The hippo signaling pathway in development and cancer

Abstract

First discovered in Drosophila, the Hippo signaling pathway is a conserved regulator of organ size. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the oncoprotein Yki (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation and survival. Here, I review recent progress in elucidating the molecular mechanism and physiological function of Hippo signaling in Drosophila and mammals. These studies suggest that the core Hippo kinase cascade integrates multiple upstream inputs, enabling dynamic regulation of tissue homeostasis in animal development and physiology.

Figure 1. The Hippo Signaling Network in Drosophila and Mammals

(A) Signaling diagram. Corresponding proteins in Drosophila and mammals are indicated by matching colors and shapes. Direct biochemical interactions are indicated by solid lines or drawn as proteins in direct contact with each other. Dashed lines indicate genetic interactions for which no direct protein-protein interactions have been reported. Arrowed or blunted ends indicate activation or inhibition, respectively. Also shown are selected target genes. Yki- or YAP/TAZ-interacting transcription factors other than Sd (Drosophila) or TEAD (mammals) are collectively listed in a box. (B) A normal (left) and a yki-overexpressing (right) Drosophila wing imaginal disc. Image adapted from Huang et al. (2005). (C) A normal (left) and a YAP-overexpressing (right) mouse liver. Image adapted from Dong et al. (2007). The dramatic increase in organ size induced by Yki/YAP overexpression illustrates the potent growth-regulatory activity of Hippo signaling in Drosophila and mammals.