Objective: Increased matrix stiffness is sensed by the collagen-binding receptor tyrosine kinase discoidin domain receptor 1 (DDR1). We have previously shown that DDR1 stimulates a positive feedback loop to increase its own expression in vascular smooth muscle cells (VSMCs). The transcriptional co-factors YAP/TAZ are stiffness sensing molecules that have not previously been investigated in DDR1 signaling. Here, we test the hypothesis that DDR1 signals through YAP/TAZ to auto-regulate its own expression.

Approach and Results: We used vascular smooth muscle cells (VSMCs) from wild-type and DDR1 knockout mice stimulated with collagen and/or substrates of different stiffness. We show that DDR1 controls YAP/TAZ nuclear localization and activity, whereas knockdown of YAP/TAZ attenuates DDR1 expression. In response to increased substrate stiffness, collagen stimulation, or RhoA activation, YAP/TAZ translocate to the nucleus and bind to chromatin. Finally, collagen stimulation promotes increased YAP/TAZ association with the Ddr1 promoter.

Conclusions: These findings reveal the mechanism by which DDR1 regulates YAP/TAZ activity which can then mediate positive feedback regulation of DDR1 expression by promoting transcription of the DDR1 gene.

目的：胶原结合受体酪氨酸激酶盘状结构域受体 1 (DDR1) 可感知基质硬度的增加。我们之前已经表明，DDR1 刺激正反馈回路以增加其在血管平滑肌细胞 (VSMC) 中的表达。转录辅助因子 YAP/TAZ 是以前未在 DDR1 信号传导中研究过的刚度感应分子。在这里，我们检验 DDR1 通过 YAP/TAZ 发出信号以自动调节其自身表达的假设。

方法和结果：我们使用来自野生型和 DDR1 敲除小鼠的血管平滑肌细胞 (VSMC)，这些小鼠用胶原蛋白和/或不同硬度的底物刺激。我们表明 DDR1 控制 YAP/TAZ 核定位和活动，而 YAP/TAZ 的敲低会减弱 DDR1 的表达。为响应增加的底物硬度、胶原蛋白刺激或 RhoA 激活，YAP/TAZ 易位至细胞核并与染色质结合。最后，胶原蛋白刺激促进了增加的 YAP/TAZ 与Ddr1启动子的关联。

结论：这些发现揭示了 DDR1 调节 YAP/TAZ 活性的机制，进而可以通过促进 DDR1 基因的转录来介导 DDR1 表达的正反馈调节。