The
Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Notch is present in all metazoans, and vertebrates possess four different notch receptors, referred to as
NOTCH1Notch homolog 1, translocation-associated , also known as NOTCH1, is a human gene encoding a single-pass transmembrane receptor.A deficiency can be associated with bicuspid aortic valve....
,
NOTCH2Neurogenic locus notch homolog protein 2 is a protein that in humans is encoded by the NOTCH2 gene.NOTCH2 is associated with Alagille syndrome.-Interactions:NOTCH2 has been shown to interact with JAG1, JAG2, Delta-like 1 and GSK3B....
,
NOTCH3Neurogenic locus notch homolog protein 3 is a protein that in humans is encoded by the NOTCH3 gene.-Further reading:-External links:...
, and
NOTCH4Neurogenic locus notch homolog protein 4 is a protein that in humans is encoded by the NOTCH4 gene.-Further reading:...
. The Notch receptor is a single-pass
transmembrane receptor protein. It is a hetero-oligomer composed of a large
extracellularIn cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
portion, which associates in a
calciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft grey alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust...
-dependent, non-covalent interaction with a smaller piece of the Notch protein composed of a short extracellular region, a single transmembrane-pass, and a small
intracellularNot to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
region.
The
Notch gene was discovered in 1917 by
Thomas Hunt MorganThomas Hunt Morgan was an American geneticist and embryologist. Morgan received his PhD from Johns Hopkins University in 1890 and researched embryology during his tenure at Bryn Mawr. Following the rediscovery of Mendelian inheritance in 1900, Morgan's research moved to the study of mutation in...
, when it was first noticed in a strain of the fruit fly
Drosophila melanogasterDrosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is commonly known as the common fruit fly or vinegar fly. Starting from Charles W...
with notches apparent in their wingblades.
The
Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Notch is present in all metazoans, and vertebrates possess four different notch receptors, referred to as
NOTCH1Notch homolog 1, translocation-associated , also known as NOTCH1, is a human gene encoding a single-pass transmembrane receptor.A deficiency can be associated with bicuspid aortic valve....
,
NOTCH2Neurogenic locus notch homolog protein 2 is a protein that in humans is encoded by the NOTCH2 gene.NOTCH2 is associated with Alagille syndrome.-Interactions:NOTCH2 has been shown to interact with JAG1, JAG2, Delta-like 1 and GSK3B....
,
NOTCH3Neurogenic locus notch homolog protein 3 is a protein that in humans is encoded by the NOTCH3 gene.-Further reading:-External links:...
, and
NOTCH4Neurogenic locus notch homolog protein 4 is a protein that in humans is encoded by the NOTCH4 gene.-Further reading:...
. The Notch receptor is a single-pass
transmembrane receptor protein. It is a hetero-oligomer composed of a large
extracellularIn cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
portion, which associates in a
calciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft grey alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust...
-dependent, non-covalent interaction with a smaller piece of the Notch protein composed of a short extracellular region, a single transmembrane-pass, and a small
intracellularNot to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
region.
Discovery
The
Notch gene was discovered in 1917 by
Thomas Hunt MorganThomas Hunt Morgan was an American geneticist and embryologist. Morgan received his PhD from Johns Hopkins University in 1890 and researched embryology during his tenure at Bryn Mawr. Following the rediscovery of Mendelian inheritance in 1900, Morgan's research moved to the study of mutation in...
, when it was first noticed in a strain of the fruit fly
Drosophila melanogasterDrosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is commonly known as the common fruit fly or vinegar fly. Starting from Charles W...
with notches apparent in their wingblades. Its molecular analysis and sequencing was undertaken in the 1980s.
Mechanism of action
The Notch
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
sits like a trigger spanning the
cell membraneThe cell membrane is the biological membrane separating the interior of a cell from the outside environment....
, with part of it inside and part outside.
LigandIn biochemistry and pharmacology, a ligand is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as...
proteins binding to the extracellular domain induce proteolytic cleavage and release of the intracellular domain, which enters the
cell nucleusIn cell biology, the nucleus , also sometimes referred to as the "control center", is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as...
to alter
gene expressionGene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as rRNA genes or tRNA genes, the product is a functional RNA...
.
Because most ligands are also transmembrane proteins, the receptor is normally triggered only from direct cell-to-cell contact. In this way, groups of cells can organise themselves, such that, if one cell expresses a given trait, this may be switched off in neighbour cells by the inter-cellular Notch signal. In this way, groups of cells influence one another to make large structures.
The
Notch cascade consists of Notch and Notch
ligandsIn biochemistry and pharmacology, a ligand is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as...
, 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. elegansCaenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
.
Function
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:
- neuron
A neuron is an excitable cell in the nervous system that processes and transmits information by electrochemical signaling. Neurons are the core components of the brain, the vertebrate spinal cord, the invertebrate ventral nerve cord, and the peripheral nerves...
al function and development
- stabilization of arterial endothelial fate and angiogenesis
Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over this, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for new blood vessel formation by...
- regulation of crucial cell communication events between endocardium
The endocardium is the innermost layer of tissue that lines the chambers of the heart. Its cells, embryologically and biologically, are similar to the endothelial cells that line blood vessels....
and myocardium during both the formation of the valve primordial and ventricularIn the heart, a ventricle is a heart chamber which collects blood from an atrium and pumps it out of the heart...
development and differentiation
- cardiac valve homeostasis, as well as implications in other human disorders involving the cardiovascular system
- timely cell lineage specification of both endocrine and exocrine pancreas
The exocrine pancreas has ducts that are arranged in clusters called acini . Pancreatic secretions are secreted into the lumen of the acinus, and then accumulate in intralobular ducts that drain to the main pancreatic duct, which drains directly into the duodenum.Control of the exocrine function of...
- 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 osteoblast
An osteoblast is a mononucleate cell that is responsible for bone formation. Osteoblasts produce osteoid, which is composed mainly of Type I collagen. Osteoblasts are also responsible for mineralization of the osteoid matrix...
ic lineage, suggesting a potential therapeutic role for Notch in bone regeneration and osteoporosis
- regulation of cell-fate decision in mammary gland
Mammary glands are the organs that, in mammals, produce milk for the sustenance of the young. These exocrine glands are enlarged and modified sweat glands and give mammals their name...
s at several distinct development stages
- possibly some non-nuclear mechanisms, such as control of the actin cytoskeleton through the tyrosine kinase Abl
V-abl Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein which in humans is encoded by the ABL1 gene located on chromosome 9.- Function :...
Notch signaling is dysregulated in many cancers, and faulty Notch signaling is implicated in many diseases including
T-ALLT-cell acute lymphoblastic leukemia can refer to:* Precursor T acute lymphoblastic leukemia/lymphoma* Adult T-cell leukemia/lymphoma...
(
T-cell acute lymphoblastic leukemiaT-cell acute lymphoblastic leukemia can refer to:* Precursor T acute lymphoblastic leukemia/lymphoma* Adult T-cell leukemia/lymphoma...
),
CADASILCADASIL is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the Notch 3 gene on chromosome 19...
(Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy), MS (
Multiple SclerosisMultiple sclerosis is an idiopathic disease of suspected autoimmune cause, in which the body's immune response attacks a person's central nervous system , leading to demyelination. Disease onset usually occurs in young adults, and it is more common in females...
),
Tetralogy of FallotTetralogy of Fallot is a congenital heart defect which is classically understood to involve four anatomical abnormalities...
,
Alagille syndromeAlagille syndrome is a genetic disorder that affects the liver, heart, and other systems of the body. Problems associated with the disorder generally become evident in infancy or early childhood...
, and myriad other disease states.
Pathway
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 melanogasterDrosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is commonly known as the common fruit fly or vinegar fly. Starting from Charles W...
(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
Caenorhabditis elegansCaenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
, 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
cysteine knotCysteine is an α-amino acid with the chemical formula HO
2CCHCH
2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is nonpolar and thus cysteine is usually classified as...
motifs called
EGFEpidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
-like repeats.
Notch 1, for example, has 36 of these repeats. Each EGF-like repeat is comprised 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 glycansThe term glycan refers to a polysaccharide or oligosaccharide. Glycan may also be used to refer to the carbohydrate portion of a glycoconjugate, such as a glycoprotein, glycolipid, or a proteoglycan. Glycans usually consist solely of O-glycosidic linkages of monosaccharides...
at specific sites. An
O-glucoseGlycosylation is the enzymatic process that links saccharides to produce glycans, attached to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells . Glycosylation is a form of co-translational and post-translational...
sugar may be added between the first and second conserved cysteines, and an
O-fucoseGlycosylation is the enzymatic process that links saccharides to produce glycans, attached to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells . Glycosylation is a form of co-translational and post-translational...
may be added between the second and third conserved cysteines. These sugars are added by an as-yet-unidentified
O-glucosyltransferaseGlycosylation is the enzymatic process that links saccharides to produce glycans, attached to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells . Glycosylation is a form of co-translational and post-translational...
, and
GDP-fucose Protein O-fucosyltransferase 1GDP-fucose protein O-fucosyltransferase 1 is an enzyme responsible for adding fucose sugars in O linkage to serine or threonine residues between the second and third conserved cysteines in EGF-like repeats on the Notch protein...
(
POFUT1GDP-fucose protein O-fucosyltransferase 1 is an enzyme responsible for adding fucose sugars in O linkage to serine or threonine residues between the second and third conserved cysteines in EGF-like repeats on the Notch protein...
), respectively. The addition of
O-fucoseGlycosylation is the enzymatic process that links saccharides to produce glycans, attached to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells . Glycosylation is a form of co-translational and post-translational...
by
POFUT1GDP-fucose protein O-fucosyltransferase 1 is an enzyme responsible for adding fucose sugars in O linkage to serine or threonine residues between the second and third conserved cysteines in EGF-like repeats on the Notch protein...
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.
The
O-glucose on Notch can be further elongated to a trisaccharide with the addition of two
xyloseXylose , or wood sugar, is an aldopentose — a monosaccharide containing five carbon atoms and including an aldehyde functional group. It has chemical formula 5105. Xylose is found in the embryos of most edible plants. It was first isolated from wood by Koch...
sugars by
xylosyltransferasesXylose , or wood sugar, is an aldopentose — a monosaccharide containing five carbon atoms and including an aldehyde functional group. It has chemical formula 5105. Xylose is found in the embryos of most edible plants. It was first isolated from wood by Koch...
, and the
O-fucoseGlycosylation is the enzymatic process that links saccharides to produce glycans, attached to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells . Glycosylation is a form of co-translational and post-translational...
can be elongated to a tetrasaccharide by the ordered addition of an
N-acetylglucosamineN-Acetylglucosamine is a monosaccharide derivative of glucose. It is an amide between glucosamine and acetic acid...
(GlcNAc) sugar by an
N-AcetylglucosaminyltransferaseN-Acetylglucosamine is a monosaccharide derivative of glucose. It is an amide between glucosamine and acetic acid...
called
FringeFringe genes are important in the workings of the Notch signaling pathway.In Drosophila melanogaster the Fringe gene was identified as part of the Notch mechanism...
, the addition of a
galactoseGalactose is a type of sugar which is less sweet than glucose. It is considered a nutritive sweetener because it has food energy. Its name comes from the Ancient Greek word for milk, γάλακτος ....
by a
galactosyltransferaseGalactose is a type of sugar which is less sweet than glucose. It is considered a nutritive sweetener because it has food energy. Its name comes from the Ancient Greek word for milk, γάλακτος ....
, and the addition of a
sialic acidSialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
by a
sialyltransferaseSialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
.
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-fucoseGlycosylation is the enzymatic process that links saccharides to produce glycans, attached to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells . Glycosylation is a form of co-translational and post-translational...
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 TACE (Tumor Necrosis Factor Alpha Converting Enzyme) cleaves the Notch protein just outside the membrane. This releases the extracellular portion of Notch, which continues to interact with the ligand. The ligand plus the Notch extracellular domain is then
endocytosedEndocytosis is the process by which cells absorb molecules from outside the cell by engulfing it with their cell membrane. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma membrane or cell membrane...
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 diseaseAlzheimer's disease , also called Alzheimer disease, Senile Dementia of the Alzheimer Type or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was...
) cleaves the remaining part of the Notch protein just inside the inner leaflet of the
cell membraneThe cell membrane is the biological membrane separating the interior of a cell from the outside environment....
of the Notch-expressing cell. This releases the intracellular domain of the Notch protein, which then moves to the
nucleusIn cell biology, the nucleus , also sometimes referred to as the "control center", is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as...
, where it can regulate gene expression by activating the
transcription factorIn the field of molecular biology, a transcription factor is a protein that binds to specific DNA sequences and thereby controls the transfer of genetic information from DNA to mRNA...
CSL. Other proteins also participate in the intracellular portion of the Notch signaling cascade.
External links