Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence
2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 17, 12366-12375 p.Article in journal (Refereed) Published
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. p110 alpha was the PI3K catalytic isoform preferred by heparanase for AKT activation and cell proliferation because the p110 alpha inhibitor YM024 blocked these processes. Heparanase-induced AKT phosphorylation was low in mouse embryonic fibroblast cells expressing a RAS interaction-defective p110 alpha 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 alpha V beta 3 or alpha 5 beta 1 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 crosstalk between the heparanase receptor(s) and integrins during induction of the prosurvival PI3K-AKT pathway by heparanase.
Place, publisher, year, edition, pages
2013. Vol. 288, no 17, 12366-12375 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-200681DOI: 10.1074/jbc.M112.435172ISI: 000318157600067OAI: oai:DiVA.org:uu-200681DiVA: diva2:624769