Amino Acids

, Volume 41, Issue 4, pp 797–807 | Cite as

S100A11, a dual growth regulator of epidermal keratinocytes

  • Masakiyo Sakaguchi
  • Nam-ho HuhEmail author
Review Article


S100A11, a member of the family of S100 proteins, is a dimmer, each monomer of which has two EF-hands. Expression of S100A11 is ubiquitous in various tissues at different levels, with a high expression level in the skin. We have analyzed functions of S100A11 mainly in normal human keratinocytes (NHK) as a model cell system of human epithelial cells. High Ca2+ and transforming growth factor-β (TGF-β), two representative growth suppressors for NHK, need a common S100A11-mediated pathway in addition to unique pathways (NFAT1-mediated pathway for high Ca2+ and Smad-mediated pathway for TGF-β) for exhibiting a growth inhibitory effect. S100A11 has another action point for growth suppression in NHK. Annexin A1 (ANXA1) complexed with S100A11 efficiently binds to and inhibits cytosolic phospholipase A2 (cPLA2), the activity of which is needed for the growth of NHK. On exposure of NHK to epidermal growth factor (EGF), ANXA1 is cleaved at 12Trp, and this truncated ANXA1 loses binding capacity to S100A11, resulting in maintenance of an active state of cPLA2. On the other hand, we found that S100A11 is actively secreted by NHK. Extracellular S100A11 acts on NHK to enhance the production of EGF family proteins, resulting in growth stimulation. These findings indicate that S100A11 plays a dual role in growth regulation, being suppressive in cells and being promotive from outside of cells.


S100 protein EF-hand Cell growth Ca2+ TGF-β EGF Epithelial cell Skin Cancer p21/WAF1 RAGE 



This review partly depends on our studies, which were supported by grants from the Ministry of Health, Labor and Welfare (Research for Intractable Diseases) (N. Huh), from the Ministry of Education, Culture, Sports, Science, and Technology of Japan [Grant-in-Aid for Young Scientists (A)] (M. Sakaguchi), and from Takeda Science Foundation (M. Sakaguchi). We particularly thank our co-workers, Dr. Masayoshi Namba, Dr. Hidenori Yamada, and Dr. Keiichi Kawano.


  1. Bianchi R, Giambanco I, Arcuri C, Donato R (2003) Subcellular localization of S100A11 (S100C) in LLC-PK1 renal cells: Calcium- and protein kinase c-dependent association of S100A11 with S100B and vimentin intermediate filaments. Microsc Res Tech 60:639–651PubMedCrossRefGoogle Scholar
  2. Blott EJ, Griffiths GM (2002) Secretory lysosomes. Nat Rev Mol Cell Biol 3:122–131PubMedCrossRefGoogle Scholar
  3. Broome AM, Eckert RL (2004) Microtubule-dependent redistribution of a cytoplasmic cornified envelope precursor. J Invest Dermatol 122:29–38PubMedCrossRefGoogle Scholar
  4. Cecil DL, Terkeltaub R (2008) Transamidation by transglutaminase 2 transforms S100A11 calgranulin into a procatabolic cytokine for chondrocytes. J Immunol 180:8378–8385PubMedGoogle Scholar
  5. Cecil DL, Johnson K, Rediske J, Lotz M, Schmidt AM, Terkeltaub R (2005) Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products. J Immunol 175:8296–8302PubMedGoogle Scholar
  6. Cecil DL, Appleton CT, Polewski MD, Mort JS, Schmidt AM, Bendele A, Beier F, Terkeltaub R (2009) The pattern recognition receptor CD36 is a chondrocyte hypertrophy marker associated with suppression of catabolic responses and promotion of repair responses to inflammatory stimuli. J Immunol 182:5024–5031PubMedCrossRefGoogle Scholar
  7. Chen X, Yeung TK, Wang Z (2000) Enhanced drug resistance in cells coexpressing ErbB2 with EGF receptor or ErbB3. Biochem Biophys Res Commun 277:757–763PubMedCrossRefGoogle Scholar
  8. Danielsen EM, van Deurs B, Hansen GH (2003) “Nonclassical” secretion of annexin A2 to the lumenal side of the enterocyte brush border membrane. Biochemistry 42:14670–14676PubMedCrossRefGoogle Scholar
  9. Dempsey AC, Walsh MP, Shaw GS (2003) Unmasking the annexin I interaction from the structure of Apo-S100A11. Structure 11:887–897PubMedCrossRefGoogle Scholar
  10. Donato R (2007) RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins. Curr Mol Med 7:711–724PubMedCrossRefGoogle Scholar
  11. Garcia R, Franklin RA, McCubrey JA (2006) EGF induces cell motility and multi-drug resistance gene expression in breast cancer cells. Cell Cycle 5:2820–2826PubMedCrossRefGoogle Scholar
  12. Gerke V, Moss SE (2002) Annexins: from structure to function. Physiol Rev 82:331–371PubMedGoogle Scholar
  13. Ghavami S, Rashedi I, Dattilo BM, Eshraghi M, Chazin WJ, Hashemi M, Wesselborg S, Kerkhoff C, Los M (2008) S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol 83:1484–1492PubMedCrossRefGoogle Scholar
  14. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97:889–901PubMedCrossRefGoogle Scholar
  15. Holt OJ, Gallo F, Griffiths GM (2006) Regulating secretory lysosomes. J Biochem 140:7–12PubMedCrossRefGoogle Scholar
  16. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER, Vijay S, Nitecki D et al (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 270:25752–25761PubMedCrossRefGoogle Scholar
  17. Horiuchi S, Unno Y, Usui H, Shikata K, Takaki K, Koito W, Sakamoto Y, Nagai R, Makino K, Sasao A, Wada J, Makino H (2005) Pathological roles of advanced glycation end product receptors SR-A and CD36. Ann N Y Acad Sci 1043:671–675PubMedCrossRefGoogle Scholar
  18. Hudson BI, Kalea AZ, Del Mar Arriero M, Harja E, Boulanger E, D’Agati V, Schmidt AM (2008) Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem 283:34457–34468PubMedCrossRefGoogle Scholar
  19. Inada H, Naka M, Tanaka T, Davey GE, Heizmann CW (1999) Human S100A11 exhibits differential steady-state RNA levels in various tissues and a distinct subcellular localization. Biochem Biophys Res Commun 263:135–138PubMedCrossRefGoogle Scholar
  20. Jono T, Miyazaki A, Nagai R, Sawamura T, Kitamura T, Horiuchi S (2002) Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) serves as an endothelial receptor for advanced glycation end products (AGE). FEBS Lett 511:170–174PubMedCrossRefGoogle Scholar
  21. Keller M, Ruegg A, Werner S, Beer HD (2008) Active caspase-1 is a regulator of unconventional protein secretion. Cell 132:818–831PubMedCrossRefGoogle Scholar
  22. Kim KM, Kim DK, Park YM, Kim CK, Na DS (1994) Annexin-I inhibits phospholipase A2 by specific interaction, not by substrate depletion. FEBS Lett 343:251–255PubMedCrossRefGoogle Scholar
  23. Kim S, Ko J, Kim JH, Choi EC, Na DS (2001a) Differential effects of annexins I, II, III, and V on cytosolic phospholipase A2 activity: specific interaction model. FEBS Lett 489:243–248PubMedCrossRefGoogle Scholar
  24. Kim SW, Rhee HJ, Ko J, Kim YJ, Kim HG, Yang JM, Choi EC, Na DS (2001b) Inhibition of cytosolic phospholipase A2 by annexin I. Specific interaction model and mapping of the interaction site. J Biol Chem 276:15712–15719PubMedCrossRefGoogle Scholar
  25. Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM (1999) N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 274:31740–31749PubMedCrossRefGoogle Scholar
  26. Kouno T, Mizuguchi M, Sakaguchi M, Makino E, Mori Y, Shinoda H, Aizawa T, Demura M, Huh NH, Kawano K (2008) The structure of S100A11 fragment explains a local structural change induced by phosphorylation. J Pept Sci 14:1129–1138PubMedCrossRefGoogle Scholar
  27. Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM (1997) Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272:17810–17814PubMedCrossRefGoogle Scholar
  28. Landriscina M, Soldi R, Bagala C, Micucci I, Bellum S, Tarantini F, Prudovsky I, Maciag T (2001) S100A13 participates in the release of fibroblast growth factor 1 in response to heat shock in vitro. J Biol Chem 276:22544–22552PubMedCrossRefGoogle Scholar
  29. Leclerc E, Fritz G, Weibel M, Heizmann CW, Galichet A (2007) S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains. J Biol Chem 282:31317–31331PubMedCrossRefGoogle Scholar
  30. Leclerc E, Fritz G, Vetter SW, Heizmann CW (2009a) Binding of S100 proteins to RAGE: an update. Biochim Biophys Acta 1793:993–1007PubMedCrossRefGoogle Scholar
  31. Leclerc E, Sturchler E, Vetter SW, Heizmann CW (2009b) Crosstalk between calcium, amyloid beta and the receptor for advanced glycation endproducts in Alzheimer’s disease. Rev Neurosci 20:95–110PubMedCrossRefGoogle Scholar
  32. Mailliard WS, Haigler HT, Schlaepfer DD (1996) Calcium-dependent binding of S100C to the N-terminal domain of annexin I. J Biol Chem 271:719–725PubMedCrossRefGoogle Scholar
  33. Mambula SS, Stevenson MA, Ogawa K, Calderwood SK (2007) Mechanisms for Hsp70 secretion: crossing membranes without a leader. Methods 43:168–175PubMedCrossRefGoogle Scholar
  34. Matsunaga H, Ueda H (2006) Evidence for serum-deprivation-induced co-release of FGF-1 and S100A13 from astrocytes. Neurochem Int 49:294–303PubMedCrossRefGoogle Scholar
  35. Matsuzawa Y, Kiuchi Y, Toyomura K, Matsumoto I, Nakamura H, Fujino H, Murayama T, Kawashima T (2009) Activation of cytosolic phospholipase A2alpha by epidermal growth factor (EGF) and phorbol ester in HeLa cells: different effects of inhibitors for EGF receptor, protein kinase C, Src, and C-Raf. J Pharmacol Sci 111:182–192PubMedCrossRefGoogle Scholar
  36. Meyer zu Schwabedissen HE, Grube M, Dreisbach A, Jedlitschky G, Meissner K, Linnemann K, Fusch C, Ritter CA, Volker U, Kroemer HK (2006) Epidermal growth factor-mediated activation of the map kinase cascade results in altered expression and function of ABCG2 (BCRP). Drug Metab Dispos 34:524–533PubMedCrossRefGoogle Scholar
  37. Moore BW (1965) A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun 19:739–744PubMedCrossRefGoogle Scholar
  38. Mori M, Shimada H, Gunji Y, Matsubara H, Hayashi H, Nimura Y, Kato M, Takiguchi M, Ochiai T, Seki N (2004) S100A11 gene identified by in-house cDNA microarray as an accurate predictor of lymph node metastases of gastric cancer. Oncol Rep 11:1287–1293PubMedGoogle Scholar
  39. Murzik U, Hemmerich P, Weidtkamp-Peters S, Ulbricht T, Bussen W, Hentschel J, von Eggeling F, Melle C (2008) Rad54B targeting to DNA double-strand break repair sites requires complex formation with S100A11. Mol Biol Cell 19:2926–2935PubMedCrossRefGoogle Scholar
  40. Naka M, Qing ZX, Sasaki T, Kise H, Tawara I, Hamaguchi S, Tanaka T (1994) Purification and characterization of a novel calcium-binding protein, S100C, from porcine heart. Biochim Biophys Acta 1223:348–353PubMedCrossRefGoogle Scholar
  41. Nukui T, Ehama R, Sakaguchi M, Sonegawa H, Katagiri C, Hibino T, Huh NH (2008) S100A8/A9, a key mediator for positive feedback growth stimulation of normal human keratinocytes. J Cell Biochem 104:453–464PubMedCrossRefGoogle Scholar
  42. Ohgami N, Nagai R, Ikemoto M, Arai H, Kuniyasu A, Horiuchi S, Nakayama H (2001a) Cd36, a member of the class b scavenger receptor family, as a receptor for advanced glycation end products. J Biol Chem 276:3195–3202PubMedCrossRefGoogle Scholar
  43. Ohgami N, Nagai R, Miyazaki A, Ikemoto M, Arai H, Horiuchi S, Nakayama H (2001b) Scavenger receptor class B type I-mediated reverse cholesterol transport is inhibited by advanced glycation end products. J Biol Chem 276:13348–13355PubMedCrossRefGoogle Scholar
  44. Olsen E, Rasmussen HH, Celis JE (1995) Identification of proteins that are abnormally regulated in differentiated cultured human keratinocytes. Electrophoresis 16:2241–2248PubMedCrossRefGoogle Scholar
  45. Pardali K, Kurisaki A, Moren A, ten Dijke P, Kardassis D, Moustakas A (2000) Role of Smad proteins and transcription factor Sp1 in p21(Waf1/Cip1) regulation by transforming growth factor-beta. J Biol Chem 275:29244–29256PubMedCrossRefGoogle Scholar
  46. Pricci F, Leto G, Amadio L, Iacobini C, Romeo G, Cordone S, Gradini R, Barsotti P, Liu FT, Di Mario U, Pugliese G (2000) Role of galectin-3 as a receptor for advanced glycosylation end products. Kidney Int Suppl 77:S31–S39PubMedCrossRefGoogle Scholar
  47. Prudovsky I, Bagala C, Tarantini F, Mandinova A, Soldi R, Bellum S, Maciag T (2002) The intracellular translocation of the components of the fibroblast growth factor 1 release complex precedes their assembly prior to export. J Cell Biol 158:201–208PubMedCrossRefGoogle Scholar
  48. Prudovsky I, Tarantini F, Landriscina M, Neivandt D, Soldi R, Kirov A, Small D, Kathir KM, Rajalingam D, Kumar TK (2008) Secretion without Golgi. J Cell Biochem 103:1327–1343PubMedCrossRefGoogle Scholar
  49. Rauvala H, Rouhiainen A (2007) RAGE as a receptor of HMGB1 (amphoterin): roles in health and disease. Curr Mol Med 7:725–734PubMedCrossRefGoogle Scholar
  50. Rehman I, Azzouzi AR, Cross SS, Deloulme JC, Catto JW, Wylde N, Larre S, Champigneuille J, Hamdy FC (2004) Dysregulated expression of S100A11 (calgizzarin) in prostate cancer and precursor lesions. Hum Pathol 35:1385–1391PubMedCrossRefGoogle Scholar
  51. Rety S, Osterloh D, Arie JP, Tabaries S, Seeman J, Russo-Marie F, Gerke V, Lewit-Bentley A (2000) Structural basis of the Ca2+-dependent association between S100C (S100A11) and its target, the N-terminal part of annexin I. Structure 8:175–184PubMedCrossRefGoogle Scholar
  52. Rintala-Dempsey AC, Rezvanpour A, Shaw GS (2008) S100-annexin complexes—structural insights. Febs J 275:4956–4966PubMedCrossRefGoogle Scholar
  53. Robinson NA, Lapic S, Welter JF, Eckert RL (1997) S100A11, S100A10, annexin I, desmosomal proteins, small proline-rich proteins, plasminogen activator inhibitor-2, and involucrin are components of the cornified envelope of cultured human epidermal keratinocytes. J Biol Chem 272:12035–12046PubMedCrossRefGoogle Scholar
  54. Sakaguchi M, Miyazaki M, Inoue Y, Tsuji T, Kouchi H, Tanaka T, Yamada H, Namba M (2000) Relationship between contact inhibition and intranuclear S100C of normal human fibroblasts. J Cell Biol 149:1193–1206PubMedCrossRefGoogle Scholar
  55. Sakaguchi M, Miyazaki M, Takaishi M, Sakaguchi Y, Makino E, Kataoka N, Yamada H, Namba M, Huh NH (2003) S100C/A11 is a key mediator of Ca2+-induced growth inhibition of human epidermal keratinocytes. J Cell Biol 163:825–835PubMedCrossRefGoogle Scholar
  56. Sakaguchi M, Miyazaki M, Sonegawa H, Kashiwagi M, Ohba M, Kuroki T, Namba M, Huh NH (2004) PKCalpha mediates TGFbeta-induced growth inhibition of human keratinocytes via phosphorylation of S100C/A11. J Cell Biol 164:979–984PubMedCrossRefGoogle Scholar
  57. Sakaguchi M, Sonegawa H, Nukui T, Sakaguchi Y, Miyazaki M, Namba M, Huh NH (2005) Bifurcated converging pathways for high Ca2+- and TGFbeta-induced inhibition of growth of normal human keratinocytes. Proc Natl Acad Sci USA 102:13921–13926PubMedCrossRefGoogle Scholar
  58. Sakaguchi M, Murata H, Sonegawa H, Sakaguchi Y, Futami J, Kitazoe M, Yamada H, Huh NH (2007) Truncation of annexin A1 is a regulatory lever for linking epidermal growth factor signaling with cytosolic phospholipase A2 in normal and malignant squamous epithelial cells. J Biol Chem 282:35679–35686PubMedCrossRefGoogle Scholar
  59. Sakaguchi M, Sonegawa H, Murata H, Kitazoe M, Futami J, Kataoka K, Yamada H, Huh NH (2008) S100A11, an dual mediator for growth regulation of human keratinocytes. Mol Biol Cell 19:78–85PubMedCrossRefGoogle Scholar
  60. Salama I, Malone PS, Mihaimeed F, Jones JL (2008) A review of the S100 proteins in cancer. Eur J Surg Oncol 34:357–364PubMedGoogle Scholar
  61. Santini MP, Talora C, Seki T, Bolgan L, Dotto GP (2001) Cross talk among calcineurin, Sp1/Sp3, and NFAT in control of p21(WAF1/CIP1) expression in keratinocyte differentiation. Proc Natl Acad Sci USA 98:9575–9580PubMedCrossRefGoogle Scholar
  62. Seemann J, Weber K, Gerke V (1997) Annexin I targets S100C to early endosomes. FEBS Lett 413:185–190PubMedCrossRefGoogle Scholar
  63. Sonegawa H, Nukui T, Li DW, Takaishi M, Sakaguchi M, Huh NH (2007) Involvement of deterioration in S100C/A11-mediated pathway in resistance of human squamous cancer cell lines to TGF beta-induced growth suppression. J Mol Med 85:753–762PubMedCrossRefGoogle Scholar
  64. Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405:354–360PubMedCrossRefGoogle Scholar
  65. Tamura Y, Adachi H, Osuga J, Ohashi K, Yahagi N, Sekiya M, Okazaki H, Tomita S, Iizuka Y, Shimano H, Nagai R, Kimura S, Tsujimoto M, Ishibashi S (2003) FEEL-1 and FEEL-2 are endocytic receptors for advanced glycation end products. J Biol Chem 278:12613–12617PubMedCrossRefGoogle Scholar
  66. Tanaka M, Adzuma K, Iwami M, Yoshimoto K, Monden Y, Itakura M (1995) Human calgizzarin; one colorectal cancer-related gene selected by a large scale random cDNA sequencing and northern blot analysis. Cancer Lett 89:195–200PubMedCrossRefGoogle Scholar
  67. Todoroki H, Kobayashi R, Watanabe M, Minami H, Hidaka H (1991) Purification, characterization, and partial sequence analysis of a newly identified EF-hand type 13-kDa Ca2+-binding protein from smooth muscle and non-muscle tissues. J Biol Chem 266:18668–18673PubMedGoogle Scholar
  68. Tu CL, Oda Y, Komuves L, Bikle DD (2004) The role of the calcium-sensing receptor in epidermal differentiation. Cell Calcium 35:265–273PubMedCrossRefGoogle Scholar
  69. Wein S, Fauroux M, Laffitte J, de Nadai P, Guaini C, Pons F, Comera C (2004) Mediation of annexin 1 secretion by a probenecid-sensitive ABC-transporter in rat inflamed mucosa. Biochem Pharmacol 67:1195–1202PubMedCrossRefGoogle Scholar
  70. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691PubMedCrossRefGoogle Scholar
  71. Yeh CH, Sturgis L, Haidacher J, Zhang XN, Sherwood SJ, Bjercke RJ, Juhasz O, Crow MT, Tilton RG, Denner L (2001) Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. Diabetes 50:1495–1504PubMedCrossRefGoogle Scholar
  72. Zhao XQ, Naka M, Muneyuki M, Tanaka T (2000) Ca2+-dependent inhibition of actin-activated myosin ATPase activity by S100C (S100A11), a novel member of the S100 protein family. Biochem Biophys Res Commun 267:77–79PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of Cell BiologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan

Personalised recommendations