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An overview of signaling pathways regulating YAP/TAZ activity

Heng BC, Zhang X, Aubel D, Bai Y, Li X, Wei Y, et al.

Cell Mol Life Sci, 2021 Jan;78(2):497-512.
PMID: 32748155 DOI: 10.1007/s00018-020-03579-8

YAP and TAZ are ubiquitously expressed homologous proteins originally identified as penultimate effectors of the Hippo signaling pathway, which plays a key role in maintaining mammalian tissue/organ size. Presently, it is known that YAP/TAZ also interact with various non-Hippo signaling pathways, and have diverse roles in multiple biological processes, including cell proliferation, tissue regeneration, cell lineage fate determination, tumorigenesis, and mechanosensing. In this review, we first examine the various microenvironmental cues and signaling pathways that regulate YAP/TAZ activation, through the Hippo and non-Hippo signaling pathways. This is followed by a brief summary of the interactions of YAP/TAZ with TEAD1-4 and a diverse array of other non-TEAD transcription factors. Finally, we offer a critical perspective on how increasing knowledge of the regulatory mechanisms of YAP/TAZ signaling might open the door to novel therapeutic applications in the interrelated fields of biomaterials, tissue engineering, regenerative medicine and synthetic biology.

Matched MeSH terms: Receptors, Notch/metabolism
Fulltext Expression Profiling of Notch Signalling Pathway and Gamma-Secretase Activity in the Brain of Ts1Cje Mouse Model of Down Syndrome

Yusof HH, Lee HC, Seth EA, Wu X, Hewitt CA, Scott HS, et al.

J Mol Neurosci, 2019 Apr;67(4):632-642.
PMID: 30758748 DOI: 10.1007/s12031-019-01275-2

Notch signalling pathway is involved in the proliferation of neural progenitor cells (NPCs), to inhibit neuronal cell commitment and to promote glial cell fate. Notch protein is cleaved by gamma-secretase, a multisubunit transmembrane protein complex that releases the Notch intracellular domain (NICD) and subsequently activates the downstream targets. Down syndrome (DS) individuals exhibit an increased number of glial cells (particularly astrocytes), and reduced number of neurons suggesting the involvement of Notch signalling pathway in the neurogenic-to-gliogenic shift in DS brain. Ts1Cje is a DS mouse model that exhibit similar neuropathology to human DS individuals. To date, the spatiotemporal gene expression of the Notch and gamma-secretase genes have not been characterised in Ts1Cje mouse brain. Understanding the expression pattern of Notch and gamma-secretase genes may provide a better understanding of the underlying mechanism that leads to the shift. Gene expression analysis using RT-qPCR was performed on early embryonic and postnatal development of DS brain. In the developing mouse brain, mRNA expression analysis showed that gamma-secretase members (Psen1, Pen-2, Aph-1b, and Ncstn) were not differentially expressed. Notch2 was found to be downregulated in the developing Ts1Cje brain samples. Postnatal gene expression study showed complex expression patterns and Notch1 and Notch2 genes were found to be significantly downregulated in the hippocampus at postnatal day 30. Results from RT-qPCR analysis from E15.5 neurosphere culture showed an increase of expression of Psen1, and Aph-1b but downregulation of Pen-2 and Ncstn genes. Gamma-secretase activity in Ts1Cje E15.5 neurospheres was significantly increased by fivefold. In summary, the association and the role of Notch and gamma-secretase gene expression throughout development with neurogenic-to-gliogenic shift in Ts1Cje remain undefined and warrant further validation.

Matched MeSH terms: Receptors, Notch/metabolism
Notch signaling and ghost cell fate in the calcifying cystic odontogenic tumor

Siar CH, Kawakami T, Buery RR, Nakano K, Tomida M, Tsujigiwa H, et al.

Eur J Med Res, 2011 Nov 10;16(11):501-6.
PMID: 22027644

Notch signaling is an evolutionarily conserved mechanism that enables adjacent cells to adopt different fates. Ghost cells (GCs) are anucleate cells with homogeneous pale eosinophilic cytoplasm and very pale to clear central areas (previous nucleus sites). Although GCs are present in a variety of odontogenic lesions notably the calcifying cystic odontogenic tumor (CCOT), their nature and process of formation remains elusive. The aim of this study was to investigate the role of Notch signaling in the cell fate specification of GCs in CCOT. Immunohistochemical staining for four Notch receptors (Notch1, Notch2, Notch3 and Notch4) and three ligands (Jagged1, Jagged2 and Delta1) was performed on archival tissues of five CCOT cases. Level of positivity was quantified as negative (0), mild (+), moderate (2+) and strong (3+). Results revealed that GCs demonstrated overexpression for Notch1 and Jagged1 suggesting that Notch1-Jagged1 signaling might serve as the main transduction mechanism in cell fate decision for GCs in CCOT. Protein localizations were largely membranous and/or cytoplasmic. Mineralized GCs also stained positive implicating that the calcification process might be associated with upregulation of these molecules. The other Notch receptors and ligands were weak to absent in GCs and tumoral epithelium. Stromal endothelium and fibroblasts were stained variably positive.

Matched MeSH terms: Receptors, Notch/metabolism*
Fulltext Hypoxic culture conditions as a solution for mesenchymal stem cell based regenerative therapy

Haque N, Rahman MT, Abu Kasim NH, Alabsi AM

ScientificWorldJournal, 2013;2013:632972.
PMID: 24068884 DOI: 10.1155/2013/632972

Cell-based regenerative therapies, based on in vitro propagation of stem cells, offer tremendous hope to many individuals suffering from degenerative diseases that were previously deemed untreatable. Due to the self-renewal capacity, multilineage potential, and immunosuppressive property, mesenchymal stem cells (MSCs) are considered as an attractive source of stem cells for regenerative therapies. However, poor growth kinetics, early senescence, and genetic instability during in vitro expansion and poor engraftment after transplantation are considered to be among the major disadvantages of MSC-based regenerative therapies. A number of complex inter- and intracellular interactive signaling systems control growth, multiplication, and differentiation of MSCs in their niche. Common laboratory conditions for stem cell culture involve ambient O₂ concentration (20%) in contrast to their niche where they usually reside in 2-9% O₂. Notably, O₂ plays an important role in maintaining stem cell fate in terms of proliferation and differentiation, by regulating hypoxia-inducible factor-1 (HIF-1) mediated expression of different genes. This paper aims to describe and compare the role of normoxia (20% O₂) and hypoxia (2-9% O₂) on the biology of MSCs. Finally it is concluded that a hypoxic environment can greatly improve growth kinetics, genetic stability, and expression of chemokine receptors during in vitro expansion and eventually can increase efficiency of MSC-based regenerative therapies.

Matched MeSH terms: Receptors, Notch/metabolism
Fulltext The FBXW7-NOTCH interactome: A ubiquitin proteasomal system-induced crosstalk modulating oncogenic transformation in human tissues

Kar R, Jha SK, Ojha S, Sharma A, Dholpuria S, Raju VSR, et al.

Cancer Rep (Hoboken), 2021 08;4(4):e1369.
PMID: 33822486 DOI: 10.1002/cnr2.1369

BACKGROUND: Ubiquitin ligases or E3 ligases are well programmed to regulate molecular interactions that operate at a post-translational level. Skp, Cullin, F-box containing complex (or SCF complex) is a multidomain E3 ligase known to mediate the degradation of a wide range of proteins through the proteasomal pathway. The three-dimensional domain architecture of SCF family proteins suggests that it operates through a novel and adaptable "super-enzymatic" process that might respond to targeted therapeutic modalities in cancer.
RECENT FINDINGS: Several F-box containing proteins have been characterized either as tumor suppressors (FBXW8, FBXL3, FBXW8, FBXL3, FBXO1, FBXO4, and FBXO18) or as oncogenes (FBXO5, FBXO9, and SKP2). Besides, F-box members like βTrcP1 and βTrcP2, the ones with context-dependent functionality, have also been studied and reported. FBXW7 is a well-studied F-box protein and is a tumor suppressor. FBXW7 regulates the activity of a range of substrates, such as c-Myc, cyclin E, mTOR, c-Jun, NOTCH, myeloid cell leukemia sequence-1 (MCL1), AURKA, NOTCH through the well-known ubiquitin-proteasome system (UPS)-mediated degradation pathway. NOTCH signaling is a primitive pathway that plays a crucial role in maintaining normal tissue homeostasis. FBXW7 regulates NOTCH protein activity by controlling its half-life, thereby maintaining optimum protein levels in tissue. However, aberrations in the FBXW7 or NOTCH expression levels can lead to poor prognosis and detrimental outcomes in patients. Therefore, the FBXW7-NOTCH axis has been a subject of intense study and research over the years, especially around the interactome's role in driving cancer development and progression. Several studies have reported the effect of FBXW7 and NOTCH mutations on normal tissue behavior. The current review attempts to critically analyze these mutations prognostic value in a wide range of tumors. Furthermore, the review summarizes the recent findings pertaining to the FBXW7 and NOTCH interactome and its involvement in phosphorylation-related events, cell cycle, proliferation, apoptosis, and metastasis.
CONCLUSION: The review concludes by positioning FBXW7 as an effective diagnostic marker in tumors and by listing out recent advancements made in cancer therapeutics in identifying protocols targeting the FBXW7-NOTCH aberrations in tumors.

Matched MeSH terms: Receptors, Notch/metabolism
Zebrafish phenotypic screen identifies novel Notch antagonists

Velaithan V, Okuda KS, Ng MF, Samat N, Leong SW, Faudzi SM, et al.

Invest New Drugs, 2017 04;35(2):166-179.
PMID: 28058624 DOI: 10.1007/s10637-016-0423-y

Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

Matched MeSH terms: Receptors, Notch/metabolism
Immunolocalization of notch signaling protein molecules in a maxillary chondrosarcoma and its recurrent tumor

Siar CH, Ha KO, Aung LO, Nakano K, Tsujigiwa H, Nagatsuka H, et al.

Eur J Med Res, 2010 Oct 25;15(10):456-60.
PMID: 21156405

BACKGROUND: notch receptors are critical determinants of cell fate in a variety of organisms. Notch signaling is involved in the chondrogenic specification of neural crest cells. Aberrant Notch activity has been implicated in numerous human diseases including cancers; however its role in chondrogenic tumors has not been clarified.
METHOD: tissue samples from a case of primary chondrosarcoma of the maxilla and its recurrent tumor were examined immunohistochemically for Notch1-4 and their ligands (Jagged1, Jagged2 and Delta1) expression.
RESULTS: both primary and recurrent tumors were histopathologically diagnosed as conventional hyaline chondrosarcoma (WHO Grade I). Hypercellular tumor areas strongly expressed Notch3 and Jagged1 in spindle and pleomorphic cells suggesting up-regulation of these protein molecules at sites of tumor proliferation. Expression patterns were distinct with some overlap. Differentiated malignant and atypical chondrocytes demonstrated variable expression levels of Jagged1, and weak to absent staining for Notch1, 4 and Delta1. Protein immunolocalization was largely membranous and cytoplasmic, sometimes outlining the lacunae of malignant chondrocytes. Hyaline cartilage demonstrated a diffuse or granular precipitation of Jagged1 suggesting presence of soluble Jagged1 activity at sites of abnormal chondrogenesis. No immunoreactivity for the other Notch members was observed. Calcified cartilage was consistently Notch-negative indicating down-regulation of Notch with cartilage maturation. Stromal components namely endothelial cells and fibroblasts variably expressed Notch1, 3 and Jagged1 but were mildly or non-reactive for the other members.
CONCLUSIONS: Results indicate that Notch signaling pathway may participate in cellular differentiation and proliferation in chondrosarcoma. Findings implicate Notch3 and Jagged1 as key molecules that influence the differentiation and maturation of cells of chondrogenic lineage.

Matched MeSH terms: Receptors, Notch/metabolism
Squamous odontogenic tumor of the mandible: a case report demonstrating immunoexpression of Notch1, 3, 4, Jagged1 and Delta1

Siar CH, Nakano K, Ng KH, Tomida M, Nagatsuka H, Kawakami T

Eur J Med Res, 2010 Apr 08;15(4):180-4.
PMID: 20554499

BACKGROUND: Squamous odontogenic tumor (SOT) is a rare benign odontogenic epithelial neoplasm. A slow-growing painless expansive swelling is the common presenting symptom. Histopathologically, SOT can be easily misdiagnosed as an acanthomatous ameloblastoma. Although Notch receptors and ligands have been shown to play a role in cell fate decisions in ameloblastomas, the role of these cell signaling molecules in SOT is unknown.
CASE REPORT: This paper describes a case of SOT affecting the anterior mandible of a 10-year-old Indian female. The patient was treated by local surgical excision and there has been no follow-up clinical record of recurrence 5 years after primary treatment. Histo?pathological examination revealed a solid, locally-infiltrative neoplasm composed of bland-looking squamatoid islands scattered in a mature fibrous connective tissue stroma and the diagnosis was SOT. Immunohistochemical evaluation showed positive reactivity of varying intensity in the neoplastic epithelial cells for Notch1, Notch3, Notch4, and their ligands Jagged1 and Delta1. Expression patterns showed considerable overlap. No immunoreactivity was detected for Notch2 and Jagged2.
CONCLUSIONS: Present findings suggest that Notch receptors and their ligands play differential roles in the cytodifferentiation of SOT.

Matched MeSH terms: Receptors, Notch/metabolism*
Cimigenoside functions as a novel γ-secretase inhibitor and inhibits the proliferation or metastasis of human breast cancer cells by γ-secretase/Notch axis

Jia H, Liu M, Wang X, Jiang Q, Wang S, Santhanam RK, et al.

Pharmacol Res, 2021 Jul;169:105686.
PMID: 34022397 DOI: 10.1016/j.phrs.2021.105686

Breast cancer (BC) occurrence and development tremendously affect female health. Currently breast cancer targeted drugs are still scarce. Natural products have become the main source of targeted drug for breast cancer due to low toxicity and high efficiency. Cimigenoside, natural compound isolated and purified from Cimicifuga dahurica (Turcz.) Maxim has been suggested to utilize for breast cancer treatment, however the mechanism of action has not been elucidated yet. In this article, the antitumor potential of Cimigenoside against breast cancer in vitro and in vivo study. Moreover, we further predicted the possible binding mode of Cimigenoside with γ-secretase through molecular docking studies. The results show that Cimigenoside has a significant inhibitory effect towards the proliferation or metastasis of breast cancer cells via suppressing the Notch signaling pathway-mediated mitochondrial apoptosis and EMT (epithelial mesenchymal transition). In terms of mechanism, Cimigenoside could inhibit the activation of PSEN-1, the catalytic subunit of γ-secretase, and also by cleaving the Notch protein mediated by PSEN-1. Overall, our findings provide scientific support to utilize Cimigenoside as an effective targeted drug for clinical treatment of BC.

Matched MeSH terms: Receptors, Notch/metabolism*