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Notch proteins are a
family
Family (from la, familia) is a Social group, group of people related either by consanguinity (by recognized birth) or Affinity (law), affinity (by marriage or other relationship). The purpose of the family is to maintain the well-being of its ...
of type-1
transmembrane protein
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
s that form a core component of the
Notch signaling pathway
The Notch signaling pathway is a highly Conserved sequence, conserved cell signaling system present in most animals. Mammals possess four different Notch proteins, notch receptors, referred to as NOTCH1, NOTCH2, Notch 3, NOTCH3, and NOTCH4. The ...
, which is highly conserved in
metazoans
Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in ...
. The Notch
extracellular domain
An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction.A notable ...
mediates interactions with DSL family
ligands
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
, allowing it to participate in
juxtacrine signaling
In biology, juxtacrine signalling (or contact-dependent signalling) is a type of cell–cell or cell–extracellular matrix signalling in multicellular organisms that requires close contact. In this type of signalling, a ligand on one surface bin ...
. The Notch intracellular domain acts as a
transcriptional activator
A transcriptional activator is a protein (transcription factor) that increases transcription of a gene or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and, ...
when in complex with CSL family
transcription factors
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...
. Members of this Type 1 transmembrane protein family share several core structures, including an extracellular domain consisting of multiple
epidermal growth factor
Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds.
EGF was originally descr ...
(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 Within the field of developmental biology, one goal is to understand how a particular cell develops into a final cell type, known as fate determination. Within an embryo, several processes play out at the cellular and tissue level to create an organ ...
decisions. Much of what is known about Notch function comes from studies done in ''
Caenorhabditis elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...
'' (''C.elegans'') and ''
Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...
.'' Human homologs have also been identified, but details of Notch function and interactions with its ligands are not well known in this context.
Discovery
Notch was discovered in a
mutant
In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
''Drosophila'' in March 1913 in the lab of
Thomas Hunt Morgan
Thomas Hunt Morgan (September 25, 1866 – December 4, 1945) 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 tha ...
.
This mutant emerged after several generations of crossing out and back-crossing beaded winged flies with wild type flies and was first characterized by John S. Dexter. The most frequently observed phenotype in Notch mutant flies is the appearance of a concave serration at the most distal end of the wings, for which the
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
is named, accompanied by the absence of marginal bristles. This mutant was found to be a
sex-linked
Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome ( autosome). In humans, these are termed X-linked recessive, ...
dominant on the
X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
that could only be observed in heterozygous females as it was lethal in males and homozygous females.
The first Notch
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
was established in 1917 by C.W. Metz and C.B. Bridges. In the late 1930s, studies of fly
embryogenesis
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
done by Donald F. Poulson provided the first indication of Notch's role in development. Notch-8 mutant males exhibited a lack of the inner
germ layer
A germ layer is a primary layer of cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans (animals that are sister taxa to the sponges) produce two or three pr ...
s, the
endoderm
Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...
and
mesoderm
The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical E ...
, that resulted in failure to undergo later
morphogenesis
Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of devel ...
embryonic lethality. Later studies in early ''Drosophila''
neurogenesis
Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
provided some of the first indications of Notch's roll in cell-cell signaling, as the
nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
in Notch mutants was developed by sacrificing hypodermal cells.
Starting in the 1980s researchers began to gain further insights into Notch function through genetic and molecular experiments. Genetic screens conducted in ''Drosophila'' led to the identification of several proteins that play a central role in Notch signaling, including Enhancer of split,
Master mind, Delta, Suppressor of Hairless (CSL), and Serrate. At the same time, the Notch gene was successfully sequenced
and cloned, providing insights into the molecular architecture of Notch proteins and led to identification of Notch
homologs
A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same locus (genetics), loci where they pr ...
in ''
Caenorhabditis elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...
'' (''C. elegans'')
and eventually in
mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
s.
In the early 1990s Notch was increasingly implicated as the receptor of a previously unknown intercellular signal pathway
in which the Notch intercellular domain (NICD) is transported to the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucle ...
where it acts as a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
to directly regulate target genes. The release of the NICD was found to be as a result of proteolytic cleavage of the transmembrane protein through the actions of the
γ-secretase complex catalytic subunit
Presenilin
Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset ...
. This was a significant interaction as Presenilin is implicated in the development of Alzheimer's disease. This and further research into the mechanism of Notch signaling led to research that would further connect Notch to a wide range of human diseases.
Structure
''Drosophila'' contain a single Notch protein, ''C''. ''elegans'' contain two redundant notch paralogs, Lin-12 and GLP-1,
and humans have four Notch variants, Notch 1-4. Although variations exist between homologs, there are a set of highly conserved structures found in all Notch family proteins. The protein can broadly be split into the Notch extracellular domain (NECD) and Notch intracellular domain (NICD) joined together by a single-pass transmembrane domain (TM).
The NECD contains 36 EGF repeats in ''Drosophila'',
28-36 in humans, and 13 and 10 in ''C. elegans'' Lin-12 and GLP-1 respectively. These repeats are heavily modified through
O-glycoslyation and the addition of specific O-linked glycans has been shown to be necessary for proper function. The EGF repeats are followed by three
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
-rich Lin-12/Notch Repeats (LNR) and a heterodimerization (HD) domain. Together the LNR and HD compose the negative regulatory region adjacent to the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
and help prevent signaling in the absence of ligand binding.
NICD acts as a transcription factor that is released after ligand binding triggers its cleavage. It contains a nuclear localization sequence (NLS) that mediates its translocation to the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucle ...
, where it forms a transcriptional complex along with several other transcription factors. Once in the nucleus, several
ankyrin repeat
The ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and ''Drosophila'' Notch. Domains consisting of ankyrin tandem repeats mediate prote ...
s and the RAM domain interactions between the NICD and CSL proteins to form a transcriptional activation complex. In humans, an additional PEST domain plays a role in NICD degradation.
Function
Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an
evolutionarily conserved
In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids ( DNA and RNA) or proteins across species ( orthologous sequences), or within a genome ( paralogous sequences), or between donor and receptor tax ...
intercellular
signaling pathway
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
that regulates interactions between physically adjacent cells. In
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. This protein functions as a receptor for membrane bound ligands, and may play multiple roles during development.
A deficiency can be associated with
bicuspid aortic valve
Bicuspid aortic valve (aka BAV) is a form of heart disease in which two of the leaflets of the aortic valve fuse during development in the womb resulting in a two-leaflet (bicuspid) valve instead of the normal three-leaflet (tricuspid) valve. BA ...
.
There is evidence that activated Notch 1 and
Notch 3
Neurogenic locus notch homolog protein 3 (Notch 3) is a protein that in humans is encoded by the ''NOTCH3'' gene.
Function
This gene encodes the third discovered human homologue of the ''Drosophila melanogaster'' type I membrane protein notch ...
promote differentiation of progenitor cells into
astroglia
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
.
Notch 1, then activated before birth, induces
radial glia
Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and ol ...
differentiation,
but postnatally induces the differentiation into
astrocyte
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
s.
One study shows that Notch-1 cascade is activated by
Reelin
Reelin, encoded by the ''RELN'' gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this import ...
in an unidentified way.
Reelin and Notch1 cooperate in the development of the
dentate gyrus
The dentate gyrus (DG) is part of the hippocampal formation in the temporal lobe of the brain, which also includes the hippocampus and the subiculum. The dentate gyrus is part of the hippocampal trisynaptic circuit and is thought to contribute ...
, according to another.
Ligand interactions
Notch signaling is triggered via direct cell-to-cell contact, mediated by interactions between the Notch receptor protein in the signal receiving cell and a ligand in an adjacent signal transmitting cell. These type 1 single pass transmembrane proteins fall into the Delta/Serrate/Lag-2 (DSL) family of proteins which is named after the three canonical Notch ligands.
Delta and Serrate are found in ''Drosophila'' while Lag-2 is found in ''C. elegans''. Humans contain 3 Delta homologs, Delta-like 1, 3, and 4, as well as two Serrate homologs,
Jagged 1
Jagged1 (''JAG1'') is one of five cell surface proteins (Ligand (biochemistry), ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establi ...
and
2. Notch proteins consist of a relatively short intracellular domain and a large extracellular domain with one or more
EGF motifs and a N-terminal DSL-binding motif. EGF repeats 11-12 on the Notch extracellular domain have been shown to be necessary and sufficient for ''trans'' signaling interactions between Notch and its ligands. Additionally, EGF repeats 24-29 have been implicated in inhibition of ''cis'' interactions between Notch and ligands co-expressed in the same cell.
Proteolysis
In order for a signaling event to occur, the Notch protein must be cleaved at several sites. In humans, Notch is first cleaved in the NRR domain by Furin while being processed in the
trans-Golgi network
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...
before being presented on the cell surface as a heterodimer. ''Drosophila'' Notch does not require this cleavage for signaling to occur, and there is some evidence that suggests that LIN-12 and GLP-1 are cleaved at this site in ''C. elegans''.
Release of the NICD is achieved after an additional two cleavage events to Notch. Binding of Notch to a DSL ligand results in a conformational change that exposes a cleavage site in the NECD. Enzymatic proteolysis at this site is carried out by a A Disintegrin and Metalloprotease domain (ADAM) family protease. This protein is called Kuzbanian in ''Drosopihla'', sup-17 in ''C. elegans'', and ADAM10 in humans. After proteolytic cleavage, the released NECD is endocytosed into the signal transmitting cell, leaving behind only a small extracellular portion of Notch. This truncated Notch protein can then be recognized by a γ-secretase that cleaves the third site found in the TM domain.
Human homologs
Notch-1
Notch-2
Notch-2 (''Neurogenic locus notch homolog protein 2'') is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''NOTCH2''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
NOTCH2 is associated with
Alagille syndrome
Alagille syndrome is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and t ...
and
Hajdu–Cheney syndrome
Hajdu–Cheney syndrome, also called acroosteolysis with osteoporosis and changes in skull and mandible, arthrodentoosteodysplasia and Cheney syndrome, is an extremely rare autosomal dominant congenital disorder of the connective tissue characteri ...
.
Notch-3
Notch-4
See also
*
Notch signaling pathway
The Notch signaling pathway is a highly Conserved sequence, conserved cell signaling system present in most animals. Mammals possess four different Notch proteins, notch receptors, referred to as NOTCH1, NOTCH2, Notch 3, NOTCH3, and NOTCH4. The ...
Notes
References
*
*
*
{{InterPro content, IPR000800
Protein families
Single-pass transmembrane proteins