Heparanase enhances nerve-growth-factor-induced PC12 cell neuritogenesis via the p38 MAPK pathway
Heparanase enhances nerve-growth-factor-induced PC12 cell neuritogenesis via the p38 MAPK pathway
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DOI：
10.1042/bj20110167
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发表时间：
2011-12-01
影响因子：
4.1
通讯作者：
Ding, Kan
中科院分区：
文献类型：
--
作者：
Cui, Hengxiang;Shao, Chenghao;Ding, Kan
乙酰肝素酶参与HSPG（HS蛋白聚糖）的HS（硫酸乙酰肝素）链的切割，因此参与ECM（细胞外基质）和BM（基底膜）的重塑。在本研究中，我们发现NGF（神经生长因子）促进了类肝素酶转录因子EGFR 1（早期生长反应1）的核富集，并显着诱导大鼠肾上腺嗜铬细胞瘤（PC 12）细胞中类肝素酶的表达。NGF受体TrkA（tyrosine kinase receptor A）的拮抗剂K252a可降低NGF诱导的PC12细胞乙酰肝素酶蛋白表达。肝素酶抑制剂苏拉明可降低PC12细胞中的肝素酶，并阻断NGF诱导的PC12神经突形成。乙酰肝素酶的稳定过表达通过磷酸化激活p38 MAPK（丝裂原活化蛋白激酶），并增强NGF诱导的神经突起生长，而乙酰肝素酶的敲低则削弱了这一过程。然而，过表达具有Y156A突变的潜在乙酰肝素酶原仍然导致增强的NGF诱导的神经突生长和增加的p38 MAPK磷酸化。SB203580对p38 MAPK的抑制抑制了野生型和突变型乙酰肝素酶对NGF诱导的轴突发生的促进作用。在PC12细胞中转染野生型或突变型乙酰肝素酶可以恢复乙酰肝素酶敲低导致的分化受损。本研究的结果表明，乙酰肝素酶，至少在非酶的形式，可能会促进神经生长因子诱导的轴突通过p38 MAPK途径。
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 nonenzymatic form, may promote NGF-induced neuritogenesis via the p38 MAPK pathway.