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Notch Family Proteins

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Notch Family Proteins

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Notch Family Proteins Background

The Notch gene encodes a class of highly conserved cell surface receptors that regulate the development of various biological cells, from sea urchins to humans. Notch signal affects many processes of normal cell morphogenesis, including differentiation of pluripotent progenitor cells, apoptosis, cell proliferation, and formation of cell boundaries. Phenotypic changes caused by mutations in Notch loci, indicating diversity of Notch signaling. The Notch signaling pathway is a highly conserved system found in many multicellular organisms. Mammals are known to express four different gap receptors, Notch1, Notch2, Notch3 and Notch4. Notch signaling is critical in a variety of developmental processes, including neurogenesis, myogenesis, angiogenesis, regulation of hematopoiesis and epithelial to mesenchymal transition, and tissue homeostasis. A gap receptor is a transmembrane protein composed of a large extracellular domain that reversibly binds to the extracellular domain of Notch in a calcium-dependent manner. Abnormal Notch signaling leads to important signaling events that promote cancer development and autoimmune diseases.

Notch Family Proteins

NOTCH1

Notch homolog 1 is a human gene encoding a one-way transmembrane receptor. This gene encodes a member of the Notch family. Notch family members play a role in various developmental processes by controlling cell fate. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells. In Drosophila, the interaction of the gap with its cell-binding ligand (δ, jagged) establishes an intercellular signaling pathway that plays a key role in development. Gap-ligand homologs have also been identified in humans, but the precise interactions between these ligands and human gap homologs remain to be determined. The protein is cleaved in the trans-Golgi network and is present on the cell surface as a heterodimer. This protein acts as a receptor for membrane-bound ligands and may play multiple roles during development.

Notch Family Proteins Figure 1. Protein structure of Notch homolog 1.

NOTCH2

Neurogenic locus nick homologous protein 2 is a protein encoded by the NOTCH2 gene in humans. Gap 2 is a member of the Gap family. Notch family members play a role in various developmental processes by controlling cell fate. Notch signaling network is an evolutionarily conserved intercellular signaling pathway that regulates the interaction between physically adjacent cells. The protein is cleaved in the trans-Golgi network and exists as a heterodimer on the cell surface. The protein acts as a receptor for membrane-bound ligands and may play a role in blood vessel, kidney, and liver development.

Notch Family Proteins Figure 2. Protein structure of NOTCH2.

Triggering

Because most ligands are also transmembrane proteins, receptors are typically triggered only by direct cell-to-cell contact. In this way, the population of cells can be organized by themselves such that if a cell expresses a given trait, it can be shut down in adjacent cells by an intercellular Notch signal. In this way, the cell populations influence each other to form a large structure.

The Notch cascade consists of Notch and Notch ligands, as well as intracellular proteins that transmit Notch signaling to the nucleus. The Notch/Lin-12/Glp-1 receptor family was found to be involved in the regulation of cell fate during the development of Drosophila and Caenorhabditis elegans. When puberty is reached, the Notch signaling pathway begins to inhibit new cell growth and stabilize the adult neural network.

Notch Family Proteins Figure 3. Notch protein pathway.

Notch Ligands

Notch ligands (Figure 4) are type I transmembrane proteins. Drosophila Notch ligands have two homologues Delta and Serrate, the nematode Notch ligand is LAG2. Hence the Notch ligand is also known as DSL protein. A number of Notch ligands are also found in vertebrate, the Delta homology is called Delta-like molecules, and the Serrate homology is called Jagged. Currently, human Notch ligands are found to have DLL 1, 3, 4 and Jagged 1, 2. Ligand Extracellular DSL domains are highly conserved in evolution and are essential for ligand-receptor binding to activate Notch signaling. Intracellular domain of Notch ligands is short, only contains 70 amino acid residues, the function has not yet been clarified. Recent studies have found that the intracellular domain of Delta 1 can induce cell growth inhibition. It is speculated that the intracellular segment of the ligand may be similar with the receptor intracellular domain to have the function of signal transduction, but the specific mechanism needs further study.

Notch Family Proteins Figure 4. Structures of human Notch ligands: JAG1, JAG2, DLL1, DLL3, DLL4, DLK1, and DLK2.

Notch Signal Pathway and Diseases

Notch signaling pathway has a very conserved mechanism in signal transduction, and abnormalities in this regulatory mechanism often lead to congenital genetic diseases. Mutations in related genes in the Notch signaling pathway have been linked to genetic diseases such as CADASIL, Algier Syndrome, and gastric hypoplasia. CADASIL is an autosomal dominant hereditary cerebral artery disease with subdural necrosis and white matter encephalopathy. The pathogenesis is mainly due to the deletion or insertion of cysteine residues in the extracellular domain of the Notch 3 gene expressed on vascular smooth muscle cells. Aligile syndrome is an autosomal dominant genetic disease that can cause developmental defects in many organs, such as the heart, liver, and kidneys.

Notch Family Proteins Figure 5. A micrograph showing punctate immunostaining (brown) with a Notch 3 antibody, as is characteristic in CADASIL.

Reference:

  1. Vardar D.; et al. Nuclear magnetic resonance structure of a prototype Lin12-Notch repeat module from human Notch1. Biochemistry. 2003,42 (23): 7061–7.

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