Disintegrin and metalloproteinase domain-containing protein 12 (previously Meltrin) is an enzyme that in humans is encoded by the ADAM12gene.[5][6] 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.[7]
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.[8]
Clinical Significanceedit
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%.[9]
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.[12]
^ abcGRCh38: Ensembl release 89: ENSG00000148848 – Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000054555 – Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Gilpin BJ, Loechel F, Mattei MG, Engvall E, Albrechtsen R, Wewer UM (Feb 1998). "A novel, secreted form of human ADAM 12 (meltrin alpha) provokes myogenesis in vivo". J. Biol. Chem. 273 (1): 157–66. doi:10.1074/jbc.273.1.157. PMID 9417060.
^Kveiborg M, Albrechtsen R, Couchman JR, Wewer UM (Jun 2008). "Cellular roles of ADAM12 in health and disease". Int. J. Biochem. Cell Biol. 40 (9): 1685–702. doi:10.1016/j.biocel.2008.01.025. PMID 18342566.
^Yagami-Hiromasa T, Sato T, Kurisaki T, Kamijo K, Nabeshima Y, Fujisawa-Sehara A (1995). "A metalloprotease-disintegrin participating in myoblast fusion". Nature. 377 (6550): 652–6. Bibcode:1995Natur.377..652Y. doi:10.1038/377652a0. PMID 7566181. S2CID 4348744.
^"Entrez Gene: ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha)".
^Nyren-Erickson EK, Jones JM, Srivastava DK, Mallik S (2013). "A disintegrin and metalloproteinase-12 (ADAM12): function, roles in disease progression, and clinical implications". Biochim. Biophys. Acta. 1830 (10): 4445–55. doi:10.1016/j.bbagen.2013.05.011. PMC3740046. PMID 23680494.
^Estrella C, Rocks N, Paulissen G, Quesada-Calvo F, Noel A, Vilain E, Lassalle P, Tillie-Leblond I, Cataldo D, Gosset P (2009). "Role of a disintegrin and metalloprotease-12 in neutrophil recruitment induced by airway epithelium". Am. J. Respir. Cell Mol. Biol. 41 (4): 449–58. doi:10.1165/rcmb.2008-0124OC. hdl:2268/5767. PMID 19213876.
^Dzirasa K (2017-08-02). "A brilliant approach to study the basis of intelligence?". Science Translational Medicine. 9 (401). doi:10.1126/scitranslmed.aao0978. ISSN 1946-6234. S2CID 44125138.
^Galliano MF, Huet C, Frygelius J, Polgren A, Wewer UM, Engvall E (May 2000). "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. doi:10.1074/jbc.275.18.13933. PMID 10788519.
^Loechel F, Fox JW, Murphy G, Albrechtsen R, Wewer UM (Nov 2000). "ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3". Biochem. Biophys. Res. Commun. 278 (3): 511–5. doi:10.1006/bbrc.2000.3835. PMID 11095942.
^Kang Q, Cao Y, Zolkiewska A (Jul 2001). "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. doi:10.1074/jbc.M101162200. PMID 11313349.
Further readingedit
Kang Q, Cao Y, Zolkiewska A (2001). "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. doi:10.1074/jbc.M101162200. PMID 11313349.
Loechel F, Gilpin BJ, Engvall E, Albrechtsen R, Wewer UM (1998). "Human ADAM 12 (meltrin alpha) is an active metalloprotease". J. Biol. Chem. 273 (27): 16993–7. doi:10.1074/jbc.273.27.16993. PMID 9642263.
Howard L, Nelson KK, Maciewicz RA, Blobel CP (1999). "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. doi:10.1074/jbc.274.44.31693. PMID 10531379.
Galliano MF, Huet C, Frygelius J, Polgren A, Wewer UM, Engvall E (2000). "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. doi:10.1074/jbc.275.18.13933. PMID 10788519.
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 (2000). "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. doi:10.1083/jcb.149.5.1143. PMC2174829. PMID 10831617.
Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ (2000). "ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3". J. Biol. Chem. 275 (24): 18574–80. doi:10.1074/jbc.M002172200. PMID 10849447.
Eto K, Puzon-McLaughlin W, Sheppard D, Sehara-Fujisawa A, Zhang XP, Takada Y (2001). "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. doi:10.1074/jbc.M001953200. PMID 10944520.
Loechel F, Fox JW, Murphy G, Albrechtsen R, Wewer UM (2001). "ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3". Biochem. Biophys. Res. Commun. 278 (3): 511–5. doi:10.1006/bbrc.2000.3835. PMID 11095942.
Suzuki A, Kadota N, Hara T, Nakagami Y, Izumi T, Takenawa T, Sabe H, Endo T (2000). "Meltrin alpha cytoplasmic domain interacts with SH3 domains of Src and Grb2 and is phosphorylated by v-Src". Oncogene. 19 (51): 5842–50. doi:10.1038/sj.onc.1203986. PMID 11127814.
Kawaguchi N, Xu X, Tajima R, Kronqvist P, Sundberg C, Loechel F, Albrechtsen R, Wewer UM (2002). "ADAM 12 protease induces adipogenesis in transgenic mice". Am. J. Pathol. 160 (5): 1895–903. doi:10.1016/S0002-9440(10)61136-4. PMC1850877. PMID 12000741.
Cao Y, Kang Q, Zhao Z, Zolkiewska A (2002). "Intracellular processing of metalloprotease disintegrin ADAM12". J. Biol. Chem. 277 (29): 26403–11. doi:10.1074/jbc.M110814200. PMID 12000744.
Abram CL, Seals DF, Pass I, Salinsky D, Maurer L, Roth TM, Courtneidge SA (2003). "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. doi:10.1074/jbc.M300267200. PMID 12615925.
Le Pabic H, Bonnier D, Wewer UM, Coutand A, Musso O, Baffet G, Clément B, Théret N (2003). "ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling". Hepatology. 37 (5): 1056–66. doi:10.1053/jhep.2003.50205. PMID 12717386. S2CID 32722392.
Kawaguchi N, Sundberg C, Kveiborg M, Moghadaszadeh B, Asmar M, Dietrich N, Thodeti CK, Nielsen FC, Möller P, Mercurio AM, Albrechtsen R, Wewer UM (2004). "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. doi:10.1242/jcs.00699. PMID 12915587.
Mori S, Tanaka M, Nanba D, Nishiwaki E, Ishiguro H, Higashiyama S, Matsuura N (2003). "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. doi:10.1074/jbc.M306393200. PMID 12952982.
Laigaard J, Sørensen T, Fröhlich C, Pedersen BN, Christiansen M, Schiøtt K, Uldbjerg N, Albrechtsen R, Clausen HV, Ottesen B, Wewer UM (2004). "ADAM12: a novel first-trimester maternal serum marker for Down syndrome". Prenat. Diagn. 23 (13): 1086–91. doi:10.1002/pd.762. PMID 14691998. S2CID 32888570.
External linksedit
The MEROPS online database for peptidases and their inhibitors: M12.212
adam12, television, show, adam, disintegrin, metalloproteinase, domain, containing, protein, previously, meltrin, enzyme, that, humans, encoded, gene, splice, variants, long, form, transmembrane, region, shorter, variant, soluble, lacks, transmembrane, cytopla. For the television show see Adam 12 Disintegrin and metalloproteinase domain containing protein 12 previously Meltrin is an enzyme that in humans is encoded by the ADAM12 gene 5 6 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 7 ADAM12IdentifiersAliasesADAM12 ADAM12 OT1 CAR10 MCMP MCMPMltna MLTN MLTNA ADAM metallopeptidase domain 12External IDsOMIM 602714 MGI 105378 HomoloGene 74862 GeneCards ADAM12Gene location Human Chr Chromosome 10 human 1 Band10q26 2Start126 012 381 bp 1 End126 388 477 bp 1 Gene location Mouse Chr Chromosome 7 mouse 2 Band7 7 F3Start133 484 928 bp 2 End133 833 875 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inplacentastromal cell of endometriumtibiagallbladderlactiferous ductsmooth muscle tissueperiodontal fiberadipose tissueislet of Langerhansamniotic fluidTop expressed incalvariabody of femurbelly cordhuman mandiblelesser wing of sphenoid boneuterusdermisleft lung lobeinternal carotid arteryfossaMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionSH3 domain binding peptidase activity metalloendopeptidase activity protein binding hydrolase activity metal ion binding metallopeptidase activityCellular componentintegral component of membrane extracellular region membrane nucleoplasm plasma membraneBiological processcell adhesion myoblast fusion proteolysis extracellular matrix organization positive regulation of angiogenesisSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez803811489EnsemblENSG00000148848ENSMUSG00000054555UniProtO43184Q61824RefSeq mRNA NM 021641NM 001288973NM 001288974NM 001288975NM 003474NM 007400RefSeq protein NP 001275902NP 001275903NP 001275904NP 003465NP 067673NP 031426Location UCSC Chr 10 126 01 126 39 MbChr 7 133 48 133 83 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Function 2 Clinical Significance 3 Interactions 4 References 5 Further reading 6 External linksFunction editThis 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 8 Clinical Significance editADAM 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 9 ADAM12 has also been implicated in the development of pathology in various cancers hypertension liver fibrogenesis and asthma 10 In asthma ADAM12 is upregulated in lung epithelium in response to TNF alpha 11 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 12 Interactions editADAM12 has been shown to interact with ACTN2 13 IGFBP3 14 15 and PIK3R1 16 References edit a b c GRCh38 Ensembl release 89 ENSG00000148848 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000054555 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Gilpin BJ Loechel F Mattei MG Engvall E Albrechtsen R Wewer UM Feb 1998 A novel secreted form of human ADAM 12 meltrin alpha provokes myogenesis in vivo J Biol Chem 273 1 157 66 doi 10 1074 jbc 273 1 157 PMID 9417060 Kveiborg M Albrechtsen R Couchman JR Wewer UM Jun 2008 Cellular roles of ADAM12 in health and disease Int J Biochem Cell Biol 40 9 1685 702 doi 10 1016 j biocel 2008 01 025 PMID 18342566 Yagami Hiromasa T Sato T Kurisaki T Kamijo K Nabeshima Y Fujisawa Sehara A 1995 A metalloprotease disintegrin participating in myoblast fusion Nature 377 6550 652 6 Bibcode 1995Natur 377 652Y doi 10 1038 377652a0 PMID 7566181 S2CID 4348744 Entrez Gene ADAM12 ADAM metallopeptidase domain 12 meltrin alpha Danforth s Obstetrics and Gynecology 10th Edition Copyright c 2008 Lippincott Williams amp Wilkins Chapter 7 Prenatal Diagnosis Page 113 Nyren Erickson EK Jones JM Srivastava DK Mallik S 2013 A disintegrin and metalloproteinase 12 ADAM12 function roles in disease progression and clinical implications Biochim Biophys Acta 1830 10 4445 55 doi 10 1016 j bbagen 2013 05 011 PMC 3740046 PMID 23680494 Estrella C Rocks N Paulissen G Quesada Calvo F Noel A Vilain E Lassalle P Tillie Leblond I Cataldo D Gosset P 2009 Role of a disintegrin and metalloprotease 12 in neutrophil recruitment induced by airway epithelium Am J Respir Cell Mol Biol 41 4 449 58 doi 10 1165 rcmb 2008 0124OC hdl 2268 5767 PMID 19213876 Dzirasa K 2017 08 02 A brilliant approach to study the basis of intelligence Science Translational Medicine 9 401 doi 10 1126 scitranslmed aao0978 ISSN 1946 6234 S2CID 44125138 Galliano MF Huet C Frygelius J Polgren A Wewer UM Engvall E May 2000 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 doi 10 1074 jbc 275 18 13933 PMID 10788519 Shi Z Xu W Loechel F Wewer UM Murphy LJ Jun 2000 ADAM 12 a disintegrin metalloprotease interacts with insulin like growth factor binding protein 3 J Biol Chem 275 24 18574 80 doi 10 1074 jbc M002172200 PMID 10849447 Loechel F Fox JW Murphy G Albrechtsen R Wewer UM Nov 2000 ADAM 12 S cleaves IGFBP 3 and IGFBP 5 and is inhibited by TIMP 3 Biochem Biophys Res Commun 278 3 511 5 doi 10 1006 bbrc 2000 3835 PMID 11095942 Kang Q Cao Y Zolkiewska A Jul 2001 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 doi 10 1074 jbc M101162200 PMID 11313349 Further reading editKang Q Cao Y Zolkiewska A 2001 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 doi 10 1074 jbc M101162200 PMID 11313349 Loechel F Gilpin BJ Engvall E Albrechtsen R Wewer UM 1998 Human ADAM 12 meltrin alpha is an active metalloprotease J Biol Chem 273 27 16993 7 doi 10 1074 jbc 273 27 16993 PMID 9642263 Howard L Nelson KK Maciewicz RA Blobel CP 1999 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 doi 10 1074 jbc 274 44 31693 PMID 10531379 Galliano MF Huet C Frygelius J Polgren A Wewer UM Engvall E 2000 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 doi 10 1074 jbc 275 18 13933 PMID 10788519 Iba K Albrechtsen R Gilpin B Frohlich C Loechel F Zolkiewska A Ishiguro K Kojima T Liu W Langford JK Sanderson RD Brakebusch C Fassler R Wewer UM 2000 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 doi 10 1083 jcb 149 5 1143 PMC 2174829 PMID 10831617 Shi Z Xu W Loechel F Wewer UM Murphy LJ 2000 ADAM 12 a disintegrin metalloprotease interacts with insulin like growth factor binding protein 3 J Biol Chem 275 24 18574 80 doi 10 1074 jbc M002172200 PMID 10849447 Eto K Puzon McLaughlin W Sheppard D Sehara Fujisawa A Zhang XP Takada Y 2001 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 doi 10 1074 jbc M001953200 PMID 10944520 Loechel F Fox JW Murphy G Albrechtsen R Wewer UM 2001 ADAM 12 S cleaves IGFBP 3 and IGFBP 5 and is inhibited by TIMP 3 Biochem Biophys Res Commun 278 3 511 5 doi 10 1006 bbrc 2000 3835 PMID 11095942 Suzuki A Kadota N Hara T Nakagami Y Izumi T Takenawa T Sabe H Endo T 2000 Meltrin alpha cytoplasmic domain interacts with SH3 domains of Src and Grb2 and is phosphorylated by v Src Oncogene 19 51 5842 50 doi 10 1038 sj onc 1203986 PMID 11127814 Kawaguchi N Xu X Tajima R Kronqvist P Sundberg C Loechel F Albrechtsen R Wewer UM 2002 ADAM 12 protease induces adipogenesis in transgenic mice Am J Pathol 160 5 1895 903 doi 10 1016 S0002 9440 10 61136 4 PMC 1850877 PMID 12000741 Cao Y Kang Q Zhao Z Zolkiewska A 2002 Intracellular processing of metalloprotease disintegrin ADAM12 J Biol Chem 277 29 26403 11 doi 10 1074 jbc M110814200 PMID 12000744 Abram CL Seals DF Pass I Salinsky D Maurer L Roth TM Courtneidge SA 2003 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 doi 10 1074 jbc M300267200 PMID 12615925 Le Pabic H Bonnier D Wewer UM Coutand A Musso O Baffet G Clement B Theret N 2003 ADAM12 in human liver cancers TGF beta regulated expression in stellate cells is associated with matrix remodeling Hepatology 37 5 1056 66 doi 10 1053 jhep 2003 50205 PMID 12717386 S2CID 32722392 Kawaguchi N Sundberg C Kveiborg M Moghadaszadeh B Asmar M Dietrich N Thodeti CK Nielsen FC Moller P Mercurio AM Albrechtsen R Wewer UM 2004 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 doi 10 1242 jcs 00699 PMID 12915587 Mori S Tanaka M Nanba D Nishiwaki E Ishiguro H Higashiyama S Matsuura N 2003 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 doi 10 1074 jbc M306393200 PMID 12952982 Laigaard J Sorensen T Frohlich C Pedersen BN Christiansen M Schiott K Uldbjerg N Albrechtsen R Clausen HV Ottesen B Wewer UM 2004 ADAM12 a novel first trimester maternal serum marker for Down syndrome Prenat Diagn 23 13 1086 91 doi 10 1002 pd 762 PMID 14691998 S2CID 32888570 External links editThe MEROPS online database for peptidases and their inhibitors M12 212 ADAM12 on the Atlas of Genetics and Oncology Human ADAM12 genome location and ADAM12 gene details page in the UCSC Genome Browser Portal nbsp Biology 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