Biology:S100-A4

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.

References

  1. ↑ "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. doi:10.1073/pnas.82.2.570. PMID 3155863. Bibcode: 1985PNAS...82..570S. 
  2. ↑ "Entrez Gene: S100A4 S100 calcium binding protein A4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6275. 
  3. ↑ "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. October 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R. 
  4. ↑ "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. doi:10.1074/jbc.275.15.11141. PMID 10753920. 
  5. ↑ "Therapeutic targeting of tumor growth and angiogenesis with a novel anti-S100A4 monoclonal antibody.". PLOS ONE 8 (9): e72480. September 2013. doi:10.1371/journal.pone.0072480. PMID 24023743. Bibcode: 2013PLoSO...872480H. 
  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.

Further reading

External links

  • Overview of all the structural information available in the PDB for UniProt: P26447 (Protein S100-A4) at the PDBe-KB.



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