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Cell Syst. 2018 Jun 27;6(6):692-708.e13. doi: 10.1016/j.cels.2018.05.006. Epub 2018 Jun 18.

Quantitative Analysis Reveals that Actin and Src-Family Kinases Regulate Nuclear YAP1 and Its Export.

Author information

1
Tumour Cell Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Cell and Developmental Biology Department, University College London, London WC1E 6BT, UK.
2
Tumour Cell Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
3
High Throughput Screening, The Francis Crick Institute, London NW1 1AT, UK.
4
Transcription Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
5
Tumour Cell Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK. Electronic address: robert.jenkins@crick.ac.uk.
6
Tumour Cell Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK. Electronic address: erik.sahai@crick.ac.uk.

Abstract

The transcriptional regulator YAP1 is critical for the pathological activation of fibroblasts. In normal fibroblasts, YAP1 is located in the cytoplasm, while in activated cancer-associated fibroblasts, it is nuclear and promotes the expression of genes required for pro-tumorigenic functions. Here, we investigate the dynamics of YAP1 shuttling in normal and activated fibroblasts, using EYFP-YAP1, quantitative photobleaching methods, and mathematical modeling. Imaging of migrating fibroblasts reveals the tight temporal coupling of cell shape change and altered YAP1 localization. Both 14-3-3 and TEAD binding modulate YAP1 shuttling, but neither affects nuclear import. Instead, we find that YAP1 nuclear accumulation in activated fibroblasts results from Src and actomyosin-dependent suppression of phosphorylated YAP1 export. Finally, we show that nuclear-constrained YAP1, upon XPO1 depletion, remains sensitive to blockade of actomyosin function. Together, these data place nuclear export at the center of YAP1 regulation and indicate that the cytoskeleton can regulate YAP1 within the nucleus.

KEYWORDS:

Src-family kinases; YAP1; actomyosin cytoskeleton; fibroblast; mathematical modeling; nuclear export; photobleaching

PMID:
29909276
PMCID:
PMC6035388
DOI:
10.1016/j.cels.2018.05.006
[Indexed for MEDLINE]
Free PMC Article

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