Metazoan organ development requires a strict control of cell proliferation, growth and death. Studies in Drosophila melanogaster have identified the Hippo (Hpo) pathway as one of the major signalling pathways required for tissue size control.
The Hpo pathway controls the final tissue and organ size by both inhibiting cell proliferation and promoting apoptosis. At the core of the pathway lies a kinase cascade comprised of the Ste20-related kinase Hpo and the Dbf2-related kinase Warts (Wts).
Hpo and Wts, together with their respective scaffold proteins Salvador (Sav) and Mob as Tumour Suppressor (Mats), phosphorylate and inhibit the transcriptional co-activator Yorkie (Yki). Recent work in vertebrates indicates that the growth control function of Hpo signalling is conserved and is relevant to mammalian tumour formation.
The key open question in Hpo signalling remains what cues control its activity, to ensure precisely the correct amount of growth inhibitory signal to specify organism size. The upstream regulation of the Hpo pathway is complex, integrating many inputs.
Firstly, through the KEM (Kibra/Expanded/Merlin) and AMOT complexes, which associate with the apical polarity protein Crumbs (Crb), the basolateral determinant Scribble and junctional components such as α-catenin, Hpo signalling is believed to respond to cell-cell contact integrity and apico-basal polarity. Indeed, the Hpo pathway is a mediator of contact inhibition of growth in cell culture and many mutations that perturb cell-cell contacts or polarity lead to de-repression of Yki target genes.
Secondly, the atypical cadherins Fat (Ft) and Dachsous (Ds) are thought to repress the core kinase cascade by inactivating the myosin Dachs and the LIM domain protein Zyxin.
Thirdly, mechanical forces, sensed through the actin cytoskeleton, have also been shown to modulate Yki/YAP activity, but the molecular mechanism remains unclear.
Finally, G-protein coupled receptors (GPCRs) have recently been shown to modulate Hpo pathway activity through at least two distinct mechanisms. Thus, the Hpo pathway is believed to respond to a variety of signals such as local tissue architecture (cell crowding, tissue mechanics) as well as diffusible signals (GPCR ligands).