S100A4

Fig1. Biological processes associated with S100A4. (Kjetil Boye, 2010)

What is S100A4 protein?

S100A4 (S100 calcium binding protein A4) gene is a protein coding gene which situated on the long arm of chromosome 1 at locus 1q21. 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. The S100A4 protein is consisted of 101 amino acids and its molecular mass is approximately 11.7 kDa.

What is the function of S100A4 protein?

S100A4 protein is a secreted protein belonging to the S100 protein family. It is involved in a variety of cellular processes, such as cell growth, differentiation, apoptosis, inflammation and so on. In particular, the S100A4 protein plays an important role in the development and progression of tumors. It can promote the invasion and metastasis of tumor cells, inhibit the apoptosis of tumor cells, and participate in the regulation of tumor microenvironment.

S100A4 Related Signaling Pathway

The S100A4 protein, also known as Metastasin-1 or Mts1, It activates MAPK (mitogen-activated protein kinase), NF-κB (nuclear factor κB) and other signaling pathways by interacting with the Receptor for Advanced Glycation End products (RAGE), and affects a variety of cell functions. In addition, S100A4 affects the function of downstream effectors such as Calmodulin kinase, calmodulin, and calcium/calmodulin dependent protein kinase II (CaMKII) by regulating intracellular calcium ion concentration. It also interacts with actin and other cytoskeleton-associated proteins and is involved in cytoskeletal recombination and cell motility. S100A4 may also affect cell cycle regulation and apoptosis.

Fig2. Silencing of S100A4 downregulated the PI3K/Akt/mTOR pathway, enhanced autophagy, and promoted wound healing of rabbit cornea after alkali burn. (Yulin Wang, 2020)

S100A4 Related Diseases

S100A4 plays an important role in tumor invasion and metastasis and is considered to be a marker of malignant transformation and poor prognosis. In addition, S100A4 is also associated with a variety of diseases such as inflammatory diseases, bone diseases, cardiovascular diseases, and neurological diseases, and further affects the development and progression of diseases by participating in biological processes such as cell proliferation, migration, and apoptosis.

Bioapplications of S100A4

S100A4's role in promoting tumor growth and metastasis makes it a potential target for cancer therapy. The development of small molecule inhibitor or antibody drugs targeting S100A4 can help inhibit the proliferation and aggressiveness of cancer cells.

Case study 1: Yana Qi, 2022

Metastasis is the major cause of cancer-related mortalities. A tumor-supportive microenvironment, also known as the premetastatic niche at secondary tumor sites, plays a crucial role in metastasis. Remodeling of the extracellular matrix (ECM) is essential for premetastatic niche formation, especially for circulating tumor cell colonization. However, the underlying molecular mechanism that contributes to this effect remains unclear. Here, the researchers developed a lung metastasis model with 4T1 breast cancer cells and found that the metastasis critically depended on the early recruitment of macrophages to the lung. Disruption of macrophage recruitment reduced fibroblast activation and lung metastasis. Furthermore, they identified the secreted protein S100A4, which is produced by M2 macrophages and participates in fibroblast activation and ECM protein deposition via the ERK signaling pathway. Collectively, these results indicate that recruiting S100A4-expressing inflammatory macrophages plays a vital role in ECM remodeling in the premetastatic niche and may act as a potential therapeutic target for breast cancer lung metastasis.

Fig1. L929 cells were treated with rS100A4 at different concentrations, and the protein levels of α-SMA and fibronectin were assessed via western blotting.

Fig2. The migration ability of the control and rS100A4-treated groups was evaluated by Transwell assays (∗P < 0.05).

Case study 2: Anfei Liu, 2023

Lung metastasis is the leading cause of breast cancer-related death. The tumor microenvironment contributes to the metastatic colonization of tumor cells in the lungs. Tumor secretory factors are important mediators for the adaptation of cancer cells to foreign microenvironments. Here, the researchers report that tumor-secreted stanniocalcin 1 (STC1) promotes the pulmonary metastasis of breast cancer by enhancing the invasiveness of tumor cells and promoting angiogenesis and lung fibroblast activation in the metastatic microenvironment. The results show that STC1 modifies the metastatic microenvironment through its autocrine action on breast cancer cells. Specifically, STC1 upregulates the expression of S100 calcium-binding protein A4 (S100A4) by facilitating the phosphorylation of EGFR and ERK signaling in breast cancer cells. S100A4 mediates the effect of STC1 on angiogenesis and lung fibroblasts. Importantly, S100A4 knockdown diminishes STC1-induced lung metastasis of breast cancer. Moreover, activated JNK signaling upregulates STC1 expression in breast cancer cells with lung-tropism.

Fig3. Western blot analysis and the quantification of S100A4 of MDA-MB-231 cells with or without 1-h pretreatment with 100 ng/mL of rhSTC1.

Fig4. Validation of S100A4 knockdown and overexpression in human breast cancer cell lines, MDA-MB-231-STC1 and LM2-shSTC1, by Western blot analyses.

S100A4 has several biochemical functions, for example, RAGE receptor binding,actin binding,calcium ion binding. Some of the functions are cooperated with other proteins, some of the functions could acted by S100A4 itself. We selected most functions S100A4 had, and list some proteins which have the same functions with S100A4. You can find most of the proteins on our site.

S100A4 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with S100A4 here. Most of them are supplied by our site. Hope this information will be useful for your research of S100A4.

TP53;S100B;MDM2;AREGB;BTC