Persistent cell motility requires transcriptional feedback of cytoskeletal – focal adhesion equilibrium by YAP/TAZ
Preprint posted on 15 February 2018 https://doi.org/10.1101/265744
Cell migration requires the coordination of actomyosin contraction, F-actin processing, and focal adhesion remodeling. The environment plays a key role, as cells interpret both chemical and mechanical signals to alter their behavior. These signals interface with the machinery that regulates tension, actin processing and focal adhesion turnover, and can also alter gene expression. But is there a role for transcription in directing cell migration? Can the environment-mediated changes in transcription influence cell behavior? These are the questions under debate in this preprint. Mason and colleagues uncover a feedback mechanism by which the mechanosensitive YAP/TAZ transcription factors affect cell migration. To model this process, they use endothelial colony forming cells (ECFCs), circulating endothelial progenitors that play a role in forming new vasculature during wound repair and development.
What are the key findings?
By using ECFC cells, the authors confirm that YAP/TAZ are mechanosensitive – they are capable of sensing both matrix stiffness and cell density, and become nuclear (and therefore active) in stiffer and less crowded environments.
Surprisingly, chemical inhibition of transcription or depletion of YAP/TAZ reduces the speed and directionality of migration. The effect is not due to reduced expression of cytoskeletal components, which generally have half-lives greater than the experimental time window and are found in excess, nor failure to initiate cell polarisation.
Instead, YAP/TAZ-depleted cells show increased anchorage to the matrix, and increased cytoskeletal prestress: a larger amount of actin stress fibers, greater number of focal adhesions and focal adhesion length, and greater amount of phosphorylated myosin light chain. This shows that YAP/TAZ activity is essential for motility in ECFC cells.
How is it that YAP/TAZ transcriptional activity alters cell behavior, if it is not related to cytoskeletal gene expression? Upon YAP/TAZ depletion, the authors identify a rapid increase in expression of NUAK2, a kinase which deactivates the myosin light chain phosphatase and therefore reduces actomyosin contractility. Abrogating NUAK2 expression in YAP/TAZ-depleted cells mostly rescues migration, focal adhesion size and the amount of stress fibers.
Does this apply in a more complex 3D system, when the endothelial progenitor cells have to organize and form new vasculature, and sense their environment? The authors’ data suggest that it does: when YAP/TAZ activity or levels are reduced, either in cells transplanted in vivo, or in aorta explant cultures, vascular sprouting was also reduced.
Why this is cool
As a non-cell mechanics person (I work on cell fate decisions in stem cells), I found this a really interesting study. It provides a mechanism by which cells can rapidly sense and respond to the environment, either as individuals or during collective cell migration.
YAP/TAZ have also been shown to coordinate cell fate decisions in different systems. For example, modulation of YAP/TAZ causes defects in branching morphogenesis in the developing lung and kidney1,2. It would be interesting to see whether in such systems YAP/TAZ were able to coordinate morphogenesis with cell fate specification. Furthermore, could the YAP/TAZ feedback system on the cytoskeleton also allow cells to collectively sense a preferred path of migration within matrices with varying stiffness?
- Reginensi, A., Enderle, L., Gregorieff, A., Johnson, R. L., Wrana, J. L. & McNeill, H. A critical role for NF2 and the Hippo pathway in branching morphogenesis. Nature Communications 7, 12309 (2016).
- Lin, C., Yao, E., Zhang, K., Jiang, X., Croll, S., Thompson-Peer, K. & Chuang, P.-T. YAP is essential for mechanical force production and epithelial cell proliferation during lung branching morphogenesis. eLife 6, 14665 (2017).
Posted on: 27 February 2018 , updated on: 6 March 2018Read preprint
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