The Hippo signaling pathway controls organ growth and stem cell behavior in animals by regulating cell proliferation and apoptosis. It was first identified in Drosophila, and subsequently named after an essential kinase of this pathway, Hippo (Hpo) [1] . It has been shown to regulate cell growth in various mammalian systems, including cardiac muscle and respiratory epithelium [2, 3].

Similar to Drosophila, the core of the mammalian Hippo pathway consists of the MST and LATS kinases, which are orthologs of Hpo and Wts in Drosophila, respectively. In response to various upstream stimuli, MST1/2 kinases activate the LATS1/2 kinases, which in turn phosphorylate Serine residues in the transcription co-activators YAP and TAZ (Yki in Drosophila) [4, 5]. Once phosphorylated, YAP/TAZ forms a complex with 14-3-3 proteins, which sequesters both proteins within the cytoplasm and tags them for degradation. However, when LATS kinase is inhibited, and YAP/TAZ is left unphosphorylated, they will bind to TEAD, and accumulate in the nucleus. Although YAP/TAZ are unable to bind to DNA themselves, TEAD does, activating the transcription of genes which leads to cell proliferation. This pathway is known as the “canonical? Hippo signalling pathway.

YAP/TAZ may also occur independently of LATS kinase, and this is known as “non-canonical? Hippo signalling. 

The Hippo signalling pathway is regulated by mechanical signals from the extracellular matrix (ECM). Cell detachment, or disruption of the actin cytoskeleton, activates the LATS1/2 kinases which subsequently phosphorylate and inhibit YAP/TAZ [6].

The influence of mechanical cues on the function of YAP/TAZ is further evident through the effect of substrate stiffness on the localization of these proteins, and their subsequent transcriptional activity [7]. When cultured on soft substrates, YAP/TAZ is ultimately degraded; however, when cells are grown on stiff substrates, they are localized to the nucleus where they initiate transcription. Recent findings have also implicated the proteins in the regulation of alternative signalling pathways including the canonical Wnt signaling pathway and the TGFβべーた signalling pathway [8]. Furthermore, specific proteins that regulate the initial phosphorylation events in the Hpo pathway are believed to be regulated by mechanical cues. Merlin, or NF2, promotes a Merlin-Wts/Lats interaction upon disruption of the cytoskeleton and is thus a potential mediator of actin-regulated Hippo signaling [9]. 

Importantly, the Hippo signalling pathway does not function in isolation, but is instead influenced by a vast array of other proteins. Proteomic studies have revealed protein-protein interactions between distinct networks in various systems. For example, Kwon et al. [10] found 153 high-confidence interacting proteins in the Drosophila Hippo pathway, while Wang et al. [11] and Couzens et al. [12] identified high-confidence networks of 343 and 445 proteins in the human Hippo pathway, respectively.