Dataset Information

Role of ?-Catenin and its mechanosensing properties in regulating Hippo/YAP-dependent tissue growth.

ABSTRACT: ?-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila ?-Catenin (?-Cat) in growth regulation of the wing epithelium. We found that different ?-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. ?-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a negative regulator of Hippo signaling to AJs but also through a mechanism independent of Ajuba recruitment to AJs. Both mechanosensory regions of ?-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for ?-Cat function in the wing, individual M domains (M1, M2, M3) have opposing effects on growth regulation. In particular, M1 limits Ajuba recruitment. Loss of M1 causes Ajuba hyper-recruitment to AJs, promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin is not responsible for this effect. Moreover, disruption of mechanosensing of the ?-Cat ABD affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that ?-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.

SUBMITTER: Sarpal R

PROVIDER: S-EPMC6863567 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Role of α-Catenin and its mechanosensing properties in regulating Hippo/YAP-dependent tissue growth.

Sarpal Ritu R Yan Victoria V Kazakova Lidia L Sheppard Luka L Yu Jessica C JC Fernandez-Gonzalez Rodrigo R Tepass Ulrich U

PLoS genetics 20191107 11

α-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila α-Catenin (α-Cat) in growth regulation of the wing epithelium. We found that different α-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. α-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a ne ...[more]

PMID: 31697683

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Project description: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.

Dataset Information

Role of ?-Catenin and its mechanosensing properties in regulating Hippo/YAP-dependent tissue growth.

Publications

Role of α-Catenin and its mechanosensing properties in regulating Hippo/YAP-dependent tissue growth.

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