title: Heparanase enhances nerve-growth-factor-induced PC12 cell neuritogenesis via the p38 MAPK pathway.
abstract: Heparanase is involved in the cleavage of the HS (heparan sulfate) chain of HSPGs (HS proteoglycans) and hence participates in remodelling of the ECM (extracellular matrix) and BM (basement membrane). In the present study we have shown that NGF (nerve growth factor) promoted nuclear enrichment of EGR1 (early growth response 1), a transcription factor for heparanase, and markedly induced heparanase expression in rat adrenal pheochromocytoma (PC12) cells. K252a, an antagonist of the NGF receptor TrkA (tyrosine kinase receptor A), decreased heparanase protein expression induced by NGF in PC12 cells. Suramin, a heparanase inhibitor, decreased heparanase in PC12 cells and blocked NGF-induced PC12 neuritogenesis. Stable overexpression of heparanase activated p38 MAPK (mitogen-activated protein kinase) by phosphorylation and enhanced the neurite outgrowth induced by NGF, whereas knock down of heparanase impaired this process. However, overexpression of latent pro-heparanase with a Y156A mutation still led to enhanced NGF-induced neurite outgrowth and increased p38 MAPK phosphorylation. Inhibition of p38 MAPK by SB203580 suppressed the promotion of NGF-induced neuritogenesis by the wild-type and mutant heparanase. The impaired differentiation by knock down of heparanase could be restored by transfection of wild-type or mutant heparanase in PC12 cells. The results of the present study suggest that heparanase, at least in the non-enzymatic form, may promote NGF-induced neuritogenesis via the p38 MAPK pathway.
authors.affiliation: Glycochemistry and Glycobiology Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hengxiang
authors.initials: H
authors.lastname: Cui
authors.forename: Chenghao
authors.initials: C
authors.lastname: Shao
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Wenjie
authors.initials: W
authors.lastname: Yu
authors.forename: Jianping
authors.initials: J
authors.lastname: Fang
authors.forename: Weishi
authors.initials: W
authors.lastname: Yu
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Kan
authors.initials: K
authors.lastname: Ding
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D005966:Glucuronidase / Q000037:antagonists & inhibitors; D026121:Indole Alkaloids / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D020917:Receptor, trkA / Q000037:antagonists & inhibitors; D013498:Suramin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*; D000099175:Heparanase
chemical_list: D002227:Carbazoles; D005966:Glucuronidase; D026121:Indole Alkaloids; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D013498:Suramin; D048051:p38 Mitogen-Activated Protein Kinases; D000099175:Heparanase; C049985:staurosporine aglycone