found that VEGF induces the activation of the Rho dependent kinase ( ROCK ) downstream from vascular endothelial growth factor receptor ( VEGFR) 2 "

Proline-rich tyrosine kinase-2 (Pyk2) → VEGF: " Proline-rich tyrosine kinase-2 (Pyk2) is also activated in response to VEGF "

Tyr407 → Pyk2: " Interestingly, ROCK mediated phosphorylation of Ser732 is essential for Pyk2 dependent phosphorylation of Tyr407 , because the latter is abrogated in cells expressing a FAK mutant that is nonphosphorylatable on Ser732 "

Manually curated Databases

  • IRef Hprd Interaction: PTK2 — PTK2B (in vitro)
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: Hsp90 (HSP90AA1) → alphav/beta3 Integrin/Vitronectin complex (VTN-ITGAV-ITGB3) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: Hsp90 (HSP90AA1) → VEGFR2 (dimer)/VEGFA (dimer) complex (KDR-VEGFA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: Hsp90 (HSP90AA1) → VEGFR2 (dimer)/VEGFA (dimer)/Hsp90/alphav/beta3 Integrin/Vitronectin complex (KDR-VEGFA-HSP90AA1-VTN-ITGAV-ITGB3) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: alphav/beta3 Integrin/Vitronectin complex (VTN-ITGAV-ITGB3) → VEGFR2 (dimer)/VEGFA (dimer) complex (KDR-VEGFA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: alphav/beta3 Integrin/Vitronectin complex (VTN-ITGAV-ITGB3) → VEGFR2 (dimer)/VEGFA (dimer)/Hsp90/alphav/beta3 Integrin/Vitronectin complex (KDR-VEGFA-HSP90AA1-VTN-ITGAV-ITGB3) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: VEGFR2 (dimer)/VEGFA (dimer) complex (KDR-VEGFA) → VEGFR2 (dimer)/VEGFA (dimer)/Hsp90/alphav/beta3 Integrin/Vitronectin complex (KDR-VEGFA-HSP90AA1-VTN-ITGAV-ITGB3) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: ROCK1 (ROCK1) → FAK (PTK2) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: alphav/beta3 Integrin/VEGFR2/VEGFA (dimer) complex (KDR-VEGFA-ITGAV-ITGB3) → PYK2 (PTK2B) (modification, activates)
    Evidence: assay
  • NCI Pathway Database Integrins in angiogenesis: Hsp90 (HSP90AA1) → ROCK (ROCK1) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: Hsp90 (HSP90AA1) → alphav/beta3 Integrin complex (ITGAV-ITGB3) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: Hsp90 (HSP90AA1) → VEGF/Rho/ROCK/alphav/beta3 Integrin complex (KDR-VEGFA-HSP90AA1-RHOA-ROCK1-ITGAV-ITGB3) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: Hsp90 (HSP90AA1) → Vitronectin (VTN) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: Hsp90 (HSP90AA1) → VEGFR2 homodimer/VEGFA homodimer complex (KDR-VEGFA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: Hsp90 (HSP90AA1) → RhoA (RHOA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: ROCK (ROCK1) → alphav/beta3 Integrin complex (ITGAV-ITGB3) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: ROCK (ROCK1) → VEGF/Rho/ROCK/alphav/beta3 Integrin complex (KDR-VEGFA-HSP90AA1-RHOA-ROCK1-ITGAV-ITGB3) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: ROCK (ROCK1) → Vitronectin (VTN) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: ROCK (ROCK1) → VEGFR2 homodimer/VEGFA homodimer complex (KDR-VEGFA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: ROCK (ROCK1) → RhoA (RHOA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: alphav/beta3 Integrin complex (ITGAV-ITGB3) → VEGF/Rho/ROCK/alphav/beta3 Integrin complex (KDR-VEGFA-HSP90AA1-RHOA-ROCK1-ITGAV-ITGB3) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: alphav/beta3 Integrin complex (ITGAV-ITGB3) → Vitronectin (VTN) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: alphav/beta3 Integrin complex (ITGAV-ITGB3) → VEGFR2 homodimer/VEGFA homodimer complex (KDR-VEGFA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: alphav/beta3 Integrin complex (ITGAV-ITGB3) → RhoA (RHOA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: VEGF/Rho/ROCK/alphav/beta3 Integrin complex (KDR-VEGFA-HSP90AA1-RHOA-ROCK1-ITGAV-ITGB3) → VEGFR2 homodimer/VEGFA homodimer complex (KDR-VEGFA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: VEGF/Rho/ROCK/alphav/beta3 Integrin complex (KDR-VEGFA-HSP90AA1-RHOA-ROCK1-ITGAV-ITGB3) → RhoA (RHOA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: Vitronectin (VTN) → VEGFR2 homodimer/VEGFA homodimer complex (KDR-VEGFA) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: Vitronectin (VTN) → RhoA (RHOA) (modification, activates)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: VEGFR2 homodimer/VEGFA homodimer complex (KDR-VEGFA) → RhoA (RHOA) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: FAK/Paxillin complex (PTK2-PXN) → Paxillin (PXN) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: FAK/Paxillin complex (PTK2-PXN) → FAK (PTK2) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: Paxillin (PXN) → FAK (PTK2) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: VEGF/Rho/ROCK/alphav/beta3 Integrin complex (KDR-VEGFA-HSP90AA1-RHOA-ROCK1-ITGAV-ITGB3) → FAK (PTK2) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database Signaling events mediated by VEGFR1 and VEGFR2: PYK2 (PTK2B) → FAK (PTK2) (modification, activates)
    Evidence: assay
  • NCI Pathway Database Integrins in angiogenesis: FAK/Paxillin complex (PTK2-PXN) → Paxillin (PXN) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: FAK/Paxillin complex (PTK2-PXN) → FAK (PTK2) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: Paxillin (PXN) → FAK (PTK2) (modification, collaborate)
    Evidence: assay, physical interaction
  • NCI Pathway Database Integrins in angiogenesis: alphav/beta3 Integrin/VEGFR2/VEGFA (dimer) complex (KDR-VEGFA-ITGAV-ITGB3) → VEGFR2 homodimer/VEGFA homodimer complex (KDR-VEGFA) (modification, collaborate)
  • NCI Pathway Database Integrins in angiogenesis: alphav/beta3 Integrin/VEGFR2/VEGFA (dimer) complex (KDR-VEGFA-ITGAV-ITGB3) → alphav/beta3 Integrin complex (ITGAV-ITGB3) (modification, collaborate)
  • NCI Pathway Database Integrins in angiogenesis: VEGFR2 homodimer/VEGFA homodimer complex (KDR-VEGFA) → alphav/beta3 Integrin complex (ITGAV-ITGB3) (modification, collaborate)
  • NCI Pathway Database Integrins in angiogenesis: PYK2 (PTK2B) → FAK (PTK2) (modification, activates)
    Evidence: mutant phenotype, assay, physical interaction
  • Reactome Reaction: VEGFA → SHB (reaction)
  • Reactome Reaction: PTK2 → ITGB3 (reaction)
  • Reactome Reaction: SRC → SHB (indirect_complex)
  • Reactome Reaction: ITGB3 → SRC (reaction)
  • Reactome Reaction: ITGAV → KDR (reaction)
  • Reactome Reaction: SRC → KDR (reaction)
  • Reactome Reaction: ROCK1 → VEGFA (reaction)
  • Reactome Reaction: PTK2 → ITGAV (reaction)
  • Reactome Reaction: SRC → VEGFA (indirect_complex)
  • Reactome Reaction: PTK2 → KDR (reaction)
  • Reactome Reaction: SRC → ROCK2 (reaction)
  • Reactome Reaction: ITGAV → SRC (reaction)
  • Reactome Reaction: KDR → KDR (reaction)
  • Reactome Reaction: PTK2 → PTK2B (reaction)
  • Reactome Reaction: ROCK2 → VEGFA (reaction)
  • Reactome Reaction: RHOA → VEGFA (reaction)
  • Reactome Reaction: PTK2 → VEGFA (reaction)
  • Reactome Reaction: PTK2 → RHOA (reaction)
  • Reactome Reaction: SRC → ROCK1 (reaction)
  • Reactome Reaction: ITGB3 → VEGFA (reaction)
  • Reactome Reaction: KDR → ROCK2 (reaction)
  • Reactome Reaction: SRC → VEGFA (reaction)
  • Reactome Reaction: HSP90AA1 → RHOA (reaction)
  • Reactome Reaction: PTK2 → HSP90AA1 (indirect_complex)
  • Reactome Reaction: HSP90AA1 → VEGFA (reaction)
  • Reactome Reaction: PTK2 → ROCK2 (reaction)
  • Reactome Reaction: HSP90AA1 → SRC (direct_complex)
  • Reactome Reaction: HSP90AA1 → KDR (reaction)
  • Reactome Reaction: HSP90AA1 → ITGB3 (reaction)
  • Reactome Reaction: ITGB3 → KDR (reaction)
  • Reactome Reaction: KDR → ROCK1 (reaction)
  • Reactome Reaction: ITGAV → SHB (reaction)
  • Reactome Reaction: PTK2B → SRC (reaction)
  • Reactome Reaction: HSP90AA1 → SHB (indirect_complex)
  • Reactome Reaction: KDR → VEGFA (reaction)
  • Reactome Reaction: ITGB3 → SHB (reaction)
  • Reactome Reaction: HSP90AA1 → ROCK1 (reaction)
  • Reactome Reaction: PTK2B → VEGFA (reaction)
  • Reactome Reaction: RHOA → SRC (reaction)
  • Reactome Reaction: VEGFA → VEGFA (reaction)
  • Reactome Reaction: ITGAV → VEGFA (reaction)
  • Reactome Reaction: PTK2 → ROCK1 (reaction)
  • Reactome Reaction: PTK2B → HSP90AA1 (reaction)
  • Reactome Reaction: ROCK1 → SHB (reaction)
  • Reactome Reaction: SRC → KDR (indirect_complex)
  • Reactome Reaction: HSP90AA1 → KDR (indirect_complex)
  • Reactome Reaction: PTK2B → KDR (reaction)
  • Reactome Reaction: RHOA → KDR (reaction)
  • Reactome Reaction: ROCK2 → SHB (reaction)
  • Reactome Reaction: PTK2 → SRC (indirect_complex)
  • Reactome Reaction: RHOA → SHB (reaction)
  • Reactome Reaction: KDR → SHB (reaction)
  • Reactome Reaction: HSP90AA1 → VEGFA (indirect_complex)
  • Reactome Reaction: HSP90AA1 → ITGAV (reaction)
  • Reactome Reaction: HSP90AA1 → ROCK2 (reaction)
  • Reactome Reaction: PTK2B → SHB (reaction)
In total, 76 gene pairs are associated to this article in curated databases