Role of α-Catenin and its mechanosensing properties in the regulation of 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 that does not involve junctional recruitment of Ajuba. Further, 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 cause Ajuba hyper-recruitment to AJs promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin it is not responsible for this effect. Moreover, disruption of mechanosensing of the -Cat actin-binding domain 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.