YAP Nuclear Localization in the Absence of Cell-Cell Contact Is Mediated by a Filamentous Actin-dependent, Myosin II- and Phospho-YAP-independent Pathway during Extracellular Matrix Mechanosensing
Autor: | Robert S. Fischer, Duojia Pan, Clare M. Waterman, Arupratan Das |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Active Transport Cell Nucleus Cell Cycle Proteins macromolecular substances Biology Mechanotransduction Cellular Biochemistry Filamentous actin Contractility Mice 03 medical and health sciences Cell Line Tumor Cell Adhesion medicine Animals Humans Phosphorylation Mechanotransduction Cytoskeleton Molecular Biology Cells Cultured Adaptor Proteins Signal Transducing Cell Nucleus Myosin Type II YAP-Signaling Proteins Cell Biology Phosphoproteins Actin cytoskeleton Extracellular Matrix Cell biology Actin Cytoskeleton Cell nucleus 030104 developmental biology medicine.anatomical_structure Protein Processing Post-Translational Nuclear localization sequence |
Zdroj: | Journal of Biological Chemistry. 291:6096-6110 |
ISSN: | 0021-9258 |
Popis: | Cell-cell contact inhibition and the mechanical environment of cells have both been shown to regulate YAP nuclear localization to modulate cell proliferation. Changes in cellular contractility by genetic, pharmacological, and matrix stiffness perturbations regulate YAP nuclear localization. However, because contractility and F-actin organization are interconnected cytoskeletal properties, it remains unclear which of these distinctly regulates YAP localization. Here we show that in the absence of cell-cell contact, actomyosin contractility suppresses YAP phosphorylation at Ser(112), however, neither loss of contractility nor increase in YAP phosphorylation is sufficient for its nuclear exclusion. We find that actin cytoskeletal integrity is essential for YAP nuclear localization, and can override phosphoregulation or contractility-mediated regulation of YAP nuclear localization. This actin-mediated regulation is conserved during mechanotransduction, as substrate compliance increased YAP phosphorylation and reduced cytoskeletal integrity leading to nuclear exclusion of both YAP and Ser(P)(112)-YAP. These data provide evidence for two actin-mediated pathways for YAP regulation; one in which actomyosin contractility regulates YAP phosphorylation, and a second that involves cytoskeletal integrity-mediated regulation of YAP nuclear localization independent of contractility. We suggest that in non-contact inhibited cells, this latter mechanism may be important in low stiffness regimes, such as may be encountered in physiological environments. |
Databáze: | OpenAIRE |
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