NT5E
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5′-nucleotidase (5′-NT), also known as ecto-5′-nucleotidase or CD73 (
cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
73), is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''NT5E''
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 ...
. CD73 commonly serves to convert
AMP #REDIRECT Amp {{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
to
adenosine Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
.


Transcription factor binding sites

NT5E contains binding sites for
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 ...
AP-2, SMAD proteins, SP-1 and elements responsive to c-AMP , which can be found in c-AMP promoter parts. SMADs 2, 3, 4 and 5 and SP-1 are binding to the NT5E promoter in rats, as was proven in chromatin immunoprecipitation assays. Due to the fact, that the human and rat NT5E transcripts are 89% identical, human NT5E could be also regulated by SMAD proteins.


Function

Ecto-5-prime-nucleotidase (5-prime-ribonucleotide phosphohydrolase; EC 3.1.3.5) catalyzes the conversion at neutral pH of purine 5-prime mononucleotides to nucleosides, the preferred substrate being
AMP #REDIRECT Amp {{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
. The enzyme consists of a dimer of 2 identical 70-kD subunits bound by a glycosyl phosphatidyl inositol linkage to the external face of the plasma membrane. The enzyme is used as a marker of
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
differentiation. Consequently, a deficiency of NT5 occurs in a variety of immunodeficiency diseases (e.g., see MIM 102700, MIM 300300). Other forms of 5-prime nucleotidase exist in the cytoplasm and lysosomes and can be distinguished from ecto-NT5 by their substrate affinities, requirement for divalent magnesium ion, activation by ATP, and inhibition by inorganic phosphate. Rare allelic variants are associated with a syndrome of adult-onset
calcification of joints and arteries Arterial calcification due to CD73 deficiency or Calcification of joints and arteries is a rare genetic disorder affecting adults.Nitschke Y, Rutsch F (2012) Genetics in arterial calcification: Lessons learned From rare diseases. Trends Cardiovasc ...
(CALJA) affecting the iliac, femoral, and tibial arteries reducing circulation in the legs and the joints of the hands and feet causing pain.


Immunosuppression

NT5E (CD73) is a surface
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
which is expressed on multiple cells. This enzyme mediates the gradual hydrolysis of the autocrine and paracrine danger signals of ATP and ADP to anti-inflammatory
adenosine Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
. Immune suppression mediated by adenosinergic pathways is very important for maintaining immune system homeostasis. Immune suppressive functions of
T regulatory cells T, or t, is the twentieth letter in the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''tee'' (pronounced ), plural ''tees''. It is der ...
are also dependent on CD73 expression. Treg's generally suppress the immune response. They affect proliferation and function of T cell. CD73 also occurs on anergic CD4 + T cells, thereby maintaining self tolerance to healthy tissues as well as protecting the fetus from the mother's immune system during pregnancy. Also described was adenosine generated by NT5E, which limits the inflammatory immune response by negative feedback in
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
which express the
adenosine receptor The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a di ...
.


As a drug target

Some tumours have upregulation and overexpression of CD73 so it has been proposed as a drug target for cancer therapy. An anti-CD73 antibody CPI-006 has started early stage
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s as a treatment for advanced cancers.


Systemic lupus erythematosus

Specialized immune cells such as myeloid-derived suppressor cells and regulatory T cells also mediate their effects via adenosine generated by local ectonucleotidase. In some cases of lupus patients, adequate T cell expression of CD73 is missing, which shows an impaired regulatory function of T cells.


Cancer

NT5E can act as an immune inhibitory control molecule. Free adenosine generated by NT5E inhibits cellular immune responses and thereby promotes immune escape of tumor cells. Due to enzymatic and non-enzymatic properties, CD73 is involved in cancer-related processes and is upregulated in many cancers such as
leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
,
glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
,
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
,
oesophageal The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...
,
prostate The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...
,
ovarian 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 body. T ...
and
breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
. It is an important key molecule in cancer regulation and development and is involved in tumor progression. In addition, NT5E functions as an
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 be ...
and
signaling molecule 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 ...
and can regulate cellular signaling with
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
components such as
fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
and
laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...
. This can mediate the metastatic and invasive properties of cancer. In mouse breast and prostate cancer tumor models as well as in breast cancer xenograft model, NT5E was confirmed to support tumor
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
. His expression promotes invasion and metastasis of murine and human melanoma cells and human breast cancer cells. Tumor infiltration by cells which express NT5E such as myeloid derived suppressor cells (MDSC), Treg's,
dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...
(DC) leads to accumulation of adenosine. Subsequently,
cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
signaling is triggered in
T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
that express the adenosine
A2A receptor The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it. Structure This protein is a member of the G protein-coupled receptor (GPCR) family which possess seven transmembrane alph ...
.
Adenosine receptor The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a di ...
are also expressed on
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
, DCs, MDSC and
natural killer cell Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repres ...
(NK). Thus, adenosine may inhibit the function of these immune cells. In addition, the tumor cells may also express adenosine A1 and A3 receptors associated with Gαi proteins, promoting both the migration and proliferation of tumor cells. Especially due to its beneficial effects in mouse tumor model, anti-CD73 therapy is now a promising approach to cancer treatment in the future. CD73 inhibitor are currently being tested in clinical trials for the cancer treatment.


miRNA

MicroRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
are small non-coding
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
molecules which regulate
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
at posttranscriptional level via binding to mRNA. This leads to degradation of the target mRNA molecule or translational repression. In tumor cells the miRNA expression pattern often change and therefore affect the surface NT5E, which as result interfere the anti-tumor immune response. For example, studies confirm the role of the miR30 family in NT5E regulation. Upon miR-30a-5p expression, NT5E expression was decreased.


See also

*
Cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
* Arterial calcification due to CD73 deficiency


References


Further reading

* * * * * * * * * * * * * * * *


External links

* * {{Clusters of differentiation Clusters of differentiation