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. 1999 Mar 1;338(Pt 2):325–333.

Complete sequence of the human mucin MUC4: a putative cell membrane-associated mucin.

N Moniaux 1, S Nollet 1, N Porchet 1, P Degand 1, A Laine 1, J P Aubert 1
PMCID: PMC1220057  PMID: 10024507

Abstract

The MUC4 gene, which encodes a human epithelial mucin, is expressed in various epithelial tissues, just as well in adult as in poorly differentiated cells in the embryo and fetus. Its N-terminus and central sequences have previously been reported as comprising a 27-residue peptide signal, followed by a large domain varying in length from 3285 to 7285 amino acid residues. The present study establishes the whole coding sequence of MUC4 in which the C-terminus is 1156 amino acid residues long and shares a high degree of similarity with the rat sialomucin complex (SMC). SMC is a heterodimeric glycoprotein complex composed of mucin (ascites sialoglycoprotein 1, ASGP-1) and transmembrane (ASGP-2) subunits. The same organization is found in MUC4, where the presence of a GlyAspProHis proteolytic site may cleave the large precursor into two subunits, MUC4alpha and MUC4beta. Like ASGP-2, which binds the receptor tyrosine kinase p185(neu), MUC4beta possesses two epidermal growth factor-like domains, a transmembrane sequence and a potential phosphorylated site. MUC4, the human homologue of rat SMC, may be a heterodimeric bifunctional cell-surface glycoprotein of 2.12 micrometers. These results confer a new biological role for MUC4 as a ligand for ErbB2 in cell signalling.

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Selected References

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  1. Aubert J. P., Porchet N., Crepin M., Duterque-Coquillaud M., Vergnes G., Mazzuca M., Debuire B., Petitprez D., Degand P. Evidence for different human tracheobronchial mucin peptides deduced from nucleotide cDNA sequences. Am J Respir Cell Mol Biol. 1991 Aug;5(2):178–185. doi: 10.1165/ajrcmb/5.2.178. [DOI] [PubMed] [Google Scholar]
  2. Audie J. P., Janin A., Porchet N., Copin M. C., Gosselin B., Aubert J. P. Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization. J Histochem Cytochem. 1993 Oct;41(10):1479–1485. doi: 10.1177/41.10.8245407. [DOI] [PubMed] [Google Scholar]
  3. Audie J. P., Tetaert D., Pigny P., Buisine M. P., Janin A., Aubert J. P., Porchet N., Boersma A. Mucin gene expression in the human endocervix. Hum Reprod. 1995 Jan;10(1):98–102. doi: 10.1093/humrep/10.1.98. [DOI] [PubMed] [Google Scholar]
  4. Balagué C., Audié J. P., Porchet N., Real F. X. In situ hybridization shows distinct patterns of mucin gene expression in normal, benign, and malignant pancreas tissues. Gastroenterology. 1995 Sep;109(3):953–964. doi: 10.1016/0016-5085(95)90406-9. [DOI] [PubMed] [Google Scholar]
  5. Balagué C., Gambús G., Carrato C., Porchet N., Aubert J. P., Kim Y. S., Real F. X. Altered expression of MUC2, MUC4, and MUC5 mucin genes in pancreas tissues and cancer cell lines. Gastroenterology. 1994 Apr;106(4):1054–1061. doi: 10.1016/0016-5085(94)90767-6. [DOI] [PubMed] [Google Scholar]
  6. Bobek L. A., Liu J., Sait S. N., Shows T. B., Bobek Y. A., Levine M. J. Structure and chromosomal localization of the human salivary mucin gene, MUC7. Genomics. 1996 Feb 1;31(3):277–282. doi: 10.1006/geno.1996.0049. [DOI] [PubMed] [Google Scholar]
  7. Braga V. M., Pemberton L. F., Duhig T., Gendler S. J. Spatial and temporal expression of an epithelial mucin, Muc-1, during mouse development. Development. 1992 Jun;115(2):427–437. doi: 10.1242/dev.115.2.427. [DOI] [PubMed] [Google Scholar]
  8. Buisine M. P., Devisme L., Savidge T. C., Gespach C., Gosselin B., Porchet N., Aubert J. P. Mucin gene expression in human embryonic and fetal intestine. Gut. 1998 Oct;43(4):519–524. doi: 10.1136/gut.43.4.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Burchell J., Wang D., Taylor-Papadimitriou J. Detection of the tumour-associated antigens recognized by the monoclonal antibodies HMFG-1 and 2 in serum from patients with breast cancer. Int J Cancer. 1984 Dec 15;34(6):763–768. doi: 10.1002/ijc.2910340605. [DOI] [PubMed] [Google Scholar]
  10. Carraway K. L., 3rd, Cantley L. C. A neu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell. 1994 Jul 15;78(1):5–8. doi: 10.1016/0092-8674(94)90564-9. [DOI] [PubMed] [Google Scholar]
  11. Carraway K. L., Carraway C. A., Carraway K. L., 3rd Roles of ErbB-3 and ErbB-4 in the physiology and pathology of the mammary gland. J Mammary Gland Biol Neoplasia. 1997 Apr;2(2):187–198. doi: 10.1023/a:1026360032602. [DOI] [PubMed] [Google Scholar]
  12. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  13. Costa M. J., Walls J., Trelford J. D. c-erbB-2 oncoprotein overexpression in uterine cervix carcinoma with glandular differentiation. A frequent event but not an independent prognostic marker because it occurs late in the disease. Am J Clin Pathol. 1995 Dec;104(6):634–642. doi: 10.1093/ajcp/104.6.634. [DOI] [PubMed] [Google Scholar]
  14. Debailleul V., Laine A., Huet G., Mathon P., d'Hooghe M. C., Aubert J. P., Porchet N. Human mucin genes MUC2, MUC3, MUC4, MUC5AC, MUC5B, and MUC6 express stable and extremely large mRNAs and exhibit a variable length polymorphism. An improved method to analyze large mRNAs. J Biol Chem. 1998 Jan 9;273(2):881–890. doi: 10.1074/jbc.273.2.881. [DOI] [PubMed] [Google Scholar]
  15. Desseyn J. L., Buisine M. P., Porchet N., Aubert J. P., Degand P., Laine A. Evolutionary history of the 11p15 human mucin gene family. J Mol Evol. 1998 Jan;46(1):102–106. doi: 10.1007/pl00006276. [DOI] [PubMed] [Google Scholar]
  16. Dufosse J., Porchet N., Audie J. P., Guyonnet Duperat V., Laine A., Van-Seuningen I., Marrakchi S., Degand P., Aubert J. P. Degenerate 87-base-pair tandem repeats create hydrophilic/hydrophobic alternating domains in human mucin peptides mapped to 11p15. Biochem J. 1993 Jul 15;293(Pt 2):329–337. doi: 10.1042/bj2930329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gendler S. J., Lancaster C. A., Taylor-Papadimitriou J., Duhig T., Peat N., Burchell J., Pemberton L., Lalani E. N., Wilson D. Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin. J Biol Chem. 1990 Sep 5;265(25):15286–15293. [PubMed] [Google Scholar]
  18. Gross M. S., Guyonnet-Duperat V., Porchet N., Bernheim A., Aubert J. P., Nguyen V. C. Mucin 4 (MUC4) gene: regional assignment (3q29) and RFLP analysis. Ann Genet. 1992;35(1):21–26. [PubMed] [Google Scholar]
  19. Gullick W. J. The role of the epidermal growth factor receptor and the c-erbB-2 protein in breast cancer. Int J Cancer Suppl. 1990;5:55–61. doi: 10.1002/ijc.2910460708. [DOI] [PubMed] [Google Scholar]
  20. Gum J. R., Hicks J. W., Swallow D. M., Lagace R. L., Byrd J. C., Lamport D. T., Siddiki B., Kim Y. S. Molecular cloning of cDNAs derived from a novel human intestinal mucin gene. Biochem Biophys Res Commun. 1990 Aug 31;171(1):407–415. doi: 10.1016/0006-291x(90)91408-k. [DOI] [PubMed] [Google Scholar]
  21. Gum J. R., Jr, Hicks J. W., Toribara N. W., Siddiki B., Kim Y. S. Molecular cloning of human intestinal mucin (MUC2) cDNA. Identification of the amino terminus and overall sequence similarity to prepro-von Willebrand factor. J Biol Chem. 1994 Jan 28;269(4):2440–2446. [PubMed] [Google Scholar]
  22. Gum J. R., Jr, Ho J. J., Pratt W. S., Hicks J. W., Hill A. S., Vinall L. E., Roberton A. M., Swallow D. M., Kim Y. S. MUC3 human intestinal mucin. Analysis of gene structure, the carboxyl terminus, and a novel upstream repetitive region. J Biol Chem. 1997 Oct 17;272(42):26678–26686. doi: 10.1074/jbc.272.42.26678. [DOI] [PubMed] [Google Scholar]
  23. Guzman K., Bader T., Nettesheim P. Regulation of MUC5 and MUC1 gene expression: correlation with airway mucous differentiation. Am J Physiol. 1996 May;270(5 Pt 1):L846–L853. doi: 10.1152/ajplung.1996.270.5.L846. [DOI] [PubMed] [Google Scholar]
  24. Ho S. B., Niehans G. A., Lyftogt C., Yan P. S., Cherwitz D. L., Gum E. T., Dahiya R., Kim Y. S. Heterogeneity of mucin gene expression in normal and neoplastic tissues. Cancer Res. 1993 Feb 1;53(3):641–651. [PubMed] [Google Scholar]
  25. Jentoft N. Why are proteins O-glycosylated? Trends Biochem Sci. 1990 Aug;15(8):291–294. doi: 10.1016/0968-0004(90)90014-3. [DOI] [PubMed] [Google Scholar]
  26. Kapitanović S., Radosević S., Kapitanović M., Andelinović S., Ferencić Z., Tavassoli M., Primorać D., Sonicki Z., Spaventi S., Pavelic K. The expression of p185(HER-2/neu) correlates with the stage of disease and survival in colorectal cancer. Gastroenterology. 1997 Apr;112(4):1103–1113. doi: 10.1016/s0016-5085(97)70120-3. [DOI] [PubMed] [Google Scholar]
  27. Khatri I. A., Forstner G. G., Forstner J. F. The carboxyl-terminal sequence of rat intestinal mucin RMuc3 contains a putative transmembrane region and two EGF-like motifs. Biochim Biophys Acta. 1997 May 22;1326(1):7–11. doi: 10.1016/s0005-2736(97)00063-1. [DOI] [PubMed] [Google Scholar]
  28. Kokai Y., Cohen J. A., Drebin J. A., Greene M. I. Stage- and tissue-specific expression of the neu oncogene in rat development. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8498–8501. doi: 10.1073/pnas.84.23.8498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kyte J., Doolittle R. F. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982 May 5;157(1):105–132. doi: 10.1016/0022-2836(82)90515-0. [DOI] [PubMed] [Google Scholar]
  30. Lan M. S., Batra S. K., Qi W. N., Metzgar R. S., Hollingsworth M. A. Cloning and sequencing of a human pancreatic tumor mucin cDNA. J Biol Chem. 1990 Sep 5;265(25):15294–15299. [PubMed] [Google Scholar]
  31. Ligtenberg M. J., Kruijshaar L., Buijs F., van Meijer M., Litvinov S. V., Hilkens J. Cell-associated episialin is a complex containing two proteins derived from a common precursor. J Biol Chem. 1992 Mar 25;267(9):6171–6177. [PubMed] [Google Scholar]
  32. Lupu R., Colomer R., Zugmaier G., Sarup J., Shepard M., Slamon D., Lippman M. E. Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. Science. 1990 Sep 28;249(4976):1552–1555. doi: 10.1126/science.2218496. [DOI] [PubMed] [Google Scholar]
  33. Meden H., Kuhn W. Overexpression of the oncogene c-erbB-2 (HER2/neu) in ovarian cancer: a new prognostic factor. Eur J Obstet Gynecol Reprod Biol. 1997 Feb;71(2):173–179. doi: 10.1016/s0301-2115(96)02630-9. [DOI] [PubMed] [Google Scholar]
  34. Nollet S., Moniaux N., Maury J., Petitprez D., Degand P., Laine A., Porchet N., Aubert J. P. Human mucin gene MUC4: organization of its 5'-region and polymorphism of its central tandem repeat array. Biochem J. 1998 Jun 15;332(Pt 3):739–748. doi: 10.1042/bj3320739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ogata S., Uehara H., Chen A., Itzkowitz S. H. Mucin gene expression in colonic tissues and cell lines. Cancer Res. 1992 Nov 1;52(21):5971–5978. [PubMed] [Google Scholar]
  36. Pemberton L., Taylor-Papadimitriou J., Gendler S. J. Antibodies to the cytoplasmic domain of the MUC1 mucin show conservation throughout mammals. Biochem Biophys Res Commun. 1992 May 29;185(1):167–175. doi: 10.1016/s0006-291x(05)80971-4. [DOI] [PubMed] [Google Scholar]
  37. Pigny P., Guyonnet-Duperat V., Hill A. S., Pratt W. S., Galiegue-Zouitina S., d'Hooge M. C., Laine A., Van-Seuningen I., Degand P., Gum J. R. Human mucin genes assigned to 11p15.5: identification and organization of a cluster of genes. Genomics. 1996 Dec 15;38(3):340–352. doi: 10.1006/geno.1996.0637. [DOI] [PubMed] [Google Scholar]
  38. Porchet N., Nguyen V. C., Dufosse J., Audie J. P., Guyonnet-Duperat V., Gross M. S., Denis C., Degand P., Bernheim A., Aubert J. P. Molecular cloning and chromosomal localization of a novel human tracheo-bronchial mucin cDNA containing tandemly repeated sequences of 48 base pairs. Biochem Biophys Res Commun. 1991 Mar 15;175(2):414–422. doi: 10.1016/0006-291x(91)91580-6. [DOI] [PubMed] [Google Scholar]
  39. Rossi E. A., McNeer R. R., Price-Schiavi S. A., Van den Brande J. M., Komatsu M., Thompson J. F., Carraway C. A., Fregien N. L., Carraway K. L. Sialomucin complex, a heterodimeric glycoprotein complex. Expression as a soluble, secretable form in lactating mammary gland and colon. J Biol Chem. 1996 Dec 27;271(52):33476–33485. doi: 10.1074/jbc.271.52.33476. [DOI] [PubMed] [Google Scholar]
  40. Shankar V., Pichan P., Eddy R. L., Jr, Tonk V., Nowak N., Sait S. N., Shows T. B., Schultz R. E., Gotway G., Elkins R. C. Chromosomal localization of a human mucin gene (MUC8) and cloning of the cDNA corresponding to the carboxy terminus. Am J Respir Cell Mol Biol. 1997 Mar;16(3):232–241. doi: 10.1165/ajrcmb.16.3.9070607. [DOI] [PubMed] [Google Scholar]
  41. Shekels L. L., Hunninghake D. A., Tisdale A. S., Gipson I. K., Kieliszewski M., Kozak C. A., Ho S. B. Cloning and characterization of mouse intestinal MUC3 mucin: 3' sequence contains epidermal-growth-factor-like domains. Biochem J. 1998 Mar 15;330(Pt 3):1301–1308. doi: 10.1042/bj3301301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sheng Z., Wu K., Carraway K. L., Fregien N. Molecular cloning of the transmembrane component of the 13762 mammary adenocarcinoma sialomucin complex. A new member of the epidermal growth factor superfamily. J Biol Chem. 1992 Aug 15;267(23):16341–16346. [PubMed] [Google Scholar]
  43. Sherblom A. P., Buck R. L., Carraway K. L. Purification of the major sialoglycoproteins of 13762 MAT-B1 and MAT-C1 rat ascites mammary adenocarcinoma cells by density gradient centrifugation in cesium chloride and guanidine hydrochloride. J Biol Chem. 1980 Jan 25;255(2):783–790. [PubMed] [Google Scholar]
  44. Sherblom A. P., Carraway K. L. A complex of two cell surface glycoproteins from ascites mammary adenocarcinoma cells. J Biol Chem. 1980 Dec 25;255(24):12051–12059. [PubMed] [Google Scholar]
  45. Slamon D. J., Godolphin W., Jones L. A., Holt J. A., Wong S. G., Keith D. E., Levin W. J., Stuart S. G., Udove J., Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
  46. Toribara N. W., Roberton A. M., Ho S. B., Kuo W. L., Gum E., Hicks J. W., Gum J. R., Jr, Byrd J. C., Siddiki B., Kim Y. S. Human gastric mucin. Identification of a unique species by expression cloning. J Biol Chem. 1993 Mar 15;268(8):5879–5885. [PubMed] [Google Scholar]
  47. Vos H. L., de Vries Y., Hilkens J. The mouse episialin (Muc1) gene and its promoter: rapid evolution of the repetitive domain in the protein. Biochem Biophys Res Commun. 1991 Nov 27;181(1):121–130. doi: 10.1016/s0006-291x(05)81390-7. [DOI] [PubMed] [Google Scholar]
  48. Wada T., Qian X. L., Greene M. I. Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell. 1990 Jun 29;61(7):1339–1347. doi: 10.1016/0092-8674(90)90697-d. [DOI] [PubMed] [Google Scholar]
  49. Wu K., Fregien N., Carraway K. L. Molecular cloning and sequencing of the mucin subunit of a heterodimeric, bifunctional cell surface glycoprotein complex of ascites rat mammary adenocarcinoma cells. J Biol Chem. 1994 Apr 22;269(16):11950–11955. [PubMed] [Google Scholar]
  50. Yu C. J., Shun C. T., Yang P. C., Lee Y. C., Shew J. Y., Kuo S. H., Luh K. T. Sialomucin expression is associated with erbB-2 oncoprotein overexpression, early recurrence, and cancer death in non-small-cell lung cancer. Am J Respir Crit Care Med. 1997 Apr;155(4):1419–1427. doi: 10.1164/ajrccm.155.4.9105088. [DOI] [PubMed] [Google Scholar]

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