MIA3, ARNT, D320, TANGO, TANGO1, UNQ6077, melanoma inhibitory activity family member 3, MIA family member 3, ER export factor, MIA SH3 domain ER export factor 3, ODCD2
Melanoma inhibitory activity protein 3 (MIA3), also known as transport and
Golgi organization protein 1 (TANGO1), is a
protein that in humans is encoded by the MIA3gene on
chromosome 1.[4][5] It is ubiquitously expressed in many tissues and cell types.[6] 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.[7] This function suggests that it plays a role in assembly of extracellular matrix (ECM) and
bone formation.[8] MIA3 has been demonstrated to contribute to both
tumor suppression[9][10] and progression.[11] The MIA3 gene also contains one of 27
loci associated with increased risk of
coronary artery disease.[12]. 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.
MIA3 is a member of the
MIA/
OTOR family.[5] The full-length protein spans 1,907
amino acids and localizes to the ER exit sites. It contains an
N-terminal,
SH3-like domain, two predicted
transmembrane domains, a
coiled-coiled domain, and a
C-terminal,
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, 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.[5][7]
Function
Unlike other members in the MIA gene family, MIA3 is broadly expressed, except in the cells belonging to the
hematopoietic system. High levels of MIA3 expression are observed both in embryonic and adult tissues.[13] MIA3 resides at the
ER exit site and functions as a guide for loading the cargo molecule
collagen VII into
COPII 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).[7][14] 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, and
mural cells, indicating its participation in chondrocyte maturation and bone
mineralization.[8] MIA3 has been suggested as a tumor suppressor in malignant
melanoma,
colorectal cancer, and
hepatoma, and induction of expression of MIA3 results in a significant decrease in motility and invasive potential.[9][10] On the other hand, it has also been found that MIA3 promotes
angiogenesis and
lymphangiogenesis by upregulating platelet-derived growth factor beta (
PDGF-b) polypeptide and
neuropolin 2 in oral
squamous cell carcinoma.[11]
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.[15][16][17][18] 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,[11][15] esophageal squamous cell carcinoma,[19]lung cancer with nodal or distant
metastasis and cervical cancer.[15] In addition, melanoma inhibitory activity gene family expression is also associated with poor prognosis among cancer patients overall.[11][20][21][22][23] 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.[15][21]
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 therapy. The study was based on a community
cohort study (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).[12]
^
abcdSasahira T, Kirita T, Yamamoto K, Ueda N, Kurihara M, Matsushima S, Bhawal UK, Bosserhoff AK, Kuniyasu H (August 2014). "Transport and Golgi organisation protein 1 is a novel tumour progressive factor in oral squamous cell carcinoma". European Journal of Cancer. 50 (12): 2142–51.
doi:
10.1016/j.ejca.2014.05.006.
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^Bosserhoff AK, Moser M, Buettner R (July 2004). "Characterization and expression pattern of the novel MIA homolog TANGO". Gene Expression Patterns. 4 (4): 473–9.
doi:
10.1016/j.modgep.2003.12.002.
PMID15183315.
^Chang PN, Yap WN, Lee DT, Ling MT, Wong YC, Yap YL (2009-01-01). "Evidence of gamma-tocotrienol as an apoptosis-inducing, invasion-suppressing, and chemotherapy drug-sensitizing agent in human melanoma cells". Nutrition and Cancer. 61 (3): 357–66.
doi:
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^Jia Y, Wang N, Wang J, Tian H, Ma W, Wang K, Tan B, Zhang G, Yang S, Bai B, Cheng Y (January 2014). "Down-regulation of stromal caveolin-1 expression in esophageal squamous cell carcinoma: a potent predictor of lymph node metastases, early tumor recurrence, and poor prognosis". Annals of Surgical Oncology. 21 (1): 329–36.
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