WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy

Qi, Sixian; Zhu, Yuwen; Liu, Xincheng; Li, Pengyue; Wang, Yebin; Zeng, Yan; Yu, Aijuan; Wang, Yu; Sha, Zhao; Zhong, Zhenxing; Zhu, Rui; Yuan, Hai‐Xin; Ye, Dan; Huang, Shenglin; Chen, Ling; Xu, Yanhui; Zhou, Dawang; Zhang, Lei; Yu, Fa‐Xing

doi:10.1016/j.molcel.2022.03.027

Cited by 44 publications

(41 citation statements)

References 79 publications

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“…29 MST1/ 2 also facilitates the binding between MOB1A/B and LATS1/2. 30 Recently, Sixian Qi et al 31 showed that this process was mediated by WWC proteins (WWC1/2/3), which act as scaffold proteins. Besides, except for MST1/2, MAP4K family proteins have also been reported to participate in the activation of LATS1/2 without the direct involvement of SAV.…”

Section: Key Components Of the Hippo Pathwaymentioning

confidence: 99%

“…SuperHippo, a designed WWC-derived protein, was shown to inhibit YAP/TAZ activity by inducing the phosphorylation of LATS1/2 due to the requirement of the WWC protein in the activation of LATS1/2. 31 Inhibition of TEAD and/or the YAP-TEAD interaction. YAP-TEAD interaction inhibitors currently offer the diverse potential to target the Hippo pathway.…”

Section: Dysregulation Of the Hippo Pathway And Human Diseasesmentioning

confidence: 99%

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The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

103

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As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in the regulation of numerous biological processes. Thus, substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway, as well as its physiological functions, such as cell proliferation and differentiation, organ growth, embryogenesis, and tissue regeneration/wound healing. However, dysregulation of the Hippo pathway can cause a variety of diseases, including cancer, eye diseases, cardiac diseases, pulmonary diseases, renal diseases, hepatic diseases, and immune dysfunction. Therefore, therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases. Here, we review the key components and upstream signals of the Hippo pathway, as well as the critical physiological functions controlled by the Hippo pathway. Additionally, diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.

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Section: Key Components Of the Hippo Pathwaymentioning

confidence: 99%

Section: Dysregulation Of the Hippo Pathway And Human Diseasesmentioning

confidence: 99%

The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

103

View full text Add to dashboard Cite

show abstract

“…LATS1 acts as a tumor suppressor in various human cancers [ 20 ]. Our previous study showed that an E3 ligase of LATS1 could destabilize the protein level of LATS1 by inducing its ubiquitination [ 12 ].…”

Section: Resultsmentioning

confidence: 99%

The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer

Hong

et al. 2023

J Exp Clin Cancer Res

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Background Posttranscriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. M6A modifications in cancer cells are dynamic and reversible and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of breast cancer cell proliferation and metabolism through m6A methylation in the Hippo pathway. Methods A combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal a map of m6A modifications in breast cancer tissues and cells. We conducted RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis to identify the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells. The expression and biological functions of m6A proteins were confirmed in breast cancer cells in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway was affected by m6A regulation of LATS1 in breast cancer cells. Results We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway. Conclusions In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway.

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“…Cells were incubated at 37 C with 5% CO2. NF2 KO, SAV1 KO, MST1/2 dKO, LATS1/2 dKO, MOB1A/B dKO, WWC1/2/3 tKO, and MAP4K3-7 5KO HEK293A cells were described previously (Meng et al, 2015;Plouffe et al, 2016;Qi et al, 2022). KIRREL1 KO HEK293A cells were generated in this study using CRISPR/Cas9 system.…”

Section: Mouse Modelsmentioning

confidence: 99%

WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy

Cited by 44 publications

References 79 publications

The Hippo signalling pathway and its implications in human health and diseases

The Hippo signalling pathway and its implications in human health and diseases

The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer

Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in YAP/TAZ-active cancers

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