Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review CD9 (CD9 molecule) Laure Humbert, Mario Chevrette The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada (LH, MC) Published in Atlas Database: August 2009 Online updated version : http://AtlasGeneticsOncology.org/Genes/CD9ID995ch12p13.html DOI: 10.4267/2042/44793 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Pseudogene Identity None. Other names: 5H9; BA2; P24; GIG2; MIC3; MRP-1; BTCC-1; DRAP-27; TSPAN29 HGNC (Hugo): CD9 Location: 12p13.31 Local order: The CD9 gene is located between the VWF and the ATP5J2P5 genes. Protein Description CD9 is a member of the transmembrane 4 superfamily, also called the tetraspanin family. As other tetraspanins, CD9 is a cell-surface protein containing four hydrophobic transmembrane domains (indicated in green) and two extracellular domains (illustrated in violet). CD9 consists of 228 amino acids and weighs 24-27 kDa. CD9 contains four small and highly conserved hydrophobic transmembrane domains (24-27 amino acids); a small N-terminal (11 amino acids) and a C-terminal cytoplasmic (7 amino acids) tails, and a very small intracellular domain (4 amino acids). The remaining part of the protein is composed of two extracellular domains (also called loops; a small one of 20 amino acids and a large one of 83 amino acids). Two disulfide bonds, generated by four well-conserved cysteine residues (C), stabilize the large extracellular domain. CD9 also contains a tetraspanin signature (amino acids 65-89) and a CCG motif (amino acids 152 to 154), but lacks DNA/RNA Description The gene spans 38 kb of DNA, including a 10 kb intron separating the first two exons. CD9 encodes 8 exons, ranging from 63 to 109 base pairs. The coding sequence is highly conserved between species. The promoter contains neither TATA nor CAAT boxes, but does contain several consensus sequences for the binding of transcription factors (GATA, ETS, E2F, NFkB, AP2) as well as three putative Sp1 binding sites. Transcription The CD9 transcribed RNA has 1246 bases, of which 684 bases (from 112 (Met) to 795 (Val)) encode the protein. Genomic organisation of the CD9 gene on chromosome 12. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 630 CD9 (CD9 molecule) Humbert L, Chevrette M Structure of the CD9 protein. other motifs found on other tetraspanins (DW, PxSc3, Gc4). Homology Although there are variations in the amino acid sequence in the extracellular loops, the CD9 protein sequence is very well conserved between species (90% between human, mice and rat). CD9 share also some homologies with other tetraspanins, particularly in the transmembrane domains. Expression CD9 is expressed by a variety of hematopoietic and epithelial cells. It is transiently expressed during development of spinal motoneurons and other fetal nervous system sites, as well as in hematopoietic development. CD9 is glycosylated (the glycosylation site is in the first extracellular loop unlike most glycosylated tetraspanins where the site is located in the second extracellular loop) and acylated. CD9 is also phosphorylated on tyrosine following B-cell activation. CD9 is up-regulated on activated B and T lymphocytes. Mutations Note Although no genomic CD9 mutation has been reported, in prostate cancer, there is mention of cDNA mutation compatible with an RNA editing mechanism. So far, CD9 has never been implicated in gene fusion that could result in a modified protein. Localisation In normal cells, CD9 localizes mainly in the membranes while in cancer cells the protein may also be detected throughout the cytoplasm. Implicated in Function Various cancers CD9 can interact or form complexes with many other proteins, including other tetraspanins, integrins, EWI molecules, TGF-a, diphtheria toxin receptor, receptor tyrosine kinase, pregnancy specific glycoproteins, and proteins of the immune system such as MHC class II molecules and members of the Ig superfamily. Moreover, probably because of its localization in the cell membrane, CD9 is involved in platelet activation and aggregation, as well as in cell adhesion, spreading, cell motility and tumor metastasis. CD9 also regulates paranodal junction formation, and is required for gamete fusion. Furthermore, CD9 promotes muscle cell fusion and supports myotube maintenance. Note Decreased expression of the CD9 protein has been associated with many types of cancer. Disease - Expressed in 90% of non-T cell acute lymphoblastic leukemia cells and in 50% of chronic lymphocytic leukemia and acute myeloblastic leukemia. - Expression inversely correlated with metastatic potential of melanoma. - Expression suppresses motility and metastasis of carcinoma cells. - Reduction of expression correlated with poor prognosis in breast, lung and colon carcinomas. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 631 CD9 (CD9 molecule) Humbert L, Chevrette M References gene: characterization of the 5'-flanking region. Oncogene. 1996 Aug 1;13(3):481-6 Boucheix C, Nguyen-van-Cong, Perrot JY, Foubert C, Gross MS, Weil D, Laisney V, Rosenfeld C, Frezal J. Assignment to chromosome 12 of the gene coding for the human cell surface antigen CD9(p24) using the monoclonal antibody ALB6. Ann Genet. 1985;28(1):19-24 Miyake M, Nakano K, Itoi SI, Koh T, Taki T. Motility-related protein-1 (MRP-1/CD9) reduction as a factor of poor prognosis in breast cancer. Cancer Res. 1996 Mar 15;56(6):1244-9 Cajot JF, Sordat I, Silvestre T, Sordat B. Differential display cloning identifies motility-related protein (MRP1/CD9) as highly expressed in primary compared to metastatic human colon carcinoma cells. Cancer Res. 1997 Jul 1;57(13):2593-7 Rendu F, Boucheix C, Lebret M, Bourdeau N, Benoit P, Maclouf J, Soria C, Levy-Toledano S. Mechanisms of the mAb ALB6(CD9) induced human platelet activation: comparison with thrombin. Biochem Biophys Res Commun. 1987 Aug 14;146(3):1397-404 Maecker HT, Todd SC, Levy S. The tetraspanin superfamily: molecular facilitators. FASEB J. 1997 May;11(6):428-42 Horváth G, Serru V, Clay D, Billard M, Boucheix C, Rubinstein E. CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82. J Biol Chem. 1998 Nov 13;273(46):3053743 Seehafer JG, Tang SC, Slupsky JR, Shaw AR. The functional glycoprotein CD9 is variably acylated: localization of the variably acylated region to a membrane-associated peptide containing the binding site for the agonistic monoclonal antibody 50H.19. Biochim Biophys Acta. 1988 Dec 2;957(3):399-410 Cook GA, Wilkinson DA, Crossno JT Jr, Raghow R, Jennings LK. The tetraspanin CD9 influences the adhesion, spreading, and pericellular fibronectin matrix assembly of Chinese hamster ovary cells on human plasma fibronectin. Exp Cell Res. 1999 Sep 15;251(2):356-71 Boucheix C, Benoit P, Frachet P, Billard M, Worthington RE, Gagnon J, Uzan G. Molecular cloning of the CD9 antigen. A new family of cell surface proteins. J Biol Chem. 1991 Jan 5;266(1):117-22 Tachibana I, Hemler ME. Role of transmembrane 4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance. J Cell Biol. 1999 Aug 23;146(4):893-904 Ikeyama S, Koyama M, Yamaoko M, Sasada R, Miyake M. Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med. 1993 May 1;177(5):1231-7 Rubinstein E, Benoit P, Billard M, Plaisance S, Prenant M, Uzan G, Boucheix C. Organization of the human CD9 gene. Genomics. 1993 Apr;16(1):132-8 Miyado K, Yamada G, Yamada S, Hasuwa H, Nakamura Y, Ryu F, Suzuki K, Kosai K, Inoue K, Ogura A, Okabe M, Mekada E. Requirement of CD9 on the egg plasma membrane for fertilization. Science. 2000 Jan 14;287(5451):321-4 Si Z, Hersey P. Expression of the neuroglandular antigen and analogues in melanoma. CD9 expression appears inversely related to metastatic potential of melanoma. Int J Cancer. 1993 Apr 22;54(1):37-43 Seigneuret M, Delaguillaumie A, Lagaudrière-Gesbert C, Conjeaud H. Structure of the tetraspanin main extracellular domain. A partially conserved fold with a structurally variable domain insertion. J Biol Chem. 2001 Oct 26;276(43):40055-64 Tole S, Patterson PH. Distribution of CD9 in the developing and mature rat nervous system. Dev Dyn. 1993 Jun;197(2):94106 Ishibashi T, Ding L, Ikenaka K, Inoue Y, Miyado K, Mekada E, Baba H. Tetraspanin protein CD9 is a novel paranodal component regulating paranodal junctional formation. J Neurosci. 2004 Jan 7;24(1):96-102 Higashiyama M, Taki T, Ieki Y, Adachi M, Huang CL, Koh T, Kodama K, Doi O, Miyake M. Reduced motility related protein1 (MRP-1/CD9) gene expression as a factor of poor prognosis in non-small cell lung cancer. Cancer Res. 1995 Dec 15;55(24):6040-4 Kovalenko OV, Metcalf DG, DeGrado WF, Hemler ME. Structural organization and interactions of transmembrane domains in tetraspanin proteins. BMC Struct Biol. 2005 Jun 28;5:11 Wang JC, Bégin LR, Bérubé NG, Chevalier S, Aprikian AG, Gourdeau H, Chevrette M. Down-regulation of CD9 expression during prostate carcinoma progression is associated with CD9 mRNA modifications. Clin Cancer Res. 2007 Apr 15;13(8):2354-61 Shaw AR, Domanska A, Mak A, Gilchrist A, Dobler K, Visser L, Poppema S, Fliegel L, Letarte M, Willett BJ. Ectopic expression of human and feline CD9 in a human B cell line confers beta 1 integrin-dependent motility on fibronectin and laminin substrates and enhanced tyrosine phosphorylation. J Biol Chem. 1995 Oct 13;270(41):24092-9 This article should be referenced as such: Le Naour F, Prenant M, Francastel C, Rubinstein E, Uzan G, Boucheix C. Transcriptional regulation of the human CD9 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) Humbert L, Chevrette M. CD9 (CD9 molecule). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):630-632. 632