Upstream Regulation of the Hippo Pathway

Studies of the Hippo signaling pathway have revealed a highly complex network of interacting regulatory mechanisms that together control pathway output and tissue growth. An overriding theme of this regulation is that it functions to link basic cellular architecture and processes to pathway function, thereby allowing tissue growth to be coordinated with cell shape and tissue morphogenesis. One such mechanism involves the transmembrane protein Crumbs and its partner Expanded, which recruit and activate the core kinases, Tao-1, Hippo, and Warts, to the junctional cortex. In parallel, Kibra and its partner Merlin recruit and activate pathway components at the apicomedial cell cortex. Both mechanisms physically and functionally interact with apical and basolateral polarity components, leading to significant cross talk between these pathways. Importantly, mechanical tension, generated within cells by actomyosin contractile networks and transmitted between cells through intercellular junctions, controls pathway output via multiple mechanisms in distinct cellular domains. In this review, we discuss these regulatory mechanisms, with particular attention to those that function upstream of the core kinases, their organization within epithelial cells, and how this organization allows cells to sense mechanical tension to shape growth in developing tissues.