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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 MIA3 gene on chromosome 1.[1][2] It is ubiquitously expressed in many tissues and cell types.[3] 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.[4] This function suggests that it plays a role in assembly of extracellular matrix (ECM) and bone formation.[5] MIA3 has been demonstrated to contribute to both tumor suppression[6][7] and progression.[8] The MIA3 gene also contains one of 27 loci associated with increased risk of coronary artery disease.[9]. 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 cargo export.



The MIA3 gene resides on chromosome 1 at the band 1q41 and includes 32 exons.[1] This gene produces 4 isoforms through alternative splicing.[2]


MIA3 is a member of the MIA/OTOR family.[2] 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.[2][4]


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.[10] 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).[4][11] 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.[5] 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.[6][7] 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.[8]

Clinical significanceEdit

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.[12][13][14][15] 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 MarkerEdit

It was found that melanoma inhibitory activity gene family members are frequently expressed in human tumors such as squamous cell carcinoma,[8][12] esophageal squamous cell carcinoma,[16] lung cancer with nodal or distant metastasis and cervical cancer.[12] In addition, melanoma inhibitory activity gene family expression is also associated with poor prognosis among cancer patients overall.[8][17][18][19][20] 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.[12][18]

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).[9]


  1. ^ a b "MIA3 MIA family member 3, ER export factor [Homo sapiens (human)] – Gene – NCBI". Retrieved 2016-08-19.
  2. ^ a b c d "MIA3 – Melanoma inhibitory activity protein 3 precursor – Homo sapiens (Human) – MIA3 gene & protein". Retrieved 2016-08-19.
  3. ^ "BioGPS – your Gene Portal System". Retrieved 2016-08-19.
  4. ^ a b c Saito K, Chen M, Bard F, Chen S, Zhou H, Woodley D, Polischuk R, Schekman R, Malhotra V (2009-03-06). "TANGO1 facilitates cargo loading at endoplasmic reticulum exit sites". Cell. 136 (5): 891–902. doi:10.1016/j.cell.2008.12.025. PMID 19269366.
  5. ^ a b Wilson DG, Phamluong K, Li L, Sun M, Cao TC, Liu PS, Modrusan Z, Sandoval WN, Rangell L, Carano RA, Peterson AS, Solloway MJ (May 2011). "Global defects in collagen secretion in a Mia3/TANGO1 knockout mouse". The Journal of Cell Biology. 193 (5): 935–51. doi:10.1083/jcb.201007162. PMC 3105544. PMID 21606205.
  6. ^ a b Arndt S, Bosserhoff AK (December 2006). "TANGO is a tumor suppressor of malignant melanoma". International Journal of Cancer. 119 (12): 2812–20. doi:10.1002/ijc.22242. PMID 17044017.
  7. ^ a b Arndt S, Bosserhoff AK (October 2007). "Reduced expression of TANGO in colon and hepatocellular carcinomas". Oncology Reports. 18 (4): 885–91. doi:10.3892/or.18.4.885. PMID 17786351.
  8. ^ a b c d Sasahira 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. PMID 24889917.
  9. ^ a b Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMC 4608367. PMID 25748612.
  10. ^ 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. PMID 15183315.
  11. ^ Saito K, Yamashiro K, Ichikawa Y, Erlmann P, Kontani K, Malhotra V, Katada T (July 2011). "cTAGE5 mediates collagen secretion through interaction with TANGO1 at endoplasmic reticulum exit sites". Molecular Biology of the Cell. 22 (13): 2301–8. doi:10.1091/mbc.E11-02-0143. PMC 3128532. PMID 21525241.
  12. ^ a b c d Lougheed JC, Holton JM, Alber T, Bazan JF, Handel TM (May 2001). "Structure of melanoma inhibitory activity protein, a member of a recently identified family of secreted proteins". Proceedings of the National Academy of Sciences of the United States of America. 98 (10): 5515–20. doi:10.1073/pnas.091601698. PMC 33244. PMID 11331761.
  13. ^ Homsi J, Cubitt CL, Zhang S, Munster PN, Yu H, Sullivan DM, Jove R, Messina JL, Daud AI (June 2009). "Src activation in melanoma and Src inhibitors as therapeutic agents in melanoma". Melanoma Research. 19 (3): 167–75. doi:10.1097/CMR.0b013e328304974c. PMID 19434004.
  14. ^ 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:10.1080/01635580802567166. PMID 19373609.
  15. ^ Sasahira T, Kirita T, Nishiguchi Y, Kurihara M, Nakashima C, Bosserhoff AK, Kuniyasu H (April 2016). "A comprehensive expression analysis of the MIA gene family in malignancies: MIA gene family members are novel, useful markers of esophageal, lung, and cervical squamous cell carcinoma". Oncotarget. 7: 31137–52. doi:10.18632/oncotarget.9082. PMC 5058745. PMID 27145272.
  16. ^ 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. doi:10.1245/s10434-013-3225-x. PMID 23982252.
  17. ^ El Fitori J, Kleeff J, Giese NA, Guweidhi A, Bosserhoff AK, Büchler MW, Friess H (February 2005). "Melanoma Inhibitory Activity (MIA) increases the invasiveness of pancreatic cancer cells". Cancer Cell International. 5 (1): 3. doi:10.1186/1475-2867-5-3. PMC 551595. PMID 15710044.
  18. ^ a b Sasahira T, Kirita T, Kurihara M, Yamamoto K, Bhawal UK, Bosserhoff AK, Kuniyasu H (August 2010). "MIA-dependent angiogenesis and lymphangiogenesis are closely associated with progression, nodal metastasis and poor prognosis in tongue squamous cell carcinoma". European Journal of Cancer. 46 (12): 2285–94. doi:10.1016/j.ejca.2010.04.027. PMID 20570137.
  19. ^ Kurihara M, Kirita T, Sasahira T, Ohmori H, Matsushima S, Yamamoto K, Bosserhoff AK, Kuniyasu H (April 2013). "Protumoral roles of melanoma inhibitory activity 2 in oral squamous cell carcinoma". British Journal of Cancer. 108 (7): 1460–9. doi:10.1038/bjc.2013.27. PMC 3629429. PMID 23511560.
  20. ^ "Biomarkers and surrogate endpoints: preferred definitions and conceptual framework". Clinical Pharmacology and Therapeutics. 69 (3): 89–95. March 2001. doi:10.1067/mcp.2001.113989. PMID 11240971.