The regulatory networks of the Hippo signaling pathway in cancer development

Wang, Maonan; Dai, Manli; Wang, Dan; Xiong, Wei; Guo, Can

doi:10.7150/jca.62402

Cited by 23 publications

(19 citation statements)

References 126 publications

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“…This raises the possibility that CAs inhibition influences the experimental observations. Indeed, the linkage between CAs and TEAD-YAP/TAZ in the Hippo pathway has been reported [64]. Similarly, the interpretation of cellular studies using 5932 and 5946 may require caution on off-target effects through CA inhibition.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments

2022

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A multi-target small molecule modulator is advantageous for treating complicated diseases such as cancers. However, the strategy and application for discovering a multi-target modulator have been less reported. This study presents the dual inhibitors for kinase and carbonic anhydrase (CA) predicted by machine learning (ML) classifiers, and validated by biochemical and biophysical experiments. ML trained by CA I and CA II inhibitor molecular fingerprints predicted candidates from the protein-specific bioactive molecules approved or under clinical trials. For experimental tests, three sulfonamide-containing kinase inhibitors, 5932, 5946, and 6046, were chosen. The enzyme assays with CA I, CA II, CA IX, and CA XII have allowed the quantitative comparison in the molecules’ inhibitory activities. While 6046 inhibited weakly, 5932 and 5946 exhibited potent inhibitions with 100 nM to 1 mM inhibitory constants. The ML screening was extended for finding CAs inhibitors of all known kinase inhibitors. It found XMU-MP-1 as another potent CA inhibitor with an approximate 30 nM inhibitory constant for CA I, CA II, and CA IX. Differential scanning fluorimetry confirmed the direct interaction between CAs and small molecules. Cheminformatics studies, including docking simulation, suggest that each molecule possesses two separate functional moieties: one for interaction with kinases and the other with CAs.

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Section: Discussionmentioning

confidence: 99%

Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments

2022

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“…Therefore, identifying these key DNA binding factors and uncovering the regulation mechanisms in different contexts, such as in pluripotent and adult stem cells, will be beneficial for the stem cell research and regeneration medicine in future. Moreover, dysregulation of the Hippo pathway has also been observed in various cancers [ 82 , 83 ], and therefore, targeting of this pathway represents a very promising strategy for cancer treatment. However, the issue as we discussed in this review is also existed in YAP/TAZ-associated cancers.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Context-dependent transcriptional regulations of YAP/TAZ in stem cell and differentiation

Luo

2022

Stem Cell Res Ther

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Hippo pathway is initially identified as a master regulator for cell proliferation and organ size control, and the subsequent researches show this pathway is also involved in development, tissue regeneration and homeostasis, inflammation, immunity and cancer. YAP/TAZ, the downstream effectors of Hippo pathway, usually act as coactivators and are dependent on other transcription factors to mediate their transcriptional outputs. In this review, we will first provide an overview on the core components and regulations of Hippo pathway in mammals, and then systematically summarize the identified transcriptional factors or partners that are responsible for the transcriptional output of YAP/TAZ in stem cell and differentiation. More than that, we will discuss the potential applications and future directions based on these findings.

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“…Activation of LATS1/2 can lead to the phosphorylation of the activator YAP. Elevated levels of phosphorylated YAP expression can cause the proliferation of Esophageal cancer cells ( 127 ).…”

Section: The Pathophysiological Functions Of Sharpinmentioning

confidence: 99%

Advances in the Structural and Physiological Functions of SHARPIN

Wang

2022

Front. Immunol.

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SHARPIN was initially found as a SHANK-associated protein. SHARPIN can be used as an important component to form the linear ubiquitin chain assembly complex (LUBAC) with HOIL-1L, HOIP to produce a linear ubiquitin chain connected N-terminal Met1, playing a critical role in various cellular processes including NF-κB signaling, inflammation, embryogenesis and apoptosis. SHARPIN alone can also participate in many critical physiological activities and cause various disorders such as chronic dermatitis, tumor, and Alzheimer’s disease. Mice with spontaneous autosomal recessive mutations in the SHARPIN protein mainly exhibit chronic dermatitis and immunodeficiency with elevated IgM. Additionally, SHARPIN alone also plays a key role in various cellular events, such as B cells activation and platelet aggregation. Structural studies of the SHARPIN or LUBAC have been reported continuously, advancing our understanding of it at the molecular level. However, the full-length structure of the SHARPIN or LUBAC was lagging, and the molecular mechanism underlying these physiological processes is also unclear. Herein, we summarized the currently resolved structure of SHARPIN as well as the emerging physiological role of SHARPIN alone or in LUBAC. Further structural and functional study of SHARPIN will provide insight into the role and underlying mechanism of SHARPIN in disease, as well as its potential application in therapeutic.

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The regulatory networks of the Hippo signaling pathway in cancer development

Cited by 23 publications

References 126 publications

Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments

Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments

Context-dependent transcriptional regulations of YAP/TAZ in stem cell and differentiation

Advances in the Structural and Physiological Functions of SHARPIN

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