CD99 explained

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.^{[1] [2] [3]} 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.^[4]

Expression

It is expressed on all leukocytes but highest on thymocytes^{[5] [6] [7]} and is believed to augment T-cell adhesion^{[8] [9]} and apoptosis of double positive T cells.^[10] It has been found in endothelial cells and in the periodontium, including gingival fibroblasts and gingival epithelial cells. It also participates in migration and activation.^[11] There is also experimental evidence that it binds to cyclophilin A.^[12]

It is found on the cell surface of Ewing's sarcoma tumors ^[13] and is positive in granulosa cell tumors.^[14] 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.^[15] 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.^[4] 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.

Reducing CD99 expression results in higher β-III tubulin expression and more neurite outgrowth.

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.^[16]

Men appear to express higher levels of CD99 than women.^{[17] [18]}

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.^[19] In patients with non-small cell lung cancer (NSCLC), higher CD99 expression in the stroma results in better prognosis.^[20]

Interactions

There is evidence that through suppressing β1 integrin affinity, CD99 inhibits cell-extracellular matrix adhesion.^[21]

Further reading

• Goodfellow PJ, Mondello C, Darling SM, Pym B, Little P, Goodfellow PN . 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 . 1988 . 2456574 . 10.1073/pnas.85.15.5605 . 281808 . 1988PNAS...85.5605G . free .
• Banting GS, Pym B, Darling SM, Goodfellow PN . The MIC2 gene product: epitope mapping and structural prediction analysis define an integral membrane protein . Mol. Immunol. . 26 . 2 . 181–8 . 1989 . 2465491 . 10.1016/0161-5890(89)90100-4 .
• Gelin C, Aubrit F, Phalipon A, Raynal B, Cole S, Kaczorek M, Bernard A . The E2 antigen, a 32 kd glycoprotein involved in T-cell adhesion processes, is the MIC2 gene product . EMBO J. . 8 . 11 . 3253–9 . 1989 . 10.1002/j.1460-2075.1989.tb08485.x . 2479542 . 401451 .
• Darling SM, Goodfellow PJ, Pym B, Banting GS, Pritchard C, Goodfellow PN . Molecular genetics of MIC2: a gene shared by the human X and Y chromosomes . Cold Spring Harb. Symp. Quant. Biol. . 51 . 1. 205–12 . 1987 . 3472717 . 10.1101/SQB.1986.051.01.025 .
• Buckle V, Mondello C, Darling S, Craig IW, Goodfellow PN . Homologous expressed genes in the human sex chromosome pairing region . Nature . 317 . 6039 . 739–41 . 1985 . 4058580 . 10.1038/317739a0 . 1985Natur.317..739B . 4236963 .
• Dworzak MN, Fritsch G, Buchinger P, Fleischer C, Printz D, Zellner A, Schöllhammer A, Steiner G, Ambros PF, Gadner H . Flow cytometric assessment of human MIC2 expression in bone marrow, thymus, and peripheral blood . Blood . 83 . 2 . 415–25 . 1994 . 10.1182/blood.V83.2.415.415 . 7506950 . free .
• Choi EY, Park WS, Jung KC, Kim SH, Kim YY, Lee WJ, Park SH . 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 . 1998 . 10.4049/jimmunol.161.2.749 . 9670951 . free .
• Gordon MD, Corless C, Renshaw AA, Beckstead J . CD99, keratin, and vimentin staining of sex cord-stromal tumors, normal ovary, and testis . Mod. Pathol. . 11 . 8 . 769–73 . 1998 . 9720506 .
• Fouchet C, Gane P, Cartron JP, Lopez C . Quantitative analysis of XG blood group and CD99 antigens on human red cells . Immunogenetics . 51 . 8–9 . 688–94 . 2000 . 10941840 . 10.1007/s002510000193 . 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 . Immunoreactivity of CD99 in stomach cancer . J. Korean Med. Sci. . 17 . 4 . 483–9 . 2003 . 12172043 . 10.3346/jkms.2002.17.4.483. 3054910 .
• Lee HJ, Kim E, Jee B, Hahn JH, Han K, Jung KC, Park SH, Lee H . Functional involvement of src and focal adhesion kinase in a CD99 splice variant-induced motility of human breast cancer cells . . 34 . 3 . 177–83 . 2003 . 12216109 . 10.1038/emm.2002.26 . free .
• Veräjäkorva E, Laato M, Pöllänen P . CD 99 and CD 106 (VCAM-1) in human testis . Asian J. Androl. . 4 . 4 . 243–8 . 2003 . 12508122 .
• Gil MC, Lee MH, Seo JI, Choi YL, Kim MK, Jung KC, Park SH, Kim TJ . Characterization and epitope mapping of two monoclonal antibodies against human CD99 . . 34 . 6 . 411–8 . 2004 . 12526082 . 10.1038/emm.2002.58 . free .
• Yoon SS, Jung KI, Choi YL, Choi EY, Lee IS, Park SH, Kim TJ . Engagement of CD99 triggers the exocytic transport of ganglioside GM1 and the reorganization of actin cytoskeleton . FEBS Lett. . 540 . 1–3 . 217–22 . 2003 . 12681511 . 10.1016/S0014-5793(03)00268-0 . 2932584 . free .
• Kim MK, Choi YL, Kim MK, Kim SH, Choi EY, Park WS, Bae YM, Woo SK, Park SH . 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 . 2003 . 12832073 . 10.1016/S0014-5793(03)00567-2 . 22487044 . free .
• Jung KC, Kim NH, Park WS, Park SH, Bae Y . The CD99 signal enhances Fas-mediated apoptosis in the human leukemic cell line, Jurkat . FEBS Lett. . 554 . 3 . 478–84 . 2003 . 14623115 . 10.1016/S0014-5793(03)01224-9 . 21588654 .
• Lee EJ, Lee HG, Park SH, Choi EY, Park SH . CD99 type II is a determining factor for the differentiation of primitive neuroectodermal cells . . 35 . 5 . 438–47 . 2004 . 14646598 . 10.1038/emm.2003.57 . free .
• Mahmood MN, Salama ME, Chaffins M, Ormsby AH, Ma CK, Linden MD, Lee MW . 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 . 2004 . 14744088 . 10.1034/j.1600-0560.2003.00126.x . 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 . 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 . 2004 . 15184883 . 10.1038/sj.onc.1207741 . free .

Notes and References

1. Web site: Entrez Gene: CD99 CD99 molecule.
2. Goodfellow P, Banting G, Sheer D, Ropers HH, Caine A, Ferguson-Smith MA, Povey S, Voss R . Genetic evidence that a Y-linked gene in man is homologous to a gene on the X chromosome . Nature . 302 . 5906 . 346–9 . 1983 . 6188056 . 10.1038/302346a0 . 1983Natur.302..346G . 4273099 .
3. Krisanaprakornkit S, Chotjumlong P, Pata S, Chruewkamlow N, Reutrakul V, Kasinrerk W . CD99 ligation induces intercellular cell adhesion molecule-1 expression and secretion in human gingival fibroblasts . Arch. Oral Biol. . 58 . 1 . 82–93 . January 2013 . 22795566 . 10.1016/j.archoralbio.2012.06.011 .
4. Book: ((Leong AS-Y)), Cooper K, ((Leong FJW-M)) . 2003 . Manual of Diagnostic Cytology . 2nd . Greenwich Medical Media, Ltd. . 145–146 . 978-1-84110-100-2 .
5. Aussel C, Bernard G, Breittmayer JP, Pelassy C, Zoccola D, Bernard A . Monoclonal antibodies directed against the E2 protein (MIC2 gene product) induce exposure of phosphatidylserine at the thymocyte cell surface . Biochemistry . 32 . 38 . 10096–101 . September 1993 . 8399135 . 10.1021/bi00089a027 .
6. Dworzak MN, Fritsch G, Buchinger P, Fleischer C, Printz D, Zellner A, Schöllhammer A, Steiner G, Ambros PF, Gadner H . Flow cytometric assessment of human MIC2 expression in bone marrow, thymus, and peripheral blood . Blood . 83 . 2 . 415–25 . January 1994 . 10.1182/blood.V83.2.415.415 . 7506950 . free .
7. Choi EY, Park WS, Jung KC, Kim SH, Kim YY, Lee WJ, Park SH. 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 . July 1998 . 10.4049/jimmunol.161.2.749 . 9670951 . free .
8. Bernard G, Raimondi V, Alberti I, Pourtein M, Widjenes J, Ticchioni M, Bernard A. CD99 (E2) up-regulates alpha4beta1-dependent T cell adhesion to inflamed vascular endothelium under flow conditions . European Journal of Immunology . 30 . 10 . 3061–5 . October 2000 . 11069091 . 10.1002/1521-4141(200010)30:10<3061::AID-IMMU3061>3.0.CO;2-M . free .
9. Kasinrerk W, Tokrasinwit N, Moonsom S, Stockinger H . 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 . January 2000 . 10709783 . 10.1016/S0165-2478(99)00165-0.
10. Bernard G, Breittmayer JP, de Matteis M, Trampont P, Hofman P, Senik A, Bernard A . Apoptosis of immature thymocytes mediated by E2/CD99 . Journal of Immunology . 158 . 6 . 2543–50 . March 1997 . 10.4049/jimmunol.158.6.2543 . 9058785 . free .
11. Oh KI, Kim BK, Ban YL, Choi EY, Jung KC, Lee IS, Park SH . CD99 activates T cells via a costimulatory function that promotes raft association of TCR complex and tyrosine phosphorylation of TCR zeta . . 39 . 2 . 176–84 . April 2007 . 17464179 . 10.1038/emm.2007.20 . free .
12. Kim HJ, Chong KH, Kang SW, Lee JR, Kim JY, Hahn MJ, Kim TJ. Identification of cyclophilin A as a CD99-binding protein by yeast two-hybrid screening . Immunology Letters . 95 . 2 . 155–9 . September 2004 . 15388255 . 10.1016/j.imlet.2004.07.001 .
13. 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 . CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis . J. Clin. Invest. . 120 . 3 . 668–80 . March 2010 . 20197622 . 2827943 . 10.1172/JCI36667 .
14. Web site: CD99 . NordiQC . 2010-09-15 . https://web.archive.org/web/20110720192310/http://www.nordiqc.org/Run-12/Assessment/assessment-CD99.htm . 2011-07-20 . dead .
15. Seol HJ, Chang JH, Yamamoto J, Romagnuolo R, Suh Y, Weeks A, Agnihotri S, Smith CA, Rutka JT . Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells . Genes Cancer . 3 . 9–10 . 535–49 . September 2012 . 23486730 . 3591096 . 10.1177/1947601912473603 .
16. Zhou XH, Huang XP, Huang ZP, Wang ZQ, Zhao T . [CD99 regulates redifferentiation of classical Hodgkin's lymphoma cell line L428 towards B cells] . zh . Nan Fang Yi Ke da Xue Xue Bao . 33 . 2 . 235–8 . February 2013 . 23443779 .
17. Lefèvre N, Corazza F, Duchateau J, Desir J, Casimir G . Sex differences in inflammatory cytokines and CD99 expression following in vitro lipopolysaccharide stimulation . Shock . 38 . 1 . 37–42 . July 2012 . 22575993 . 10.1097/SHK.0b013e3182571e46 . 7092987 . free .
18. Web site: 2024-04-09 . Men Appear To Express Higher Levels Of CD99 Than Women: Insights And Implications . 2024-06-09 . en-US.
19. Hong J, Park S, Park J, Jang SJ, Ahn HK, Sym SJ, Cho EK, Shin DB, Lee JH . CD99 expression and newly diagnosed diffuse large B-cell lymphoma treated with rituximab-CHOP immunochemotherapy . Ann. Hematol. . 91 . 12 . 1897–906 . December 2012 . 22864685 . 10.1007/s00277-012-1533-z . 26024499 .
20. 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 . CD99 is a novel prognostic stromal marker in non-small cell lung cancer . Int. J. Cancer . 131 . 10 . 2264–73 . November 2012 . 22392539 . 10.1002/ijc.27518 . 10052485 .
21. Lee KJ, Lee SH, Yadav BK, Ju HM, Kim MS, Park JH, Jeoung D, Lee H, Hahn JH . The activation of CD99 inhibits cell-extracellular matrix adhesion by suppressing β(1) integrin affinity . BMB Rep . 45 . 3 . 159–64 . March 2012 . 22449702 . 10.5483/BMBRep.2012.45.3.159. free .