Syndecan-4 tunes cell mechanics by activating the kindlin-integrin-RhoA pathway
Syndecan-4 tunes cell mechanics by activating the kindlin-integrin-RhoA pathway
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DOI：
10.1038/s41563-019-0567-1
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发表时间：
2020-01-06
期刊：
影响因子：
41.2
通讯作者：
Hernandez, Armando E. del Rio
中科院分区：
文献类型：
--
作者：
Chronopoulos, Antonios;Thorpe, Stephen D.;Hernandez, Armando E. del Rio
细胞对局部张力的反应机制表明，syndecan-4与EGFR协同作用，引发机械信号级联反应，通过PI 3 K/kindlin-2介导的整合素激活，导致适应性细胞硬化，过去几十年的广泛研究已经确定整合素是使细胞能够响应外部机械信号的主要跨膜受体。我们在这里揭示了一种机制，syndecan-4调谐细胞力学响应局部张力通过协调的机械化学信号反应，涉及激活其他两个受体：表皮生长因子受体和β 1整合素。多配体蛋白聚糖-4上的张力以PI 3 K依赖性方式诱导kindlin-2/β 1整联蛋白/RhoA轴的细胞范围活化。此外，多配体蛋白聚糖-4介导的细胞-细胞外基质界面的张力是yes相关蛋白激活所必需的。多配体蛋白聚糖-4上的细胞外张力触发胞质结构域中的构象变化，其可变区对于对力的机械适应是必不可少的，从而促进多配体蛋白聚糖-4/α-辅肌动蛋白/F-肌动蛋白分子支架在珠粘附处的组装。这种多配体蛋白聚糖-4的机械转导途径应该对更广泛的机械生物学领域有直接的影响。
A mechanism of cell response to localized tension shows that syndecan-4 synergizes with EGFR to elicit a mechanosignalling cascade that leads to adaptive cell stiffening through PI3K/kindlin-2 mediated integrin activation.Extensive research over the past decades has identified integrins to be the primary transmembrane receptors that enable cells to respond to external mechanical cues. We reveal here a mechanism whereby syndecan-4 tunes cell mechanics in response to localized tension via a coordinated mechanochemical signalling response that involves activation of two other receptors: epidermal growth factor receptor and beta 1 integrin. Tension on syndecan-4 induces cell-wide activation of the kindlin-2/beta 1 integrin/RhoA axis in a PI3K-dependent manner. Furthermore, syndecan-4-mediated tension at the cell-extracellular matrix interface is required for yes-associated protein activation. Extracellular tension on syndecan-4 triggers a conformational change in the cytoplasmic domain, the variable region of which is indispensable for the mechanical adaptation to force, facilitating the assembly of a syndecan-4/alpha-actinin/F-actin molecular scaffold at the bead adhesion. This mechanotransduction pathway for syndecan-4 should have immediate implications for the broader field of mechanobiology.