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 β1 integrin. Tension on syndecan-4 induces cell-wide activation of the kindlin-2/β1 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/α-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.

过去几十年的广泛研究已确定整合素是使细胞能够对外部机械信号作出反应的主要跨膜受体。我们在这里揭示了一种机制，即 syndecan-4 通过协调的机械化学信号反应来调节细胞力学以响应局部张力，该反应涉及激活另外两种受体：表皮生长因子受体和 β1 整合素。syndecan-4 上的张力以 PI3K 依赖性方式诱导 kindlin-2/β1 整合素/RhoA 轴的全细胞激活。此外，yes 相关蛋白激活需要 syndecan-4 介导的细胞-细胞外基质界面张力。syndecan-4上的细胞外张力触发细胞质结构域的构象变化，其可变区域对于机械适应力是必不可少的，促进syndecan-4 / α-肌动蛋白/ F-肌动蛋白分子支架在珠子粘附处的组装。syndecan-4 的这种机械转导途径应该对更广泛的机械生物学领域产生直接影响。