Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2013, PMID: 23504323

Characterization of heparanase-induced phosphatidylinositol 3-kinase-AKT activation and its integrin dependence.

Riaz, Anjum; Ilan, Neta; Vlodavsky, Israel; Li, Jin-Ping; Johansson, Staffan

Heparanase functions as a heparan sulfate-degrading enzyme and as a ligand for an unidentified signaling receptor(s). Here, several reactions involved in the activation of the PI3K-AKT pathway by latent heparanase were characterized. Protein suppression using specific siRNAs revealed that heparanase-induced phosphorylation of AKT at Ser-473 was RICTOR-mTOR-dependent, whereas ILK and PAK1/2 were dispensable. p110α was the PI3K catalytic isoform preferred by heparanase for AKT activation and cell proliferation because the p110α inhibitor YM024 blocked these processes. Heparanase-induced AKT phosphorylation was low in mouse embryonic fibroblast cells expressing a RAS interaction-defective p110α compared with wild type cells, indicating that RAS has an important role in the PI3K-AKT activation. The response to heparanase was also inefficient in suspension cultures of several cell lines, suggesting a requirement of integrins in this pathway. Adhesion via either αVβ3 or α5β1 promoted heparanase-induced AKT phosphorylation, and a stronger effect was seen when both integrins were engaged. Simultaneous inhibition of FAK and PYK2 using a chemical inhibitor, or suppression of their expression, inhibited heparanase-induced AKT activation and cell proliferation. Stimulation of cells with heparanase enhanced their resistance against oxidative stress- or growth factor starvation-induced apoptosis. These results demonstrate that there is an intimate cross-talk between the heparanase receptor(s) and integrins during induction of the prosurvival PI3K-AKT pathway by heparanase.

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Text Mining Data

3-Kinase-AKT → Heparanase: " Characterization of Heparanase induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence "

Phosphatidylinositol 3-Kinase-AKT → Heparanase: " Characterization of Heparanase induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence "

AKT → RICTOR-mTOR: " Protein suppression using specific siRNAs revealed that heparanase induced phosphorylation of AKT at Ser-473 was RICTOR-mTOR dependent , whereas ILK and PAK1/2 were dispensable "

AKT → RICTOR-mTOR: " Protein suppression using specific siRNAs revealed that heparanase induced phosphorylation of AKT at Ser-473 was RICTOR-mTOR dependent , whereas ILK and PAK1/2 were dispensable "

AKT → heparanase: " Protein suppression using specific siRNAs revealed that heparanase induced phosphorylation of AKT at Ser-473 was RICTOR-mTOR dependent, whereas ILK and PAK1/2 were dispensable "

AKT → Heparanase: " Heparanase induced AKT phosphorylation was low in mouse embryonic fibroblast cells expressing a RAS interaction-defective p110a compared with wild type cells, indicating that RAS has an important role in the PI3K-AKT activation "

AKT → heparanase: " Adhesion via either aVß3 or a5ß1 promoted heparanase induced AKT phosphorylation, and a stronger effect was seen when both integrins were engaged "

AKT → heparanase: " Simultaneous inhibition of FAK and PYK2 using a chemical inhibitor, or suppression of their expression, inhibited heparanase induced AKT activation and cell proliferation "

AKT → PYK2: " Simultaneous inhibition of FAK and PYK2 using a chemical inhibitor, or suppression of their expression, inhibited heparanase induced AKT activation and cell proliferation "

Manually curated Databases

No curated data.