S100A4 (S100 Calcium Binding Protein A4)
Metastasin-1: A key regulator of metastasis, epithelial-mesenchymal transition (EMT), and tumor progression, with emerging roles in inflammation and fibrosis.
Gene Information Card
| Symbol | S100A4 |
|---|---|
| Full Name | S100 calcium binding protein A4 |
| Gene Type | Protein coding |
| Chromosomal Location | 1q21.3 |
| NCBI Gene ID | 6275 ncbi.nlm.nih.gov/gene/6275 |
| Ensembl ID | ENSG00000196154 |
| UniProt ID | P26447 |
| OMIM ID | 114210 |
| HGNC ID | 10495 |
| Aliases | CAPL, MTS1, P9KA, 18A2, 42A, pEL98, metastasin |
Description
S100A4, also known as metastasin-1, is a member of the S100 family of EF-hand calcium-binding proteins. It is a multifunctional protein involved in the regulation of cell cycle progression, cell motility, angiogenesis, and extracellular matrix remodeling. S100A4 is a well-established promoter of tumor metastasis, primarily through its role in inducing epithelial-mesenchymal transition (EMT) and enhancing cellular invasiveness. Its expression is elevated in various cancers and is often correlated with poor patient prognosis. Beyond oncology, S100A4 also plays significant roles in inflammatory responses and fibrotic diseases.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (Metastasis) | S100A4 promotes metastasis by binding to p53, inhibiting its tumor suppressor function, and by interacting with cytoskeletal proteins like non-muscle myosin II to enhance cell motility. It also induces EMT and upregulates matrix metalloproteinases (MMPs) to facilitate invasion. | Strong evidence from numerous studies across multiple cancer types (breast, colorectal, lung, gastric, pancreatic) showing correlation with metastatic potential and poor survival. Functional studies in animal models confirm its causal role in metastasis. |
| Rheumatoid Arthritis | S100A4 is overexpressed in the synovium of rheumatoid arthritis patients. It contributes to the inflammatory process by stimulating the production of pro-inflammatory cytokines and matrix-degrading enzymes, and by promoting the invasive phenotype of synovial fibroblasts. | Evidence from clinical samples and experimental arthritis models. S100A4 expression is elevated in the inflamed synovium and its inhibition reduces joint inflammation and destruction in animal models. |
| Pulmonary Fibrosis | S100A4 is a marker of fibroblasts that have undergone a transition from epithelial cells (EMT) in the lung. It contributes to fibrosis by promoting fibroblast proliferation, migration, and myofibroblast differentiation, leading to excessive extracellular matrix deposition. | Evidence from human idiopathic pulmonary fibrosis (IPF) lung tissue and mouse models of bleomycin-induced fibrosis. S100A4+ cells are identified as a major source of myofibroblasts. |
| Liver Fibrosis | Similar to pulmonary fibrosis, S100A4 is expressed in activated hepatic stellate cells and myofibroblasts, contributing to the progression of liver fibrosis by promoting cell proliferation and matrix production. | Evidence from human liver cirrhosis samples and experimental models of liver injury. S100A4 expression correlates with the severity of fibrosis. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lymphoid tissue (spleen, lymph nodes) | Not specified | High expression in immune cells, particularly T-cells and macrophages. |
| Bone marrow | Not specified | Expressed in hematopoietic progenitor cells and certain immune cell subsets. |
| Lung | Not specified | Expressed in fibroblasts and immune cells; elevated in fibrotic conditions. |
| Breast | Not specified | Low in normal epithelium; highly expressed in tumor-associated stroma and invasive cancer cells. |
| Colon | Not specified | Low in normal mucosa; elevated in invasive carcinoma cells and tumor stroma. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| MDA-MB-231 (Breast Cancer) | Not specified | High expression; associated with highly invasive and metastatic phenotype. |
| A549 (Lung Cancer) | Not specified | Moderate expression; can be induced by TGF-β to promote EMT. |
| HCT116 (Colorectal Cancer) | Not specified | Expression is variable; linked to metastatic potential. |
| THP-1 (Monocyte/Macrophage) | Not specified | High expression; upregulated upon differentiation and activation. |
| Fibroblasts (Primary) | Not specified | Expression is low in quiescent fibroblasts but highly upregulated in activated myofibroblasts. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Not well characterized | Somatic mutations are rare in S100A4. The primary mechanism of dysregulation is transcriptional upregulation rather than mutation. | Rare | The gene is frequently overexpressed in cancers due to promoter hypomethylation and transcription factor activation (e.g., TWIST1, SNAI1), rather than through activating mutations. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations are not commonly described in human diseases. However, knockdown or knockout studies in cell lines and animal models demonstrate a significant reduction in cell motility, invasion, and metastatic potential, confirming its pro-metastatic function.
Gain of Function (GOF)
Gain-of-function is primarily achieved through transcriptional overexpression. Increased S100A4 protein levels enhance cell migration, invasion, and EMT, promoting metastasis. This is the predominant mechanism in cancer.
Dominant Negative (DN)
No dominant-negative mutations have been described for S100A4. Its function is largely dependent on its expression level and interaction with partners like p53 and myosin II.
View complete mutation data：
Gene Ontology (GO)
| • calcium ion binding | • protein homodimerization activity |
| • protein heterodimerization activity | • identical protein binding |
| • metal ion binding | • cytoskeleton organization |
| • cell migration | • epithelial to mesenchymal transition |
| • angiogenesis | • response to hypoxia |
| • positive regulation of cell population proliferation | • regulation of apoptotic process |
| • extracellular matrix organization |
Pathways
• p53 signaling pathway
• Epithelial to mesenchymal transition (EMT)
• Cytoskeletal signaling
• TGF-beta signaling pathway
• Wnt signaling pathway
Protein Summary
The S100A4 protein is a small (11.5 kDa) dimeric protein that binds calcium. Upon calcium binding, it undergoes a conformational change, exposing a hydrophobic pocket that allows it to interact with target proteins. Key targets include p53 (inhibiting its pro-apoptotic function), non-muscle myosin II (promoting cell motility), and liprin-β1 (influencing cell adhesion). Through these interactions, S100A4 regulates cell cycle progression, cytoskeletal dynamics, and cell survival, thereby driving the invasive and metastatic behavior of cancer cells. It is also secreted into the extracellular space where it can act as a cytokine to stimulate angiogenesis and recruit inflammatory cells.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| S100A4 Knockout HEK293 Cell Line | EDJ-KQ2884 | Human | 6275 | Details Get a Quote |
| S100A4 Knockout A-549 Cell Line | EDJ-KQ23944 | Human | 6275 | Details Get a Quote |
| S100A4 Knockout HCT 116 Cell Line | EDJ-KQ23945 | Human | 6275 | Details Get a Quote |
| S100A4 Knockout HeLa Cell Line | EDJ-KQ23946 | Human | 6275 | Details Get a Quote |
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