Stiffness-responsive feedback autoregulation of DDR1 expression is mediated by a DDR1-YAP/TAZ axis

Matrix Biol. 2022 Jun:110:129-140. doi: 10.1016/j.matbio.2022.05.004. Epub 2022 May 11.

Abstract

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.

Keywords: Collagen; Discoidin domain receptor 1; Smooth muscle; Stiffness; YAP/TAZ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / metabolism
  • Animals
  • Discoidin Domain Receptor 1 / genetics
  • Discoidin Domain Receptor 1 / metabolism*
  • Feedback
  • Homeostasis
  • Mice
  • Myocytes, Smooth Muscle* / metabolism
  • Transcription Factors / genetics
  • YAP-Signaling Proteins / metabolism

Substances

  • Transcription Factors
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Acyltransferases
  • tafazzin protein, mouse
  • Ddr1 protein, mouse
  • Discoidin Domain Receptor 1