ADAM12 explained

Disintegrin and metalloproteinase domain-containing protein 12 (previously Meltrin) is an enzyme that in humans is encoded by the ADAM12 gene.^{[1] [2]} ADAM12 has two splice variants: ADAM12-L, the long form, has a transmembrane region and ADAM12-S, a shorter variant, is soluble and lacks the transmembrane and cytoplasmic domains.^[3]

Function

This gene encodes a member of the ADAM (a disintegrin and metalloprotease) protein family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. This gene has two alternatively spliced transcripts: a shorter secreted form and a longer membrane-bound form. The shorter form is found to stimulate myogenesis.^[4]

Clinical Significance

ADAM 12, a metalloprotease that binds insulin growth factor binding protein-3 (IGFBP-3), appears to be an effective early Down syndrome marker. Decreased levels of ADAM 12 may be detected in cases of trisomy 21 as early as 8 to 10 weeks gestation. Maternal serum ADAM 12 and PAPP-A levels at 8 to 9 weeks gestation in combination with maternal age yielded a 91% detection rate for Down syndrome at a 5% false-positive rate. When nuchal translucency data from approximately 12 weeks gestation was added, this increased the detection rate to 97%.^[5]

ADAM12 has also been implicated in the development of pathology in various cancers, hypertension, liver fibrogenesis, and asthma.^[6] In asthma, ADAM12 is upregulated in lung epithelium in response to TNF-alpha.^[7]

In a study of about 1200 persons with extremely high intelligence (IQ about 170), variants of the gene were associated with high IQ compared with a general population.^[8]

Interactions

ADAM12 has been shown to interact with:

• ACTN2,^[9]
• IGFBP3,^{[10] [11]} and
• PIK3R1.^[12]

Further reading

• Kang Q, Cao Y, Zolkiewska A . Direct interaction between the cytoplasmic tail of ADAM 12 and the Src homology 3 domain of p85alpha activates phosphatidylinositol 3-kinase in C2C12 cells. . J. Biol. Chem. . 276 . 27 . 24466–72 . 2001 . 11313349 . 10.1074/jbc.M101162200 . free .
• Loechel F, Gilpin BJ, Engvall E, Albrechtsen R, Wewer UM . Human ADAM 12 (meltrin alpha) is an active metalloprotease. . J. Biol. Chem. . 273 . 27 . 16993–7 . 1998 . 9642263 . 10.1074/jbc.273.27.16993 . free .
• Howard L, Nelson KK, Maciewicz RA, Blobel CP . Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1. . J. Biol. Chem. . 274 . 44 . 31693–9 . 1999 . 10531379 . 10.1074/jbc.274.44.31693 . free .
• Galliano MF, Huet C, Frygelius J, Polgren A, Wewer UM, Engvall E . Binding of ADAM12, a marker of skeletal muscle regeneration, to the muscle-specific actin-binding protein, alpha -actinin-2, is required for myoblast fusion. . J. Biol. Chem. . 275 . 18 . 13933–9 . 2000 . 10788519 . 10.1074/jbc.275.18.13933 . free .
• Iba K, Albrechtsen R, Gilpin B, Fröhlich C, Loechel F, Zolkiewska A, Ishiguro K, Kojima T, Liu W, Langford JK, Sanderson RD, Brakebusch C, Fässler R, Wewer UM . The cysteine-rich domain of human ADAM 12 supports cell adhesion through syndecans and triggers signaling events that lead to beta1 integrin-dependent cell spreading. . J. Cell Biol. . 149 . 5 . 1143–56 . 2000 . 10831617 . 2174829 . 10.1083/jcb.149.5.1143 .
• Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ . ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3. . J. Biol. Chem. . 275 . 24 . 18574–80 . 2000 . 10849447 . 10.1074/jbc.M002172200 . free .
• Eto K, Puzon-McLaughlin W, Sheppard D, Sehara-Fujisawa A, Zhang XP, Takada Y . RGD-independent binding of integrin alpha9beta1 to the ADAM-12 and -15 disintegrin domains mediates cell-cell interaction. . J. Biol. Chem. . 275 . 45 . 34922–30 . 2001 . 10944520 . 10.1074/jbc.M001953200 . free .
• Loechel F, Fox JW, Murphy G, Albrechtsen R, Wewer UM . ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. . Biochem. Biophys. Res. Commun. . 278 . 3 . 511–5 . 2001 . 11095942 . 10.1006/bbrc.2000.3835 .
• Suzuki A, Kadota N, Hara T, Nakagami Y, Izumi T, Takenawa T, Sabe H, Endo T . Meltrin alpha cytoplasmic domain interacts with SH3 domains of Src and Grb2 and is phosphorylated by v-Src. . Oncogene . 19 . 51 . 5842–50 . 2000 . 11127814 . 10.1038/sj.onc.1203986 . free .
• Kawaguchi N, Xu X, Tajima R, Kronqvist P, Sundberg C, Loechel F, Albrechtsen R, Wewer UM . ADAM 12 protease induces adipogenesis in transgenic mice. . Am. J. Pathol. . 160 . 5 . 1895–903 . 2002 . 12000741 . 1850877 . 10.1016/S0002-9440(10)61136-4 .
• Cao Y, Kang Q, Zhao Z, Zolkiewska A . Intracellular processing of metalloprotease disintegrin ADAM12 . J. Biol. Chem. . 277 . 29 . 26403–11 . 2002 . 12000744 . 10.1074/jbc.M110814200 . free .
• Abram CL, Seals DF, Pass I, Salinsky D, Maurer L, Roth TM, Courtneidge SA . The adaptor protein fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells . J. Biol. Chem. . 278 . 19 . 16844–51 . 2003 . 12615925 . 10.1074/jbc.M300267200 . free .
• Le Pabic H, Bonnier D, Wewer UM, Coutand A, Musso O, Baffet G, Clément B, Théret N . ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling . Hepatology . 37 . 5 . 1056–66 . 2003 . 12717386 . 10.1053/jhep.2003.50205 . 32722392 . free .
• Kawaguchi N, Sundberg C, Kveiborg M, Moghadaszadeh B, Asmar M, Dietrich N, Thodeti CK, Nielsen FC, Möller P, Mercurio AM, Albrechtsen R, Wewer UM . ADAM12 induces actin cytoskeleton and extracellular matrix reorganization during early adipocyte differentiation by regulating beta1 integrin function . J. Cell Sci. . 116 . Pt 19 . 3893–904 . 2004 . 12915587 . 10.1242/jcs.00699 . free .
• Mori S, Tanaka M, Nanba D, Nishiwaki E, Ishiguro H, Higashiyama S, Matsuura N . PACSIN3 binds ADAM12/meltrin alpha and up-regulates ectodomain shedding of heparin-binding epidermal growth factor-like growth factor . J. Biol. Chem. . 278 . 46 . 46029–34 . 2003 . 12952982 . 10.1074/jbc.M306393200 . free .
• Laigaard J, Sørensen T, Fröhlich C, Pedersen BN, Christiansen M, Schiøtt K, Uldbjerg N, Albrechtsen R, Clausen HV, Ottesen B, Wewer UM . ADAM12: a novel first-trimester maternal serum marker for Down syndrome . Prenat. Diagn. . 23 . 13 . 1086–91 . 2004 . 14691998 . 10.1002/pd.762 . 32888570 .

External links

• The MEROPS online database for peptidases and their inhibitors: M12.212
• ADAM12 on the Atlas of Genetics and Oncology

Notes and References

1. Gilpin BJ, Loechel F, Mattei MG, Engvall E, Albrechtsen R, Wewer UM . A novel, secreted form of human ADAM 12 (meltrin alpha) provokes myogenesis in vivo . J. Biol. Chem. . 273 . 1 . 157–66 . Feb 1998 . 9417060 . 10.1074/jbc.273.1.157 . free .
2. Kveiborg M, Albrechtsen R, Couchman JR, Wewer UM . Cellular roles of ADAM12 in health and disease . Int. J. Biochem. Cell Biol. . 40 . 9 . 1685–702 . Jun 2008 . 18342566 . 10.1016/j.biocel.2008.01.025 .
3. Yagami-Hiromasa T, Sato T, Kurisaki T, Kamijo K, Nabeshima Y, Fujisawa-Sehara A . A metalloprotease-disintegrin participating in myoblast fusion. . Nature . 377 . 6550 . 652–6 . 1995 . 7566181 . 10.1038/377652a0 . 1995Natur.377..652Y . 4348744 .
4. Web site: Entrez Gene: ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha).
5. Danforth's Obstetrics and Gynecology, 10th Edition; Copyright ©2008 Lippincott Williams & Wilkins; Chapter 7: Prenatal Diagnosis, Page 113
6. Nyren-Erickson EK, Jones JM, Srivastava DK, Mallik S . A disintegrin and metalloproteinase-12 (ADAM12): function, roles in disease progression, and clinical implications . Biochim. Biophys. Acta . 1830 . 10 . 4445–55 . 2013 . 23680494 . 10.1016/j.bbagen.2013.05.011 . 3740046.
7. Estrella C, Rocks N, Paulissen G, Quesada-Calvo F, Noel A, Vilain E, Lassalle P, Tillie-Leblond I, Cataldo D, Gosset P . Role of a disintegrin and metalloprotease-12 in neutrophil recruitment induced by airway epithelium . Am. J. Respir. Cell Mol. Biol. . 41 . 4 . 449–58 . 2009 . 19213876 . 10.1165/rcmb.2008-0124OC . 2268/5767 . free .
8. Dzirasa . Kafui . 2017-08-02 . A brilliant approach to study the basis of intelligence? . Science Translational Medicine . en . 9 . 401 . 10.1126/scitranslmed.aao0978 . 44125138 . 1946-6234.
9. Galliano MF, Huet C, Frygelius J, Polgren A, Wewer UM, Engvall E . Binding of ADAM12, a marker of skeletal muscle regeneration, to the muscle-specific actin-binding protein, alpha -actinin-2, is required for myoblast fusion . J. Biol. Chem. . 275 . 18 . 13933–9 . May 2000 . 10788519 . 10.1074/jbc.275.18.13933. free .
10. Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ . ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3 . J. Biol. Chem. . 275 . 24 . 18574–80 . Jun 2000 . 10849447 . 10.1074/jbc.M002172200 . free .
11. Loechel F, Fox JW, Murphy G, Albrechtsen R, Wewer UM . ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3 . Biochem. Biophys. Res. Commun. . 278 . 3 . 511–5 . Nov 2000 . 11095942 . 10.1006/bbrc.2000.3835 .
12. Kang Q, Cao Y, Zolkiewska A . Direct interaction between the cytoplasmic tail of ADAM 12 and the Src homology 3 domain of p85alpha activates phosphatidylinositol 3-kinase in C2C12 cells . J. Biol. Chem. . 276 . 27 . 24466–72 . Jul 2001 . 11313349 . 10.1074/jbc.M101162200 . free .