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2016 ; 291
(12
): 6096-110
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gab.com Text
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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
#MMPMID26757814
Das A
; Fischer RS
; Pan D
; Waterman CM
J Biol Chem
2016[Mar]; 291
(12
): 6096-110
PMID26757814
show ga
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.
|Actin Cytoskeleton/metabolism
[MESH]
|Active Transport, Cell Nucleus
[MESH]
|Adaptor Proteins, Signal Transducing/*metabolism
[MESH]