Hippo signaling is intrinsically regulated during cell cycle progression by APC/C^Cdh1

Kim, Wantae,Cho, Yong Suk,Wang, Xiaohui,Park, Ogyi,Ma, Xueyan,Kim, Hanjun,Gan, Wenjian,Jho, Eek-hoon,Cha, Boksik,Jeung, Yun-ji,Zhang, Lei,Gao, Bin,Wei, Wenyi,Jiang, Jin,Chung, Kyung-Sook,Yang, Yingzi National Academy of Sciences 2019 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.116 No.19

<P><B>Significance</B></P><P>The Hippo signaling pathway is evolutionarily conserved in the animal kingdom and plays essential roles in regulating tissue growth during development and regeneration. We have identified APC/C<SUP>Cdh1</SUP>, a core component of cell cycle control machinery, as an evolutionarily conserved and previously unknown regulator of large tumor suppressor (LATS) kinases, which critically inhibit the YAP/TAZ transcription factors in transducing Hippo signaling. Our results suggest a model that APC/C<SUP>Cdh1</SUP> destabilizes LATS1/2 kinases in G1 phase of the cell cycle, leading to increased YAP/TAZ activities that promote G1/S transition by upregulating downstream gene expression, including <I>E2F1</I>. Our findings have important implications for a link between cell proliferation and LATS-regulated YAP/TAZ activities.</P><P>The Hippo-YAP/TAZ signaling pathway plays a pivotal role in growth control during development and regeneration and its dysregulation is widely implicated in various cancers. To further understand the cellular and molecular mechanisms underlying Hippo signaling regulation, we have found that activities of core Hippo signaling components, large tumor suppressor (LATS) kinases and YAP/TAZ transcription factors, oscillate during mitotic cell cycle. We further identified that the anaphase-promoting complex/cyclosome (APC/C)<SUP>Cdh1</SUP> E3 ubiquitin ligase complex, which plays a key role governing eukaryotic cell cycle progression, intrinsically regulates Hippo signaling activities. CDH1 recognizes LATS kinases to promote their degradation and, hence, YAP/TAZ regulation by LATS phosphorylation is under cell cycle control. As a result, YAP/TAZ activities peak in G1 phase. Furthermore, we show in <I>Drosophila</I> eye and wing development that Cdh1 is required in vivo to regulate the LATS homolog Warts with a conserved mechanism. Cdh1 reduction increased Warts levels, which resulted in reduction of the eye and wing sizes in a Yorkie dependent manner. Therefore, LATS degradation by APC/C<SUP>Cdh1</SUP> represents a previously unappreciated and evolutionarily conserved layer of Hippo signaling regulation.</P>

Inhibition of the interaction between Hippo/YAP and Akt signaling with ursolic acid and 3′3-diindolylmethane suppresses esophageal cancer tumorigenesis

Ruo Yu Meng,Cong Shan Li,Dan Hu,Soon-Gu Kwon,Hua Jin,Ok Hee Chai,Ju-Seog Lee,김수미 대한약리학회 2023 The Korean Journal of Physiology & Pharmacology Vol.27 No.5

Hippo/YAP signaling hinders cancer progression. Inactivation of this pathway contributes to the development of esophageal cancer by activation of Akt. However, the possible interaction between Akt and Hippo/YAP pathways in esophageal cancer progression is unclear. In this study, we found that ursolic acid (UA) plus 3′3-diindolylmethane (DIM) efficiently suppressed the oncogenic Akt/Gsk-3β signaling pathway while activating the Hippo tumor suppressor pathway in esophageal cancer cells. Moreover, the addition of the Akt inhibitor LY294002 and the PI3K inhibitor 3-methyladenine enhanced the inhibitory effects of UA plus DIM on Akt pathway activation and further stimulated the Hippo pathway, including the suppression of YAP nuclear translocation in esophageal cancer cells. Silencing YAP under UA plus DIM conditions significantly increased the activation of the tumor suppressor PTEN in esophageal cancer cells, while decreasing p-Akt activation, indicating that the Akt signaling pathway could be down-regulated in esophageal cancer cells by targeting PTEN. Furthermore, in a xenograft nude mice model, UA plus DIM treatment effectively diminished esophageal tumors by inactivating the Akt pathway and stimulating the Hippo signaling pathway. Thus, our study highlights a feedback loop between the PI3K/Akt and Hippo signaling pathways in esophageal cancer cells, implying that a low dose of UA plus DIM could serve as a promising chemotherapeutic combination strategy in the treatment of esophageal cancer.

The role of extracellular biophysical cues in modulating the Hippo-YAP pathway

( Jung-soon Mo ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.2

The Hippo signaling pathway plays an essential role in adult-tissue homeostasis and organ-size control. In Drosophila and vertebrates, it consists of a highly conserved kinase cascade, which involves MST and Lats that negatively regulate the activity of the downstream transcription coactivators, YAP and TAZ. By interacting with TEADs and other transcription factors, they mediate both proliferative and antiapoptotic gene expression and thus regulate tissue repair and regeneration. Dysregulation or mutation of the Hippo pathway is linked to tumorigenesis and cancer development. Recent studies have uncovered multiple upstream inputs, including cell density, mechanical stress, G-protein-coupled receptor (GPCR) signaling, and nutrients, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway as effector of these biophysical cues and its potential implications in tissue homeostasis and cancer. [BMB Reports 2017; 50(2): 71-78]

Insulin receptor substrate 2: a bridge between Hippo and AKT pathways

( Sun-hye Jeong ),( Dae-sik Lim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.5

NAFLD induces the development of advanced liver diseases such as NASH and liver cancer. Therefore, understanding the mechanism of NAFLD development is critical for its prevention and treatment. Ablation of PTEN or Hippo pathway components induces liver cancer in a murine model by hyperactive AKT or YAP/TAZ, respectively. Although the regulation of these two pathways occurs in the same hepatocyte, the details of crosstalk between Hippo-YAP/TAZ and PTEN-AKT pathways in liver homeostasis and tumo-rigenesis still remain unclear. Here, we found that depletion of both PTEN and SAV1 in liver promotes spontaneous NAFLD and liver cancer through hyperactive AKT via YAP/TAZ-mediated up-regulation of IRS2 transcription. Conversely, NAFLD is rescued by both ablation of YAP/TAZ and activation of the Hippo pathway. Furthermore, human HCC patients with NAFLD showed strong correlation between YAP/TAZ and IRS2 or phospho-AKT expression. Finally, the inhibition of AKT by MK-2206 treatment attenuates NAFLD development and tumorigenesis. Our findings indicate that Hippo pathway interacts with AKT signaling during the intervention with IRS2 to prevent NAFLD and liver cancer. [BMB Reports: Perspective 2018; 51(5): 209-210]

Hippo Signaling Circuit and Divergent Tissue Growth in Mammalian Eye

Moon, Kyeong Hwan,Kim, Jin Woo Korean Society for Molecular and Cellular Biology 2018 Molecules and cells Vol.41 No.4

Vertebrate organ development is accompanied by demarcation of tissue compartments, which grow coordinately with their neighbors. Hence, perturbing the coordinative growth of neighboring tissue compartments frequently results in organ malformation. The growth of tissue compartments is regulated by multiple intercellular and intracellular signaling pathways, including the Hippo signaling pathway that limits the growth of various organs. In the optic neuroepithelial continuum, which is partitioned into the retina, retinal pigment epithelium (RPE) and ciliary margin (CM) during eye development, the Hippo signaling activity operates differentially, as it does in many tissues. In this review, we summarize recent studies that have explored the relationship between the Hippo signaling pathway and growth of optic neuroepithelial compartments. We will focus particularly on the roles of a tumor suppressor, neurofibromin 2 (NF2), whose expression is not only dependent on compartment-specific transcription factors, but is also subject to regulation by a Hippo-Yap feedback signaling circuit.

Hepatic Hippo signaling inhibits development of hepatocellular carcinoma

Yuchen Liu,Xiaohui Wang,Yingzi Yang 대한간학회 2020 Clinical and Molecular Hepatology(대한간학회지) Vol.26 No.4

Primary liver cancer is one of the most common cancer worldwide. Hepatocellular carcinoma (HCC) in particular, is the second leading cause of cancer deaths in the world. The Hippo signaling pathway has emerged as a major oncosuppressive pathway that plays critical roles inhibiting hepatocyte proliferation, survival, and HCC formation. A key component of the Hippo pathway is the inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcription factors by the Hippo kinase cascade. Aberrant activation of YAP or TAZ has been found in several human cancers including HCC. It is also well established that YAP/TAZ activation in hepatocytes causes HCC in mouse models, indicating that YAP/TAZ are potential therapeutic targets for human liver cancer. In this review, we summarize the recent findings regarding the multifarious roles of Hippo/YAP/TAZ in HCC development, and focus on their cell autonomous roles in controlling hepatocyte proliferation, differentiation, survival and metabolism as well as their non-cell autonomous in shaping the tumor microenvironment.

Hippo Signaling Circuit and Divergent Tissue Growth in Mammalian Eye

문경환,김진우 한국분자세포생물학회 2018 Molecules and cells Vol.41 No.4

Vertebrate organ development is accompanied by demarcation of tissue compartments, which grow coordinately with their neighbors. Hence, perturbing the coordinative growth of neighboring tissue compartments frequently results in organ malformation. The growth of tissue compartments is regulated by multiple intercellular and intracellular signaling pathways, including the Hippo signaling pathway that limits the growth of various organs. In the optic neuroepithelial continuum, which is partitioned into the retina, retinal pigment epithelium (RPE) and ciliary margin (CM) during eye development, the Hippo signaling activity operates differentially, as it does in many tissues. In this review, we summarize recent studies that have explored the relationship between the Hippo signaling pathway and growth of optic neuroepi-thelial compartments. We will focus particularly on the roles of a tumor suppressor, neurofibromin 2 (NF2), whose expression is not only dependent on compartment-specific transcription factors, but is also subject to regulation by a Hippo-Yap feedback signaling circuit.

Hippo-YAP/TAZ pathway regulation: the crucial roles of lncRNAs in cancer

장원이,임미정,노정욱,강지훈,김완연 한국통합생물학회 2023 Animal cells and systems Vol.27 No.1

The Hippo signaling pathway is a conserved signaling pathway that regulates cell proliferation,apoptosis, and differentiation and plays essential roles in the maintenance of organ size andtissue homeostasis. Also, this signaling pathway is a critical regulator of malignant progressionin a wide range of cancers. Furthermore, it has been established that YAP and TAZ are majoreffectors of the Hippo signaling pathway and transcription co-activators that regulate theexpressions of genes involved in cell growth and differentiation. Long non-coding RNAs(lncRNAs) are transcripts longer than 200 nucleotides involved in several biological processes,including chromatin remodeling, transcriptional regulation, and post-transcriptional processing. Evidence suggests that the aberrant expression and dysregulation of lncRNAs contribute to thedevelopment and progression of various malignancies by acting as oncogenes or tumorsuppressors. In addition, many studies have shown that lncRNAs can directly or indirectlyregulate the Hippo-YAP/TAZ signaling pathway in cancer. Here, we overview the roles played bylncRNAs in tumor progression with focus on their regulation of the Hippo-YAP/TAZ signalingpathway and discuss their potential usages as clinical biomarkers and therapeutic targets.

유방암세포에서 LATS1/2 활성에 의한 당귀 추출물의 항암효과

김초롱,김남빈,정한솔,신유수,모정순 한의병리학회 2020 동의생리병리학회지 Vol.34 No.4

The Hippo-YAP signaling pathway is critical for cell proliferation, survival, and self-renewal in both Drosophila and mammals. Disorder of Hippo-YAP pathway leads to tumor development, progression and poor prognosis in various cancers. YAP/TAZ are the key downstream effectors of the Hippo pathway and they can be inhibited through LATS1/2, core kinases in the Hippo pathway, mediated phosphorylation. In this study, we investigated the effect of Angelica gigas Nakai extract (AGNE) on Hippo-YAP/TAZ pathway. First, ANGE induced YAP/TAZ phosphorylation and dissociation of the YAP/TAZ-TEAD transcription complex. By qRT-PCR, we found that ANGE inhibits the expression of YAP/TAZ-TEAD target gene, CTGF and CYR61. In addition, the transcriptional activity of YAP/TAZ was not suppressed significantly in LATS1/2 double-knockout (DKO) cells by ANGE compared to LATS1/2 wild-type (WT) cells, which means AGNE inhibits YAP/TAZ signaling through direct action on LATS1/2. Further, it was confirmed that AGNE-induced activation of LATS1/2 inhibited the migration potential of the vector-expressing cells by suppressing YAP/TAZ activity. The reduced migration potential was restored in active YAP-TEAD expressing cells. Taken together, the results of this study indicate that ANGE downregulates YAP/TAZ signaling in cells through the activation of LATS1/2.

Dishevelling Wnt and Hippo

( Nam Hee Kim ),( Yoonmi Lee ),( Jong In Yook ) 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.9

As highly conserved signaling cascades of multicellular organisms, Wnt and Hippo pathways control a wide range of cellular activities, including cell adhesion, fate determination, cell cycle, motility, polarity, and metabolism. Dysregulation of those pathways are implicated in many human diseases, including cancer. Similarly to β-catenin in the Wnt pathway, the YAP transcription co-activator is a major player in Hippo. Although the intracellular dynamics of YAP are well-known to largely depend on phosphorylation by LATS and AMPK kinases, the molecular effector of YAP cytosolic translocation remains unidentified. Recently, we reported that the Dishevelled (DVL), a key scaffolding protein between canonical and non-canonical Wnt pathway, is responsible for nuclear export of phosphorylated YAP. The DVL is also required for YAP intracellular trafficking induced by E-cadherin, α-catenin, or metabolic stress. Note that the p53/LATS2 and LKB1/AMPK tumor suppressor axes, commonly inactivated in human cancer, govern the reciprocal inhibition between DVL and YAP. Conversely, loss of the tumor suppressor allows co-activation of YAP and Wnt independent of epithelial polarity or contact inhibition in human cancer. These observations provide novel mechanistic insight into (1) a tight molecular connection merging the Wnt and Hippo pathways, and (2) the importance of tumor suppressor contexts with respect to controlled proliferation and epithelial polarity regulated by cell adhesion. [BMB Reports: Perspective 2018; 51(9): 425-426]