S100A4 explained

Protein S100-A4 (S100A4) is a protein that in humans is encoded by the S100A4 gene.^[1]

Function

The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in motility, invasion, and tubulin polymerization. Chromosomal rearrangements and altered expression of this gene have been implicated in tumor metastasis. Multiple alternatively spliced variants, encoding the same protein, have been identified.^[2]

Interactions

S100A4 has been shown to interact with S100 calcium binding protein A1.^{[3] [4]}

Therapeutic targeting for cancer

S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. Research demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model. Conversely, when silencing S100A4 by shRNA technology, a dramatic decrease in tumor development of the pancreatic MIA PaCa-2 cell line was observed. Based on these results 5C3 was developed, a neutralizing monoclonal antibody against S100A4. This antibody abolished endothelial cell migration, tumor growth and angiogenesis in immunodeficient mouse xenograft models of MiaPACA-2 and M21-S100A4 cells. It is concluded that extracellular S100A4 inhibition is an attractive approach for the treatment of human cancer.^[5]

S100A4 is highly associated with components of the cytoskeleton and when this gene is upregulated, it changes the cell’s morphology, making it more susceptible to invasion from proteins, such as cathepsin B and cyclin B1, that contribute to metastasis.^[6] Together, these factors form polyploid giant cancer cells (PGCCs), which are highly proliferative and invasive. Experimental knockout therapy data have suggested that S100A4 exhibits a form of control over cathepsin B and cyclin B1, and that suppressing it can reduce the invasive capabilities of PGCCs and their daughter cells. Studies on invasive breast cancer have found that S100A4 plays a major role in high-density collagen deposition, which is one of the clinical symptoms of tumor metastasis. Significantly higher levels of S100A4 were found in samples that exhibited lymph node metastasis than in those that didn’t, indicating that abnormal collagen deposition could be contributed to by S100A4.^[7] Not only does overexpression of S100A4 contribute to the formation of various cancers, but it also contributes to pathological factors associated with cancer and its progression.

Further reading

• Kalluri R, Neilson EG . Epithelial-mesenchymal transition and its implications for fibrosis . J. Clin. Invest. . 112 . 12 . 1776–84 . 2003 . 14679171 . 297008 . 10.1172/JCI20530 .
• Garrett SC, Varney KM, Weber DJ, Bresnick AR . S100A4, a mediator of metastasis . J. Biol. Chem. . 281 . 2 . 677–80 . 2006 . 16243835 . 10.1074/jbc.R500017200 . free .
• Tarabykina S, Griffiths TR, Tulchinsky E, Mellon JK, Bronstein IB, Kriajevska M . Metastasis-associated protein S100A4: spotlight on its role in cell migration . Curr Cancer Drug Targets . 7 . 3 . 217–28 . 2007 . 17504119 . 10.2174/156800907780618329 .
• Tulchinsky E, Ford HL, Kramerov D, Reshetnyak E, Grigorian M, Zain S, Lukanidin E . Transcriptional analysis of the mts1 gene with specific reference to 5' flanking sequences . Proc. Natl. Acad. Sci. U.S.A. . 89 . 19 . 9146–50 . 1992 . 1329089 . 50082 . 10.1073/pnas.89.19.9146 . 1992PNAS...89.9146T . free .
• Engelkamp D, Schäfer BW, Erne P, Heizmann CW . S100 alpha, CAPL, and CACY: molecular cloning and expression analysis of three calcium-binding proteins from human heart . Biochemistry . 31 . 42 . 10258–64 . 1992 . 1384693 . 10.1021/bi00157a012 .
• Tomida Y, Terasawa M, Kobayashi R, Hidaka H . Calcyclin and calvasculin exist in human platelets . Biochem. Biophys. Res. Commun. . 189 . 3 . 1310–6 . 1992 . 1482346 . 10.1016/0006-291X(92)90216-8 .
• Ambartsumian N, Tarabykina S, Grigorian M, Tulchinsky E, Hulgaard E, Georgiev G, Lukanidin E . Characterization of two splice variants of metastasis-associated human mts1 gene . Gene . 159 . 1 . 125–30 . 1995 . 7607566 . 10.1016/0378-1119(94)00778-Q .
• 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 . 1995 . 7759097 . 10.1016/0888-7543(95)80005-7 .
• Takenaga K, Nakamura Y, Sakiyama S, Hasegawa Y, Sato K, Endo H . Binding of pEL98 protein, an S100-related calcium-binding protein, to nonmuscle tropomyosin . J. Cell Biol. . 124 . 5 . 757–68 . 1994 . 8120097 . 2119958 . 10.1083/jcb.124.5.757 .
• Pedrocchi M, Schäfer BW, Durussel I, Cox JA, Heizmann CW . Purification and characterization of the recombinant human calcium-binding S100 proteins CAPL and CACY . Biochemistry . 33 . 21 . 6732–8 . 1994 . 8204608 . 10.1021/bi00187a045 .
• 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 . Proc. Natl. Acad. Sci. U.S.A. . 90 . 14 . 6547–51 . 1993 . 8341667 . 46969 . 10.1073/pnas.90.14.6547 . 1993PNAS...90.6547E . free .
• Ford HL, Silver DL, Kachar B, Sellers JR, Zain SB . Effect of Mts1 on the structure and activity of nonmuscle myosin II . Biochemistry . 36 . 51 . 16321–7 . 1997 . 9405067 . 10.1021/bi971182l .
• Liu JH, Wei S, Burnette PK, Gamero AM, Hutton M, Djeu JY . Functional association of TGF-beta receptor II with cyclin B . Oncogene . 18 . 1 . 269–75 . 1999 . 9926943 . 10.1038/sj.onc.1202263 . free .
• Wang G, Rudland PS, White MR, Barraclough R . Interaction in vivo and in vitro of the metastasis-inducing S100 protein, S100A4 (p9Ka) with S100A1 . J. Biol. Chem. . 275 . 15 . 11141–6 . 2000 . 10753920 . 10.1074/jbc.275.15.11141 . free .
• Tarabykina S, Kriajevska M, Scott DJ, Hill TJ, Lafitte D, Derrick PJ, Dodson GG, Lukanidin E, Bronstein I . Heterocomplex formation between metastasis-related protein S100A4 (Mts1) and S100A1 as revealed by the yeast two-hybrid system . FEBS Lett. . 475 . 3 . 187–91 . 2000 . 10869553 . 10.1016/S0014-5793(00)01652-5 . 1105525 .
• Tarabykina S, Scott DJ, Herzyk P, Hill TJ, Tame JR, Kriajevska M, Lafitte D, Derrick PJ, Dodson GG, Maitland NJ, Lukanidin EM, Bronstein IB . The dimerization interface of the metastasis-associated protein S100A4 (Mts1): in vivo and in vitro studies . J. Biol. Chem. . 276 . 26 . 24212–22 . 2001 . 11278510 . 10.1074/jbc.M009477200 . free .
• Grigorian M, Andresen S, Tulchinsky E, Kriajevska M, Carlberg C, Kruse C, Cohn M, Ambartsumian N, Christensen A, Selivanova G, Lukanidin E . Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction . J. Biol. Chem. . 276 . 25 . 22699–708 . 2001 . 11278647 . 10.1074/jbc.M010231200 . free .
• Chen H, Fernig DG, Rudland PS, Sparks A, Wilkinson MC, Barraclough R . Binding to intracellular targets of the metastasis-inducing protein, S100A4 (p9Ka) . Biochem. Biophys. Res. Commun. . 286 . 5 . 1212–7 . 2001 . 11527429 . 10.1006/bbrc.2001.5517 .
• Zhang H, Wang Z, Ding Y, Wang G, Wang X, Bartlam M, Tang H, Liu Y, Jiang F, Barraclough R, Rudland PS, Rao Z . Crystallization and preliminary crystallographic analysis of a metastasis-inducing protein, human S100A4 . Acta Crystallogr. D . 58 . Pt 1 . 127–9 . 2002 . 11752788 . 10.1107/S090744490101650X . 2002AcCrD..58..127Z .

Notes and References

1. Stoler A, Bouck N . Identification of a single chromosome in the normal human genome essential for suppression of hamster cell transformation . Proc. Natl. Acad. Sci. U.S.A. . 82 . 2 . 570–4 . March 1985 . 3155863 . 397082 . 10.1073/pnas.82.2.570 . 1985PNAS...82..570S . free .
2. Web site: Entrez Gene: S100A4 S100 calcium binding protein A4.
3. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
4. Wang G, Rudland PS, White MR, Barraclough R . Interaction in vivo and in vitro of the metastasis-inducing S100 protein, S100A4 (p9Ka) with S100A1 . J. Biol. Chem. . 275 . 15 . 11141–6 . April 2000 . 10753920 . 10.1074/jbc.275.15.11141 . free .
5. Hernández JL, Padilla L, Dakhel S, Coll T, Hervas R, Adan J, Masa M, Mitjans F, Martinez JM, Coma S, Rodríguez L, Noé V, Ciudad CJ, Blasco F, Messeguer R . Therapeutic targeting of tumor growth and angiogenesis with a novel anti-S100A4 monoclonal antibody. . PLOS ONE . 8. e72480. September 2013 . 9 . 24023743. 10.1371/journal.pone.0072480 . 3762817. 2013PLoSO...872480H . free .
6. Fei F, Liu K, Li C, et al. Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer. Front Oncol. 2020;10:182.
7. Wen X, Yu X, Tian Y, et al. Quantitative shear wave elastography in primary invasive breast cancers, based on collagen-S100A4 pathology, indicates axillary lymph node metastasis. Quant Imaging Med Surg. 2020;10(3):624-633.