| First Author | Ngai D | Year | 2022 |
| Journal | Matrix Biol | Volume | 110 |
| Pages | 129-140 | PubMed ID | 35562016 |
| Mgi Jnum | J:326139 | Mgi Id | MGI:7293953 |
| Doi | 10.1016/j.matbio.2022.05.004 | Citation | Ngai D, et al. (2022) Stiffness-responsive feedback autoregulation of DDR1 expression is mediated by a DDR1-YAP/TAZ axis. Matrix Biol 110:129-140 |
| abstractText | 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. |
