S100A4, a Mediator of Metastasis (2005)

The transition from benign tumor growth to malignancy is manifested by the ability of tumor cells to traverse tissue barriers and invade surrounding tissues. The traversal of basement membrane barriers is thought to be the critical event in the initiation of the metastatic cascade and, as described by the three-step hypothesis of metastasis, involves attachment to the extracellular matrix, local proteolysis, and subsequent migration (1Stetler-Stevenson W.G. Aznavoorian S. Liotta L.A. Annu. Rev. Cell Biol. 1993; 9: 541-573Crossref PubMed Scopus (1523) Google Scholar). In recent years, a number of specific genes have been identified, the expressions of which correlate with tumorigenesis and/or metastatic potential. S100A4 is a member of the S100 family of calcium-binding proteins that is directly involved in tumor metastasis. This report reviews the animal and cellular studies implicating S100A4 in the establishment of the metastatic phenotype and examines the biochemical properties of S100A4 that are relevant to its role as a metastasis factor. In humans there are now over 20 S100 family members that are distributed tissue specifically (2Zimmer D.B. Cornwall E.H. Landar A. Song W. Brain Res. Bull. 1995; 37: 417-429Crossref PubMed Scopus (816) Google Scholar, 3Heizmann C.W. Fritz G. Schafer B.W. Front Biosci. 2002; 7: 1356-1368Crossref PubMed Google Scholar, 4Marenholz I. Heizman C.W. Fritz G. Biochem. Biophys. Res. Commun. 2004; 322: 1111-1122Crossref PubMed Scopus (677) Google Scholar). The first family members were discovered in the brain by Moore (5Moore B. Biochem. Biophys. Res. Commun. 1965; 19: 739-744Crossref PubMed Scopus (1336) Google Scholar) and given the name S100 because they are soluble in 100% saturated ammonium sulfate (5Moore B. Biochem. Biophys. Res. Commun. 1965; 19: 739-744Crossref PubMed Scopus (1336) Google Scholar). As for most S100 family members, S100A4 is a symmetric homodimer stabilized by noncovalent interactions between two helices from each subunit (helices 1, 4, 1′,4′) that form an X-type four-helix bundle (Fig. 1). Each S100A4 subunit has two EF-hand Ca2+-binding domains: a pseudo-EF-hand or S100-hand and a typical EF-hand (CaKD = 2.6 μm) (6Dukhanina E.A. Dukhanin A.S. Lomonosov M.Y. Lukanidin E.M. Georgiev G.P. FEBS Lett. 1997; 410: 403-406Crossref PubMed Scopus (29) Google Scholar), which are brought into close proximity by a small two-stranded antiparallel β-sheet (7Vallely K.M. Rustandi R.R. Ellis K.C. Varlamova O. Bresnick A.R. Weber D.J. Biochemistry. 2002; 41: 12670-12680Crossref PubMed Scopus (67) Google Scholar). The pseudo-EF-hand differs from prototypical EF-hands because it is composed of 14 residues (rather than 12) and coordinates calcium weakly via backbone carbonyl oxygen atoms rather than with side chain oxygen atoms of Asp, Glu, Asn, or Gln (8Strynadka N.C. James M.N. Annu. Rev. Biochem. 1989; 58: 951-998Crossref PubMed Google Scholar, 9Weber D.J. Rustandi R.R. Zimmer D. Pochet R. Calcium: the Molecular Basis of Calcium Action in Biology and Medicine. Kluwer Academic Publishers, Netherlands2000: 469-487Google Scholar, 10Dutta K. Cox C.J. Huang H. Basavappa R. Pascal S.M. Biochemistry. 2002; 41: 4239-4245Crossref PubMed Scopus (14) Google Scholar). For S100A4, the pseudo-EF-hand is formed by helices 1 and 2 and is similar in conformation to other members of the S100 family. The orientation of helices 3 and 4 in the S100A4 typical EF-hand is similar to only one other member of the S100 protein family, S100A6 (11Maler L. Potts B.C. Chazin W.J. J. Biomol. NMR. 1999; 13: 233-247Crossref PubMed Scopus (43) Google Scholar), and less like other S100 family members for which three-dimensional structures are available in the calcium-free state (12Drohat A.C. Tjandra N. Baldisseri D.M. Weber D.J. Protein Sci. 1999; 8: 800-809Crossref PubMed Scopus (90) Google Scholar, 13Rustandi R.R. Baldisseri D.M. Inman K.G. Nizner P. Hamilton S.M. Landar A. Landar A. Zimmer D.B. Weber D.J. Biochemistry. 2002; 41: 788-796Crossref PubMed Scopus (62) Google Scholar). The difference in the position of helix 3 in the apo-state of these S100 proteins is due to variations in the amino acid sequence in the C terminus of helix 4 and in loop 2 (the hinge region) and is used to subclassify the S100 protein family (7Vallely K.M. Rustandi R.R. Ellis K.C. Varlamova O. Bresnick A.R. Weber D.J. Biochemistry. 2002; 41: 12670-12680Crossref PubMed Scopus (67) Google Scholar). For S100A4, there is a C-terminal loop following helix 4 that is quite long and very basic, which makes it particularly unique when compared with other S100 proteins. In general, the “hinge region” and the C-terminal loop of S100 proteins are involved in target protein binding; therefore, the lack of sequence homology in these regions provides a means for S100 proteins to interact with specific binding partners (14Kligman D. Hilt D. Trends Biochem. Sci. 1988; 13: 437-443Abstract Full Text PDF PubMed Scopus (480) Google Scholar). S100A4 and most other dimeric S100 proteins undergo a relatively large conformational change in the typical EF-hand upon binding calcium, which exposes a hydrophobic binding pocket comprising residues in helices 3 and 4, the hinge region, and the C-terminal loop. This calcium-dependent conformational change is necessary for S100A4 to interact with its protein targets and generate a biological effect (11Maler L. Potts B.C. Chazin W.J. J. Biomol. NMR. 1999; 13: 233-247Crossref PubMed Scopus (43) Google Scholar, 15Bhattacharya S. Large E. Heizmann C.W. Hemmings B. Chazin W.J. Biochemistry. 2003; 42: 14416-14426Crossref PubMed Scopus (82) Google Scholar, 16Smith S.P. Shaw G.S. Biochem. Cell Biol. 1998; 76: 324-333Crossref PubMed Scopus (62) Google Scholar, 17Inman K.G. Yang R. Rustandi R.R. Miller K.E. Baldisseri D.M. Weber D.J. J. Mol. Biol. 2002; 324: 1003-1014Crossref PubMed Scopus (72) Google Scholar, 18Rustandi R.R. Baldisseri D.M. Weber D.J. Nat. Struct. Biol. 2000; 7: 570-574Crossref PubMed Scopus (292) Google Scholar). Similar to other S100 proteins (19Markowitz J. Rustandi R.R. Varney K.M. Wilder P.T. Udan R. Wu S.L. Horrocks W.D. Weber D.J. Biochemistry. 2005; 44: 7305-7314Crossref PubMed Scopus (53) Google Scholar), target binding significantly enhances the calcium binding affinity (KD ∼ 0.2 μm) of S100A4 (6Dukhanina E.A. Dukhanin A.S. Lomonosov M.Y. Lukanidin E.M. Georgiev G.P. FEBS Lett. 1997; 410: 403-406Crossref PubMed Scopus (29) Google Scholar). This provides a mechanism for the formation of a high affinity complex in vivo that occurs only when calcium, S100A4, and one of its target proteins are present (Fig. 1). The S100A4 gene was cloned independently by several groups under various names, including metastasin (Mts1), fibroblast-specific protein (FSP1), 18A2, pEL98, p9Ka, 42A, CAPL, and calvasculin (20Ebralidze A. Tulchinsky E. Grigorian M. Afanasyeva A. Senin V. Revazova E. Lukanidin E. Genes Dev. 1989; 3: 1086-1093Crossref PubMed Scopus (313) Google Scholar, 21Strutz F. Okada H. Lo C.W. Danoff T. Carone R.L. Tomaszewski J.E. Neilson E.G. J. Cell Biol. 1995; 130: 393-405Crossref PubMed Scopus (892) Google Scholar, 22Jackson-Grusby L.L. Swiergiel J. Linzer D.I. Nucleic Acids Res. 1987; 15: 6677-6690Crossref PubMed Scopus (90) Google Scholar, 23Goto K. Endo H. Fujiyoshi T. J. Biochem. (Tokyo). 1988; 103: 48-53Crossref PubMed Scopus (70) Google Scholar, 24Barraclough R. Savin J. Dube S.K. Rudland P.S. J. Mol. Biol. 1987; 198: 13-20Crossref PubMed Scopus (78) Google Scholar, 25Masiakowski P. Shooter E.M. Proc. Natl. Acad. Sci. U. 1988; 85: 1277-1281Crossref PubMed Scopus (124) Google Scholar, 26Engelkamp D. Schafer B.W. Erne P. Heizmann C.W. Biochemistry. 1992; 31: 10258-10264Crossref PubMed Scopus (79) Google Scholar, 27Watanabe Y. Kobayashi R. Ishikawa T. Hidaka H. Arch. Biochem. Biophys. 1992; 292: 563-569Crossref PubMed Scopus (46) Google Scholar). Initial cloning efforts identified S100A4 as a highly expressed transcript in growth-stimulated cultured cells (23Goto K. Endo H. Fujiyoshi T. J. Biochem. (Tokyo). 1988; 103: 48-53Crossref PubMed Scopus (70) Google Scholar, 28Linzer D.I. Nathans D. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 4271-4275Crossref PubMed Scopus (130) Google Scholar) and metastatic tumor cell lines (20Ebralidze A. Tulchinsky E. Grigorian M. Afanasyeva A. Senin V. Revazova E. Lukanidin E. Genes Dev. 1989; 3: 1086-1093Crossref PubMed Scopus (313) Google Scholar) and during morphogenic conversion from an epithelial to mesenchymal phenotype (21Strutz F. Okada H. Lo C.W. Danoff T. Carone R.L. Tomaszewski J.E. Neilson E.G. J. Cell Biol. 1995; 130: 393-405Crossref PubMed Scopus (892) Google Scholar). In addition, S100A4 expression levels are up-regulated during oncogenic transformation (29De Vouge M.W. Mukherjee B.B. Oncogene. 1992; 7: 109-119PubMed Google Scholar, 30Takenaga K. Nakamura Y. Endo H. Sakiyama S. Jpn. J. Cancer Res. 1994; 85: 831-839Crossref PubMed Scopus (87) Google Scholar). Northern blot analyses indicate that S100A4 is expressed in several adult mouse and rat tissues, with high expression found in the spleen, thymus, bone marrow, T-lymphocytes, neutrophils, and macrophages (31Grigorian M.S. Tulchinsky E.M. Zain S. Ebralidze A.K. Kramerov D.A. Kriajevska M.V. Georgiev G.P. Lukanidin E.M. Gene (Amst.). 1993; 135: 229-238Crossref PubMed Scopus (98) Google Scholar, 32Takenaga K. Nakamura Y. Sakiyama S. Cell Struct. Funct. 1994; 19: 133-141Crossref PubMed Scopus (55) Google Scholar). Immunohistochemical analysis of rat tissues shows that S100A4 is expressed in some absorptive and keratinized epithelia, in the parietal cells of the stomach, and in a subset of cells of the immune system in the blood, bone marrow, spleen, and lymph nodes (33Gibbs F.E. Barraclough R. Platt-Higgins A. Rudland P.S. Wilkinson M.C. Parry E.W. J. Histochem. Cytochem. 1995; 43: 169-180Crossref PubMed Scopus (58) Google Scholar). Similar studies examining S100A4 expression during mouse development demonstrate that S100A4 is highly expressed in embryonic macrophages, as well as in differentiating mesenchymal tissues (34Klingelhofer J. Ambartsumian N.S. Lukanidin E.M. Dev. Dyn. 1997; 210: 87-95Crossref PubMed Scopus (48) Google Scholar). S100A4 expression is also observed in metastatic cancers. Immunohistochemical analyses of human cancers shows significant S100A4 expression in breast, pancreatic, prostate, gallbladder, esophageal, gastric, lung, and thyroid carcinomas (35Pedersen K.B. Nesland J.M. Fodstad O. Maelandsmo G.M. Br. J. Cancer. 2002; 87: 1281-1286Crossref PubMed Scopus (71) Google Scholar, 36Rosty C. Ueki T. Argani P. Jansen M. Yeo C.J. Cameron J.L. Hruban R.H. Goggins M. Am. J. Pathol. 2002; 160: 45-50Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 37Gupta S. Hussain T. MacLennan G.T. Fu P. Patel J. Mukhtar H. J. Clin. Oncol. 2003; 21: 106-112Crossref PubMed Scopus (121) Google Scholar, 38Nakamura T. Ajiki T. Murao S. Kamigaki T. Maeda S. Ku Y. Kuroda Y. Int. J. Oncol. 2002; 20: 937-941PubMed Google Scholar, 39Ninomiya I. Ohta T. Fushida S. Endo Y. Hashimoto T. Yagi M. Fujimura T. Nishimura G. Tani T. Shimizu K. Yonemura Y. Heizmann C.W. Schafer B.W. Sasaki T. Miwa K. Int. J. Oncol. 2001; 18: 715-720PubMed Google Scholar, 40Yonemura Y. Endou Y. Kimura K. Fushida S. Bandou E. Taniguchi K. Kinoshita K. Ninomiya I. Sugiyama K. Heizmann C.W. Schafer B.W. Sasaki T. Clin. Cancer Res. 2000; 6: 4234-4242PubMed Google Scholar, 41Kimura K. Endo Y. Yonemura Y. Heizmann C.W. Schafer B.W. Watanabe Y. Sasaki T. Int. J. Oncol. 2000; 16: 1125-1131PubMed Google Scholar, 42Ito Y. Yoshida H. Tomoda C. Uruno T. Miya A. Kobayashi K. Matsuzuka F. Kakudo K. Kuma K. Miyauchi A. Oncology. 2004; 67: 397-402Crossref PubMed Scopus (33) Google Scholar). In these cancers S100A4 expression is found at elevated levels compared with normal tissue, suggesting that enhanced S100A4 expression contributes to manifestation of a metastatic phenotype. Studies in rodents have provided evidence supporting the direct involvement of S100A4 in tumor progression and metastasis. The role of S100A4 in cancer has been examined most widely in breast cancer models, which have demonstrated that overexpression of S100A4 in nonmetastatic mammary tumor cells confers a metastatic phenotype (43Davies B.R. Davies M.P. Gibbs F.E. Barraclough R. Rudland P.S. Oncogene. 1993; 8: 999-1008PubMed Google Scholar, 44Grigorian M. Ambartsumian N. Lykkesfeldt A.E. Bastholm L. Elling F. Georgiev G. Lukanidin E. Int. J. Cancer. 1996; 67: 831-841Crossref PubMed Scopus (105) Google Scholar). Transgenic mice that overexpress S100A4 in the mammary epithelium are phenotypically indistinguishable from wild-type mice (45Ambartsumian N.S. Grigorian M.S. Larsen I.F. Karlstrom O. Sidenius N. Rygaard J. Georgiev G. Lukanidin E. Oncogene. 1996; 13: 1621-1630PubMed Google Scholar), demonstrating that S100A4 itself is not tumorigenic; however, transgenic mouse models of breast cancer have shown that S100A4 expression correlates with metastasis. MMTV-neu and GRS/A animals are characterized by a high incidence of mammary tumors that rarely metastasize; overexpression of S100A4 in the mammary epithelium of these animals causes more invasive primary tumors and the appearance of metastases in the lungs (45Ambartsumian N.S. Grigorian M.S. Larsen I.F. Karlstrom O. Sidenius N. Rygaard J. Georgiev G. Lukanidin E. Oncogene. 1996; 13: 1621-1630PubMed Google Scholar, 46Davies M.P. Rudland P.S. Robertson L. Parry E.W. Jolicoeur P. Barraclough R. Oncogene. 1996; 13: 1631-1637PubMed Google Scholar). The link between S100A4 and metastasis is further supported by knockdown experiments, as inhibition of S100A4 expression by antisense or anti-ribozyme techniques suppresses the metastatic capacity of S100A4-expressing tumor cells in animal models of lung carcinoma and osteosarcoma (47Maelandsmo G.M. Hovig E. Skrede M. Engebraaten O. Florenes V.A. Myklebost O. Grigorian M. Lukanidin E. Scanlon K.J. Fodstad O. Cancer Res. 1996; 56: 5490-5498PubMed Google Scholar, 48Takenaga K. Nakamura Y. Sakiyama S. Oncogene. 1997; 14: 331-337Crossref PubMed Scopus (141) Google Scholar). In addition, recent studies demonstrate that when transgenic mice expressing the polyoma virus middle T antigen are crossed with mice carrying null alleles for S100A4, they display a significant decrease in lung metastases (49Xue C. Plieth D. Venkov C. Xu C. Neilson E.G. Cancer Res. 2003; 63: 3386-3394PubMed Google Scholar). Altogether these observations suggest that S100A4 is not simply a marker for metastatic disease but rather has a causal role in mediating this process. The association between S100A4 expression and metastasis observed in animal studies has led to a number of studies examining the utility of S100A4 expression as a prognostic marker in human cancers. In a retrospective study of 349 invasive human breast cancer specimens, S100A4 expression and other variables were evaluated for their prognostic significance over a period of 14–20 years (50Platt-Higgins A.M. Renshaw C.A. West C.R. Winstanley J.H. De Silva Rudland S. Barraclough R. Rudland P.S. Int. J. Cancer. 2000; 89: 198-208Crossref PubMed Google Scholar, 51Rudland P.S. Platt-Higgins A. Renshaw C. West C.R. Winstanley J.H. Robertson L. Barraclough R. Cancer Res. 2000; 60: 1595-1603PubMed Google Scholar). Analysis of patients with carcinomas that stain positively for S100A4 expression demonstrated that S100A4 expression is highly correlated with patient death. In addition to breast cancer, S100A4 has been shown to be a prognostic marker in a number of human cancers, including esophageal-squamous cancers (39Ninomiya I. Ohta T. Fushida S. Endo Y. Hashimoto T. Yagi M. Fujimura T. Nishimura G. Tani T. Shimizu K. Yonemura Y. Heizmann C.W. Schafer B.W. Sasaki T. Miwa K. Int. J. Oncol. 2001; 18: 715-720PubMed Google Scholar), non-small lung cancers (41Kimura K. Endo Y. Yonemura Y. Heizmann C.W. Schafer B.W. Watanabe Y. Sasaki T. Int. J. Oncol. 2000; 16: 1125-1131PubMed Google Scholar), primary gastric cancers (40Yonemura Y. Endou Y. Kimura K. Fushida S. Bandou E. Taniguchi K. Kinoshita K. Ninomiya I. Sugiyama K. Heizmann C.W. Schafer B.W. Sasaki T. Clin. Cancer Res. 2000; 6: 4234-4242PubMed Google Scholar), malignant melanomas (52Andersen K. Nesland J.M. Holm R. Florenes V.A. Fodstad O. Maelandsmo G.M. Mod. Pathol. 2004; 17: 990-997Crossref PubMed Scopus (81) Google Scholar), prostate cancers (37Gupta S. Hussain T. MacLennan G.T. Fu P. Patel J. Mukhtar H. J. Clin. Oncol. 2003; 21: 106-112Crossref PubMed Scopus (121) Google Scholar, 53Saleem M. Adhami V.M. Ahmad N. Gupta S. Mukhtar H. Clin. Cancer Res. 2005; 11: 147-153PubMed Google Scholar), bladder cancers (54Davies B.R. O'Donnell M. Durkan G.C. Rudland P.S. Barraclough R. Neal D.E. Mellon J.K. J. Pathol. 2002; 196: 292-299Crossref PubMed Scopus (112) Google Scholar), and pancreatic carcinomas (36Rosty C. Ueki T. Argani P. Jansen M. Yeo C.J. Cameron J.L. Hruban R.H. Goggins M. Am. J. Pathol. 2002; 160: 45-50Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 55Iacobuzio-Donahue C.A. Ashfaq R. Maitra A. Adsay N.V. Shen-Ong G.L. Berg K. Hollingsworth M.A. Cameron J.L. Yeo C.J. Kern S.E. Goggins M. Hruban R.H. Cancer Res. 2003; 63: 8614-8622PubMed Google Scholar). The universality of S100A4 expression in a variety of cancers illustrates the potential use of S100A4 as a marker for tumor metastasis and disease progression. The majority of the human, mouse, and rat S100 genes, including S100A4, are located as a gene cluster on chromosomes 1q21, 3f3, and 2q34, respectively (56Ravasi T. Hsu K. Goyette J. Schroder K. Yang Z. Rahimi F. Miranda L.P. Alewood P.F. Hume D.A. Geczy C. Genomics. 2004; 84: 10-22Crossref PubMed Scopus (126) Google Scholar). The mouse S100A4 gene consists of three exons and two introns (57Lukanidin E.M. Georgiev G.P. Curr. 1996; Google Scholar). The first is and the used of the the the and the and the the C-terminal The human S100A4 gene 4 and the is located the and is In addition, there are two of the human S100A4 as a of the N. S. Grigorian M. Tulchinsky E. E. Georgiev G. Lukanidin E. Gene (Amst.). 1995; PubMed Scopus Google Scholar). The two display expression in human tissues and tumor cell lines (57Lukanidin E.M. Georgiev G.P. Curr. 1996; Google however, the significance of this with to gene or protein is not The S100A4 an R. R. C. D. Barraclough R. Cancer Res. 2003; 63: Google Scholar), and of the S100A4 gene is by and located the first which several E. Kramerov D. E. Lukanidin E. Zain S. Oncogene. 1993; 8: Google Scholar, E.M. Georgiev G.P. Lukanidin E.M. Oncogene. 1996; Google Scholar, E. E. Georgiev G. Lukanidin E. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M.A. I. Wu P. Lukanidin E.M. Tulchinsky E.M. Nucleic Acids 2001; PubMed Scopus Google Scholar). of the S100A4 gene is with E. Kramerov D. E. Grigorian M. Zain S. Lukanidin E. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: PubMed Scopus Google Scholar, D. Rudland P.S. Barraclough R. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus (14) Google Scholar, E. Grigorian M. T. Georgiev G. Lukanidin E. Biophys. 1995; PubMed Scopus (43) Google Scholar). protein C of S100A4 has phenotype in the period but in a incidence of tumors in The of the mice is with than C. B. A. Grigorian M. E. T. Kriajevska M. Schafer B.W. Heizmann C.W. Lukanidin E. Ambartsumian N. Oncogene. 2004; PubMed Scopus Google Scholar). In addition, recent studies that following of a highly carcinoma cell into tumor development and the formation metastases are B. J. Berg C. Grigorian M. Lukanidin E. Ambartsumian N. Cancer Res. 2005; PubMed Scopus Google Scholar). observations suggest that S100A4 expression in also to tumor progression and metastasis. proteins have been identified as S100A4 including M. M. E. O. Tulchinsky E. Grigorian M. Ambartsumian N. Lukanidin E. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), H. K. T. H. S. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), the tumor protein M. S. Tulchinsky E. Kriajevska M. C. C. M. Ambartsumian N. A. G. Lukanidin E. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), and proteins involved in and cell as and the chain of K. Nakamura Y. Sakiyama S. Y. K. Endo H. J. Cell Biol. 1994; PubMed Scopus Google Scholar, Y. N. H. T. S. Ishikawa R. K. Y. Hidaka H. FEBS Lett. 1993; 324: PubMed Scopus (81) Google Scholar, M.V. M.N. Grigorian M.S. Ambartsumian N.S. Georgiev G.P. Lukanidin E.M. J. Biol. 1994; Full Text PDF PubMed Google Scholar). In of these the of these protein targets with S100A4 is calcium-dependent and the cellular of these proteins to in the calcium (Fig. 1). has been a that S100 proteins as have other S100 family members as targets S. Kriajevska M. D.J. D. Lukanidin E. I. FEBS Lett. 2000; PubMed Scopus Google Scholar, G. Rudland P.S. Barraclough R. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Heizmann C.W. A. Cell Res. 1999; PubMed Scopus Google Scholar, N. C. R. J. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is not as was in for several S100 R.R. Baldisseri D.M. Inman K.G. Nizner P. Hamilton S.M. Landar A. Landar A. Zimmer D.B. Weber D.J. Biochemistry. 2002; 41: 788-796Crossref PubMed Scopus (62) Google Scholar, G. Rudland P.S. Barraclough R. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), and from the for for the S100 proteins A.C. E. D. Weber D.J. Protein Sci. 1997; 6: PubMed Scopus Google Scholar). The which was identified S. Kriajevska M. D.J. D. Lukanidin E. I. FEBS Lett. 2000; PubMed Scopus Google Scholar, G. Rudland P.S. Barraclough R. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), is not with in of S100A4 and S. Kriajevska M. D.J. D. Lukanidin E. I. FEBS Lett. 2000; PubMed Scopus Google Scholar) some the of this in S100 including S100A4, the tumor Similar to S100A4 with the C terminus of and protein C of the tumor in M. S. Tulchinsky E. Kriajevska M. C. C. M. Ambartsumian N. A. G. Lukanidin E. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. C. D. S. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: PubMed Scopus Google Scholar, C. M. G. L. Y. K. J. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the between and or S100A4 from binding to its sequence M. S. Tulchinsky E. Kriajevska M. C. C. M. Ambartsumian N. A. G. Lukanidin E. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. C. Zimmer D. Rustandi R.R. Weber D.J. F. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus (126) Google it was that S100A4 be a of an of genes in S100A4-expressing cells that the expression of several genes are up-regulated genes are and up-regulated and some genes are M. S. Tulchinsky E. Kriajevska M. C. C. M. Ambartsumian N. A. G. Lukanidin E. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). of these genes are are of S100A4 expression on genes from in the cell lines used in the various the potential between S100A4 and S100A4 expression the of an invasive phenotype. This is not due to the interactions of S100A4 with but is the of direct interactions with other targets as proteins. S100A4 to the of and the state B. Zain Biochemistry. 1997; PubMed Scopus (79) Google Scholar, A. Varlamova O. Bresnick A.R. Biochemistry. 2003; 42: PubMed Scopus Google Scholar). The S100A4 binding to residues in the C-terminal of the of the chain A. Varlamova O. Bresnick A.R. Biochemistry. 2003; 42: PubMed Scopus Google Scholar, M. S. I. N. Lomonosov M. K. Georgiev G. Lukanidin E. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). studies demonstrate that the S100A4 binding a at S100A4 binding is not by on the at which is located of the S100A4 binding in the S100A4 binding Bresnick A.R. Biochemistry. 2005; 44: PubMed Scopus Google Scholar). inhibition of and of demonstrate that chain at the in addition to calcium mechanism for the to its on cell S100A4 cellular by the orientation and of cellular S100A4-expressing cells display side and during as compared with cells that not and A. R. these are due to the specific of S100A4 with these suggest that S100A4 the metastatic phenotype the of cellular and is evidence that S100 proteins have extracellular however, their mechanism of S100A4 is by in and of tumor cells and the of S100A4 by Y. Kobayashi R. Ishikawa T. Hidaka H. Arch. Biochem. Biophys. 1992; 292: 563-569Crossref PubMed Scopus (46) Google Scholar, B. J. B. A. S. C. T. Ambartsumian N. Lukanidin E. Grigorian M. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, in S100A4 transgenic S100A4 in the of animals N. J. Grigorian M. C. Kriajevska M. Tulchinsky E. Georgiev G. V. E. Rygaard J. R. Y. Lukanidin E. Oncogene. 2001; 20: PubMed Scopus Google Scholar). S100A4 and as a of tumor cells B. J. B. A. S. C. T. Ambartsumian N. Lukanidin E. Grigorian M. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). In osteosarcoma inhibition of S100A4 expression significantly and expression K. Hovig E. T. Fodstad O. Maelandsmo G.M. Cancer Res. 1999; Google Scholar), and oncogenic transformation of cells and S100A4 expression H. K. H. Clin. 2000; 18: PubMed Scopus Google Scholar), suggesting that the of S100A4 and contributes to the invasive phenotype. S100A4 has been shown to an This by tissue on the cell to generate which is to A. A. A. M. I. G. D. V. J. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). S100A4 also metastasis by of the extracellular and as a and tumor S100A4 is as a of metastasis, the by which it an invasive phenotype are not well and studies to the involvement of S100A4 in at two in the metastatic of the extracellular and cellular the of S100A4 its protein targets and these interactions cellular to be and of the by which S100A4 its the biochemical for the of S100A4 to normal and metastatic and into the for the invasive of tumor This be to the use of S100A4 as a marker and as a target for for