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2016 ; 110
(11
): 2540-2550
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A Computational Model of YAP/TAZ Mechanosensing
#MMPMID27276271
Sun M
; Spill F
; Zaman MH
Biophys J
2016[Jun]; 110
(11
): 2540-2550
PMID27276271
show ga
In cell proliferation, stem cell differentiation, chemoresistance, and tissue
organization, the ubiquitous role of YAP/TAZ continues to impact our fundamental
understanding in numerous physiological and disease systems. YAP/TAZ is an
important signaling nexus integrating diverse mechanical and biochemical signals,
such as ECM stiffness, adhesion ligand density, or cell-cell contacts, and thus
strongly influences cell fate. Recent studies show that YAP/TAZ mechanical
sensing is dependent on RhoA-regulated stress fibers. However, current
understanding of YAP/TAZ remains limited due to the unknown interaction between
the canonical Hippo pathway and cell tension. Furthermore, the multiscale
relationship connecting adhesion signaling to YAP/TAZ activity through
cytoskeleton dynamics remains poorly understood. To identify the roles of key
signaling molecules in mechanical signal sensing and transduction, we present a,
to our knowledge, novel computational model of the YAP/TAZ signaling pathway.
This model converts extracellular-matrix mechanical properties to biochemical
signals via adhesion, and integrates intracellular signaling cascades associated
with cytoskeleton dynamics. We perform perturbations of molecular levels and
sensitivity analyses to predict how various signaling molecules affect YAP/TAZ
activity. Adhesion molecules, such as FAK, are predicted to rescue YAP/TAZ
activity in soft environments via the RhoA pathway. We also found that changes of
molecule concentrations result in different patterns of YAP/TAZ stiffness
response. We also investigate the sensitivity of YAP/TAZ activity to ECM
stiffness, and compare with that of SRF/MAL, which is another important regulator
of differentiation. In addition, the model shows that the unresolved synergistic
effect of YAP/TAZ activity between the mechanosensing and the Hippo pathways can
be explained by the interaction of LIM-kinase and LATS. Overall, our model
provides a, to our knowledge, novel platform for studying YAP/TAZ activity in the
context of integrating different signaling pathways. This platform can be used to
gain, to our knowledge, new fundamental insights into roles of key molecular and
mechanical regulators on development, tissue engineering, or tumor progression.
|*Computer Simulation
[MESH]
|*Models, Biological
[MESH]
|Actins/metabolism
[MESH]
|Adaptor Proteins, Signal Transducing/*metabolism
[MESH]
|Algorithms
[MESH]
|Cytoskeleton/metabolism
[MESH]
|Elasticity
[MESH]
|Extracellular Matrix/*metabolism
[MESH]
|Intracellular Signaling Peptides and Proteins/*metabolism
[MESH]
|Mechanotransduction, Cellular/*physiology
[MESH]
|Myelin and Lymphocyte-Associated Proteolipid Proteins/metabolism
[MESH]
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