State Key Laboratory of Medical Genomics at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Hypertension, Shanghai Key Laboratory of Vascular Biology, 200025, Shanghai, China.
Mol Immunol. 2010 Aug;47(14):2405-10. doi: 10.1016/j.molimm.2010.03.015. Epub 2010 Jun 2.
Plasmin is recognized as a potent signaling molecule in particular human monocytes, inducing a pro-inflammatory response. Recently, the annexin A2 heterotetramer, a plasmin receptor, was described at the surface of the human monocytes. Plasmin is initiating a signaling in monocytes by cleavage of the annexin A2 subunit of the receptor and the apparent dissociation of the heterotetramer at the surface of cell. However, the exact mechanism linking this dissociation and the activation of the intracellular pathway remains undefined. Here we report that the molecular mechanism of monocyte activation may rely on a new molecule containing the amino-terminal end of annexin A2 (A2NP) generated by plasmin cleavage of its receptor - the annexin A2 heterotetramer - as in vitro A2NP is able to mimic plasmin activation of the tyrosine kinase JAK1 and STAT3 and the subsequent increase in expression and release of monocyte/macrophage chemoattractant protein (MCP)-1, which is a major chemokine released by monocytes/macrophages. Additionally, we show that plasmin-induced the phosphorylation of STAT3 is similar to that of IL-6 and IL-31, and protease-activated receptor 1 does not affect plasmin-induced cytokine MCP-1 release in human monocytes. Finally, our data demonstrate that plasmin triggers the production of MCP-1 in macrophages in vivo. Thus, A2NP generated by plasmin cleavage of the annexin A2 heterotetramer could serve as a new proteolytically generated signaling molecule activating an associated transmembrane co-receptor, such as type I cytokine receptors.
纤溶酶被认为是一种有效的信号分子，特别是在人类单核细胞中，可诱导促炎反应。最近，纤溶酶受体 annexin A2 异四聚体在人类单核细胞表面被描述。纤溶酶通过切割受体的 annexin A2 亚基并使细胞表面的异四聚体明显解离，从而在单核细胞中引发信号转导。然而，将这种解离与细胞内途径的激活联系起来的确切机制仍未确定。在这里，我们报告单核细胞激活的分子机制可能依赖于一种新的分子，该分子含有 annexin A2 的氨基末端（A2NP），由其受体 - annexin A2 异四聚体的纤溶酶切割产生，因为体外 A2NP 能够模拟纤溶酶激活酪氨酸激酶 JAK1 和 STAT3，以及随后单核细胞/巨噬细胞趋化蛋白（MCP）-1 的表达和释放增加，MCP-1 是单核细胞/巨噬细胞释放的主要趋化因子。此外，我们表明，纤溶酶诱导的 STAT3 磷酸化与 IL-6 和 IL-31 相似，并且蛋白酶激活受体 1 不会影响人单核细胞中纤溶酶诱导的细胞因子 MCP-1 释放。最后，我们的数据表明，纤溶酶在体内触发巨噬细胞产生 MCP-1。因此，由 annexin A2 异四聚体的纤溶酶切割产生的 A2NP 可以作为一种新的蛋白水解生成的信号分子，激活相关的跨膜共受体，如 I 型细胞因子受体。
