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

被引：106

作者：

Ege, Nil ^{[1
,2
]}

Dowbaj, Anna M. ^{[1
]}

Jiang, Ming ^{[3
]}

Howell, Michael ^{[3
]}

Hooper, Steven ^{[1
]}

Foster, Charles ^{[4
]}

Jenkins, Robert P. ^{[1
]}

Sahai, Erik ^{[1
]}

机构：

[1] Francis Crick Inst, Tumour Cell Biol Lab, London NW1 1AT, England

[2] UCL, Cell & Dev Biol Dept, London WC1E 6BT, England

[3] Francis Crick Inst, High Throughput Screening, London NW1 1AT, England

[4] Francis Crick Inst, Transcript Lab, London NW1 1AT, England

来源：

CELL SYSTEMS | 2018年 / 6卷 / 06期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

CANCER-ASSOCIATED FIBROBLASTS; HIPPO SIGNALING PATHWAY; FLUORESCENCE RECOVERY; GROWTH-CONTROL; ORGAN SIZE; MECHANOTRANSDUCTION PATHWAY; SUBCELLULAR-LOCALIZATION; TYROSINE PHOSPHORYLATION; TISSUE-GROWTH; LIVING CELLS;

D O I：

10.1016/j.cels.2018.05.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 photo-bleaching 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.

引用

页码：692 / +

页数：30

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