CD9 explained

CD9 is a gene encoding a protein that is a member of the transmembrane 4 superfamily also known as the tetraspanin family. It is a cell surface glycoprotein that consists of four transmembrane regions and has two extracellular loops that contain disulfide bonds which are conserved throughout the tetraspanin family.^{[1] [2] [3]} Also containing distinct palmitoylation sites that allows CD9 to interact with lipids and other proteins.^{[4] [5]}

Function

Tetraspanin proteins are involved in a multitude of biological processes such as adhesion, motility, membrane fusion, signaling and protein trafficking.^[6] Tetraspanins play a role in many biological processes because of their ability to interact with many different proteins including interactions between each other. Their distinct palmitoylation sites allow them to organize on the membrane into tetraspanin-enriched microdomains (TEM). These TEMs are thought to play a role in many cellular processes including exosome biogenesis.^[7] CD9 is commonly used as a marker for exosomes as it is contained on their surface.^{[8] [9]}

However, in some cases CD9 plays a larger role in the ability of exosomes to be more or less pathogenic. Shown in HIV-1 infection, exosomes are able to enhance HIV-1 entry through tetraspanin CD9 and CD81.^[10] However, expression of CD9 on the cellular membrane seems to decrease the viral entry of HIV-1.^{[11] [12]}

CD9 has a diverse role in cellular processes as it has also been shown to trigger platelet activation and aggregation.^[13] It forms a alphaIIbbeta3-CD9-CD63 complex on the surface of platelets that interacts directly with other cells such as neutrophils which may assist in immune response.^{[14] [15]} In addition, the protein appears to promote muscle cell fusion and support myotube maintenance.^{[16] [17]} Also, playing a key role in egg-sperm fusion during mammalian fertilization. While oocytes are ovulated, CD9-deficient oocytes do not properly fuse with sperm upon fertilization.^[18] CD9 is located in the microvillar membrane of the oocytes and also appears to intervene in maintaining the normal shape of oocyte microvilli.^[19]

CD9 can also modulate cell adhesion^[20] and migration.^{[21] [22]} This function makes CD9 of interest when studying cancer and cancer metastasis. However, it seems CD9 has a varying role in different types of cancers. Studies showed that CD9 expression levels have an inverse correlation to metastatic potential or patient survival. The over expression of CD9 was shown to decrease metastasis in certain types of melanoma, breast, lung, pancreas and colon carcinomas.^{[23] [24] [25] [26] [27]} However in other studies, CD9 has been shown to increase migration or be highly expressed in metastatic cancers in various cell lines such as lung cancer, scirrhous-type gastric cancer, hepatocellular carcinoma,^[28] acute lymphoblastic leukemia,^[29] and breast cancer. Suggesting based on the cancer CD9 can be a tumor suppressor or promotor. ^[30] It has also been suggested that CD9 has an effect on the ability for cancer cells to develop chemoresistance.

Additionally, CD9 has been shown to block adhesion of Staphylococcus aureus to wounds. The adhesion is essential for infection of the wound.^[31] This suggests that CD9 could be of possible use to as treatment for skin infection by Staphylococcus aureus.

Interactions

CD9 has been shown to interact with:

• CD117,^[32]
• CD29^[33]
• CD46,^[34]
• CD49c,^{[35] [36]}
• CD81,^{[37] [38]}
• PTGFRN,^{[39] [40]}
• TSPAN4.^[41]
  • CD63 ADAM17 ^[42]
• CD81^[43]

See also

• Tetraspanin
• Myogenesis
• Fertilisation

Further reading

• Horejsí V, Vlcek C . Novel structurally distinct family of leucocyte surface glycoproteins including CD9, CD37, CD53 and CD63 . FEBS Letters . 288 . 1–2 . 1–4 . August 1991 . 1879540 . 10.1016/0014-5793(91)80988-F . 26316623 .
• Berditchevski F . Complexes of tetraspanins with integrins: more than meets the eye . Journal of Cell Science . 114 . Pt 23 . 4143–51 . December 2001 . 10.1242/jcs.114.23.4143 . 11739647 .
• Ninomiya H, Sims PJ . The human complement regulatory protein CD59 binds to the alpha-chain of C8 and to the "b"domain of C9 . The Journal of Biological Chemistry . 267 . 19 . 13675–80 . July 1992 . 10.1016/S0021-9258(18)42266-1 . 1377690 . free .
• Miyake M, Koyama M, Seno M, Ikeyama S . Identification of the motility-related protein (MRP-1), recognized by monoclonal antibody M31-15, which inhibits cell motility . The Journal of Experimental Medicine . 174 . 6 . 1347–54 . December 1991 . 1720807 . 2119050 . 10.1084/jem.174.6.1347 .
• 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 . The Journal of Biological Chemistry . 266 . 1 . 117–22 . January 1991 . 10.1016/S0021-9258(18)52410-8 . 1840589 . free .
• Iwamoto R, Senoh H, Okada Y, Uchida T, Mekada E . An antibody that inhibits the binding of diphtheria toxin to cells revealed the association of a 27-kDa membrane protein with the diphtheria toxin receptor . The Journal of Biological Chemistry . 266 . 30 . 20463–9 . October 1991 . 10.1016/S0021-9258(18)54947-4 . 1939101 . free .
• Benoit P, Gross MS, Frachet P, Frézal J, Uzan G, Boucheix C, Nguyen VC . Assignment of the human CD9 gene to chromosome 12 (region P13) by use of human specific DNA probes . Human Genetics . 86 . 3 . 268–72 . January 1991 . 1997380 . 10.1007/bf00202407 . 27178985 .
• Lanza F, Wolf D, Fox CF, Kieffer N, Seyer JM, Fried VA, Coughlin SR, Phillips DR, Jennings LK . 6 . cDNA cloning and expression of platelet p24/CD9. Evidence for a new family of multiple membrane-spanning proteins . The Journal of Biological Chemistry . 266 . 16 . 10638–45 . June 1991 . 10.1016/S0021-9258(18)99271-9 . 2037603 . free .
• Higashihara M, Takahata K, Yatomi Y, Nakahara K, Kurokawa K . Purification and partial characterization of CD9 antigen of human platelets . FEBS Letters . 264 . 2 . 270–4 . May 1990 . 2358073 . 10.1016/0014-5793(90)80265-K . 42129059 .
• Masellis-Smith A, Shaw AR . CD9-regulated adhesion. Anti-CD9 monoclonal antibody induce pre-B cell adhesion to bone marrow fibroblasts through de novo recognition of fibronectin . Journal of Immunology . 152 . 6 . 2768–77 . March 1994 . 10.4049/jimmunol.152.6.2768 . 7511626 . 23491895 . free .
• Chalupny NJ, Kanner SB, Schieven GL, Wee SF, Gilliland LK, Aruffo A, Ledbetter JA . Tyrosine phosphorylation of CD19 in pre-B and mature B cells . The EMBO Journal . 12 . 7 . 2691–6 . July 1993 . 7687539 . 413517 . 10.1002/j.1460-2075.1993.tb05930.x .
• Rubinstein E, Benoit P, Billard M, Plaisance S, Prenant M, Uzan G, Boucheix C . Organization of the human CD9 gene . Genomics . 16 . 1 . 132–8 . April 1993 . 8486348 . 10.1006/geno.1993.1150 .
• Schmidt C, Künemund V, Wintergerst ES, Schmitz B, Schachner M . CD9 of mouse brain is implicated in neurite outgrowth and cell migration in vitro and is associated with the alpha 6/beta 1 integrin and the neural adhesion molecule L1 . Journal of Neuroscience Research . 43 . 1 . 12–31 . January 1996 . 8838570 . 10.1002/jnr.490430103 . 84774340 .
• Sincock PM, Mayrhofer G, Ashman LK . Localization of the transmembrane 4 superfamily (TM4SF) member PETA-3 (CD151) in normal human tissues: comparison with CD9, CD63, and alpha5beta1 integrin . The Journal of Histochemistry and Cytochemistry . 45 . 4 . 515–25 . April 1997 . 9111230 . 10.1177/002215549704500404 . free .
• Rubinstein E, Poindessous-Jazat V, Le Naour F, Billard M, Boucheix C . CD9, but not other tetraspans, associates with the beta1 integrin precursor . European Journal of Immunology . 27 . 8 . 1919–27 . August 1997 . 9295027 . 10.1002/eji.1830270815 . 42866423 .
• Cho, J.H., Kim, E., Son, Y. et al. (2020). CD9 induces cellular senescence and aggravates atherosclerotic plaque formation. Cell Death & Differentiation https://doi.org/10.1038/s41418-020-0537-9

Notes and References

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2. Web site: CD9 CD9 molecule [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2019-12-04.
3. Web site: CD9 Gene - GeneCards CD9 Protein CD9 Antibody. www.genecards.org. 2019-12-04.
4. Yáñez-Mó M, Barreiro O, Gordon-Alonso M, Sala-Valdés M, Sánchez-Madrid F . Tetraspanin-enriched microdomains: a functional unit in cell plasma membranes . Trends in Cell Biology . 19 . 9 . 434–46 . September 2009 . 19709882 . 10.1016/j.tcb.2009.06.004 .
5. Yang XH, Kovalenko OV, Kolesnikova TV, Andzelm MM, Rubinstein E, Strominger JL, Hemler ME . Contrasting effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization . The Journal of Biological Chemistry . 281 . 18 . 12976–85 . May 2006 . 16537545 . 10.1074/jbc.M510617200 . free .
6. Hemler ME . Tetraspanin functions and associated microdomains . Nature Reviews. Molecular Cell Biology . 6 . 10 . 801–11 . October 2005 . 16314869 . 10.1038/nrm1736 . 5906694 .
7. Perez-Hernandez D, Gutiérrez-Vázquez C, Jorge I, López-Martín S, Ursa A, Sánchez-Madrid F, Vázquez J, Yáñez-Mó M . 6 . The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes . The Journal of Biological Chemistry . 288 . 17 . 11649–61 . April 2013 . 23463506 . 3636856 . 10.1074/jbc.M112.445304 . free .
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17. Charrin S, Latil M, Soave S, Polesskaya A, Chrétien F, Boucheix C, Rubinstein E . Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81 . Nature Communications . 4 . 1674 . 2013 . 23575678 . 10.1038/ncomms2675 . 2013NatCo...4.1674C . free .
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19. Runge KE, Evans JE, He ZY, Gupta S, McDonald KL, Stahlberg H, Primakoff P, Myles DG . 6 . Oocyte CD9 is enriched on the microvillar membrane and required for normal microvillar shape and distribution . Developmental Biology . 304 . 1 . 317–25 . April 2007 . 17239847 . 10.1016/j.ydbio.2006.12.041 .
20. Machado-Pineda Y, Cardeñes B, Reyes R, López-Martín S, Toribio V, Sánchez-Organero P, Suarez H, Grötzinger J, Lorenzen I, Yáñez-Mó M, Cabañas C . 6 . CD9 Controls Integrin α5β1-Mediated Cell Adhesion by Modulating Its Association With the Metalloproteinase ADAM17 . Frontiers in Immunology . 9 . 2474 . 2018 . 30455686 . 6230984 . 10.3389/fimmu.2018.02474 . free .
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22. Miki Y, Yashiro M, Okuno T, Kitayama K, Masuda G, Hirakawa K, Ohira M . CD9-positive exosomes from cancer-associated fibroblasts stimulate the migration ability of scirrhous-type gastric cancer cells . British Journal of Cancer . 118 . 6 . 867–877 . March 2018 . 29438363 . 5886122 . 10.1038/bjc.2017.487 .
23. Mimori K, Mori M, Shiraishi T, Tanaka S, Haraguchi M, Ueo H, Shirasaka C, Akiyoshi T . 6 . Expression of ornithine decarboxylase mRNA and c-myc mRNA in breast tumours . International Journal of Oncology . 12 . 3 . 597–601 . March 1998 . 9472098 . 10.3892/ijo.12.3.597 .
24. Higashiyama M, Taki T, Ieki Y, Adachi M, Huang CL, Koh T, Kodama K, Doi O, Miyake M . 6 . Reduced motility related protein-1 (MRP-1/CD9) gene expression as a factor of poor prognosis in non-small cell lung cancer . Cancer Research . 55 . 24 . 6040–4 . December 1995 . 8521390 . 10.1016/0169-5002(96)87780-4 .
25. 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 . The Journal of Experimental Medicine . 177 . 5 . 1231–7 . May 1993 . 8478605 . 2191011 . 10.1084/jem.177.5.1231 .
26. Sho M, Adachi M, Taki T, Hashida H, Konishi T, Huang CL, Ikeda N, Nakajima Y, Kanehiro H, Hisanaga M, Nakano H, Miyake M . 6 . Transmembrane 4 superfamily as a prognostic factor in pancreatic cancer . International Journal of Cancer . 79 . 5 . 509–16 . October 1998 . 9761121 . 10.1002/(sici)1097-0215(19981023)79:5<509::aid-ijc11>3.0.co;2-x . 19842716 .
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28. Lin Q, Peng S, Yang Y . Inhibition of CD9 expression reduces the metastatic capacity of human hepatocellular carcinoma cell line MHCC97-H . International Journal of Oncology . 53 . 1 . 266–274 . July 2018 . 29749468 . 10.3892/ijo.2018.4381 . free .
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31. Ventress JK, Partridge LJ, Read RC, Cozens D, MacNeil S, Monk PN . Peptides from Tetraspanin CD9 Are Potent Inhibitors of Staphylococcus Aureus Adherence to Keratinocytes . PLOS ONE . 11 . 7 . e0160387 . 2016-07-28 . 27467693 . 4965146 . 10.1371/journal.pone.0160387 . 2016PLoSO..1160387V . free .
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33. Mazzocca A, Carloni V, Sciammetta S, Cordella C, Pantaleo P, Caldini A, Gentilini P, Pinzani M . 6 . Expression of transmembrane 4 superfamily (TM4SF) proteins and their role in hepatic stellate cell motility and wound healing migration . Journal of Hepatology . 37 . 3 . 322–30 . September 2002 . 12175627 . 10.1016/s0168-8278(02)00175-7 .
34. Lozahic S, Christiansen D, Manié S, Gerlier D, Billard M, Boucheix C, Rubinstein E . CD46 (membrane cofactor protein) associates with multiple beta1 integrins and tetraspans . European Journal of Immunology . 30 . 3 . 900–7 . March 2000 . 10741407 . 10.1002/1521-4141(200003)30:3<900::AID-IMMU900>3.0.CO;2-X . free .
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42. Gutiérrez-López MD, Gilsanz A, Yáñez-Mó M, Ovalle S, Lafuente EM, Domínguez C, Monk PN, González-Alvaro I, Sánchez-Madrid F, Cabañas C . 6 . The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9 . Cellular and Molecular Life Sciences . 68 . 19 . 3275–92 . October 2011 . 21365281 . 10.1007/s00018-011-0639-0 . 23682577 . 11115118 .
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