Melanoma inhibitory activity protein 3 (MIA3), also known as transport and Golgi organization protein 1 (TANGO1), is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''MIA3''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which a ...

. It is ubiquitously expressed in many tissues and cell types. MIA3 localizes to the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

(ER) exit site, where it binds bulky cargo molecules such as collagens and creates mega transport carriers for the export of cargoes from the ER. This function suggests that it plays a role in assembly of extracellular matrix (ECM) and

bone formation Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in th ...

. MIA3 has been demonstrated to contribute to both

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

suppression and progression. The ''MIA3'' gene also contains one of 27 loci associated with increased risk of

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

.. A TANGO1 like protein called TALI is expressed in liver and intestine and shown to be required for the export of bulky very Low density lipoproteins (VLDL) and chylomicrons. TANGO1 and TALI assemble into rings around COPII coats and this function is necessary for export of bulky cargoes. The discovery of TANGO1 and understanding its function has revealed that cargo export from the ER is not be vesicles but involves transient tunnels between the ER exit site and the next compartment of the secretory pathway. Biallelic Mutations in TANGO1 cause syndrome disease and complete loss of TANGO1 leads of defects in bone mineralization. These findings highlight the significance of TANGO1 in building and ER exit site, controlling the quantities and quality of cargo exported, which is necessary for life.Membrane permeant peptides of TANGO1 affect hyper collagen secretion in normal and cells of patients with scleroderma, and in a zebra fish model of wound healing. These findings raise the possibility of targeting TANGO1 to control skin scarring, wound healing and fibrosis.

Structure

Gene

The ''MIA3'' gene resides on chromosome 1 at the band 1q41 and includes 32

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s. This gene produces 4

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

through

alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

Protein

MIA3 is a member of the

MIA Mia, Mía, MIA, or M.I.A. may refer to: Music Artists * M.I.A. (rapper) (born 1975), English rapper and singer * M.I.A. (American band), 1980s punk rock band from Orange County, California * MIA. (German band), a German rock/pop band formed i ...

/ OTOR family. The full-length protein spans 1,907

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s and localizes to the ER exit sites. It contains an

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

, SH3-like domain, two predicted

transmembrane domain A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...

s, a coiled-coiled domain, and a

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy 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 t ...

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

-rich domain. The SH3-like domain faces the ER lumen, where it can bind cargo for COPII carrier biogenesis, while the proline-rich domain faces the

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

, where it can bind the COPII components Sec23/24. Of the two predicted transmembrane domains, only one actually crosses the membrane, whereas the second likely forms a

hairpin structure Stem-loops are nucleic acid secondary structural elements which form via intramolecular base pairing in single-stranded DNA or RNA. They are also referred to as hairpins or hairpin loops. A stem-loop occurs when two regions of the same nucleic ...

that is only embedded in but not crossing the membrane.

Function

Unlike other members in the MIA gene family, MIA3 is broadly expressed, except in the cells belonging to the

hematopoietic system The haematopoietic system ( spelled hematopoietic system in American English) is the system in the body involved in the creation of the cells of blood. Structure Stem cells Haematopoietic stem cells (HSCs) reside in the medulla of the bone ( ...

. High levels of MIA3 expression are observed both in embryonic and adult tissues. MIA3 resides at the ER exit site and functions as a guide for loading the cargo molecule

collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

VII into

COPII The coat protein complex II, or COPII, is a group of proteins that facilitate the formation of vesicles to transport proteins from the endoplasmic reticulum to the Golgi apparatus or endoplasmic-reticulum–Golgi intermediate compartment. Thi ...

carriers, which mediates the exit of secretory protein out of the ER with the help of cutaneous T-cell lymphoma–associated antigen 5 ( cTAGE-5). A recent study indicates that MIA3 is also involved in the secretion of other collagens, including collagens I, II, III, IV, and IX, from

chondrocyte Chondrocytes (, ) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word '' chondroblast'' is commonly used to describe an immatu ...

fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...

endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

, and

mural cell Mural cells are the generalized name of cell population in the microcirculation that is comprised of Vascular smooth muscle, vascular smooth muscle cells (vSMCs), and pericytes. Both types are in close contact with the endothelial cells lining the ...

s, indicating its participation in chondrocyte maturation and bone mineralization. MIA3 has been suggested as a tumor suppressor in malignant

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...

, and

hepatoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. HCC most common ...

, and induction of expression of MIA3 results in a significant decrease in motility and invasive potential. On the other hand, it has also been found that MIA3 promotes

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 mainly by processes of sprouting and ...

and

lymphangiogenesis Lymphangiogenesis is the formation of lymphatic vessels from pre-existing lymphatic vessels in a method believed to be similar to angiogenesis (blood vessel development). Lymphangiogenesis plays an important physiological role in homeostasis, me ...

by upregulating platelet-derived growth factor beta ( PDGF-b) polypeptide and neuropolin 2 in oral

squamous cell carcinoma Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...

Clinical significance

In humans, MIA3 was first discovered as an important constituent in the growth and adhesion in malignant

cells. As it is secreted from both

s and melanoma cells, it also plays a role in the metastasis of melanomas as well as

cartilage Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...

development. It has been established that melanoma inhibitory gene family members serve several tumor-related functions that are subjected to a variety of human malignancies.

Clinical Marker

It was found that melanoma inhibitory activity gene family members are frequently expressed in human tumors such as

, esophageal squamous cell carcinoma,

lung cancer Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...

with nodal or distant

metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

and cervical cancer. In addition, melanoma inhibitory activity gene family expression is also associated with poor prognosis among cancer patients overall. Nevertheless, further research is needed to determine the association between melanoma inhibitory family member expression and its diagnostic, prognostic and therapeutic relevance in clinical oncology. Additionally, a multi-locus genetic risk score study, based on a combination of 27 loci including the MIA3 gene, identified individuals at increased risk for both incidence and recurrent

events, as well as an enhanced clinical benefit from

statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...

therapy. The study was based on a community

cohort study A cohort study is a particular form of longitudinal study that samples a Cohort (statistics), cohort (a group of people who share a defining characteristic, typically those who experienced a common event in a selected period, such as birth or gra ...

(the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).

References

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