
-   Expression of S100A4 was increased during liver fibrotic stage and declined during resolution in CCl4-induced reversible liver fibrosis in rats. There was significant correlation and concordance between expression of S100A4 and serum TGF-beta1. The S100A4 protein is directly involved in the expression of the tissue degrading matrix metalloprotease MMP-13, which plays important roles in the remodeling of liver fibrosis [PMID: 26721462].
-   Basic C-terminal residue (residue 101) enhances the affinity between S100A4 and its best characterized target, a recombinant C-terminal fragment of non-muscle myosin II heavy chain isoform A (NMMHC-IIA), which promoted metastasis in a metastasis assay in rat [PMID: 18784356]. S100A4-induced invasiveness in malignant tumor cells is partially caused by down-regulation of E-cadherin [PMID: 10811984]. Potential target genes regulated by S100A4 which involves in cancer progression include EZRIN, RUNX1 and WISP1 (which were induced by S100A4), and ANXA10 and IL1RN (which were repressed by S100A4) [PMID: 16367903].
-   NF-kappaB is a central player in cancer development and progression, S100A4 activates NF-kappaB by inducing phosphorylation of IKKalpha/beta, leading to increased IkappaBalpha phosphorylation. S100A4-induced NF-kappaB activation was independent of the putative S100 protein receptor RAGE and the Ser/Thr kinases MEKK1, NIK and AKT [PMID: 20507646].

## 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].
