In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids or proteins across species, or within a genome, or between donor and receptor taxa. Conservation indicates that a sequence has been maintained by natural selection.
Notch proteins are a family of Type-1 transmembrane proteins that form a core component of the Notch signaling pathway, which is highly conserved in metazoans. The Notch extracellular domain (NECD) mediates interactions with DSL family ligands, allowing it to participate in juxtacrine signaling.The Notch intracellular domain (NICD) acts as a transcriptional activator when in complex with CSL family transcription factors. Members of this Type 1 transmembrane protein family share several core structures, including an extracellular domain consisting of multiple epidermal growth factor (EGF)-like repeats and an intracellular domain transcriptional activation domain (TAD). Notch family members operate in a variety of different tissues and play a role in a variety of developmental processes by controlling cell fate decisions. Much of what is known about Notch function comes from studies done in Caenorhabditis elegans (C.elegans) and Drosophila melanogaster. Human homologs have also been identified, but details of Notch function and interactions with its ligands are not well known in this context.
Neurogenic locus notch homolog protein 3 is a protein that in humans is encoded by the NOTCH3 gene.
Notch signaling promotes proliferative signaling during neurogenesis, and its activity is inhibited by Numb to promote neural differentiation. It plays a major role in the regulation of embryonic development.
Protein numb homolog is a protein that in humans is encoded by the NUMB gene.
Drosophila melanogaster is a species of fly in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting with Charles W. Woodworth's proposal of the use of this species as a model organism, D. melanogaster continues to be widely used for biological research in genetics, physiology, microbial pathogenesis, and life history evolution. As of 2017, eight Nobel prizes had been awarded for research using Drosophila.
Thomas Hunt Morgan was an American evolutionary biologist, geneticist, embryologist, and science author who won the Nobel Prize in Physiology or Medicine in 1933 for discoveries elucidating the role that the chromosome plays in heredity.
Michael Warren Young is an American biologist and geneticist. He has dedicated over three decades to research studying genetically controlled patterns of sleep and wakefulness within Drosophila melanogaster. During his time at Rockefeller University, his lab has made significant contributions in the field of chronobiology by identifying key genes associated with regulation of the internal clock responsible for circadian rhythms. He was able to elucidate the function of the period gene, which is necessary for the fly to exhibit normal sleep cycles. Young's lab is also attributed with the discovery of the timeless and doubletime genes, which makes proteins that are also necessary for circadian rhythm. He was awarded the 2017 Nobel Prize in Physiology or Medicine along with Jeffrey C. Hall and Michael Rosbash "for their discoveries of molecular mechanisms controlling the circadian rhythm".
The cell membrane is a biological membrane that separates the interior of all cells from the outside environment which protects the cell from its environment consisting of a lipid bilayer with embedded proteins. The cell membrane controls the movement of substances in and out of cells and organelles. In this way, it is selectively permeable to ions and organic molecules. In addition, cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity and cell signalling and serve as the attachment surface for several extracellular structures, including the cell wall, the carbohydrate layer called the glycocalyx, and the intracellular network of protein fibers called the cytoskeleton. In the field of synthetic biology, cell membranes can be artificially reassembled.
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion, or protein which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure. The instance of binding occurs over an infinitesimal range of time and space, so the rate constant is usually a very small number.
In cell biology, the nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotes usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many.
The cleavage model was first proposed in 1993 based on work done with DrosophilaNotch and C. eleganslin-12, informed by the first oncogenic mutation affecting a human Notch gene. Compelling evidence for this model was provided in 1998 by in vivo analysis in Drosophila by Gary Struhl and in cell culture by Raphael Kopan. Although this model was initially disputed, the evidence in favor of the model was irrefutable by 2001.
The receptor is normally triggered via direct cell-to-cell contact, in which the transmembrane proteins of the cells in direct contact form the ligands that bind the notch receptor. The Notch binding allows groups of cells to organize themselves such that, if one cell expresses a given trait, this may be switched off in neighbouring cells by the intercellular notch signal. In this way, groups of cells influence one another to make large structures. Thus, lateral inhibition mechanisms are key to Notch signaling. lin-12 and Notch mediate binary cell fate decisions, and lateral inhibition involves feedback mechanisms to amplify initial differences.
The Notch cascade consists of Notch and Notch ligands, as well as intracellular proteins transmitting the notch signal to the cell's nucleus. The Notch/Lin-12/Glp-1 receptor family was found to be involved in the specification of cell fates during development in Drosophila and C. elegans.
The intracellular domain of Notch forms a complex with CBF1 and Mastermind to activate transcription of target genes. The structure of the complex has been determined.
The Notch signaling pathway is important for cell-cell communication, which involves gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life. Notch signaling also has a role in the following processes:
influencing of binary fate decisions of cells that must choose between the secretory and absorptive lineages in the gut
expansion of the hematopoietic stem cell compartment during bone development and participation in commitment to the osteoblastic lineage, suggesting a potential therapeutic role for notch in bone regeneration and osteoporosis
Maturation of the notch receptor involves cleavage at the prospective extracellular side during intracellular trafficking in the Golgi complex. This results in a bipartite protein, composed of a large extracellular domain linked to the smaller transmembrane and intracellular domain. Binding of ligand promotes two proteolytic processing events; as a result of proteolysis, the intracellular domain is liberated and can enter the nucleus to engage other DNA-binding proteins and regulate gene expression.
Notch and most of its ligands are transmembrane proteins, so the cells expressing the ligands typically must be adjacent to the notch expressing cell for signaling to occur. The notch ligands are also single-pass transmembrane proteins and are members of the DSL (Delta/Serrate/LAG-2) family of proteins. In Drosophila melanogaster (the fruit fly), there are two ligands named Delta and Serrate. In mammals, the corresponding names are Delta-like and Jagged. In mammals there are multiple Delta-like and Jagged ligands, as well as possibly a variety of other ligands, such as F3/contactin.
In the nematode C. elegans, two genes encode homologous proteins, glp-1 and lin-12. There has been at least one report that suggests that some cells can send out processes that allow signaling to occur between cells that are as much as four or five cell diameters apart.
The notch extracellular domain is composed primarily of small cystine-rich motifs called EGF-like repeats.
Notch 1, for example, has 36 of these repeats. Each EGF-like repeat is composed of approximately 40 amino acids, and its structure is defined largely by six conserved cysteine residues that form three conserved disulfide bonds. Each EGF-like repeat can be modified by O-linked glycans at specific sites. An O-glucose sugar may be added between the first and second conserved cysteines, and an O-fucose may be added between the second and third conserved cysteines. These sugars are added by an as-yet-unidentified O-glucosyltransferase (except for Rumi), and GDP-fucose Protein O-fucosyltransferase 1 (POFUT1), respectively. The addition of O-fucose by POFUT1 is absolutely necessary for notch function, and, without the enzyme to add O-fucose, all notch proteins fail to function properly. As yet, the manner by which the glycosylation of notch affects function is not completely understood.
To add another level of complexity, in mammals there are three Fringe GlcNAc-transferases, named lunatic fringe, manic fringe, and radical fringe. These enzymes are responsible for something called a "fringe effect" on notch signaling. If Fringe adds a GlcNAc to the O-fucose sugar then the subsequent addition of a galactose and sialic acid will occur. In the presence of this tetrasaccharide, notch signals strongly when it interacts with the Delta ligand, but has markedly inhibited signaling when interacting with the Jagged ligand. The means by which this addition of sugar inhibits signaling through one ligand, and potentiates signaling through another is not clearly understood.
Once the notch extracellular domain interacts with a ligand, an ADAM-family metalloprotease called ADAM10, cleaves the notch protein just outside the membrane. This releases the extracellular portion of notch (NECD), which continues to interact with the ligand. The ligand plus the notch extracellular domain is then endocytosed by the ligand-expressing cell. There may be signaling effects in the ligand-expressing cell after endocytosis; this part of notch signaling is a topic of active research. After this first cleavage, an enzyme called γ-secretase (which is implicated in Alzheimer's disease) cleaves the remaining part of the notch protein just inside the inner leaflet of the cell membrane of the notch-expressing cell. This releases the intracellular domain of the notch protein (NICD), which then moves to the nucleus, where it can regulate gene expression by activating the transcription factorCSL. It was originally thought that these CSL proteins suppressed Notch target transcription. However, further research showed that, when the intracellular domain binds to the complex, it switches from a repressor to an activator of transcription. Other proteins also participate in the intracellular portion of the notch signaling cascade.
Notch signaling is initiated when Notch receptors on the cell surface engage ligands presented in trans on opposing cells. Despite the expansive size of the Notch extracellular domain, it has been demonstrated that EGF domains 11 and 12 are the critical determinants for interactions with Delta. Additional studies have implicated regions outside of Notch EGF11-12 in ligand binding. For example, Notch EGF domain 8 plays a role in selective recognition of Serrate/Jagged and EGF domains 6-15 are required for maximal signaling upon ligand stimulation. A crystal structure of the interacting regions of Notch1 and Delta-like 4 (Dll4) provided a molecular-level visualization of Notch-ligand interactions, and revealed that the N-terminal MNNL (or C2) and DSL domains of ligands bind to Notch EGF domains 12 and 11, respectively. The Notch1-Dll4 structure also illuminated a direct role for Notch O-linked fucose and glucose moieties in ligand recognition, and rationalized a structural mechanism for the glycan-mediated tuning of Notch signaling.
The Notch signaling pathway plays an important role in cell-cell communication, and further regulates embryonic development.
Notch signaling is required in the regulation of polarity. For example, mutation experiments have shown that loss of Notch signaling causes abnormal anterior-posterior polarity in somites. Also, Notch signaling is required during left-right asymmetry determination in vertebrates.
Early studies in the nematode model organism C. elegans indicate that Notch signaling has a major role in the induction of mesoderm and cell fate determination. As mentioned previously, C. elegans has two genes that encode for partially functionally redundant Notch homologs, glp-1 and lin-12. During C. elegans, GLP-1, the C. elegans Notch homolog, interacts with APX-1, the C. elegans Delta homolog. This signaling between particular blastomeres induces differentiation of cell fates and establishes the dorsal-ventral axis.
Notch signaling is central to somitogenesis. In 1995, Notch1 was shown to be important for coordinating the segmentation of somites in mice. Further studies identified the role of Notch signaling in the segmentation clock. These studies hypothesized that the primary function of Notch signaling does not act on an individual cell, but coordinates cell clocks and keep them synchronized. This hypothesis explained the role of Notch signaling in the development of segmentation and has been supported by experiments in mice and zebrafish. Experiments with Delta1 mutant mice that show abnormal somitogenesis with loss of anterior/posterior polarity suggest that Notch signaling is also necessary for the maintenance of somite borders.
During somitogenesis, a molecular oscillator in paraxial mesoderm cells dictates the precise rate of somite formation. A clock and wavefront model has been proposed in order to spatially determine the location and boundaries between somites. This process is highly regulated as somites must have the correct size and spacing in order to avoid malformations within the axial skeleton that may potentially lead to spondylocostal dysostosis. Several key components of the Notch signaling pathway help coordinate key steps in this process. In mice, mutations in Notch1, Dll1 or Dll3, Lfng, or Hes7 result in abnormal somite formation. Similarly, in humans, the following mutations have been seen to lead to development of spondylocostal dysostosis: DLL3, LFNG, or HES7.
Notch signaling is known to occur inside ciliated, differentiating cells found in the first epidermal layers during early skin development. Furthermore, it has found that presenilin-2 works in conjunction with ARF4 to regulate Notch signaling during this development. However, it remains to be determined whether gamma-secretase has a direct or indirect role in modulating Notch signaling.
Central nervous system development and function
Early findings on Notch signaling in central nervous system (CNS) development were performed mainly in Drosophila with mutagenesis experiments. For example, the finding that an embryonic lethal phenotype in Drosophila was associated with Notch dysfunction indicated that Notch mutations can lead to the failure of neural and Epidermal cell segregation in early Drosophila embryos. In the past decade, advances in mutation and knockout techniques allowed research on the Notch signaling pathway in mammalian models, especially rodents.
The Notch signaling pathway was found to be critical mainly for neural progenitor cell (NPC) maintenance and self-renewal. In recent years, other functions of the Notch pathway have also been found, including glial cell specification,neurites development, as well as learning and memory.
Neuron cell differentiation
The Notch pathway is essential for maintaining NPCs in the developing brain. Activation of the pathway is sufficient to maintain NPCs in a proliferating state, whereas loss-of-function mutations in the critical components of the pathway cause precocious neuronal differentiation and NPC depletion. Modulators of the Notch signal, e.g., the Numb protein are able to antagonize Notch effects, resulting in the halting of cell cycle and differentiation of NPCs. Conversely, the fibroblast growth factor pathway promotes Notch signaling to keep stem cells of the cerebral cortex in the proliferative state, amounting to a mechanism regulating cortical surface area growth and, potentially, gyrification. In this way, Notch signaling controls NPC self-renewal as well as cell fate specification.
A non-canonical branch of the Notch signaling pathway that involves the phosphorylation of STAT3 on the serine residue at amino acid position 727 and subsequent Hes3 expression increase (STAT3-Ser/Hes3 Signaling Axis) has been shown to regulate the number of NPCs in culture and in the adult rodent brain.
In adult rodents and in cell culture, Notch3 promotes neuronal differentiation, having a role opposite to Notch1/2. This indicates that individual Notch receptors can have divergent functions, depending on cellular context.
In vitro studies show that Notch can influence neurite development.In vivo, deletion of the Notch signaling modulator, Numb, disrupts neuronal maturation in the developing cerebellum, whereas deletion of Numb disrupts axonal arborization in sensory ganglia. Although the mechanism underlying this phenomenon is not clear, together these findings suggest Notch signaling might be crucial in neuronal maturation.
In gliogenesis, Notch appears to have an instructive role that can directly promote the differentiation of many glial cell subtypes. For example, activation of Notch signaling in the retina favors the generation of Muller glia cells at the expense of neurons, whereas reduced Notch signaling induces production of ganglion cells, causing a reduction in the number of Muller glia.
Adult brain function
Apart from its role in development, evidence shows that Notch signaling is also involved in neuronal apoptosis, neurite retraction, and neurodegeneration of ischemic stroke in the brain In addition to developmental functions, Notch proteins and ligands are expressed in cells of the adult nervous system, suggesting a role in CNS plasticity throughout life. Adult mice heterozygous for mutations in either Notch1 or Cbf1 have deficits in spatial learning and memory. Similar results are seen in experiments with presenilins1 and 2, which mediate the Notch intramembranous cleavage. To be specific, conditional deletion of presenilins at 3 weeks after birth in excitatory neurons causes learning and memory deficits, neuronal dysfunction, and gradual neurodegeneration. Several gamma secretase inhibitors that underwent human clinical trials in Alzheimer's disease and MCI patients resulted in statistically significant worsening of cognition relative to controls, which is thought to be due to its incidental effect on Notch signalling.
The Notch signaling pathway is a critical component of cardiovascular formation and morphogenesis in both development and disease. It is required for the selection of endothelial tip and stalk cells during sprouting angiogenesis.
Notch signal pathway plays a crucial role in at least three cardiac development processes: Atrioventricular canal development, myocardial development, and cardiac outflow tract (OFT) development.
Atrioventricular (AV) canal development
AV boundary formation
Notch signaling can regulate the atrioventricular boundary formation between the AV canal and the chamber myocardium. Studies have revealed that both loss- and gain-of-function of the Notch pathway results in defects in AV canal development. In addition, the Notch target genes HEY1 and HEY2 are involved in restricting the expression of two critical developmental regulator proteins, BMP2 and Tbx2, to the AV canal.
AV epithelial-mesenchymal transition (EMT)
Notch signaling is also important for the process of AV EMT, which is required for AV canal maturation. After the AV canal boundary formation, a subset of endocardial cells lining the AV canal are activated by signals emanating from the myocardium and by interendocardial signaling pathways to undergo EMT. Notch1 deficiency results in defective induction of EMT. Very few migrating cells are seen and these lack mesenchymal morphology. Notch may regulate this process by activating matrix metalloproteinase2 (MMP2) expression, or by inhibiting vascular endothelial (VE)-cadherin expression in the AV canal endocardium while suppressing the VEGF pathway via VEGFR2. In RBPJk/CBF1-targeted mutants, the heart valve development is severely disrupted, presumably because of defective endocardial maturation and signaling.
Some studies in Xenopus and in mouse embryonic stem cells indicate that cardiomyogenic commitment and differentiation require Notch signaling inhibition. Active Notch signaling is required in the ventricular endocardium for proper trabeculae development subsequent to myocardial specification by regulating BMP10, NRG1, and EphrinB2 expression. Notch signaling sustains immature cardiomyocyte proliferation in mammals  and zebrafish.
The downstream effector of Notch signaling, HEY2, was also demonstrated to be important in regulating ventricular development by its expression in the interventricular septum and the endocardial cells of the cardiac cushions. Cardiomyocyte and smooth muscle cell-specific deletion of HEY2 results in impaired cardiac contractility, malformed right ventricle, and ventricular septal defects.
Ventricular outflow tract development
During development of the aortic arch and the aortic arch arteries, the Notch receptors, ligands, and target genes display a unique expression pattern. When the Notch pathway was blocked, the induction of vascular smooth muscle cell marker expression failed to occur, suggesting that Notch is involved in the differentiation of cardiac neural crest cells into vascular cells during outflow tract development.
Activation of Notch takes place primarily in "connector" cells and cells that line patent stable blood vessels through direct interaction with the Notch ligand, Delta-like ligand 4 (Dll4), which is expressed in the endothelial tip cells. VEGF signaling, which is an important factor for migration and proliferation of endothelial cells, can be downregulated in cells with activated Notch signaling by lowering the levels of Vegf receptor transcript. Zebrafish embryos lacking Notch signaling exhibit ectopic and persistent expression of the zebrafish ortholog of VEGF3, flt4, within all endothelial cells, while Notch activation completely represses its expression.
Notch signaling may be used to control the sprouting pattern of blood vessels during angiogenesis. When cells within a patent vessel are exposed to VEGF signaling, only a restricted number of them initiate the angiogenic process. Vegf is able to induce DLL4 expression. In turn, DLL4 expressing cells down-regulate Vegf receptors in neighboring cells through activation of Notch, thereby preventing their migration into the developing sprout. Likewise, during the sprouting process itself, the migratory behavior of connector cells must be limited to retain a patent connection to the original blood vessel.
During development, definitive endoderm and ectoderm differentiates into several gastrointestinal epithelial lineages, including endocrine cells. Many studies have indicated that Notch signaling has a major role in endocrine development.
The formation of the pancreas from endoderm begins in early development. The expression of elements of the Notch signaling pathway have been found in the developing pancreas, suggesting that Notch signaling is important in pancreatic development. Evidence suggests Notch signaling regulates the progressive recruitment of endocrine cell types from a common precursor, acting through two possible mechanisms. One is the "lateral inhibition", which specifies some cells for a primary fate but others for a secondary fate among cells that have the potential to adopt the same fate. Lateral inhibition is required for many types of cell fate determination. Here, it could explain the dispersed distribution of endocrine cells within pancreatic epithelium. A second mechanism is "suppressive maintenance", which explains the role of Notch signaling in pancreas differentiation. Fibroblast growth factor10 is thought to be important in this activity, but the details are unclear.
The role of Notch signaling in the regulation of gut development has been indicated in several reports. Mutations in elements of the Notch signaling pathway affect the earliest intestinal cell fate decisions during zebrafish development. Transcriptional analysis and gain of function experiments revealed that Notch signaling targets Hes1 in the intestine and regulates a binary cell fate decision between adsorptive and secretory cell fates.
Early in vitro studies have found the Notch signaling pathway functions as down-regulator in osteoclastogenesis and osteoblastogenesis. Notch1 is expressed in the mesenchymal condensation area and subsequently in the hypertrophic chondrocytes during chondrogenesis. Overexpression of Notch signaling inhibits bone morphogenetic protein2-induced osteoblast differentiation. Overall, Notch signaling has a major role in the commitment of mesenchymal cells to the osteoblastic lineage and provides a possible therapeutic approach to bone regeneration.
Aberrant Notch signaling is a driver of T cell acute lymphoblastic leukemia (T-ALL) and is mutated in at least 65% of all T-ALL cases. Notch signaling can be activated by mutations in Notch itself, inactivating mutations in FBXW7 (a negative regulator of Notch1), or rarely by t(7;9)(q34;q34.3) translocation. In the context of T-ALL, Notch activity cooperates with additional oncogenic lesions such as c-MYC to activate anabolic pathways such as ribosome and protein biosynthesis thereby promoting leukemia cell growth.
The involvement of Notch signaling in many cancers has led to investigation of notch inhibitors (especially gamma-secretase inhibitors) as cancer treatments which are in different phases of clinical trials.As of 2013[update] at least 7 notch inhibitors were in clinical trials.MK-0752 has given promising results in an early clinical trial for breast cancer.
Synthetic Notch signaling
It is possible to engineer synthetic Notch receptors by replacing the extracellular receptor and intracellular transcriptional domains with other domains of choice. This allows researchers to select which ligands are detected, and which genes are upregulated in response. Using this technology, cells can report or change their behavior in response to contact with user-specified signals, facilitating new avenues of both basic and applied research into cell-cell signaling. Notably, this system allows multiple synthetic pathways to be engineered into a cell in parallel.
Related Research Articles
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, though the last three are not found in humans.
Paracrine signaling is a form of cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behavior of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to endocrine factors, juxtacrine interactions, and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.
Platelet-derived growth factor (PDGF) is one of numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood vessel tissue, mitogenesis, i.e. proliferation, of mesenchymal cells such as fibroblasts, osteoblasts, tenocytes, vascular smooth muscle cells and mesenchymal stem cells as well as chemotaxis, the directed migration, of mesenchymal cells. Platelet-derived growth factor is a dimeric glycoprotein that can be composed of two A subunits (PDGF-AA), two B subunits (PDGF-BB), or one of each (PDGF-AB).
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. Wnt is an acronym in the field of genetics that stands for 'Wingless/Integrated'.
Cell signaling is part of any communication process that governs basic activities of cells and coordinates all cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity, as well as normal tissue homeostasis. Errors in signaling interactions and cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases may be treated more effectively and, theoretically, artificial tissues may be created.
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include basal cell carcinoma.
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non receptor tyrosine kinases which do not possess transmembrane domains.
Argos is a secreted protein that is an inhibitor of the epidermal growth factor receptor (EGFR) pathway in Drosophila melanogaster. Argos inhibits the EGFR pathway by sequestering the EGFR ligand Spitz. Argos binds the epidermal growth factor domain of Spitz, preventing interaction between Spitz and EGFR. Argos does not directly interact with EGFR. Argos represents the first example of ligand sequestration as a mechanism of inhibition in the ErbB (EGFR) family.
Jagged1 (JAG1) is one of five cell surface proteins (ligands) that interact with 4 receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fate decisions in many organ systems. Once the JAG1-NOTCH (receptor-ligand) interactions take place, a cascade of proteolytic cleavages is triggered resulting in activation of the transcription for downstream target genes. Located on human chromosome 20, the JAG1 gene is expressed in multiple organ systems in the body and causes the autosomal dominant disorder Alagille syndrome (ALGS) resulting from loss of function mutations within the gene. JAG1 has also been designated as CD339.
Notch homolog 1, translocation-associated (Drosophila), also known as NOTCH1, is a human gene encoding a single-pass transmembrane receptor.
Neurogenic locus notch homolog 4 also known as notch 4 is a protein that in humans is encoded by the NOTCH4 gene located on chromosome 6.
Neurogenic locus notch homolog protein 2 also known as notch 2 is a protein that in humans is encoded by the NOTCH2 gene.
Delta-like protein 1 is a protein that in humans is encoded by the DLL1 gene.
Transcription factor HES1 is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.
Jagged-2 is a protein that in humans is encoded by the JAG2 gene.
Delta-like 4 is a protein that in humans is encoded by the DLL4 gene.
EGF-like domain-containing protein 7 is a protein that in humans is encoded by the EGFL7 gene. Intron 7 of EGFL7 hosts the miR-126 microRNA gene.
The STAT3-Ser/Hes3 signaling axis is a specific type of intracellular signaling pathway that regulates several fundamental properties of cells.
↑ Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israël A (Feb 2000). "A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE". Molecular Cell. 5 (2): 207–16. doi:10.1016/S1097-2765(00)80417-7. PMID10882063.
↑ Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S (Dec 1985). "Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats". Cell. 43 (3 Pt 2): 567–81. doi:10.1016/0092-8674(85)90229-6. PMID3935325.
↑ Lieber T, Kidd S, Alcamo E, Corbin V, Young MW (Oct 1993). "Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei". Genes & Development. 7 (10): 1949–65. doi:10.1101/gad.7.10.1949. PMID8406001.
↑ Singson A, Mercer KB, L'Hernault SW (Apr 1998). "The C. elegans spe-9 gene encodes a sperm transmembrane protein that contains EGF-like repeats and is required for fertilization". Cell. 93 (1): 71–9. doi:10.1016/S0092-8674(00)81147-2. PMID9546393.
↑ Nam Y, Sliz P, Song L, Aster JC, Blacklow SC (Mar 2006). "Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes". Cell. 124 (5): 973–83. doi:10.1016/j.cell.2005.12.037. PMID16530044.
↑ Munro S, Freeman M (Jul 2000). "The notch signalling regulator fringe acts in the Golgi apparatus and requires the glycosyltransferase signature motif DXD". Current Biology. 10 (14): 813–20. doi:10.1016/S0960-9822(00)00578-9. PMID10899003.
↑ Shao L, Luo Y, Moloney DJ, Haltiwanger R (Nov 2002). "O-glycosylation of EGF repeats: identification and initial characterization of a UDP-glucose: protein O-glucosyltransferase". Glycobiology. 12 (11): 763–70. doi:10.1093/glycob/cwf085. PMID12460944.
↑ Thomas GB, van Meyel DJ (Feb 2007). "The glycosyltransferase Fringe promotes Delta-Notch signaling between neurons and glia, and is required for subtype-specific glial gene expression". Development. 134 (3): 591–600. doi:10.1242/dev.02754. PMID17215308.
↑ LaVoie MJ, Selkoe DJ (Sep 2003). "The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments". The Journal of Biological Chemistry. 278 (36): 34427–37. doi:10.1074/jbc.M302659200. PMID12826675.
↑ van Eeden FJ, Granato M, Schach U, Brand M, Furutani-Seiki M, Haffter P, Hammerschmidt M, Heisenberg CP, Jiang YJ, Kane DA, Kelsh RN, Mullins MC, Odenthal J, Warga RM, Allende ML, Weinberg ES, Nüsslein-Volhard C (Dec 1996). "Mutations affecting somite formation and patterning in the zebrafish, Danio rerio". Development. 123: 153–64. PMID9007237.
↑ Huppert SS, Ilagan MX, De Strooper B, Kopan R (May 2005). "Analysis of Notch function in presomitic mesoderm suggests a gamma-secretase-independent role for presenilins in somite differentiation". Developmental Cell. 8 (5): 677–88. doi:10.1016/j.devcel.2005.02.019. PMID15866159.
↑ Lowell, S., Jones, P., Le Roux, I., Dunne, J., & Watt, F. M. (2000). Stimulation of human epidermal differentiation by Delta–Notch signalling at the boundaries of stem-cell clusters. Current Biology, 10(9), 491–500.
↑ Ezratty, E. J., Pasolli, H. A., & Fuchs, E. (2016). A Presenilin-2–ARF4 trafficking axis modulates Notch signaling during epidermal differentiation. J Cell Biol, 214(1), 89–101.
↑ Zhong W, Jiang MM, Weinmaster G, Jan LY, Jan YN (May 1997). "Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis". Development. 124 (10): 1887–97. PMID9169836.
↑ Li HS, Wang D, Shen Q, Schonemann MD, Gorski JA, Jones KR, Temple S, Jan LY, Jan YN (Dec 2003). "Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis". Neuron. 40 (6): 1105–18. doi:10.1016/S0896-6273(03)00755-4. PMID14687546.
↑ Kokubo H, Tomita-Miyagawa S, Hamada Y, Saga Y (Feb 2007). "Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2". Development. 134 (4): 747–55. doi:10.1242/dev.02777. PMID17259303.
↑ Crosby CV, Fleming PA, Argraves WS, Corada M, Zanetta L, Dejana E, Drake CJ (Apr 2005). "VE-cadherin is not required for the formation of nascent blood vessels but acts to prevent their disassembly". Blood. 105 (7): 2771–6. doi:10.1182/blood-2004-06-2244. PMID15604224.
↑ Noseda M, McLean G, Niessen K, Chang L, Pollet I, Montpetit R, Shahidi R, Dorovini-Zis K, Li L, Beckstead B, Durand RE, Hoodless PA, Karsan A (Apr 2004). "Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation". Circulation Research. 94 (7): 910–7. doi:10.1161/01.RES.0000124300.76171.C9. PMID14988227.
↑ Rones MS, McLaughlin KA, Raffin M, Mercola M (Sep 2000). "Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis". Development. 127 (17): 3865–76. PMID10934030.
1 2 Crosnier C, Vargesson N, Gschmeissner S, Ariza-McNaughton L, Morrison A, Lewis J (2005). "Delta-Notch signalling controls commitment to a secretory fate in the zebrafish intestine". Development. 132 (5): 1093–104. doi:10.1242/dev.01644. PMID15689380.
↑ Yamada T, Yamazaki H, Yamane T, Yoshino M, Okuyama H, Tsuneto M, Kurino T, Hayashi S, Sakano S (Mar 2003). "Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells". Blood. 101 (6): 2227–34. doi:10.1182/blood-2002-06-1740. PMID12411305.
↑ Watanabe N, Tezuka Y, Matsuno K, Miyatani S, Morimura N, Yasuda M, Fujimaki R, Kuroda K, Hiraki Y, Hozumi N, Tezuka K (2003). "Suppression of differentiation and proliferation of early chondrogenic cells by Notch". Journal of Bone and Mineral Metabolism. 21 (6): 344–52. doi:10.1007/s00774-003-0428-4. PMID14586790.