Two Hippo signaling modules orchestrate liver size and tumorigenesis

Abstract

The Hippo pathway is a central regulator of organ size and tumorigenesis and is commonly depicted as a kinase cascade, with an increasing number of regulatory and adaptor proteins linked to its regulation over recent years. Here, we propose that two Hippo signaling modules, MST1/2-SAV1-WWC1-3 (HPO1) and MAP4K1-7-NF2 (HPO2), together regulate the activity of LATS1/2 kinases and YAP/TAZ transcriptional co-activators. In mouse livers, the genetic inactivation of either HPO1 or HPO2 module results in partial activation of YAP/TAZ, bile duct hyperplasia, and hepatocellular carcinoma (HCC). On the contrary, inactivation of both HPO1 and HPO2 modules results in full activation of YAP/TAZ, rapid development of intrahepatic cholangiocarcinoma (iCCA), and early lethality. Interestingly, HPO1 has a predominant role in regulating organ size. HPO1 inactivation causes a homogenous YAP/TAZ activation and cell proliferation across the whole liver, resulting in a proportional and rapid increase in liver size. Thus, this study has reconstructed the order of the Hippo signaling network and suggests that LATS1/ 2 and YAP/TAZ activities are finetuned by HPO1 and HPO2 modules to cause different cell fates, organ size changes, and tumorigenesis trajectories.

Interplay of RAP2 GTPase and the cytoskeleton in Hippo pathway regulation

“…Still, YAP hyperphosphorylation by 2-DG in RAP2A/B/C-MAP4K4/6/7 6KO cells cannot be blocked as much in RAP2A/B/C-MST1/2 5KO cells. These results altogether supported a working model where RAP2 functions upstream of MAP4K in the non-canonical Hippo (Hpo2) signaling [26] to mediate phosphorylation of LATS and YAP triggered by actin disassembly and stress ( Fig. 5E) .…”

“…Our previous study demonstrated that RAP2 acts through MAP4Ks to activate LATS1/2 during mechanosensing [11], positioning RAP2 as a component of the non-canonical MAP4K-Hippo signaling pathway (Hpo2)[26] ( Fig. 2A ).…”

“…RAP2, much like NF2 and WWC1-3 [26], appears pivotal in facilitating and modulating kinase interactions within the Hippo pathway. Specifically, our results showcase RAP2’s capability to interface with LATS1/2 and upstream kinases such as MST1/2 and MAP4K1-7, providing a functional nexus for signal transduction.…”

A tale of two Hippo pathway modules

“…Over two decades of research have elucidated the core Hippo pathway kinase cascade, but its precise organization has not been fully understood. In this issue of The EMBO Journal, Qi et al (2023) Genevet et al, 2010;Yu et al, 2010;Fig 1A). In addition, NF2 and WWC1-3 target STRIPAK, a phosphatase 2A (PP2A) complex, to release its inhibitory effect on MST1/2 and MAP4Ks (Chen et al, 2019;Fig 1A).…”

“…In addition, NF2 binds and moves LATS1/ 2 onto plasma membrane, where LATS1/2 are phosphorylated and activated by MST1/2. (B) In this issue,Qi et al (2023) propose two independent Hippo pathway modules, HPO1 and HPO2, within the Hippo kinase cascade. In the HPO1 module, WWC1-3 act as "adaptor" proteins bridging the MST1/2-SAV1 complex to bind and phosphorylate LATS1/2.…”