Biology:CD9

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Crystal structure of human CD9
A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][4][5]

Function

Tetraspanin proteins are involved in a multitude of biological processes such as adhesion, motility, membrane fusion, signaling and protein trafficking.[1][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).[7][4][6] These TEMs are thought to play a role in many cellular processes including exosome biogenesis.[8] CD9 is commonly used as a marker for exosomes as it is contained on their surface.[7][6][9][10]

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.[11] However, expression of CD9 on the cellular membrane seems to decrease the viral entry of HIV-1.[12][13]

CD9 has a diverse role in cellular processes as it has also been shown to trigger platelet activation and aggregation.[14] 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.[7][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.[5] 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,[21] scirrhous-type gastric cancer,[22] 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:


See also

References

  1. ↑ 1.0 1.1 1.2 "Tetraspanins in extracellular vesicle formation and function". Frontiers in Immunology 8: 342. 2014. doi:10.3389/fimmu.2014.00442. PMID 25278937. 
  2. ↑ "CD9 CD9 molecule [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/928. 
  3. ↑ "CD9 Gene - GeneCards | CD9 Protein | CD9 Antibody". https://www.genecards.org/cgi-bin/carddisp.pl?gene=CD9. 
  4. ↑ 4.0 4.1 "Tetraspanin-enriched microdomains: a functional unit in cell plasma membranes". Trends in Cell Biology 19 (9): 434–46. September 2009. doi:10.1016/j.tcb.2009.06.004. PMID 19709882. 
  5. ↑ 5.0 5.1 "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. doi:10.1074/jbc.M510617200. PMID 16537545. 
  6. ↑ 6.0 6.1 6.2 "Tetraspanin functions and associated microdomains". Nature Reviews. Molecular Cell Biology 6 (10): 801–11. October 2005. doi:10.1038/nrm1736. PMID 16314869. 
  7. ↑ 7.0 7.1 7.2 7.3 "CD63 associates with the alphaIIb beta3 integrin-CD9 complex on the surface of activated platelets". Thrombosis and Haemostasis 85 (1): 134–41. January 2001. doi:10.1055/s-0037-1612916. PMID 11204565. 
  8. ↑ "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. doi:10.1074/jbc.M112.445304. PMID 23463506. 
  9. ↑ "Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury". Stem Cell Research 4 (3): 214–22. May 2010. doi:10.1016/j.scr.2009.12.003. PMID 20138817. 
  10. ↑ "The role of tetraspanin CD9 in osteoarthritis using three different mouse models". Biomedical Research 37 (5): 283–291. October 2016. doi:10.2220/biomedres.37.283. PMID 27784871. 
  11. ↑ "Tetraspanin blockage reduces exosome-mediated HIV-1 entry". Archives of Virology 163 (6): 1683–1689. June 2018. doi:10.1007/s00705-018-3737-6. PMID 29429034. 
  12. ↑ "Tetraspanins CD9 and CD81 modulate HIV-1-induced membrane fusion". Journal of Immunology 177 (8): 5129–37. October 2006. doi:10.4049/jimmunol.177.8.5129. PMID 17015697. 
  13. ↑ "The roles of tetraspanins in HIV-1 replication". HIV Interactions with Host Cell Proteins. Current Topics in Microbiology and Immunology. 339. Springer Berlin Heidelberg. 2009. pp. 85–102. doi:10.1007/978-3-642-02175-6_5. ISBN 978-3-642-02174-9. 
  14. ↑ "Molecular cloning of the mouse equivalent of CD9 antigen". Thrombosis Research 71 (5): 377–83. September 1993. doi:10.1016/0049-3848(93)90162-h. PMID 8236164. 
  15. ↑ "Platelet Activation: The Mechanisms and Potential Biomarkers". BioMed Research International 2016: 9060143. 2016. doi:10.1155/2016/9060143. PMID 27403440. 
  16. ↑ "Role of transmembrane 4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance". The Journal of Cell Biology 146 (4): 893–904. August 1999. doi:10.1083/jcb.146.4.893. PMID 10459022. 
  17. ↑ "Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81". Nature Communications 4: 1674. 2013. doi:10.1038/ncomms2675. PMID 23575678. Bibcode: 2013NatCo...4.1674C. 
  18. ↑ "Severely reduced female fertility in CD9-deficient mice". Science 287 (5451): 319–21. January 2000. doi:10.1126/science.287.5451.319. PMID 10634790. Bibcode: 2000Sci...287..319L. 
  19. ↑ "Oocyte CD9 is enriched on the microvillar membrane and required for normal microvillar shape and distribution". Developmental Biology 304 (1): 317–25. April 2007. doi:10.1016/j.ydbio.2006.12.041. PMID 17239847. 
  20. ↑ "CD9 Controls Integrin α5β1-Mediated Cell Adhesion by Modulating Its Association With the Metalloproteinase ADAM17". Frontiers in Immunology 9: 2474. 2018. doi:10.3389/fimmu.2018.02474. PMID 30455686. 
  21. ↑ 21.0 21.1 "Ablation of the CD9 receptor in human lung cancer cells using CRISPR/Cas alters migration to chemoattractants including IL-16". Cytokine 111: 567–570. November 2018. doi:10.1016/j.cyto.2018.05.038. PMID 29884309. 
  22. ↑ 22.0 22.1 "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. doi:10.1038/bjc.2017.487. PMID 29438363. 
  23. ↑ "Expression of ornithine decarboxylase mRNA and c-myc mRNA in breast tumours". International Journal of Oncology 12 (3): 597–601. March 1998. doi:10.3892/ijo.12.3.597. PMID 9472098. 
  24. ↑ "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. doi:10.1016/0169-5002(96)87780-4. PMID 8521390. 
  25. ↑ "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. doi:10.1084/jem.177.5.1231. PMID 8478605. 
  26. ↑ "Transmembrane 4 superfamily as a prognostic factor in pancreatic cancer". International Journal of Cancer 79 (5): 509–16. October 1998. doi:10.1002/(sici)1097-0215(19981023)79:5<509::aid-ijc11>3.0.co;2-x. PMID 9761121. 
  27. ↑ "The tetraspanin CD9 inhibits the proliferation and tumorigenicity of human colon carcinoma cells". International Journal of Cancer 121 (10): 2140–52. November 2007. doi:10.1002/ijc.22902. PMID 17582603. 
  28. ↑ "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. doi:10.3892/ijo.2018.4381. PMID 29749468. 
  29. ↑ "CD9 expression indicates a poor outcome in acute lymphoblastic leukemia". Cancer Biomarkers 21 (4): 781–786. 2018. doi:10.3233/CBM-170422. PMID 29286918. 
  30. ↑ "Tetraspanins: push and pull in suppressing and promoting metastasis". Nature Reviews. Cancer 9 (1): 40–55. January 2009. doi:10.1038/nrc2543. PMID 19078974. 
  31. ↑ "Peptides from Tetraspanin CD9 Are Potent Inhibitors of Staphylococcus Aureus Adherence to Keratinocytes". PLOS ONE 11 (7): e0160387. 2016-07-28. doi:10.1371/journal.pone.0160387. PMID 27467693. Bibcode: 2016PLoSO..1160387V. 
  32. ↑ "C-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors". Blood 99 (12): 4413–21. June 2002. doi:10.1182/blood.v99.12.4413. PMID 12036870. 
  33. ↑ 33.0 33.1 "CD63 associates with transmembrane 4 superfamily members, CD9 and CD81, and with beta 1 integrins in human melanoma". Biochemical and Biophysical Research Communications 222 (1): 13–8. May 1996. doi:10.1006/bbrc.1996.0690. PMID 8630057. 
  34. ↑ "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. doi:10.1016/s0168-8278(02)00175-7. PMID 12175627. 
  35. ↑ "CD46 (membrane cofactor protein) associates with multiple beta1 integrins and tetraspans". European Journal of Immunology 30 (3): 900–7. March 2000. doi:10.1002/1521-4141(200003)30:3<900::AID-IMMU900>3.0.CO;2-X. PMID 10741407. 
  36. ↑ "CD9 is expressed on human endometrial epithelial cells in association with integrins alpha(6), alpha(3) and beta(1)". Molecular Human Reproduction 6 (3): 252–7. March 2000. doi:10.1093/molehr/6.3.252. PMID 10694273. 
  37. ↑ "CD9 is expressed in extravillous trophoblasts in association with integrin alpha3 and integrin alpha5". Molecular Human Reproduction 5 (2): 162–7. February 1999. doi:10.1093/molehr/5.2.162. PMID 10065872. 
  38. ↑ "CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82". The Journal of Biological Chemistry 273 (46): 30537–43. November 1998. doi:10.1074/jbc.273.46.30537. PMID 9804823. 
  39. ↑ "The major CD9 and CD81 molecular partner. Identification and characterization of the complexes". The Journal of Biological Chemistry 276 (17): 14329–37. April 2001. doi:10.1074/jbc.M011297200. PMID 11278880. 
  40. ↑ "FPRP, a major, highly stoichiometric, highly specific CD81- and CD9-associated protein". The Journal of Biological Chemistry 276 (7): 4853–62. February 2001. doi:10.1074/jbc.M009859200. PMID 11087758. 
  41. ↑ "NAG-2, a novel transmembrane-4 superfamily (TM4SF) protein that complexes with integrins and other TM4SF proteins". The Journal of Biological Chemistry 272 (46): 29181–9. November 1997. doi:10.1074/jbc.272.46.29181. PMID 9360996. 
  42. ↑ "The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9". Cellular and Molecular Life Sciences 68 (19): 3275–92. October 2011. doi:10.1007/s00018-011-0639-0. PMID 21365281. 
  43. ↑ "The CD9/CD81 tetraspanin complex and tetraspanin CD151 regulate α3β1 integrin-dependent tumor cell behaviors by overlapping but distinct mechanisms". PLOS ONE 8 (4): e61834. 2013. doi:10.1371/journal.pone.0061834. PMID 23613949. Bibcode: 2013PLoSO...861834G. 

Further reading

External links




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