The history and regulatory mechanism of the Hippo pathway

Abstract

How the organ size is adjusted to the proper size during development and how organs know that they reach the original size during regeneration remain long-standing questions. Based on studies using multiple model organisms and approaches for over 20 years, a consensus has been established that the Hippo pathway plays crucial roles in controlling organ size and maintaining tissue homeostasis. Given the significance of these processes, the dysregulation of the Hippo pathway has also implicated various diseases, such as tissue degeneration and cancer. By regulating the downstream transcriptional coactivators YAP and TAZ, the Hippo pathway coordinates cell proliferation and apoptosis in response to a variety of signals including cell contact inhibition, polarity, mechanical sensation and soluble factors. Since the core components and their functions of the Hippo pathway are evolutionarily conserved, this pathway serves as a global regulator of organ size control. Therefore, further investigation of the regulatory mechanisms will provide physiological insights to better understand tissue homeostasis. In this review, the historical developments and current understandings of the regulatory mechanism of Hippo signaling pathway are discussed. [BMB Reports 2018; 51(3): 106-118].

Fig. 1

The pathophysiological function and importance of the Hippo pathway. Both intrinsic and extrinsic signals regulate the Hippo pathway that is crucial for proper developmental processes and tissue homeostasis (upper panel). As the interest and importance of the Hippo pathway is growing, so does the number of publications (bottom panel).

Fig. 2

Timeline of the major advances and discoveries in the Hippo pathway.

Fig. 3

Schematic model of the Hippo pathway and cross-talk with other signaling pathways in mammals. The Hippo pathway is a kinase cascade that consists of MST1/2-LATS1/2 and can be activated by diverse stimuli including cell density, polarity and mechanical cues to suppress YAP/TAZ transcriptional activity. Many modulators in the Hippo pathway have been added via multiple approaches (left panel). The crosstalk of the Hippo pathway with other signaling pathways such as Wnt/β-catenin, Notch and TGF-β to regulate YAP/TAZ activity (right panel).