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The role of integrin-dependent cell matrix adhesion in muscle development.

机译：整合素依赖性细胞基质粘附在肌肉发育中的作用。

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摘要

Cell adhesion is essential to cell motility and tissue integrity and is regulated by the Integrin family of transmembrane receptors. Integrin binds to ligand extracellularly and provide anchor to the intracellular cytoskeleton via adhesion scaffolding proteins. In order to link cell to the surrounding matrix Integrin needs to be activated. Intracellular activation signals induce perturbations in Integrin cytoplasmic domain that are translated into a conformational change in extracellular region for high affinity ligand binding. Integrin engagement by matrix, in turn, triggers the assembly of adhesion complexes. Such early adhesions promote cytoskeletal organization with subsequent contractile activity that exerts forces against initial Integrin-matrix adhesions. In response to force, Integrin strengthens the interaction with matrix through its clustering and successive recruitment of additional adhesion components. These bidirectional regulatory loops mediated by such interactions are largely dependent on the unique function of Integrin adhesion components.;Collectively, our results point to a dual role for Zasp as a structural scaffold. First it regulates Integrin adhesion to the extracellular matrix by interacting with the head domain of Talin at the myotendinous junctions. Second, Zasp controls sarcomere assembly by tethering the presarcomeric alpha-Actinin component to the tail domain of Talin. Zasp finding as a crucial adhesion component provides further insights on the mechanism underlying Integrin-mediated adhesion.;We demonstrate a novel role for the PDZ/LIM domain protein Zasp as a core component of Integrin adhesions. Specifically, Zasp colocalizes with Integrins at focal adhesion in cultured cells and myotendinous junctions in Drosophila embryos. In both cases elimination of Zasp modifies Integrin function causing consequently defects in cell spreading and muscle attachment. Zasp supports Integrin adhesion to the extracellular matrix that is required to withstand tensile forces exerted during cell spreading and muscle contraction. Furthermore, we found that the distribution of Zasp in muscle Z-lines is essential to orchestrate the cross-linking of alpha-Actinin and Actin filaments. Disruption of Zasp leads to loss of muscle cytoarchitecture, pointing to a larger role for Zasp in sarcomere assembly. Finally, we demonstrate that Zasp, in addition to alpha-Actinin, physically interacts with the Integrin- and Actin-bound cytoskeletal protein Talin.
机译：细胞粘附对于细胞运动和组织完整性至关重要，并受跨膜受体整合素家族的调节。整联蛋白在细胞外与配体结合，并通过粘附支架蛋白为细胞内细胞骨架提供锚定。为了将细胞链接到周围的基质，整联蛋白需要被激活。细胞内激活信号诱导整联蛋白胞质域中的扰动，其被翻译为高亲和力配体结合的胞外区域的构象变化。基质的整联蛋白的结合反过来触发粘附复合物的组装。这种早期的粘附促进细胞骨架的组织，并具有随后的收缩活性，从而产生抵抗初始整联蛋白-基质粘附的力。响应于力，整联蛋白通过其聚集和连续补充其他粘附成分来增强与基质的相互作用。这些相互作用介导的双向调节环很大程度上取决于整联蛋白粘附组分的独特功能。总的来说，我们的研究结果表明Zasp作为结构支架具有双重作用。首先，它通过与肌钙蛋白连接处的塔林头部结构域相互作用，调节整联蛋白对细胞外基质的粘附。其次，Zasp通过将肌节前α-肌动蛋白成分束缚到塔林的尾部区域来控制肌节的组装。 Zasp的发现作为至关重要的粘附成分，提供了有关整合素介导的粘附机制的进一步见解。；我们证明了PDZ / LIM域蛋白Zasp作为整合素粘附的核心成分的新作用。具体而言，Zasp与整合素在培养细胞的粘着斑处和果蝇胚胎的肌腱接头处共定位。在这两种情况下，消除Zasp都会改变整联蛋白的功能，从而导致细胞扩散和肌肉附着的缺陷。 Zasp支持整联蛋白对细胞外基质的粘附，这是承受细胞扩散和肌肉收缩过程中施加的拉力所必需的。此外，我们发现Zasp在肌肉Z线中的分布对于编排α-肌动蛋白丝和肌动蛋白丝的交联至关重要。 Zasp的破坏导致肌肉细胞结构的丧失，这表明Zasp在肌节组装中的作用更大。最后，我们证明Zasp，除了α-肌动蛋白外，还与整合素和肌动蛋白结合的细胞骨架蛋白Talin发生物理相互作用。

著录项

  • 作者

    Jani, Klodiana.;

  • 作者单位

    McGill University (Canada).;

  • 授予单位 McGill University (Canada).;
  • 学科 Cellular biology.;Molecular biology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 168 p.
  • 总页数 168
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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