1. Gene Aliases

S100 Calcium Binding Protein A4, PEL98, P9KA, 18A2, FSP1, CAPL, MTS1, 42A, S100 Calcium-Binding Protein A4 (Calcium Protein, Calvasculin, Metastasin, Murine Placental Homolog), Placental Calcium-Binding Protein, Fibroblast-Specific Protein-1, Calcium Placental Protein, Murine Placental Homolog, Protein S100-A4, Metastasin 1, Protein Mts1, Calvasculin, Leukemia Multidrug Resistance Associated Protein, Malignant Transformation Suppression 1, S100 Calcium-Binding Protein A4, Metastasin

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=S100A4&keywords=S100a4]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

Interactions with text mining support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

Vitamin D receptor pathway: The vitamin D receptor (VDR, a.k.a. NR1I1) is a nuclear receptor that responds to binding of vitamin D and subsequently forms a dimer with RXR to induce transcription of its target genes. It mainly regulates genes cytochrome P450 genes involved in xenobiotic biotransformation [https://www.wikipathways.org/pathways/WP2877.html].

Wnt/beta-Catenin Signaling: The conserved Wnt/beta-Catenin pathway regulates stem cell pluripotency and cell fate decisions during development. This developmental cascade integrates signals from other pathways, including retinoic acid, FGF, TGF-beta, and BMP, within different cell types and tissues. The Wnt ligand is a secreted glycoprotein that binds to Frizzled receptors, leading to the formation of a larger cell surface complex with LRP5/6. Frizzleds are ubiquitinated by ZNRF3 and RNF43, whose activity is inhibited by R-spondin binding to LGR5/6. In this manner R-spondins increase sensitivity of cells to the Wnt ligand. Activation of the Wnt receptor complex triggers displacement of the multifunctional kinase GSK-3beta from a regulatory APC/Axin/GSK-3beta-complex. In the absence of Wnt-signal (Off-state), beta-catenin, an integral E-cadherin cell-cell adhesion adaptor protein and transcriptional co-regulator, is targeted by coordinated phosphorylation by CK1 and the APC/Axin/GSK-3beta-complex leading to its ubiquitination and proteasomal degradation through the beta-TrCP/Skp pathway. In the presence of Wnt ligand (On-state), the co-receptor LRP5/6 is brought in complex with Wnt-bound Frizzled. This leads to activation of Dishevelled (Dvl) by sequential phosphorylation, poly-ubiquitination, and polymerization, which displaces GSK-3beta from APC/Axin through an unclear mechanism that may involve substrate trapping and/ or endosome sequestration. Stablized beta-catenin is translocated to the nucleus via Rac1 and other factors, where it binds to LEF/TCF transcription factors, displacing co-repressors and recruiting additional co-activators to Wnt target genes. Additionally, beta-catenin cooperates with several other transcription factors to regulate specific targets. Importantly, researchers have found beta-catenin point mutations in human tumors that prevent GSK-3beta phosphorylation and thus lead to its aberrant accumulation. E-cadherin, APC, R-spondin and Axin mutations have also been documented in tumor samples, underscoring the deregulation of this pathway in cancer. Wnt signaling has also been shown to promote nuclear accumulation of other transcriptional regulator implicated in cancer, such as TAZ and Snail1. Furthermore, GSK-3beta is involved in glycogen metabolism and other signaling pathways, which has made its inhibition relevant to diabetes and neurodegenerative disorders [https://www.cellsignal.com/pathways/wnt-beta-catenin-signaling-pathway, PMID: 21795396, PMID: 17101323].

Regulation of NF-kappa B signaling: Nuclear factor kappa B (NF-kappa-B) is activated by a diverse range of stimuli including cytokines, ligands of pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs) in myeloid cells, antigen-activated TCR in T-cells and by DNA damage (reviewed in Yu H et al. 2020; Zhang T et al. 2021). NF-kappa-B regulates the transcription of genes that are involved in immune and inflammatory responses, cell cycle, cell proliferation and apoptosis (Bhatt D & Ghosh S 2014; Liu T et al. 2017; Yu H et al. 2020). In unstimulated cells, NF-kappaB is sequestered in the cytosol through interactions with a class of inhibitor proteins, called NF-kappaB inhibitors (IkBs, such as NFKBIA or NFKBIB) (Jacobs MD & Harrison SC 1998). IkBs mask the nuclear localization signal (NLS) of NF-kappaB preventing its nuclear translocation (Cervantes CF et al. 2011). A key event in NF-kappaB activation involves phosphorylation of IkBs by the IkB kinase (IKK) complex which consists of CHUK, IKBKB and IKBKG subunits (Israel A 2010). The activated NF-kappaB signaling is tightly controlled at multiple levels (Dorrington MG & Fraser IDC 2019; Prescott JA et al. 2021). Dysregulated NF-kappaB activity can cause tissue damage associated with inflammatory diseases and is also linked to tumorigenesis (Aggarwal BB & Sung B 2011; Liu T et al.2017; Barnabei L et al. 2021). The regulation of NF-kappaB is cell-type-, context- , and stimulus-dependent and is crucial for orchestrating specific cellular responses (Mussbacher M et al. 2019).This Reactome module describes several molecular mechanisms that regulate TLR-mediated NF-kappaB signaling at the level of the IKK signaling complex [https://reactome.org/content/detail/R-HSA-9758274, PMID: 20507646].

GO terms:

positive chemotaxis [The directed movement of a motile cell or organism towards a higher concentration of a chemical. GO:0050918]

positive regulation of canonical NF-kappaB signal transduction [Any process that activates or increases the frequency, rate or extent of a canonical NF-kappaB signaling cascade. GO:0043123]

MSigDB Signatures:

FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP: Genes up-regulated in kidney biopsies from patients with acute transplant rejection compared to the biopsies from patients with well functioning kidneys more than 1-year post transplant. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP.html]

WP_VITAMIN_D_RECEPTOR_PATHWAY: Vitamin D receptor pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_VITAMIN_D_RECEPTOR_PATHWAY.html]

HEBERT_MATRISOME_TNBC_BONE_BRAIN_LIVER_LUNG_METASTASTASES: Matrisome proteins found in significantly higher abundance in TNBC brain, bone, liver and lung metastatases compared to normal samples. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/HEBERT_MATRISOME_TNBC_BONE_BRAIN_LIVER_LUNG_METASTASTASES.html]

LINDGREN_BLADDER_CANCER_CLUSTER_1_DN: Down-regulated genes whose expression profile is specific to Custer I of urothelial cell carcinoma (UCC) tumors. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/LINDGREN_BLADDER_CANCER_CLUSTER_1_DN.html]

NABA_SECRETED_FACTORS: Genes encoding secreted soluble factors [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NABA_SECRETED_FACTORS.html]

ZHAN_V1_LATE_DIFFERENTIATION_GENES_UP: The v1LDG up-regulated set: most variable late differentiation genes (LDG) with similar expression patterns in tonsil plasma cells (TPC) and multiple myeloma (MM) samples. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ZHAN_V1_LATE_DIFFERENTIATION_GENES_UP.html]

CHICAS_RB1_TARGETS_CONFLUENT: Genes up-regulated in confluent IMR90 cells (fibroblast) after knockdown of RB1 [GeneID=5925] by RNAi. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/CHICAS_RB1_TARGETS_CONFLUENT.html]

NAKAYAMA_SOFT_TISSUE_TUMORS_PCA1_UP: Top 100 probe sets contrubuting to the positive side of the 1st principal component; predominantly associated with spindle cell and pleomorphic sarcoma samples. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NAKAYAMA_SOFT_TISSUE_TUMORS_PCA1_UP.html]

7. Gene Descriptions

NCBI Gene Summary: 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. [provided by RefSeq, Jul 2008]

GeneCards Summary: S100A4 (S100 Calcium Binding Protein A4) is a Protein Coding gene. Diseases associated with S100A4 include Follicular Adenoma and Epidermoid Cysts. Among its related pathways are Vitamin D receptor pathway and Ca, cAMP and Lipid Signaling. Gene Ontology (GO) annotations related to this gene include RNA binding and identical protein binding. An important paralog of this gene is S100A2.

UniProtKB/Swiss-Prot Summary: Calcium-binding protein that plays a role in various cellular processes including motility, angiogenesis, cell differentiation, apoptosis, and autophagy [PMID: 16707441, PMID: 23752197, PMID: 30713770]. Increases cell motility and invasiveness by interacting with non-muscle myosin heavy chain (NMMHC) IIA/MYH9 [PMID: 16707441]. Mechanistically, promotes filament depolymerization and increases the amount of soluble myosin-IIA, resulting in the formation of stable protrusions facilitating chemotaxis. Modulates also the pro-apoptotic function of TP53 by binding to its C-terminal transactivation domain within the nucleus and reducing its protein levels [PMID: 23752197]. Within the extracellular space, stimulates cytokine production including granulocyte colony-stimulating factor and CCL24 from T-lymphocytes. In addition, stimulates T-lymphocyte chemotaxis by acting as a chemoattractant complex with PGLYRP1 that promotes lymphocyte migration via CCR5 and CXCR3 receptors [PMID: 30713770, PMID: 26654597].

8. Cellular Location of Gene Product

Distinct expression in infiltrating immune cells in all tissues. Highest levels in urinary bladder, lymphoid tissues and lung. Mainly localized to the nucleoplasm. In addition localized to the cytosol. Predicted location: Secreted, Intracellular (different isoforms) [https://www.proteinatlas.org/ENSG00000196154/subcellular]

9. Mechanistic Information

Summary

S100A4, a calcium-binding protein, is involved in the regulation of cell motility, angiogenesis, differentiation, apoptosis, and autophagy [CS: 9]. It facilitates cell motility by interacting with non-muscle myosin heavy chain IIA (MYH9) [CS: 8] and modulates apoptosis by binding to TP53 [CS: 7]. Additionally, by forming a complex with PGLYRP1, it can act as a chemoattractant to promote T-lymphocyte migration [CS: 5]. Under conditions of cellular stress or toxicity, S100A4's upregulation activates mechanisms aimed at cellular repair and survival, such as promoting the motility of cells necessary for tissue regeneration [CS: 8] or modulating cell death pathways to manage tissue damage [CS: 7].

In kidney pathologies, S100A4's response to injury or stress involves mechanisms that act to restore renal function and structure [CS: 8]. In diabetic nephropathy, S100A4's upregulation appears to induce epithelial-mesenchymal transition in podocytes, an attempt to facilitate cell migration and tissue repair in response to glomerular damage [CS: 6]. Additionally, the upregulation of S100A4 during osmotic stress implies its participation in cellular responses aimed at surviving and adapting to hypertonic environments, potentially through actions on cell differentiation and survival pathways [CS: 6]. These instances of S100A4 dysregulation illustrate the cellular attempt to counteract initial toxic events, such as podocyte detachment and osmotic imbalance, by utilizing the protein's various functions to maintain or restore kidney integrity [CS: 7].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: bone marrow (tissue enhanced) [https://www.proteinatlas.org/ENSG00000196154/tissue]

Cell type enchanced: granulocytes, hofbauer cells, kupffer cells, langerhans cells, macrophages, monocytes, t-cells (cell type enhanced) [https://www.proteinatlas.org/ENSG00000196154/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: