S100A2 explained

S100 calcium-binding protein A2 (S100A2) is a protein that in humans is encoded by the S100A2 gene^[1] and it is located on chromosome 1q21 with other S100 proteins.

Tissue and subcellular distribution

S100A2, also known as CaN19 or S100L was first isolated from bovine lung tissue.^[2] However, in human tissue it was discovered several years later, in the mammary epithelial cells.^[3] Under normal circumstances it is highly expressed in human lungs, prostate, kidneys, hair follicles and salivary and mammary glands.^[4] S100A2 is predominantly found in the nucleus, which is not very common in other S100 proteins. Moreover, it can also be found in the cytoplasm, and its distribution is rather diffuse. Its occurrence in cytoplasm is most likely dependent on calcium levels in the cell.^{[5] [6] [7]} In the extracellular environment, it can be found as a homodimer in vivo and in vitro, but it also exists in monomeric, polymeric and multimeric forms. In multimeric form, it functions as a RAGE receptor ligand.^[8]

Function

S100A2 is important in cytoskeleton organization.^[9] Also, S100A2 is induced by p53, which it interacts and participates in the transcription of p21.^{[7] [10]} It also plays a role in differentiation, regeneration of tissues and healing^{[11] [12]} and it was shown it attract eosinophils by chemotaxis.^[13]

Clinical significance

Its expression is reduced in many types of cancer, thereby distinguishing the cancerous expression profile of the other proteins of the S100 group.^{[14] [15] [16]} It has been reported that S100A2 is downregulated in lung, kidney, prostate cancer and melanoma. Chromosomal rearrangements and altered expression of this gene have also been implicated in breast cancer.^{[17] [16]} In addition, its decline is associated with poor prognosis, disease progression, increased occurrence of metastasis and increased patient mortality.^[18] Although in most cancers it has been found in reduced levels, there are studies that show that in some cases it is overproduced.^{[19] [20]}

Further reading

• Schäfer BW, Heizmann CW . The S100 family of EF-hand calcium-binding proteins: functions and pathology . Trends in Biochemical Sciences . 21 . 4 . 134–40 . April 1996 . 8701470 . 10.1016/S0968-0004(96)80167-8 .
• Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J . Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes . Electrophoresis . 13 . 12 . 960–9 . December 1992 . 1286667 . 10.1002/elps.11501301199 . 41855774 .
• Lee SW, Tomasetto C, Swisshelm K, Keyomarsi K, Sager R . Down-regulation of a member of the S100 gene family in mammary carcinoma cells and reexpression by azadeoxycytidine treatment . Proceedings of the National Academy of Sciences of the United States of America . 89 . 6 . 2504–8 . March 1992 . 1372446 . 48687 . 10.1073/pnas.89.6.2504 . 1992PNAS...89.2504L . free .
• Schäfer BW, Wicki R, Engelkamp D, Mattei MG, Heizmann CW . Isolation of a YAC clone covering a cluster of nine S100 genes on human chromosome 1q21: rationale for a new nomenclature of the S100 calcium-binding protein family . Genomics . 25 . 3 . 638–43 . February 1995 . 7759097 . 10.1016/0888-7543(95)80005-7 .
• Gimona M, Lando Z, Dolginov Y, Vandekerckhove J, Kobayashi R, Sobieszek A, Helfman DM . Ca2+-dependent interaction of S100A2 with muscle and nonmuscle tropomyosins . Journal of Cell Science . 110 (Pt 5) . 5 . 611–21 . March 1997 . 10.1242/jcs.110.5.611 . 9092943 .
• Böni R, Burg G, Doguoglu A, Ilg EC, Schäfer BW, Müller B, Heizmann CW . Immunohistochemical localization of the Ca2+ binding S100 proteins in normal human skin and melanocytic lesions . The British Journal of Dermatology . 137 . 1 . 39–43 . July 1997 . 9274623 . 10.1111/j.1365-2133.1997.tb03698.x . 2024-04-26 .
• Groves P, Finn BE, Kuźnicki J, Forsén S . A model for target protein binding to calcium-activated S100 dimers . FEBS Letters . 421 . 3 . 175–9 . January 1998 . 9468301 . 10.1016/S0014-5793(97)01535-4 . free .
• Wicki R, Franz C, Scholl FA, Heizmann CW, Schäfer BW . Repression of the candidate tumor suppressor gene S100A2 in breast cancer is mediated by site-specific hypermethylation . Cell Calcium . 22 . 4 . 243–54 . October 1997 . 9481475 . 10.1016/S0143-4160(97)90063-4 .
• Franz C, Durussel I, Cox JA, Schäfer BW, Heizmann CW . Binding of Ca2+ and Zn2+ to human nuclear S100A2 and mutant proteins . The Journal of Biological Chemistry . 273 . 30 . 18826–34 . July 1998 . 9668057 . 10.1074/jbc.273.30.18826 . free .
• Mueller A, Bächi T, Höchli M, Schäfer BW, Heizmann CW . Subcellular distribution of S100 proteins in tumor cells and their relocation in response to calcium activation . Histochemistry and Cell Biology . 111 . 6 . 453–9 . June 1999 . 10429967 . 10.1007/s004180050381 . 37677063 .
• Stradal TB, Troxler H, Heizmann CW, Gimona M . Mapping the zinc ligands of S100A2 by site-directed mutagenesis . The Journal of Biological Chemistry . 275 . 18 . 13219–27 . May 2000 . 10788426 . 10.1074/jbc.275.18.13219 . free .
• Hoyaux D, Decaestecker C, Heizmann CW, Vogl T, Schäfer BW, Salmon I, Kiss R, Pochet R . 6 . S100 proteins in Corpora amylacea from normal human brain . Brain Research . 867 . 1–2 . 280–8 . June 2000 . 10837826 . 10.1016/S0006-8993(00)02393-3 . 7614547 .
• Deshpande R, Woods TL, Fu J, Zhang T, Stoll SW, Elder JT . Biochemical characterization of S100A2 in human keratinocytes: subcellular localization, dimerization, and oxidative cross-linking . The Journal of Investigative Dermatology . 115 . 3 . 477–85 . September 2000 . 10951287 . 10.1046/j.1523-1747.2000.00078.x . free .
• Nagy N, Hoyaux D, Gielen I, Schäfer BW, Pochet R, Heizmann CW, Kiss R, Salmon I, Decaestecker C . 6 . The Ca2+-binding S100A2 protein is differentially expressed in epithelial tissue of glandular or squamous origin . Histology and Histopathology . 17 . 1 . 123–30 . January 2002 . 11813862 . 10.14670/HH-17.123 .
• Kyriazanos ID, Tachibana M, Dhar DK, Shibakita M, Ono T, Kohno H, Nagasue N . Expression and prognostic significance of S100A2 protein in squamous cell carcinoma of the esophagus . Oncology Reports . 9 . 3 . 503–10 . 2002 . 11956617 . 10.3892/or.9.3.503 .
• Zhang T, Woods TL, Elder JT . Differential responses of S100A2 to oxidative stress and increased intracellular calcium in normal, immortalized, and malignant human keratinocytes . The Journal of Investigative Dermatology . 119 . 5 . 1196–201 . November 2002 . 12445212 . 10.1046/j.1523-1747.2002.19520.x . free .
• Hibi K, Fujitake S, Takase T, Kodera Y, Ito K, Akiyama S, Shirane M, Nakao A . 6 . Identification of S100A2 as a target of the DeltaNp63 oncogenic pathway . Clinical Cancer Research . 9 . 11 . 4282–5 . September 2003 . 14519656 .

Notes and References

1. Engelkamp D, Schäfer BW, Mattei MG, Erne P, Heizmann CW . Six S100 genes are clustered on human chromosome 1q21: identification of two genes coding for the two previously unreported calcium-binding proteins S100D and S100E . Proceedings of the National Academy of Sciences of the United States of America . 90 . 14 . 6547–51 . July 1993 . 8341667 . 46969 . 10.1073/pnas.90.14.6547 . 1993PNAS...90.6547E . free .
2. Glenney JR, Kindy MS, Zokas L . Isolation of a new member of the S100 protein family: amino acid sequence, tissue, and subcellular distribution . The Journal of Cell Biology . 108 . 2 . 569–78 . February 1989 . 2521861 . 10.1083/jcb.108.2.569 . 2115452 .
3. Lee SW, Tomasetto C, Sager R . Positive selection of candidate tumor-suppressor genes by subtractive hybridization . Proceedings of the National Academy of Sciences of the United States of America . 88 . 7 . 2825–9 . April 1991 . 1849277 . 10.1073/pnas.88.7.2825 . 51332 . 1991PNAS...88.2825L . free .
4. Wolf S, Haase-Kohn C, Pietzsch J . S100A2 in cancerogenesis: a friend or a foe? . Amino Acids . 41 . 4 . 849–61 . October 2011 . 20521072 . 10.1007/s00726-010-0623-2 . 5733375 .
5. Zhang T, Woods TL, Elder JT . Differential responses of S100A2 to oxidative stress and increased intracellular calcium in normal, immortalized, and malignant human keratinocytes . en . The Journal of Investigative Dermatology . 119 . 5 . 1196–201 . November 2002 . 12445212 . 10.1046/j.1523-1747.2002.19520.x . free .
6. Ilg EC, Schäfer BW, Heizmann CW . Expression pattern of S100 calcium-binding proteins in human tumors . International Journal of Cancer . 68 . 3 . 325–32 . November 1996 . 8903474 . 10.1002/(SICI)1097-0215(19961104)68:3<325::AID-IJC10>3.0.CO;2-7 . 43244297 .
7. Mueller A, Schäfer BW, Ferrari S, Weibel M, Makek M, Höchli M, Heizmann CW . The calcium-binding protein S100A2 interacts with p53 and modulates its transcriptional activity . The Journal of Biological Chemistry . 280 . 32 . 29186–93 . August 2005 . 15941720 . 10.1074/jbc.M505000200 . free .
8. Deshpande R, Woods TL, Fu J, Zhang T, Stoll SW, Elder JT . Biochemical characterization of S100A2 in human keratinocytes: subcellular localization, dimerization, and oxidative cross-linking . The Journal of Investigative Dermatology . 115 . 3 . 477–85 . September 2000 . 10951287 . 10.1046/j.1523-1747.2000.00078.x . free .
9. Martonosi. Anthony N.. vanc. The Regulation of Cytoplasmic Ca2+ Concentration in Muscle and Nonmuscle Cells. 1983. 10.1016/b978-0-12-673001-2.50011-2. Muscle and Nonmuscle Motility. 233–357. Elsevier. 9780126730012.
10. Kirschner RD, Sänger K, Müller GA, Engeland K . Transcriptional activation of the tumor suppressor and differentiation gene S100A2 by a novel p63-binding site . Nucleic Acids Research . 36 . 9 . 2969–80 . May 2008 . 18388131 . 2396407 . 10.1093/nar/gkn132 .
11. van Dieck J, Brandt T, Teufel DP, Veprintsev DB, Joerger AC, Fersht AR . Molecular basis of S100 proteins interacting with the p53 homologs p63 and p73 . Oncogene . 29 . 14 . 2024–35 . April 2010 . 20140014 . 10.1038/onc.2009.490 . free .
12. Brown GL, Nanney LB, Griffen J, Cramer AB, Yancey JM, Curtsinger LJ, Holtzin L, Schultz GS, Jurkiewicz MJ, Lynch JB . 6 . Enhancement of wound healing by topical treatment with epidermal growth factor . The New England Journal of Medicine . 321 . 2 . 76–9 . July 1989 . 2659995 . 10.1056/NEJM198907133210203 .
13. Komada T, Araki R, Nakatani K, Yada I, Naka M, Tanaka T . Novel specific chemtactic receptor for S100L protein on guinea pig eosinophils . Biochemical and Biophysical Research Communications . 220 . 3 . 871–4 . March 1996 . 8607858 . 10.1006/bbrc.1996.0496 .
14. Maelandsmo GM, Flørenes VA, Mellingsaeter T, Hovig E, Kerbel RS, Fodstad O . Differential expression patterns of S100A2, S100A4 and S100A6 during progression of human malignant melanoma . International Journal of Cancer . 74 . 4 . 464–9 . August 1997 . 9291441 . 10.1002/(SICI)1097-0215(19970822)74:4<464::AID-IJC19>3.0.CO;2-9 . free .
15. Gupta S, Hussain T, MacLennan GT, Fu P, Patel J, Mukhtar H . Differential expression of S100A2 and S100A4 during progression of human prostate adenocarcinoma . Journal of Clinical Oncology . 21 . 1 . 106–12 . January 2003 . 12506178 . 10.1200/JCO.2003.03.024 .
16. Liu D, Rudland PS, Sibson DR, Platt-Higgins A, Barraclough R . Expression of calcium-binding protein S100A2 in breast lesions . British Journal of Cancer . 83 . 11 . 1473–9 . December 2000 . 11076656 . 10.1054/bjoc.2000.1488 . 2363420 .
17. Web site: Entrez Gene: S100A2 S100 calcium binding protein A2.
18. Suzuki F, Oridate N, Homma A, Nakamaru Y, Nagahashi T, Yagi K, Yamaguchi S, Furuta Y, Fukuda S . 6 . S100A2 expression as a predictive marker for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral cavity . Oncology Reports . 14 . 6 . 1493–8 . December 2005 . 16273244 . 10.3892/or.14.6.1493 .
19. Wang H, Zhang Z, Li R, Ang KK, Zhang H, Caraway NP, Katz RL, Jiang F . 6 . Overexpression of S100A2 protein as a prognostic marker for patients with stage I non small cell lung cancer . International Journal of Cancer . 116 . 2 . 285–90 . August 2005 . 15800916 . 10.1002/ijc.21035 . 30476718 . free .
20. Masuda T, Ishikawa T, Mogushi K, Okazaki S, Ishiguro M, Iida S, Mizushima H, Tanaka H, Uetake H, Sugihara K . 6 . Overexpression of the S100A2 protein as a prognostic marker for patients with stage II and III colorectal cancer . International Journal of Oncology . 48 . 3 . 975–82 . March 2016 . 26783118 . 10.3892/ijo.2016.3329 . 4750537 .