Melittin Modulates Keratinocyte Function through P2 Receptor-dependent ADAM Activation
Melittin Modulates Keratinocyte Function through P2 Receptor-dependent ADAM Activation
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DOI：
10.1074/jbc.m112.362756
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发表时间：
2012-07-06
影响因子：
4.8
通讯作者：
Reiss, Karina
中科院分区：
文献类型：
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作者：
Sommer, Anselm;Fries, Anja;Reiss, Karina
蜂毒肽是蜂毒的主要成分，是一种具有广谱生物学特性的两亲性阳离子肽，被认为是抗炎和抗癌剂。它调节多种细胞功能，但其潜在机制尚不清楚。在这里，我们报告蜂毒肽激活去整合素样金属蛋白酶（亚当斯）和下游事件可能有助于由肽引起的生物学效应。蜂毒肽刺激人中性粒细胞、内皮细胞和小鼠成纤维细胞中ADAM 10和ADAM 17底物的蛋白水解。在人HaCaT角质形成细胞中，蜂毒肽诱导粘附分子E-钙粘蛋白脱落和TGF-α释放，这伴随着EGF受体的反式激活和ERK 1/2磷酸化。随后是功能性后果，如角质形成细胞增殖增加和细胞迁移增强。有证据表明，ATP的释放和嘌呤能P2受体的激活参与蜂毒素诱导的ADAM激活。在ATP酶或P2受体拮抗剂存在下，E-钙粘蛋白脱落和EGFR磷酸化呈剂量依赖性降低。在HEK细胞的实验中强调了P2受体的参与，HEK细胞缺乏P2 X7受体，并且在用该受体转染后显示出对蜂毒肽刺激的反应显著增加。我们的研究提供了新的见解蜂毒肽的功能，这应该是感兴趣的，特别是在其作为抗炎或抗癌剂的潜在用途的背景下的机制。
Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-alpha, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent.