A Computational Model of YAP/TAZ Mechanosensing

📝 Abstract

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 still remains limited due to the unknown interaction between the canonical Hippo pathway and cell tension. To identify the roles of key signaling molecules in mechanical signal sensing and transduction, we present a novel computational model of the YAP/TAZ signaling pathway. This model converts ECM mechanical properties to biochemical signals via adhesion, and integrates intracellular signaling cascades associated with cytoskeleton dynamics. Adhesion molecules, such as FAK, are predicted to rescue YAP/TAZ activity in soft environments via the RhoA pathway. We found that changes of molecule concentrations result in different pattern of YAP/TAZ stiffness response. We also investigate the sensitivity of YAP/TAZ activity to ECM stiffness. 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 LIMK and LATS. Overall, our model provides a novel platform for studying YAP/TAZ activity in the context of integrating different signaling pathways. This platform can be used to gain new fundamental insights into roles of key molecular and mechanical regulators on development, tissue engineering or tumor progression.

💡 Analysis

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 still remains limited due to the unknown interaction between the canonical Hippo pathway and cell tension. To identify the roles of key signaling molecules in mechanical signal sensing and transduction, we present a novel computational model of the YAP/TAZ signaling pathway. This model converts ECM mechanical properties to biochemical signals via adhesion, and integrates intracellular signaling cascades associated with cytoskeleton dynamics. Adhesion molecules, such as FAK, are predicted to rescue YAP/TAZ activity in soft environments via the RhoA pathway. We found that changes of molecule concentrations result in different pattern of YAP/TAZ stiffness response. We also investigate the sensitivity of YAP/TAZ activity to ECM stiffness. 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 LIMK and LATS. Overall, our model provides a novel platform for studying YAP/TAZ activity in the context of integrating different signaling pathways. This platform can be used to gain new fundamental insights into roles of key molecular and mechanical regulators on development, tissue engineering or tumor progression.

📄 Content

1 A Computational Model of YAP/TAZ Mechanosensing
Keywords: pathway model, Hippo pathway, synergy, adhesion, cytoskeleton dynamics Meng Sun1, Fabian Spill2,1,* and Muhammad H. Zaman1,3,*

Department of Biomedical Engineering, 44 Cummington Street, Boston MA 02215, USA 2. Department of Mechanical Engineering, Massachusetts Institute of Technology,
77 Massachusetts Avenue, Cambridge, MA 02139, USA 3. Howard Hughes Medical Institute, Boston University, Boston, MA 02215, USA

*Corresponding author

E-mail: zaman@bu.edu (MHZ) and fspill@mit.edu (FS)

2 Abstract 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 still remains limited due to the unknown interaction between the canonical Hippo pathway and cell tension. Furthermore, the multi-scale 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 novel computational model of the YAP/TAZ signaling pathway. This model converts ECM 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 pattern 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 LIMK and LATS. Overall, our model provides a novel platform for studying YAP/TAZ activity in the context of integrating different signaling pathways. This platform can be used to gain new fundamental insights into roles of key molecular and mechanical regulators on development, tissue engineering or tumor progression.

Introduction One of the fundamental questions of cell biology is how cells organize themselves into complex tissues and three-dimensional structures. Multiple signals transmitted from neighboring cells and extracellular matrix (ECM) environment are integrated into intracellular pathways and guide cellular behavior, such as proliferation, migration and differentiation. Recent years have seen enormous progress in uncovering the roles of the transcriptional regulator YAP/TAZ, which controls organ size by integrating both physical and biochemical cues (1–3). First discovered in Drosophila, deregulation of YAP or its paralog TAZ has been found to lead to massive organ overgrowth (4). YAP/TAZ has been shown to have significant roles in regulating remarkable biological properties in development, tissue homeostasis and cancer. The activation of the most studied upstream cascade of YAP/TAZ, the canonical Hippo pathway, is mainly dependent on cell density sensing, and results in the activation of the core Hippo kinase LATS which regulates YAP/TAZ localization (1). Despite these ubiquitous roles, the mechanism of YAP/TAZ localization regulation is still poorly understood (2). One of the models suggests that activated LATS in the Hippo core complex prevents YAP/TAZ from entering the nucleus via phosphorylation, involved with further cytosolic sequestration through binding with molecules such as 14-3-3, or degradation (2, 5). YAP/TAZ lacks of a nuclear localization signal (NLS), and the machinery for their nuclear import/export is unknown (2). Thus it is an important question to investigate which molecules are involved in this nuclear transport regulation, such as RanGTPases (6). After translocating into the nucleus, YAP/TAZ acts as a transcriptional co-activator with several transcription factors and thus targets various genes, including TEAD (2). More recently, attention has been focused on mechanical regulators of YAP/TAZ activity beyond the core Hippo pathway (7). For instance, increasing stiffness of the external environment (8), or exerting static stretch (7) has been found to promote YAP/TAZ nuclear translocation and its downstream transcript

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