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

Author summary We explore the regulation of tissue and organ size which is an important consideration in normal development and health. During development, tissues reach specific sizes in proportion to the rest of the body. Uncontrolled growth can lead to malformations or promote tumor growth. Recent findings have emphasized an important role for mechanical cues in the regulation of tissue growth. Mechanical signals can, for example, arise from cytoskeletal contraction that increases tension, or from compression due to proliferation and a resulting increase in cell density that would lower tension. Mechanosensory molecules that are sensitive to changes in tissue tension can convert mechanical cues into biochemical signals that enhance or slow proliferation or cell death to adjust overall tissue size. One such mechanosensory molecule is alpha-Catenin which is a key component of cell adhesion structures that physically link cells together and couples these structures to the cytoskeleton within cells. We clarify several molecular parameters of how alpha-Catenin regulates signalling pathways that control cell proliferation and cell death. alpha-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 alpha-Catenin (alpha-Cat) in growth regulation of the wing epithelium. We found that different alpha-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. alpha-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 alpha-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for alpha-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 alpha-Cat ABD affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that alpha-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.