Nectin-3, also known as nectin cell adhesion molecule 3, 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, respon ...

that in humans is encoded by the ''NECTIN3''

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 b ...

. Nectin-3 belongs to the family of immunoglobulin(Ig)-like cellular adhesion molecules involved in Ca²⁺-independent cellular adhesion in several tissues during the development and was firstly isolated at the turn of 20th and 21st century.

Structure and localization

Nectin-3 has three splicing variants, nectin-3α, which is the biggest one, nectin-3β and the smallest variant nectin-3γ. Nectin-3α (same as the other splicing variants) is abundately expressed in

testis A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoster ...

, on slightly level it is also expressed in

heart The heart is a muscular organ found in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon diox ...

brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...

. It has been also proved that nectin-3α is together with nectin-2 localize at the junctional complex regions in small intestina absorptive epitelia. Nectin-3γ is also detectable in lung, liver and kidney. Nectin-3 is expressed not only on

epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...

as another nectins, but there was shown that, as the only member of nectin family, it is expressed also on T- lymphocytes. The structural properties of nectin-3α is similar to nectin-1, it has three Ig-like domains at the extracellular region and the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

coserved motif at the cytoplasmic region. The homology of aa ( amino aci)) of extracellular domains between Nectin-1 and Nectin-3α is 35,9%. Another splicing variants vary in the number of aa, molecular weight and the structural properties. All of them have the identical extracellular region. Nectin-3β and nectin-3γ have the same transmembrane and cytoplasmic regions, which vary from nectin-3α. Nectin-3γ lack of C-terminal domain. With the intracellular domain nectins bind their assosicated adaptor protein afadin which plays role in the formation of variety of cell-cell junctions. Nectin-3γ in not able to bind afadin due to lacking C-terminal domain. All nectins are able to form ''cis''-homo dimer interactions, which simply means they can create dimer of two alike molecules on the same cell membrane. Further, nectin-3α can also interact with Nectin-1/2α in so called ''trans''-hetero interaction.

Function

Most of the publications deal with nectin-3 regardless the splicing variants, thus this page follows this concept.

Role in neural system

Nectin-3 is expressed by

granule cell A granule is a large particle or grain. It can refer to: * Granule (cell biology), any of several submicroscopic structures, some with explicable origins, others noted only as cell type-specific features of unknown function ** Azurophilic granul ...

s in

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 ...

and the expression levels are developmentally regulated and reduced by early postnatal stress. On mice model, it has been shown that the early-life stress impaires the long-term

spatial memory In cognitive psychology and neuroscience, spatial memory is a form of memory responsible for the recording and recovery of information needed to plan a course to a location and to recall the location of an object or the occurrence of an event. Sp ...

and temporal order memory. It is also very probable that the nectin-3 in dentate gyrus neurons modulate adult

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 ...

and dendritic spine plasticity. It has been proven that combination nectin-3/nectin-1 is very important in formation of

synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses fr ...

s in brain,

hippocampus The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...

and that the formation of hetero-trans-dimers between nectin-1 and nectin-3 determines the position and size of the synapses, ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...

''. ''

In vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'', it has been shown that the function of nectin-3 is crutial during the critical periods of the

visual cortex The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus and ...

development and that it is important not only for synapses formation but also for the synaptic refinement. Also it has been proven that there is a high importance of nectin-3 for the dendritic spine densities (which simply represent the sites of synaptic contacts) on visual cortical neurons. The nectin-1/nectin-3 trans-interaction has been shown to be very important to establishing the

adhesion Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another). The forces that cause adhesion and cohesion can b ...

between the pigment and non-pigment cell layers of the ciliary epithelia, which is essential for the

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 deve ...

of the

ciliary body The ciliary body is a part of the eye that includes the ciliary muscle, which controls the shape of the lens, and the ciliary epithelium, which produces the aqueous humor. The aqueous humor is produced in the non-pigmented portion of the ciliar ...

of the eye.

Role in gametogenesis

Nectin-3 is important role player in spermatid development. The nectin-3^–/– male mice were found to have defects in the later steps of sperm

, exhibiting distorted nuclei and abnormal distribution of mitochondria. The loss of nectin-3 in male mice leads to male-specific

infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...

. It has been shown that the

chronic stress Chronic stress is the physiological or psychological response induced by a long-term internal or external stressor. The stressor, either physically present or recollected, will produce the same effect and trigger a chronic stress response. There i ...

negatively influences the amnout of nectin-3 in the testis and also the male

spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the t ...

function.

Role in transendothelial migration

As mentioned above, nectin-3 is the only nectin which is expressed on T- lymphocytes. The interaction between nectin-3 on T-cells and other nectins on

is very important in the lymphocyte transendothelial migration, ''in vitro.'' It has been shown that this process is dependent on nectin-2, which is expressed on epithelial cells, the blockation of nectin-2 or nectin-3 leads to inhibition of lymphocyte and also

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...

extravasation.

Nectin-3 in cancer

Nectin-3 is highly expressed in epithelial cancer cells of human

lung adenocarcinoma Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to d ...

. It is expressed in 80% of patients which makes it relatively strong prognostic marker. It has been shown, there are various expression patterns of nectin-3; cytoplasmic, membranous or combined. The membranous expression is connected with significantly poorer prognosis, patients with this type of expression pattern are also more likely to earlier

relapse In internal medicine, relapse or recidivism is a recurrence of a past (typically medical) condition. For example, multiple sclerosis and malaria often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or ...

and death. Increased amounts of nectin-3 are also detectable in

ovaries The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the bod ...

during the

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...

and are correlated with poor patient prognosis. The data also suggest that the possible mechanism of nectin-3 in cellular invasion and migration is by upregulating the expression of

matrix metalloproteinase Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...

s (MMPs) MMP2 and MMP9 in ovarian cancer. Contrary to previously mentioned cancers, the amount of nectin-3 negatively correlates with Pancreatic neuroendocrine tumors. The loss of this protein correlates with increased tumor progressiveness.

Interactions

Nectin-3 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizat ...

with: * MLLT4, * PARD3, *

PTPRM Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the ''PTPRM'' gene. Function The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Protein tyrosine phosphatases ...

References

{{Clusters of differentiation Cell adhesion molecules Clusters of differentiation