Heparanase induces endothelial cell migration via protein kinase B/Akt activation
Heparanase induces endothelial cell migration via protein kinase B/Akt activation
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DOI：
10.1074/jbc.m400554200
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发表时间：
2004-05-28
影响因子：
4.8
通讯作者：
Ilan, N
中科院分区：
文献类型：
--
作者：
Gingis-Velitski, S;Zetser, A;Ilan, N
肝素酶是一种哺乳动物内切糖苷酶，能在特定的链内位点降解硫酸肝素(HS)。血液传播的中性粒细胞、巨噬细胞、肥大细胞和血小板显示出被认为储存在特定颗粒中的肝素酶活性。去颗粒的乙酰肝素酶与转移的肿瘤细胞和免疫系统的激活细胞的外渗有关。通过改变细胞外基质的组成和结构完整性，或间接通过释放HS结合的促炎细胞因子和趋化因子，炎症刺激或血小板激活反应中的脱颗粒和肝素酶释放将直接促进细胞外渗。我们推测，除了这种间接作用外，释放的乙酰肝素酶还可能局部影响和激活邻近细胞，如内皮细胞。在此，我们提供了65 kDa潜伏性乙酰肝素酶加入内皮细胞可增强Akt信号的证据。肝素酶介导的Akt磷酸化与其酶活性或细胞膜HS蛋白多糖的存在无关，并可被肝素增强。此外，乙酰肝素酶的加入刺激了磷脂酰肌醇3-激酶依赖的内皮细胞的迁移和侵袭。这些结果首次表明，乙酰肝素酶激活内皮细胞，并直接引发血管生成反应。这种作用似乎是由尚未确定的乙酰肝素酶受体介导的。
Heparanase is a mammalian endoglycosidase that degrades heparan sulfate (HS) at specific intra-chain sites. Blood-borne neutrophils, macrophages, mast cells, and platelets exhibit heparanase activity that is thought to be stored in specific granules. The degranulated heparanase is implicated in extravasation of metastatic tumor cells and activated cells of the immune system. Degranulation and heparanase release in response to an inflammatory stimulus or platelet activation would facilitate cellular extravasation directly, by altering the composition and structural integrity of the extracellular matrix, or indirectly, by releasing HS-bound proinflammatory cytokines and chemokines. We hypothesized that in addition to such indirect effect, the released heparanase may also locally affect and activate neighboring cells such as endothelial cells. Here, we provide evidence that addition of the 65-kDa latent heparanase to endothelial cells enhances Akt signaling. Heparanase-mediated Akt phosphorylation was independent of its enzymatic activity or the presence of cell membrane HS proteoglycans and was augmented by heparin. Moreover, addition of heparanase stimulated phosphatidylinositol 3-kinase-dependent endothelial cell migration and invasion. These results suggest, for the first time, that heparanase activates endothelial cells and elicits angiogenic responses directly. This effect appears to be mediated by as yet unidentified heparanase receptor.