CD99

CD99 antigen (Cluster of differentiation 99), also known as MIC2 or single-chain type-1 glycoprotein, is a heavily O-glycosylated transmembrane protein that is encoded by the CD99 gene in humans.^[3][4][5] The protein has a mass of 32 kD. Unusually for a gene present on the X chromosome, the CD99 gene does not undergo X inactivation, and it was the first such pseudoautosomal gene to be discovered in humans.^[6]

CD99
Identifiers
Aliases	CD99, HBA71, MIC2, MIC2X, MIC2Y, MSK5X, CD99 molecule, CD99 molecule (Xg blood group)
External IDs	OMIM: 313470, 450000; HomoloGene: 48107; GeneCards: CD99; OMA:CD99 - orthologs
Gene location (Human) Chr. X chromosome (human)[1] Band X;Y Start 2,691,187 bp[1] End 2,741,309 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in beta cell thymus synovial joint stromal cell of endometrium olfactory bulb tendon of biceps brachii synovial membrane right coronary artery vena cava tibial nerve n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding Cellular component cytoplasm integral component of membrane plasma membrane integral component of plasma membrane membrane focal adhesion Biological process cell adhesion regulation of immune response homotypic cell-cell adhesion T cell extravasation positive regulation of neutrophil extravasation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4267 n/a Ensembl ENSG00000002586 n/a UniProt P14209 n/a RefSeq (mRNA) NM_001122898 NM_001277710 NM_002414 NM_001321367 NM_001321368 NM_001321369 NM_001321370 n/a RefSeq (protein) NP_001116370 NP_001308296 NP_001308297 NP_001308298 NP_001308299 NP_002405 n/a Location (UCSC) Chr X: 2.69 – 2.74 Mb n/a PubMed search [2] n/a
Wikidata
View/Edit Human

Expression

It is expressed on all leukocytes but highest on thymocytes^[7][8][9] and is believed to augment T-cell adhesion^[10][11] and apoptosis of double positive T cells.^[12] It has been found in endothelial cells and in the periodontium, including gingival fibroblasts and gingival epithelial cells.^[5] It also participates in migration and activation.^[13] There is also experimental evidence that it binds to cyclophilin A.^[14]

It is found on the cell surface of Ewing's sarcoma tumors ^[15] and is positive in granulosa cell tumors.^[16] It is more expressed in malignant gliomas than in the brain, and such overexpression results in higher levels of invasiveness and lower rates of survival.^[17] Antibodies to CD99 are used in diagnostic immunohistochemistry to distinguish Ewing's sarcoma from other tumours of similar histological appearance, as well as for the identification of thymic tumours, and of spindle cell tumours, such as synovial sarcoma, haemangiopericytoma, and meningioma.^[6] EWS/FLI is thought to regulate CD99, but knockdown of EWS/FLI results in only a modest reduction in CD99. When CD99 expression is knocked down in human cells with Ewing's sarcoma and those cells are grafted onto mice, tumor and bone metastasis development is reduced.^[15]

Reducing CD99 expression results in higher β-III tubulin expression and more neurite outgrowth.^[15]

Upregulating CD99 expression in the cell line L428, a Hodgkin's lymphoma line, resulted in those cells redifferentiating towards B cells. Consequently, the loss of B-cell differentiation in Hodgkin's lymphoma may be due to CD99 downregulation.^[18]

Men appear to express higher levels of CD99 than women.^[19][20]

Prognostic Value

In patients with diffuse large B-cell lymphoma (DLBCL) with the germinal center B-cell (GCB, classified according to the Muris algorithm) subtype, positive expression of CD99 resulted in better 2-year event free survival (EFS) and 2-year overall survival (OS) compared to negative expression of CD99. In patients with DLBCL with non-GCB, however, negative expression of CD99 resulted in better 2-year EFS and 2-year OS.^[21] In patients with non-small cell lung cancer (NSCLC), higher CD99 expression in the stroma results in better prognosis.^[22]

Interactions

There is evidence that through suppressing β1 integrin affinity, CD99 inhibits cell-extracellular matrix adhesion.^[23]

References

1. GRCh38: Ensembl release 89: ENSG00000002586 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Entrez Gene: CD99 CD99 molecule".
4. Goodfellow P, Banting G, Sheer D, Ropers HH, Caine A, Ferguson-Smith MA, Povey S, Voss R (1983). "Genetic evidence that a Y-linked gene in man is homologous to a gene on the X chromosome". Nature. 302 (5906): 346–9. Bibcode:1983Natur.302..346G. doi:10.1038/302346a0. PMID 6188056. S2CID 4273099.
5. Krisanaprakornkit S, Chotjumlong P, Pata S, Chruewkamlow N, Reutrakul V, Kasinrerk W (January 2013). "CD99 ligation induces intercellular cell adhesion molecule-1 expression and secretion in human gingival fibroblasts". Arch. Oral Biol. 58 (1): 82–93. doi:10.1016/j.archoralbio.2012.06.011. PMID 22795566.
6. Leong AS-Y, Cooper K, Leong FJW-M (2003). Manual of Diagnostic Cytology (2nd ed.). Greenwich Medical Media, Ltd. pp. 145–146. ISBN 978-1-84110-100-2.
7. Aussel C, Bernard G, Breittmayer JP, Pelassy C, Zoccola D, Bernard A (September 1993). "Monoclonal antibodies directed against the E2 protein (MIC2 gene product) induce exposure of phosphatidylserine at the thymocyte cell surface". Biochemistry. 32 (38): 10096–101. doi:10.1021/bi00089a027. PMID 8399135.
8. Dworzak MN, Fritsch G, Buchinger P, Fleischer C, Printz D, Zellner A, Schöllhammer A, Steiner G, Ambros PF, Gadner H (January 1994). "Flow cytometric assessment of human MIC2 expression in bone marrow, thymus, and peripheral blood". Blood. 83 (2): 415–25. doi:10.1182/blood.V83.2.415.415. PMID 7506950.
9. Choi EY, Park WS, Jung KC, Kim SH, Kim YY, Lee WJ, Park SH (July 1998). "Engagement of CD99 induces up-regulation of TCR and MHC class I and II molecules on the surface of human thymocytes". Journal of Immunology. 161 (2): 749–54. doi:10.4049/jimmunol.161.2.749. PMID 9670951.
10. Bernard G, Raimondi V, Alberti I, Pourtein M, Widjenes J, Ticchioni M, Bernard A (October 2000). "CD99 (E2) up-regulates alpha4beta1-dependent T cell adhesion to inflamed vascular endothelium under flow conditions". European Journal of Immunology. 30 (10): 3061–5. doi:10.1002/1521-4141(200010)30:10<3061::AID-IMMU3061>3.0.CO;2-M. PMID 11069091.
11. Kasinrerk W, Tokrasinwit N, Moonsom S, Stockinger H (January 2000). "CD99 monoclonal antibody induce homotypic adhesion of Jurkat cells through protein tyrosine kinase and protein kinase C-dependent pathway". Immunology Letters. 71 (1): 33–41. doi:10.1016/S0165-2478(99)00165-0. PMID 10709783.
12. Bernard G, Breittmayer JP, de Matteis M, Trampont P, Hofman P, Senik A, Bernard A (March 1997). "Apoptosis of immature thymocytes mediated by E2/CD99". Journal of Immunology. 158 (6): 2543–50. doi:10.4049/jimmunol.158.6.2543. PMID 9058785.
13. Oh KI, Kim BK, Ban YL, Choi EY, Jung KC, Lee IS, Park SH (April 2007). "CD99 activates T cells via a costimulatory function that promotes raft association of TCR complex and tyrosine phosphorylation of TCR zeta". Experimental & Molecular Medicine. 39 (2): 176–84. doi:10.1038/emm.2007.20. PMID 17464179.
14. Kim HJ, Chong KH, Kang SW, Lee JR, Kim JY, Hahn MJ, Kim TJ (September 2004). "Identification of cyclophilin A as a CD99-binding protein by yeast two-hybrid screening". Immunology Letters. 95 (2): 155–9. doi:10.1016/j.imlet.2004.07.001. PMID 15388255.
15. Rocchi A, Manara MC, Sciandra M, Zambelli D, Nardi F, Nicoletti G, Garofalo C, Meschini S, Astolfi A, Colombo MP, Lessnick SL, Picci P, Scotlandi K (March 2010). "CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis". J. Clin. Invest. 120 (3): 668–80. doi:10.1172/JCI36667. PMC 2827943. PMID 20197622.
16. "CD99". NordiQC. Archived from the original on 2011-07-20. Retrieved 2010-09-15.
17. Seol HJ, Chang JH, Yamamoto J, Romagnuolo R, Suh Y, Weeks A, Agnihotri S, Smith CA, Rutka JT (September 2012). "Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells". Genes Cancer. 3 (9–10): 535–49. doi:10.1177/1947601912473603. PMC 3591096. PMID 23486730.
18. Zhou XH, Huang XP, Huang ZP, Wang ZQ, Zhao T (February 2013). "[CD99 regulates redifferentiation of classical Hodgkin's lymphoma cell line L428 towards B cells]". Nan Fang Yi Ke da Xue Xue Bao (in Chinese). 33 (2): 235–8. PMID 23443779.
19. Lefèvre N, Corazza F, Duchateau J, Desir J, Casimir G (July 2012). "Sex differences in inflammatory cytokines and CD99 expression following in vitro lipopolysaccharide stimulation". Shock. 38 (1): 37–42. doi:10.1097/SHK.0b013e3182571e46. PMID 22575993. S2CID 7092987.
20. "Men Appear To Express Higher Levels Of CD99 Than Women: Insights And Implications". 2024-04-09. Retrieved 2024-06-09.
21. Hong J, Park S, Park J, Jang SJ, Ahn HK, Sym SJ, Cho EK, Shin DB, Lee JH (December 2012). "CD99 expression and newly diagnosed diffuse large B-cell lymphoma treated with rituximab-CHOP immunochemotherapy". Ann. Hematol. 91 (12): 1897–906. doi:10.1007/s00277-012-1533-z. PMID 22864685. S2CID 26024499.
22. Edlund K, Lindskog C, Saito A, Berglund A, Pontén F, Göransson-Kultima H, Isaksson A, Jirström K, Planck M, Johansson L, Lambe M, Holmberg L, Nyberg F, Ekman S, Bergqvist M, Landelius P, Lamberg K, Botling J, Ostman A, Micke P (November 2012). "CD99 is a novel prognostic stromal marker in non-small cell lung cancer". Int. J. Cancer. 131 (10): 2264–73. doi:10.1002/ijc.27518. PMID 22392539. S2CID 10052485.
23. Lee KJ, Lee SH, Yadav BK, Ju HM, Kim MS, Park JH, Jeoung D, Lee H, Hahn JH (March 2012). "The activation of CD99 inhibits cell-extracellular matrix adhesion by suppressing β(1) integrin affinity". BMB Rep. 45 (3): 159–64. doi:10.5483/BMBRep.2012.45.3.159. PMID 22449702.

Further reading

• Goodfellow PJ, Mondello C, Darling SM, Pym B, Little P, Goodfellow PN (1988). "Absence of methylation of a CpG-rich region at the 5' end of the MIC2 gene on the active X, the inactive X, and the Y chromosome". Proc. Natl. Acad. Sci. U.S.A. 85 (15): 5605–9. Bibcode:1988PNAS...85.5605G. doi:10.1073/pnas.85.15.5605. PMC 281808. PMID 2456574.
• Banting GS, Pym B, Darling SM, Goodfellow PN (1989). "The MIC2 gene product: epitope mapping and structural prediction analysis define an integral membrane protein". Mol. Immunol. 26 (2): 181–8. doi:10.1016/0161-5890(89)90100-4. PMID 2465491.
• Gelin C, Aubrit F, Phalipon A, Raynal B, Cole S, Kaczorek M, Bernard A (1989). "The E2 antigen, a 32 kd glycoprotein involved in T-cell adhesion processes, is the MIC2 gene product". EMBO J. 8 (11): 3253–9. doi:10.1002/j.1460-2075.1989.tb08485.x. PMC 401451. PMID 2479542.
• Darling SM, Goodfellow PJ, Pym B, Banting GS, Pritchard C, Goodfellow PN (1987). "Molecular genetics of MIC2: a gene shared by the human X and Y chromosomes". Cold Spring Harb. Symp. Quant. Biol. 51 (1): 205–12. doi:10.1101/SQB.1986.051.01.025. PMID 3472717.
• Buckle V, Mondello C, Darling S, Craig IW, Goodfellow PN (1985). "Homologous expressed genes in the human sex chromosome pairing region". Nature. 317 (6039): 739–41. Bibcode:1985Natur.317..739B. doi:10.1038/317739a0. PMID 4058580. S2CID 4236963.
• Dworzak MN, Fritsch G, Buchinger P, Fleischer C, Printz D, Zellner A, Schöllhammer A, Steiner G, Ambros PF, Gadner H (1994). "Flow cytometric assessment of human MIC2 expression in bone marrow, thymus, and peripheral blood". Blood. 83 (2): 415–25. doi:10.1182/blood.V83.2.415.415. PMID 7506950.
• Choi EY, Park WS, Jung KC, Kim SH, Kim YY, Lee WJ, Park SH (1998). "Engagement of CD99 induces up-regulation of TCR and MHC class I and II molecules on the surface of human thymocytes". J. Immunol. 161 (2): 749–54. doi:10.4049/jimmunol.161.2.749. PMID 9670951.
• Gordon MD, Corless C, Renshaw AA, Beckstead J (1998). "CD99, keratin, and vimentin staining of sex cord-stromal tumors, normal ovary, and testis". Mod. Pathol. 11 (8): 769–73. PMID 9720506.
• Fouchet C, Gane P, Cartron JP, Lopez C (2000). "Quantitative analysis of XG blood group and CD99 antigens on human red cells". Immunogenetics. 51 (8–9): 688–94. doi:10.1007/s002510000193. PMID 10941840. S2CID 19170267.
• Jung KC, Park WS, Bae YM, Hahn JH, Hahn K, Lee H, Lee HW, Koo HJ, Shin HJ, Shin HS, Park YE, Park SH (2003). "Immunoreactivity of CD99 in stomach cancer". J. Korean Med. Sci. 17 (4): 483–9. doi:10.3346/jkms.2002.17.4.483. PMC 3054910. PMID 12172043.
• Lee HJ, Kim E, Jee B, Hahn JH, Han K, Jung KC, Park SH, Lee H (2003). "Functional involvement of src and focal adhesion kinase in a CD99 splice variant-induced motility of human breast cancer cells". Experimental & Molecular Medicine. 34 (3): 177–83. doi:10.1038/emm.2002.26. PMID 12216109.
• Veräjäkorva E, Laato M, Pöllänen P (2003). "CD 99 and CD 106 (VCAM-1) in human testis". Asian J. Androl. 4 (4): 243–8. PMID 12508122.
• Gil MC, Lee MH, Seo JI, Choi YL, Kim MK, Jung KC, Park SH, Kim TJ (2004). "Characterization and epitope mapping of two monoclonal antibodies against human CD99". Experimental & Molecular Medicine. 34 (6): 411–8. doi:10.1038/emm.2002.58. PMID 12526082.
• Yoon SS, Jung KI, Choi YL, Choi EY, Lee IS, Park SH, Kim TJ (2003). "Engagement of CD99 triggers the exocytic transport of ganglioside GM1 and the reorganization of actin cytoskeleton". FEBS Lett. 540 (1–3): 217–22. doi:10.1016/S0014-5793(03)00268-0. PMID 12681511. S2CID 2932584.
• Kim MK, Choi YL, Kim MK, Kim SH, Choi EY, Park WS, Bae YM, Woo SK, Park SH (2003). "MHC class II engagement inhibits CD99-induced apoptosis and up-regulation of T cell receptor and MHC molecules in human thymocytes and T cell line". FEBS Lett. 546 (2–3): 379–84. doi:10.1016/S0014-5793(03)00567-2. PMID 12832073. S2CID 22487044.
• Jung KC, Kim NH, Park WS, Park SH, Bae Y (2003). "The CD99 signal enhances Fas-mediated apoptosis in the human leukemic cell line, Jurkat". FEBS Lett. 554 (3): 478–84. doi:10.1016/S0014-5793(03)01224-9. PMID 14623115. S2CID 21588654.
• Lee EJ, Lee HG, Park SH, Choi EY, Park SH (2004). "CD99 type II is a determining factor for the differentiation of primitive neuroectodermal cells". Experimental & Molecular Medicine. 35 (5): 438–47. doi:10.1038/emm.2003.57. PMID 14646598.
• Mahmood MN, Salama ME, Chaffins M, Ormsby AH, Ma CK, Linden MD, Lee MW (2004). "Solitary sclerotic fibroma of skin: a possible link with pleomorphic fibroma with immunophenotypic expression for O13 (CD99) and CD34". J. Cutan. Pathol. 30 (10): 631–6. doi:10.1034/j.1600-0560.2003.00126.x. PMID 14744088. S2CID 37152987.
• Cerisano V, Aalto Y, Perdichizzi S, Bernard G, Manara MC, Benini S, Cenacchi G, Preda P, Lattanzi G, Nagy B, Knuutila S, Colombo MP, Bernard A, Picci P, Scotlandi K (2004). "Molecular mechanisms of CD99-induced caspase-independent cell death and cell-cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators". Oncogene. 23 (33): 5664–74. doi:10.1038/sj.onc.1207741. PMID 15184883.

External links

• CD99+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human CD99 genome location and CD99 gene details page in the UCSC Genome Browser.