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Signal Transduction and Targeted Therapy Mar 2022The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors... (Review)
Review
The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.
Topics: Humans; Immunotherapy; Molecular Targeted Therapy; Neoplasms; Receptors, Notch; Signal Transduction; Tumor Microenvironment
PubMed: 35332121
DOI: 10.1038/s41392-022-00934-y -
Cell Feb 2016The Notch protein is one of the most mechanistically direct transmembrane receptors-the intracellular domain contains a transcriptional regulator that is released from...
The Notch protein is one of the most mechanistically direct transmembrane receptors-the intracellular domain contains a transcriptional regulator that is released from the membrane when engagement of the cognate extracellular ligand induces intramembrane proteolysis. We find that chimeric forms of Notch, in which both the extracellular sensor module and the intracellular transcriptional module are replaced with heterologous protein domains, can serve as a general platform for generating novel cell-cell contact signaling pathways. Synthetic Notch (synNotch) pathways can drive user-defined functional responses in diverse mammalian cell types. Because individual synNotch pathways do not share common signaling intermediates, the pathways are functionally orthogonal. Thus, multiple synNotch receptors can be used in the same cell to achieve combinatorial integration of environmental cues, including Boolean response programs, multi-cellular signaling cascades, and self-organized cellular patterns. SynNotch receptors provide extraordinary flexibility in engineering cells with customized sensing/response behaviors to user-specified extracellular cues.
Topics: Animals; Cell Engineering; Cell Line; Dogs; Humans; Mice; Neurons; Receptors, Notch; Signal Transduction; Synthetic Biology; Transcription, Genetic
PubMed: 26830878
DOI: 10.1016/j.cell.2016.01.012 -
Cell Apr 2009Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, the misregulation or loss of Notch signaling underlies a wide range of... (Review)
Review
Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, the misregulation or loss of Notch signaling underlies a wide range of human disorders, from developmental syndromes to adult-onset diseases and cancer. Notch signaling is remarkably robust in most tissues even though each Notch molecule is irreversibly activated by proteolysis and signals only once without amplification by secondary messenger cascades. In this Review, we highlight recent studies in Notch signaling that reveal new molecular details about the regulation of ligand-mediated receptor activation, receptor proteolysis, and target selection.
Topics: Animals; Humans; Receptors, Notch; Signal Transduction
PubMed: 19379690
DOI: 10.1016/j.cell.2009.03.045 -
Cancer Cell Oct 2018The Notch signaling pathway regulates many aspects of cancer biology. Most attention has been given to its role in the transformed cell. However, it is now clear that... (Review)
Review
The Notch signaling pathway regulates many aspects of cancer biology. Most attention has been given to its role in the transformed cell. However, it is now clear that cancer progression and metastasis depend on the bidirectional interactions between cancer cells and their environment, forming the tumor microenvironment (TME). These interactions are mediated and constantly evolve through paracrine and juxtacrine signaling. In this review, we discuss how Notch signaling takes an important part in regulating the crosstalk between the different compartments of the TME. We also address the consequences of the Notch-TME involvement from a therapeutic perspective.
Topics: Gene Expression Regulation, Neoplastic; Humans; Neoplasm Metastasis; Neoplasms; Receptors, Notch; Signal Transduction; Tumor Microenvironment
PubMed: 30146333
DOI: 10.1016/j.ccell.2018.07.009 -
Annual Review of Biophysics May 2021Notch signaling is a conserved system of communication between adjacent cells, influencing numerous cell fate decisions in the development of multicellular organisms.... (Review)
Review
Notch signaling is a conserved system of communication between adjacent cells, influencing numerous cell fate decisions in the development of multicellular organisms. Aberrant signaling is also implicated in many human pathologies. At its core, Notch has a mechanotransduction module that decodes receptor-ligand engagement at the cell surface under force to permit proteolytic cleavage of the receptor, leading to the release of the Notch intracellular domain (NICD). NICD enters the nucleus and acts as a transcriptional effector to regulate expression of Notch-responsive genes. In this article, we review and integrate current understanding of the detailed molecular basis for Notch signal transduction, highlighting quantitative, structural, and dynamic features of this developmentally central signaling mechanism. We discuss the implications of this mechanistic understanding for the functionality of the signaling pathway in different molecular and cellular contexts.
Topics: Animals; Biophysical Phenomena; Cell Nucleus; Humans; Receptors, Notch; Signal Transduction
PubMed: 33534608
DOI: 10.1146/annurev-biophys-101920-082204 -
Physiological Reviews Oct 2017Notch signaling is an evolutionarily highly conserved signaling mechanism, but in contrast to signaling pathways such as Wnt, Sonic Hedgehog, and BMP/TGF-β, Notch... (Review)
Review
Notch signaling is an evolutionarily highly conserved signaling mechanism, but in contrast to signaling pathways such as Wnt, Sonic Hedgehog, and BMP/TGF-β, Notch signaling occurs via cell-cell communication, where transmembrane ligands on one cell activate transmembrane receptors on a juxtaposed cell. Originally discovered through mutations in more than 100 yr ago, and with the first Notch gene cloned more than 30 yr ago, we are still gaining new insights into the broad effects of Notch signaling in organisms across the metazoan spectrum and its requirement for normal development of most organs in the body. In this review, we provide an overview of the Notch signaling mechanism at the molecular level and discuss how the pathway, which is architecturally quite simple, is able to engage in the control of cell fates in a broad variety of cell types. We discuss the current understanding of how Notch signaling can become derailed, either by direct mutations or by aberrant regulation, and the expanding spectrum of diseases and cancers that is a consequence of Notch dysregulation. Finally, we explore the emerging field of Notch in the control of tissue homeostasis, with examples from skin, liver, lung, intestine, and the vasculature.
Topics: Animals; Cell Communication; Disease; Growth and Development; Homeostasis; Humans; Ligands; Receptors, Notch; Signal Transduction
PubMed: 28794168
DOI: 10.1152/physrev.00005.2017 -
Cellular and Molecular Life Sciences :... May 2009The Notch gene encodes a transmembrane receptor that gave the name to the evolutionary highly conserved Notch signaling cascade. It plays a pivotal role in the... (Review)
Review
The Notch gene encodes a transmembrane receptor that gave the name to the evolutionary highly conserved Notch signaling cascade. It plays a pivotal role in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. After specific ligand binding, the intracellular part of the Notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor RBP-J. In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. Here, we review Notch signaling with a focus on gene regulatory events at Notch target genes. This is of utmost importance to understand Notch signaling since certain RBP-J associated cofactors and particular epigenetic marks determine the specificity of Notch target gene expression in different cell types. We subsequently summarize the current knowledge about Notch target genes and the physiological significance of Notch signaling in development and cancer.
Topics: Animals; Cell Physiological Phenomena; Chromatin; DNA; Gene Expression Regulation; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Leukemia; Models, Molecular; Receptors, Notch; Signal Transduction; Transcription, Genetic
PubMed: 19165418
DOI: 10.1007/s00018-009-8668-7 -
Nature May 2017The Notch signalling pathway mediates cell fate decisions and is tumour suppressive or oncogenic depending on the context. During lung development, Notch pathway...
The Notch signalling pathway mediates cell fate decisions and is tumour suppressive or oncogenic depending on the context. During lung development, Notch pathway activation inhibits the differentiation of precursor cells to a neuroendocrine fate. In small-cell lung cancer, an aggressive neuroendocrine lung cancer, loss-of-function mutations in NOTCH genes and the inhibitory effects of ectopic Notch activation indicate that Notch signalling is tumour suppressive. Here we show that Notch signalling can be both tumour suppressive and pro-tumorigenic in small-cell lung cancer. Endogenous activation of the Notch pathway results in a neuroendocrine to non-neuroendocrine fate switch in 10-50% of tumour cells in a mouse model of small-cell lung cancer and in human tumours. This switch is mediated in part by Rest (also known as Nrsf), a transcriptional repressor that inhibits neuroendocrine gene expression. Non-neuroendocrine Notch-active small-cell lung cancer cells are slow growing, consistent with a tumour-suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to neuroendocrine tumour cells, consistent with a pro-tumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumour growth and delays relapse in pre-clinical models. Thus, small-cell lung cancer tumours generate their own microenvironment via activation of Notch signalling in a subset of tumour cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select patients with small-cell lung cancer.
Topics: Animals; Cell Differentiation; Cell Proliferation; Disease Models, Animal; Female; Humans; Lung Neoplasms; Male; Mice; Neoplasm Recurrence, Local; Receptors, Notch; Repressor Proteins; Signal Transduction; Small Cell Lung Carcinoma; Tumor Microenvironment
PubMed: 28489825
DOI: 10.1038/nature22323 -
Nucleic Acids Research Aug 2022Signal transduction pathways often involve transcription factors that promote activation of defined target gene sets. The transcription factor RBPJ is the central player...
Signal transduction pathways often involve transcription factors that promote activation of defined target gene sets. The transcription factor RBPJ is the central player in Notch signaling and either forms an activator complex with the Notch intracellular domain (NICD) or a repressor complex with corepressors like KYOT2/FHL1. The balance between these two antagonizing RBPJ-complexes depends on the activation state of the Notch receptor regulated by cell-to-cell interaction, ligand binding and proteolytic cleavage events. Here, we depleted RBPJ in mature T-cells lacking active Notch signaling and performed RNA-Seq, ChIP-Seq and ATAC-seq analyses. RBPJ depletion leads to upregulation of many Notch target genes. Ectopic expression of NICD1 activates several Notch target genes and enhances RBPJ occupancy. Based on gene expression changes and RBPJ occupancy we define four different clusters, either RBPJ- and/or Notch-regulated genes. Importantly, we identify early (Hes1 and Hey1) and late Notch-responsive genes (IL2ra). Similarly, to RBPJ depletion, interfering with transcriptional repression by squelching with cofactor KYOT2/FHL1, leads to upregulation of Notch target genes. Taken together, RBPJ is not only an essential part of the Notch co-activator complex but also functions as a repressor in a Notch-independent manner.
Topics: Gene Expression Regulation; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Receptors, Notch; Signal Transduction; T-Lymphocytes
PubMed: 35848919
DOI: 10.1093/nar/gkac601 -
Trends in Endocrinology and Metabolism:... Dec 2021The Notch signaling pathway is conserved among mammalian species and controls proliferation, differentiation, and cell death in many organs throughout the body including... (Review)
Review
The Notch signaling pathway is conserved among mammalian species and controls proliferation, differentiation, and cell death in many organs throughout the body including the reproductive tract. Notch signaling plays critical roles in the development and function of both the male and female reproductive systems. Specifically, within the female reproductive tract, Notch signaling is hormone regulated and mediates key reproductive events important for ovarian and uterine function. In this review, we highlight the tissues that express Notch receptors, ligands, and downstream effectors and distinguish how these molecules regulate reproductive function in male and female mice, non-human primates, and humans. Finally, we describe some of the aberrations in Notch signaling in female reproductive pathologies and identify opportunities for future investigation.
Topics: Animals; Cell Differentiation; Female; Humans; Male; Mammals; Mice; Ovary; Receptors, Notch; Reproduction; Signal Transduction
PubMed: 34479767
DOI: 10.1016/j.tem.2021.08.002