YAP nuclear localization in the absence of cell-cell contact is mediated by a filamentous actin-dependent, Myosin IIand Phospho-YAP-independent pathway during extracellular matrix mechanosensing

Arupratan Das, Robert S. Fischer, Duojia Pan, Clare M. Waterman

Research output: Contribution to journalArticle

62 Scopus citations


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 suppressesYAPphosphorylation at Ser112, 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.

Original languageEnglish (US)
Pages (from-to)6096-6110
Number of pages15
JournalJournal of Biological Chemistry
Issue number12
Publication statusPublished - Mar 18 2016


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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