Signal integration in TGF-β, WNT, and Hippo pathways

Abstract

Complete sequences of animal genomes have revealed a remarkably small and conserved toolbox of signalling pathways, such as TGF-β and WNT that account for all biological diversity. This raises the question as to how such a limited set of cues elaborates so many diverse cell fates and behaviours. It is now clear that components of signalling pathways are physically assembled into higher order networks that ultimately dictate the biological output of pathway activity. Intertwining of pathways is thus emerging as a key feature of a large, integrated and coordinated signalling network that allows cells to read a limited set of extrinsic cues, but mount the diverse responses that underpin successful development and homeostasis. Moreover, this design principle confounds the development of effective therapeutic interventions in complex diseases, such as cancer.

Figure 1.. Integration of Cell Signalling Pathways into Higher Order Networks Sculpts Transcriptional Landscapes

A simplified schematic of Hippo, TGF-β and WNT pathway interactions is shown. Each of the indicated pathways converge on transcriptional modulators that act in the nucleus to regulate transcription of target genes by interacting with DNA-binding partners, a selection of which are indicated (lowest cluster). Extensive physical interactions between Smads, β-catenin and TAZ/YAP (nuclear halo of components) describe a network of extensive crosstalk that provides for contextual transcriptional responses. In the presence of Hippo pathway activity, TAZ/YAP are sequestered in the cytosol, where they limit both TGF-β and WNT-β-catenin activity.