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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

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

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 ...

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 ...

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

Structure

Gene

The ''MIA3'' gene resides on chromosome 1 at the band 1q41 and includes 32 exons. 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 or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

through alternative splicing.

Protein

MIA3 is a member of the

MIA Mia, MIA, or M.I.A. may refer to: Music Artists * M.I.A. (rapper) (born 1975), English rapper and singer * M.I.A. (band), 1980s punk rock band from Orange County, California * MIA., a German rock/pop band formed in 1997 * Mia (singer) (born 1983) ...

/ 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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

s and localizes to the ER exit sites. It contains an N-terminal, SH3-like domain, two predicted

transmembrane domain A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bi ...

s, a coiled-coiled domain, and a

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 ...

, proline-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 In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

, 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 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 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 (bone marrow) and have the unique ability to give rise to ...

. 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 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. This ...

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 chondrocytes, fibroblasts,

endothelial cells The endothelium 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 rest of the vessel ...

, and

mural cell Mural cells are the vascular smooth muscle cells (vSMCs), and pericytes, of the microcirculation. Both types are in close contact with the endothelial cells lining the capillaries, and are important for vascular development and stability. Mural cel ...

s, indicating its participation in chondrocyte maturation and bone mineralization. MIA3 has been suggested as a tumor suppressor in malignant melanoma, colorectal cancer, 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. It occurs in t ...

, 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 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, meta ...

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

Clinical significance

In humans, MIA3 was first discovered as an important constituent in the growth and adhesion in malignant melanoma cells. As it is secreted from both chondrocytes and melanoma cells, it also plays a role in the metastasis of melanomas as well as cartilage 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 squamous cell carcinoma, esophageal squamous cell carcinoma,

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malign ...

with nodal or distant

metastasis Metastasis is a pathogenic agent's spread 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, then ...

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 coronary artery disease events, as well as an enhanced clinical benefit from

statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low ...

therapy. The study was based on a community

cohort study A cohort study is a particular form of longitudinal study that samples a 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 graduation), performing ...

(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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