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首页> 外文学位 >Annexin A2 heterotetramer in monocyte invasiveness.
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Annexin A2 heterotetramer in monocyte invasiveness.

机译：Annexin A2异四聚体在单核细胞侵袭中的作用。

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摘要

Generation of plasmin is central to cell movement during wound healing, tumor metastasis, and inflammation, and is accelerated when plasminogen binds to cell surface receptors bearing lysine at their carboxy-terminus. The identity of the plasminogen receptor(s) responsible for regulating plasmin generation at the cell surface is currently unclear. In this study we found that the candidate plasminogen receptor, annexin A2 heterotetramer, accelerates the generation of plasmin by tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA), and that this acceleration is dependent upon lysine residues at the carboxy-terminus of the S100A10 subunit of the heterotetramer. Physiological concentrations of plasma carboxypeptidases were capable of abrogating the effect on plasmin generation, by removal of both the ultimate and penultimate lysine residues from S100A10, suggesting a possible mechanism of regulating plasmin formation in vivo. It was found that S100A10 expression was induced in the monocytoid cell lines, THP-1 and U937, by high cell culture density, which was dependent upon de novo protein synthesis. Increased cell surface expression of S100A10 was induced upon differentiation of THP-1 cells by exposure to phorbol 12-myristate 13-acetate, interferon gamma, fibronectin, and 1alpha, 25-dihydroxyvitamin D3 and correlated with an increase in cellular plasminogen binding. Annexin A2 heterotetramer localized to discrete regions of the surface of a subpopulation of cells after polarization. This distribution overlapped to a great degree with that of the uPA receptor, which is known to redistribute to the leading edge of polarized cells. Importantly, plasminogen was also found to localize to these discrete membrane regions and also largely colocalized with S100A10. Specific downregulation of S100A10 expression by small interfering RNA led to a decrease in extracellular levels of both S100A10 and annexin A2, as well as a decrease in the rate of plasminogen activation on the surface of THP-1 cells. In addition, invasion of both THP-1 cells and K562 cells through physiological extracellular matrix was inhibited by siRNA-mediated reduction of S100A10 expression. Thus the current work establishes that S100A10 is a regulated cell surface protein that is directly involved in cellular plasmin production and contributes to the invasiveness of monocytoid cells.
机译：纤溶酶的生成对于伤口愈合，肿瘤转移和炎症过程中的细胞运动至关重要，并且当纤溶酶原结合至在羧基末端带有赖氨酸的细胞表面受体时，纤溶酶的生成就会加速。目前尚不清楚负责调节细胞表面纤溶酶生成的纤溶酶原受体的身份。在这项研究中，我们发现候选纤溶酶原受体膜联蛋白A2异四聚体通过组织型纤溶酶原激活物（tPA）和尿激酶纤溶酶原激活物（uPA）促进纤溶酶的生成，并且这种加速取决于羧基上的赖氨酸残基。异四聚体的S100A10亚基的末端。通过从S100A10去除最终和倒数第二个赖氨酸残基，血浆羧肽酶的生理浓度能够消除对纤溶酶生成的影响，提示可能在体内调节纤溶酶形成。发现单核细胞系THP-1和U937通过高细胞培养密度诱导了S100A10表达，这取决于从头蛋白的合成。通过暴露于佛波醇12-肉豆蔻酸酯13-乙酸酯，干扰素γ，纤连蛋白和1α，25-二羟基维生素D3诱导THP-1细胞分化时，可诱导S100A10细胞表面表达增加，并与细胞纤溶酶原结合增加有关。膜联蛋白A2异四聚体在极化后定位于细胞亚群表面的离散区域。这种分布在很大程度上与uPA受体重叠，已知它会重新分布到极化细胞的前缘。重要的是，还发现纤溶酶原位于这些不连续的膜区域，并且在很大程度上与S100A10共定位。小干扰RNA对S100A10表达的特异性下调导致S100A10和膜联蛋白A2的细胞外水平降低，以及THP-1细胞表面的纤溶酶原激活率降低。另外，siRNA介导的S100A10表达的降低抑制了THP-1细胞和K562细胞通过生理细胞外基质的侵袭。因此，当前的工作确定了S100A10是一种受调节的细胞表面蛋白，直接参与细胞纤溶酶的产生，并有助于单核细胞的侵袭性。

著录项

  • 作者

    Fogg, Darin Kurtis.;

  • 作者单位

    University of Calgary (Canada).;

  • 授予单位 University of Calgary (Canada).;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 195 p.
  • 总页数 195
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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