Affinage

S100A4

Protein S100-A4 · UniProt P26447

Length
101 aa
Mass
11.7 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

S100A4 is a small, homodimeric EF-hand protein that binds two Ca2+ ions per monomer with low affinity and cooperativity, undergoing a Ca2+-induced conformational change but not heterodimerizing with S100B (PMID:8204608, PMID:8034656). Intracellularly, it acts on the cytoskeleton through Ca2+-dependent association with nonmuscle tropomyosin and with nonmuscle myosin-IIA, with which it co-localizes in microfilament structures (PMID:8120097, PMID:11527429); binding to myosin-IIA limits filament self-assembly, and this activity is modulated by heterocomplex formation with S100A1 (PMID:10753920, PMID:15608682). Through control of myosin-IIA dynamics S100A4 governs cell motility and protrusion stability, driving macrophage chemotaxis, podosome-mediated matrix degradation, and invasion (PMID:7928629, PMID:20519440, PMID:29282275). S100A4 is a direct determinant of metastatic potential: gain-of-function transfection induces metastasis and cooperates with the Neu oncogene in vivo, while ribozyme or siRNA depletion suppresses metastatic colonization and MMP-9-dependent invasion (PMID:9696040, PMID:8895508, PMID:8968106, PMID:21618579). It additionally functions as a nuclear and transcriptional cofactor, binding p53 and the L-isoaspartyl methyltransferase to promote p53 degradation, and binding Smad3 in a Ca2+-dependent manner to stabilize the Smad3/Smad4 complex, potentiate TGF-β signaling, and drive fibroblast activation and fibrosis (PMID:11527429, PMID:28530639, PMID:20070253, PMID:36078170). Upon secretion, extracellular S100A4 signals chiefly through the RAGE and TLR4 receptors to activate NF-κB, STAT3, AKT, ERK1/2, and Wnt/β-catenin pathways, thereby promoting smooth muscle phenotypic transition, angiogenesis, autophagy suppression, cell survival, and tissue fibrosis across vascular, cardiac, pulmonary, renal, and tendon contexts (PMID:33135065, PMID:29449540, PMID:34035222, PMID:27721024, PMID:31124787, PMID:16002749). Its expression is set by transcriptional inputs including a GC-factor repressor element, NFAT5, and serotonin-driven GATA-4 signaling (PMID:9242709, PMID:25152734, PMID:16002749).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1992 Medium

    Establishing that S100A4 is actively secreted answered whether this intracellular protein has an extracellular life, opening the door to receptor-mediated signaling models.

    Evidence Immunofluorescence of secretory distribution and Ca2+-dependent solid-phase binding to microfibril-associated glycoprotein in smooth muscle cells and fibroblasts

    PMID:1512251

    Open questions at the time
    • No receptor identified at this stage
    • Functional consequence of secretion not addressed
  2. 1994 High

    Biochemical characterization defined S100A4 as a low-affinity Ca2+-binding homodimer that does not heterodimerize with S100B, establishing it as a distinct Ca2+ sensor whose targets change with Ca2+ occupancy.

    Evidence Recombinant protein, equilibrium/flow dialysis, fluorescence spectroscopy, multimerization analysis

    PMID:8034656 PMID:8204608

    Open questions at the time
    • Physiological Ca2+ thresholds in cells unresolved
    • Identity of intracellular target polypeptides not defined here
  3. 1994 High

    Identifying tropomyosin and actin co-localization gave the first cytoskeletal targets, framing S100A4 as a Ca2+-dependent regulator of the actomyosin system.

    Evidence GST pulldown with mapped TM2 binding site, competition, fractionation, and immunofluorescence in NIH 3T3 cells

    PMID:8034656 PMID:8120097

    Open questions at the time
    • Functional effect of tropomyosin binding on filaments untested
    • Later SPR found no direct actin/tropomyosin binding, indicating context dependence
  4. 1994 Medium

    Demonstrating that S100A4 expression is sufficient to promote motility connected the cytoskeletal binding activity to a metastasis-relevant phenotype.

    Evidence Phagokinesis track assay with cDNA overexpression and cross-cell-line correlation

    PMID:7928629

    Open questions at the time
    • Molecular intermediary between S100A4 and motility not defined
    • In vivo relevance not yet tested
  5. 1998 High

    In vivo transfection and oncogene-cooperation studies established S100A4 as a causal metastasis-inducing gene rather than a correlate.

    Evidence Gene transfection into benign rat mammary cells with dose-dependent in vivo metastasis; MMTV-neu transgenic cross

    PMID:8895508 PMID:8968106 PMID:9696040

    Open questions at the time
    • Mechanism distinguishing high- vs low-expressing clones unresolved
    • Did not separate intracellular from secreted contributions
  6. 2001 Medium

    Direct affinity measurements identified myosin and p53 as preferred S100A4 partners, shifting the model toward both cytoskeletal and transcriptional/apoptotic regulation.

    Evidence Surface plasmon resonance with recombinant proteins and negative controls (actin, tropomyosin, tubulin)

    PMID:11527429

    Open questions at the time
    • Cellular consequence of p53 binding not addressed
    • Discrepancy with earlier tropomyosin/actin binding unexplained
  7. 2000 High

    Discovering the S100A4–S100A1 heterocomplex revealed an endogenous brake on S100A4's myosin-modulating and metastatic activities.

    Evidence Yeast two-hybrid, dimerization-residue mutagenesis, FRET in living cells, in vitro myosin assay, soft agar and in vivo metastasis assays

    PMID:10753920 PMID:15608682

    Open questions at the time
    • Regulation of heterocomplex formation in vivo unknown
    • Stoichiometry in cells not defined
  8. 2005 Medium

    Defining the serotonin/5-HT1B/SERT/ERK/GATA-4 axis explained how S100A4 transcription is induced and linked it to autocrine RAGE signaling in pulmonary vascular cells.

    Evidence Pharmacological inhibition, SERT siRNA, qPCR, ELISA, proliferation/migration assays in HPASMCs

    PMID:16002749

    Open questions at the time
    • Direct GATA-4 binding to the S100A4 promoter not shown
    • RAGE engagement inferred pharmacologically
  9. 2010 High

    Knockout macrophage studies mechanistically tied S100A4 loss to myosin-IIA overassembly and defective chemotaxis, grounding its motility role in a defined cell type and target.

    Evidence S100A4-/- bone marrow macrophages, in vivo recruitment, chemotaxis and myosin assembly assays

    PMID:20519440

    Open questions at the time
    • CSF-1R signaling alteration mechanism incomplete
    • Intracellular vs secreted contribution to recruitment not separated
  10. 2010 Medium

    Identification of Ca2+-dependent Smad3 binding established S100A4 as a TGF-β pathway amplifier driving MMP-9 expression and invasion.

    Evidence Co-IP with Ca2+-dependence, Smad reporter assays, siRNA, MMP-9 ELISA, Boyden chamber invasion

    PMID:20070253

    Open questions at the time
    • Structural basis of Smad3 N-terminal binding not resolved
    • Single-lab Co-IP without reciprocal genetic validation
  11. 2013 High

    Bone phenotyping showed S100A4 is required for functional osteoclastogenesis, extending its motility/adhesion role to physiological bone remodeling.

    Evidence S100A4-KO mice and shRNA knockdown with pQCT, histomorphometry, TRAP and differentiation assays

    PMID:23830916

    Open questions at the time
    • Whether effect is intracellular or secreted not resolved
    • Receptor mediating osteoclast effects not identified
  12. 2016 High

    Cross-species and cardiac/endothelial studies placed S100A4 in stress-kinase and survival signaling, defining MMP1/JNK, AKT/VEGF, and RAGE-dependent barrier disruption as downstream effectors.

    Evidence Drosophila JNK/MMP1 epistasis; cardiac KO and myocyte-specific overexpression with MI models; endothelial TEER and sRAGE inhibition with intracardiac metastasis

    PMID:27387233 PMID:27721024 PMID:27927689

    Open questions at the time
    • Context-specific switch between pro-survival and pro-metastatic outputs unexplained
    • Receptor coupling to AKT vs JNK not unified
  13. 2017 High

    Resolving two independent macrophage invasion pathways and a nuclear S100A4–methyltransferase–p53 axis clarified that S100A4 acts through both myosin-dependent and myosin-independent and nuclear mechanisms.

    Evidence S100A4-/- macrophage podosome and microtubule acetylation assays; IPF MPC co-IP with L-isoaspartyl methyltransferase, p53 degradation, gain-of-function, bleomycin in vivo model

    PMID:28530639 PMID:29282275

    Open questions at the time
    • How microtubule acetylation is controlled by S100A4 mechanistically unknown
    • Direct enzymatic link between the methyltransferase and p53 stability not fully defined
  14. 2018 Medium

    Receptor-resolved studies established RAGE/Wnt-β-catenin, TLR4/ERK/caspase-9, and NRG/ErbB4 as distinct extracellular S100A4 signaling routes controlling autophagy, immune-cell survival, and neuroprotection.

    Evidence RAGE inhibitor (FPS-ZM1) and KO autophagy tumor model; TLR4/ERK1/2 MDSC apoptosis in KO mice; ErbB4 knockdown/blockade in dopaminergic neuron models

    PMID:29449540 PMID:29556233 PMID:30083275

    Open questions at the time
    • Which receptor dominates in a given tissue not defined
    • Binding affinities to ErbB1/3/4 not quantified relative to RAGE/TLR4
  15. 2022 High

    Mechanistic dissection in fibrosis, atherosclerosis, and HCC unified S100A4's secreted role: oligomeric S100A4 signals via TLR4/NF-κB and RAGE to drive SMC phenotype switching, fibroblast activation through Smad3/Smad4 stabilization, and metastatic niche formation via exosomal STAT3/OPN.

    Evidence Oligomeric S100A4 + PDGF-BB on SMCs with NF-κB reporter and ApoE-/- neutralization; S100A4–Smad3 Co-IP with niclosamide in folic-acid nephropathy; exosomal S100A4 STAT3/OPN in HCC xenografts

    PMID:33135065 PMID:34035222 PMID:34145030 PMID:36078170

    Open questions at the time
    • Oligomeric state required for receptor engagement in vivo not fully defined
    • Whether the same secreted pool drives Smad3 stabilization and TLR4 signaling unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single Ca2+-binding protein partitions between distinct intracellular partners (myosin-IIA, p53, Smad3) and multiple extracellular receptors (RAGE, TLR4, ErbB family) to produce context-specific outcomes.
  • No structural model reconciling diverse partner binding to the dimer
  • Mechanism and regulation of S100A4 secretion not defined
  • Receptor selectivity by oligomeric state untested side by side

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005576 extracellular region 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-168256 Immune System 3
Partners
AGERERBB4MYH9S100A1SMAD3TLR4TP53TPM2

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 S100A4 (pEL98) binds nonmuscle tropomyosin isoform 2 (TM2) in a Ca2+-dependent manner; the binding site was mapped to residues 39–107 on TM2, and some S100A4 co-localizes with nonmuscle tropomyosins in microfilament bundles of NIH 3T3 cells. GST pulldown with Ca2+-dependence assay, competition with free TM2, affinity chromatography, partial amino acid sequencing, immunofluorescence co-localization, cell fractionation (Triton-soluble vs. insoluble) The Journal of cell biology High 8120097
1994 Recombinant rat S100A4 (p9Ka) forms multimers in vitro (not via disulfide bonds), binds 2 mol Ca2+/mol protein (antagonized by mono- and divalent cations), and binds to at least two intracellular polypeptides in mammary cell extracts. Immunofluorescence shows co-localization with actin filaments. Recombinant protein characterization, equilibrium dialysis, gel overlay / affinity binding assay, immunofluorescence The Journal of biological chemistry High 8034656
1992 S100A4 (calvasculin) is secreted by smooth muscle cells and fibroblasts in culture and binds the extracellular 36-kDa microfibril-associated glycoprotein (MAP) in a Ca2+-dependent manner; stoichiometry ~2.2 calvasculin/mol MAP. Immunofluorescence demonstrating granular (secretory) distribution, Ca2+-dependent solid-phase binding assay, stoichiometry analysis The Journal of biological chemistry Medium 1512251
1994 S100A4 (pEL98) expression level correlates with and is sufficient to promote cell motility and tumor cell invasiveness; transfection of pEL98 cDNA into low-motility cells directly increases motility. phagokinesis cell-track assay, cDNA transfection overexpression, Northern/Western blot correlation across cell lines Japanese journal of cancer research : Gann Medium 7928629
1998 Human S100A4 possesses metastasis-inducing capability: transfection into benign rat mammary Rama 37 cells induced metastasis in vivo only in clones expressing high levels of human S100A4, not in clones with undetectable expression. Gene transfection, in vivo metastasis assay in syngeneic rats, immunocytochemistry Oncogene High 9696040
1996 Expression of S100A4 in MMTV-neu transgenic mice cooperates with the Neu oncogene to induce macroscopic lung metastases; primary and secondary lesions express S100A4, particularly at invasion fronts. Transgenic mouse cross (MMTV-neu × S100A4 transgenic), macroscopic metastasis assessment, immunohistochemistry Oncogene High 8895508
1996 Ribozyme-mediated knockdown of S100A4 (CAPL) reduces metastatic skeletal colonization of human osteosarcoma cells in vivo without affecting proliferation or tumorigenicity, establishing S100A4 as a direct determinant of metastatic potential. Hammerhead ribozyme transfection, 5'-RACE cleavage assay, intracardiac injection metastasis model in nude rats, in vivo/in vitro proliferation assays Cancer research High 8968106
2001 S100A4 binds nonmuscle myosin and p53 (wild-type and mutant arg-175-his) with significant affinity by optical biosensor measurement; S100A4 shows greater affinity for p53 than for myosin. S100A4 does not interact with actin, tropomyosin, or tubulin under these conditions. Optical biosensor (surface plasmon resonance) binding assay with recombinant proteins Biochemical and biophysical research communications Medium 11527429
2000 S100A4 interacts with S100A1 in vivo (detected by FRET in living cells) and in vitro (affinity chromatography, gel overlay); interaction is abolished by mutagenesis of conserved dimerization residues. S100A1 modulates S100A4's inhibition of nonmuscle myosin-A self-association and phosphorylation, reduces S100A4-induced motility and growth in soft agar, and attenuates metastasis in vivo. Yeast two-hybrid, site-directed mutagenesis, affinity chromatography, gel overlay, FRET in living cells, biosensor binding assay, in vitro myosin assay, soft agar assay, in vivo metastasis model The Journal of biological chemistry / Oncogene High 10753920 15608682
1994 S100A4 (calvasculin/CAPL) is a homodimeric Ca2+-binding protein with two low-affinity Ca2+-specific sites per homodimer (K0.5 ~0.15 mM, slightly cooperative); it does not form heterodimers with S100B (CACY) in vitro, and Ca2+ binding induces conformational changes. Recombinant protein expression/purification, equilibrium dialysis (flow dialysis), fluorescence spectroscopy Biochemistry High 8204608
2005 Serotonin (5-HT) elevates S100A4 mRNA and protein in human pulmonary artery smooth muscle cells via 5-HT1B receptor and SERT, requiring pERK1/2 nuclear translocation (dependent on SERT, MAO activity, and ROS) and subsequent pGATA-4-mediated transcription; secreted S100A4 then stimulates HPASMC proliferation and migration through RAGE. Cell culture, pharmacological inhibition (SB224289, fluoxetine), siRNA knockdown of SERT, qPCR, ELISA, proliferation/migration assays Circulation research Medium 16002749
2007 S100A4 protein is upregulated in hypertrophic and infarcted rat and human hearts; recombinant S100A4 elicits hypertrophic response and promotes survival (anti-apoptotic) in cardiac myocyte cultures, with ERK1/2 activation required for both hypertrophy and survival effects. qRT-PCR, immunoblotting, confocal microscopy/fractionation, recombinant protein treatment, ERK1/2 inhibition, viability assays Cardiovascular research Medium 17466960
2010 S100A4 is required for macrophage chemotaxis and recruitment to inflammation sites in vivo; S100A4-deficient bone marrow macrophages form unstable protrusions, overassemble myosin-IIA, and exhibit altered CSF-1 receptor signaling. S100A4 gene-targeted knockout mice, in vivo peritoneal recruitment assay, in vitro chemotaxis assay, myosin assembly analysis, receptor signaling assays Molecular biology of the cell High 20519440
2017 S100A4 regulates macrophage invasion through two mechanistically distinct pathways: (1) a myosin-IIA-dependent defect in podosome rosette-mediated matrix degradation and (2) a myosin-independent increase in microtubule acetylation that increases podosome rosette stability and inhibits invasion. S100A4-/- bone marrow macrophages, podosome rosette imaging, matrix degradation assay, myosin-IIA manipulation, microtubule acetylation measurement Molecular biology of the cell High 29282275
2010 S100A4 physically and functionally interacts with Smad3 in a Ca2+-dependent manner; the S100A4-binding site is in the N-terminal region of Smad3. S100A4 potentiates Smad3 (and Smad2) transcriptional activity and increases TGF-β-induced MMP-9 expression and cell invasion; siRNA depletion reverses these effects. Co-immunoprecipitation, Ca2+-dependence assay, reporter assay for Smad transcriptional activity, siRNA knockdown, MMP-9 ELISA, Boyden chamber invasion assay The Biochemical journal Medium 20070253
2017 In IPF mesenchymal progenitor cells, nuclear S100A4 interacts with L-isoaspartyl methyltransferase to promote p53 degradation and MPC self-renewal; S100A4 gain-of-function confers fibrogenic properties to non-IPF MPCs, and S100A4 is required for conversion of a self-limited to persistent bleomycin fibrosis model in vivo. Ex vivo analysis of IPF MPCs, co-IP of S100A4 with L-isoaspartyl methyltransferase, p53 degradation assay, S100A4 overexpression in non-IPF MPCs, in vivo bleomycin mouse model with human MPC injection The Journal of clinical investigation High 28530639
2018 Extracellular S100A4 inhibits autophagy and promotes tumor cell proliferation via RAGE receptor, acting through the Wnt/β-catenin pathway; RAGE-specific inhibition abolishes S100A4-mediated autophagy suppression. S100A4-deficient mice show retarded lung tumor development with increased autophagy markers. S100A4 overexpression/siRNA knockdown, autophagy markers (LC3-II), β-catenin measurement, RAGE inhibitor (FPS-ZM1), S100A4-/- mouse tumor model Cell death & disease Medium 29449540
2018 S100A4 protects myeloid-derived suppressor cells from intrinsic apoptosis via TLR4/ERK1/2 signaling-dependent caspase-9 inhibition; S100A4-/- mice have reduced peripheral MDSCs and spontaneously reject tumors. S100A4-/- tumor models, MDSC isolation and apoptosis assays, TLR4 and ERK1/2 pathway analysis, caspase-9 activity measurement Frontiers in immunology Medium 29556233
2021 S100A4 controls PPAR-γ upregulation in macrophages, which is required for FAO induction during M2-like protumor polarization; S100A4-deficient TAMs fail to upregulate PPAR-γ-dependent CD36, reducing FA absorption and FAO, and thereby lose protumor activity. Macrophage-specific S100A4-KO mice, whole-body KO mice, IL-4 stimulation, RNA-seq, flow cytometry, Western blot, FAO measurement, FA uptake assay Journal for immunotherapy of cancer High 34145030
2021 Exosomal S100A4 from highly metastatic HCC cells activates STAT3 phosphorylation in recipient low-metastatic cells, inducing osteopontin (OPN) transcription and promoting metastasis in vitro and in vivo. Exosome isolation, iTRAQ mass spectrometry, in vitro invasion/migration assays, xenograft in vivo metastasis, STAT3 phosphorylation assay, OPN promoter analysis Signal transduction and targeted therapy Medium 34035222
2022 S100A4 interacts with Smad3 to stabilize the Smad3/Smad4 complex and promote their nuclear translocation, thereby facilitating TGF-β1-induced fibroblast activation; pharmacological inhibition with niclosamide reduces this interaction and attenuates renal fibrosis in vivo. Co-IP (S100A4–Smad3 interaction), Smad3/Smad4 complex stability assay, nuclear translocation assay, S100A4 overexpression/knockdown in renal fibroblasts, folic acid nephropathy mouse model, niclosamide treatment Cells High 36078170
2022 Extracellular oligomeric S100A4 induces NF-κB activation and, together with PDGF-BB, drives smooth muscle cell phenotypic transition to a pro-inflammatory synthetic phenotype via toll-like receptor-4; neutralization of extracellular S100A4 in a mouse atherosclerosis model decreases plaque area, necrotic core, and macrophage content while increasing contractile markers. Recombinant oligomeric S100A4 treatment of SMCs, NF-κB reporter assay, RNA-seq, TLR4 signaling assay, ApoE-/- atherosclerosis mouse model with neutralizing antibody Cardiovascular research High 33135065
2018 S100A4 neuroprotection involves signaling through ErbB4 and its ligand Neuregulin-1: neuroprotective effect requires ErbB4 expression and ErbB2/Akt signaling, and is reduced by functional blockade of NRG/ErbB4. S100A4 also binds ErbB1 (EGFR) and ErbB3. ErbB4 knockdown/overexpression, pharmacological ErbB blockade, binding assays, primary and immortalized dopaminergic neuron cell death models Theranostics Medium 30083275
2016 S100A4 elevation in Drosophila promotes metastatic dissemination of RasV12-induced tumors via activation of the stress kinase JNK and upregulation of MMP1; genetic and chemical blockade of JNK or MMP1 suppresses S100A4-mediated metastasis in this model. Drosophila genetic model (RasV12 + S100A4 overexpression), JNK reporter assay, MMP1 measurement, genetic epistasis (loss-of-function of JNK and MMP1) Cancer research Medium 27927689
2013 S100A4 deficiency increases trabecular and cortical bone mass in mice; S100A4-deficient osteoclasts are small with few nuclei and pseudopodial processes, have low surface integrins, poor adhesion capacity, impaired multinucleation, and low cathepsin K and MMP3/MMP9 content, indicating S100A4 is required for functional osteoclastogenesis and bone resorption. S100A4-KO mice, shRNA lentiviral knockdown, pQCT, histomorphometry, TRAP staining, osteoclast differentiation assay, integrin surface expression Biochimica et biophysica acta High 23830916
2019 S100A4 drives fibrotic tendon healing primarily through a cell non-autonomous (paracrine/secreted) mechanism; S100A4 haploinsufficiency decreases myofibroblast and macrophage content at injury sites; S100a4-lineage cells become α-SMA+ myofibroblasts via loss of S100a4 expression; antagonism of its putative receptor RAGE also decreases scar formation. S100a4 haploinsufficient mice, lineage tracing (S100a4-Cre), RAGE antagonist treatment, immunofluorescence quantification of myofibroblasts and macrophages, biomechanical tendon testing eLife High 31124787
2014 NFAT5 transcriptionally induces S100A4 expression in renal carcinoma cells; siRNA-mediated knockdown of NFAT5 reduces S100A4 levels and is accompanied by decreased proliferation and migration of CaKi-1 cells. NFAT5 siRNA knockdown, reporter assay for NFAT5 activity, qPCR for S100A4, proliferation and migration assays Frontiers in physiology Medium 25152734
2016 S100A4 protects cardiac myocytes against ischemic injury; cardiac myocyte-specific overexpression protects infarcted myocardium, while S100A4 KO worsens outcomes with increased apoptosis, fibrosis, and reduced capillary density. S100A4 promotes survival through AKT signaling and VEGF expression. S100A4 KO mice, cardiac myocyte-specific S100A4 overexpression transgenic mice, myocardial infarction model, apoptosis assays, Western blot (AKT phosphorylation), VEGF measurement Journal of molecular and cellular cardiology High 27721024
1997 A GC-factor binding sequence ~1,300 bp upstream of the S100A4 transcription start site acts as a cis-acting transcriptional repressor in benign mammary cells (low S100A4) but not in malignant/metastatic cells (high S100A4); GC-factor mRNA levels are inversely correlated with S100A4 mRNA across mammary cell lines. Reporter gene assay, Northern blot correlation across cell lines, identification of cis-acting element The Journal of biological chemistry Medium 9242709
2007 Nuclear (but not cytoplasmic) expression of S100A4 in cholangiocarcinoma cells increases invasiveness and metastasization; siRNA silencing of S100A4 reduces motility, invasiveness, and MMP-9 secretion without affecting proliferation in EGI-1 CCA cells. siRNA knockdown, wound healing assay, Boyden chamber invasion assay, MMP-9 zymography, xenotransplantation in SCID mice with luciferase imaging, immunohistochemistry Hepatology High 21618579
2016 Extracellular S100A4 interacts with RAGE on endothelial cells to reduce endothelial integrity (decreased TEER, reduced occludin and VE-cadherin expression) and facilitates transmigration of melanoma cells; this prometastatic effect is reduced by soluble RAGE (sRAGE). TEER measurement, Western blot for junction proteins, RAGE inhibition with sRAGE, transgenic A375 cell transmigration assay, intracardiac mouse metastasis model Biochemical and biophysical research communications Medium 27387233
2011 S100A4 co-immunoprecipitates with RAGE in diabetic rat retinas; TNF-α (but not VEGF) induces upregulation of S100A4 in human retinal microvascular endothelial cells. Co-immunoprecipitation, Western blot, ELISA, immunohistochemistry, in vitro cytokine stimulation Molecular vision Low 25253987
1998 S100A4 modulates expression of matrix metalloproteinases (MMPs) and TIMPs in osteosarcoma cells: high-CAPL-expressing cells fail to upregulate MMP-1 and MMP-9 in response to bFGF or IL-1α, and high CAPL in synergy with IL-1α reduces TIMP-1 synthesis. Ribozyme-mediated CAPL knockdown cell lines, ELISA for MMP/TIMP levels, gelatin zymography, growth factor/cytokine stimulation Anticancer research Medium 9858899
2020 S100A4 promotes hepatocellular carcinoma stemness synergistically with collagen I via RAGE and β-catenin signaling; this synergy requires both S100A4 and collagen I for maximal tumor sphere formation in vitro and tumor growth in vivo. S100A4-/- mouse hepatocarcinogenesis model (DEN/CCl4), tumor sphere formation assay, RAGE inhibition, β-catenin pathway analysis, in vivo tumor growth Oncoimmunology Medium 32117590

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target. Nature communications 383 35140215
2009 S100A4 and metastasis: a small actor playing many roles. The American journal of pathology 362 20019188
2020 Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome. Nature cancer 265 35122040
2021 S100A4 enhances protumor macrophage polarization by control of PPAR-γ-dependent induction of fatty acid oxidation. Journal for immunotherapy of cancer 209 34145030
2005 The metastasis associated protein S100A4: role in tumour progression and metastasis. British journal of cancer 201 15900299
1996 Expression of the calcium-binding protein S100A4 (p9Ka) in MMTV-neu transgenic mice induces metastasis of mammary tumours. Oncogene 176 8895508
2000 Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 162 11106237
2017 S100A4 in cancer progression and metastasis: A systematic review. Oncotarget 156 29069865
2008 S100A4: a common mediator of epithelial-mesenchymal transition, fibrosis and regeneration in diseases? Journal of molecular medicine (Berlin, Germany) 153 18322670
1994 Binding of pEL98 protein, an S100-related calcium-binding protein, to nonmuscle tropomyosin. The Journal of cell biology 153 8120097
1997 Differential expression patterns of S100A2, S100A4 and S100A6 during progression of human malignant melanoma. International journal of cancer 149 9291441
2007 S100A4 is upregulated in injured myocardium and promotes growth and survival of cardiac myocytes. Cardiovascular research 129 17466960
1996 Reversal of the in vivo metastatic phenotype of human tumor cells by an anti-CAPL (mts1) ribozyme. Cancer research 128 8968106
2005 Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease. Circulation research 125 16002749
1997 Increased expression of S100A4, a metastasis-associated gene, in human colorectal adenocarcinomas. Clinical cancer research : an official journal of the American Association for Cancer Research 124 9815629
1998 Calcium-binding protein S100A4 in health and disease. Biochimica et biophysica acta 121 9920410
2010 S100A4 regulates macrophage chemotaxis. Molecular biology of the cell 118 20519440
2003 Differential expression of S100A2 and S100A4 during progression of human prostate adenocarcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 112 12506178
1998 Human S100A4 (p9Ka) induces the metastatic phenotype upon benign tumour cells. Oncogene 104 9696040
1987 Molecular cloning and sequence of the gene for p9Ka. A cultured myoepithelial cell protein with strong homology to S-100, a calcium-binding protein. Journal of molecular biology 103 3430604
2021 Exosomal S100A4 derived from highly metastatic hepatocellular carcinoma cells promotes metastasis by activating STAT3. Signal transduction and targeted therapy 102 34035222
1998 S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis. Anticancer research 94 9703888
2019 The Multifaceted S100A4 Protein in Cancer and Inflammation. Methods in molecular biology (Clifton, N.J.) 93 30710284
1994 Involvement of S100-related calcium-binding protein pEL98 (or mts1) in cell motility and tumor cell invasion. Japanese journal of cancer research : Gann 92 7928629
2017 Role of metastasis-induced protein S100A4 in human non-tumor pathophysiologies. Cell & bioscience 89 29204268
2007 Metastasis-associated protein S100A4: spotlight on its role in cell migration. Current cancer drug targets 89 17504119
1992 S100 alpha, CAPL, and CACY: molecular cloning and expression analysis of three calcium-binding proteins from human heart. Biochemistry 89 1384693
2016 S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction. Cancers 84 27331819
2005 S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma. British journal of cancer 83 16265347
2017 Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis. The Journal of clinical investigation 79 28530639
2008 Metastasis promoter S100A4 is a potentially valuable molecular target for cancer therapy. Cancer letters 78 19059703
2004 Expression of S100A4 and Met: potential predictors for metastasis and survival in early-stage breast cancer. Oncology 76 15452371
2011 Nuclear expression of S100A4 calcium-binding protein increases cholangiocarcinoma invasiveness and metastasization. Hepatology (Baltimore, Md.) 73 21618579
2002 S100A4 (p9Ka) protein in colon carcinoma and liver metastases: association with carcinoma cells and T-lymphocytes. British journal of cancer 72 11875708
2001 Binding to intracellular targets of the metastasis-inducing protein, S100A4 (p9Ka). Biochemical and biophysical research communications 72 11527429
2002 Expression of S100A4, E-cadherin, alpha- and beta-catenin in breast cancer biopsies. British journal of cancer 71 12439718
2004 Expression of S100A4 combined with reduced E-cadherin expression predicts patient outcome in malignant melanoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 69 15133476
2020 Extracellular S100A4 as a key player in fibrotic diseases. Journal of cellular and molecular medicine 67 32307910
2000 Interaction in vivo and in vitro of the metastasis-inducing S100 protein, S100A4 (p9Ka) with S100A1. The Journal of biological chemistry 66 10753920
1994 Purification and characterization of the recombinant human calcium-binding S100 proteins CAPL and CACY. Biochemistry 61 8204608
1995 Immunocytochemical distribution of the calcium-binding protein p9Ka in normal rat tissues: variation in the cellular location in different tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 60 7822773
1980 The gross anatomy of a tRNA gene cluster at region 42A of the D. melanogaster chromosome. Cell 59 6253076
2019 Cell non-autonomous functions of S100a4 drive fibrotic tendon healing. eLife 58 31124787
1994 Cellular localization of pEL98 protein, an S100-related calcium binding protein, in fibroblasts and its tissue distribution analyzed by monoclonal antibodies. Cell structure and function 57 7954872
2014 NFAT5-mediated expression of S100A4 contributes to proliferation and migration of renal carcinoma cells. Frontiers in physiology 56 25152734
1994 Interactions in vitro of p9Ka, the rat S-100-related, metastasis-inducing, calcium-binding protein. The Journal of biological chemistry 56 8034656
1992 Isolation and characterization of a calcium-binding protein derived from mRNA termed p9Ka, pEL-98, 18A2, or 42A by the newly synthesized vasorelaxant W-66 affinity chromatography. Archives of biochemistry and biophysics 56 1731618
2024 METTL14 downregulation drives S100A4+ monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression. Signal transduction and targeted therapy 55 38627387
2018 S100A4 promotes lung tumor development through β-catenin pathway-mediated autophagy inhibition. Cell death & disease 51 29449540
2010 Significance of the S100A4 protein in psoriasis. The Journal of investigative dermatology 50 19641515
2007 Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer. Urology 46 17688917
1992 Calvasculin, an encoded protein from mRNA termed pEL-98, 18A2, 42A, or p9Ka, is secreted by smooth muscle cells in culture and exhibits Ca(2+)-dependent binding to 36-kDa microfibril-associated glycoprotein. The Journal of biological chemistry 46 1512251
2007 Hypomethylation-induced expression of S100A4 in endometrial carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 45 17673926
1998 Expression of metastasis-associated genes h-mts1 (S100A4) and nm23 in carcinoma of breast is related to disease progression. DNA and cell biology 45 9570150
2014 S100A4 is upregulated in proliferative diabetic retinopathy and correlates with markers of angiogenesis and fibrogenesis. Molecular vision 44 25253987
2008 Metastasis-inducing S100A4 protein: implication in non-malignant human pathologies. Current molecular medicine 44 18781956
2005 Mutually antagonistic actions of S100A4 and S100A1 on normal and metastatic phenotypes. Oncogene 44 15608682
2010 Functional interaction between Smad3 and S100A4 (metastatin-1) for TGF-beta-mediated cancer cell invasiveness. The Biochemical journal 43 20070253
1991 Differential regulation of S100 beta and mRNAs coding for S100-like proteins (42A and 42C) during development and after lesion of rat sciatic nerve. Journal of neuroscience research 42 1890696
2018 The S100A4 Protein Signals through the ErbB4 Receptor to Promote Neuronal Survival. Theranostics 40 30083275
2021 S100A4 in the Physiology and Pathology of the Central and Peripheral Nervous System. Cells 39 33918416
2010 Expression of protein S100A4 is a predictor of recurrence in colorectal cancer. World journal of gastroenterology 37 20712050
2018 S100A4 protects mice from high-fat diet-induced obesity and inflammation. Laboratory investigation; a journal of technical methods and pathology 36 29789685
2019 Clinical relevance of circulating MACC1 and S100A4 transcripts for ovarian cancer. Molecular oncology 35 30927479
2005 S100A4 regulates E-cadherin expression in oral squamous cell carcinoma. Cancer letters 33 16297707
2000 Metastasis-associated mts1 (S100A4) protein in the developing and adult central nervous system. The Journal of comparative neurology 33 10906702
1995 Expression of the rat, S-100-related, calcium-binding protein gene, p9Ka, in transgenic mice demonstrates different patterns of expression between these two species. DNA and cell biology 33 7546288
1994 Overexpression of the 18A2/mts1 gene and down-regulation of the TIMP-2 gene in invasive human glioma cell lines in vitro. Neuropathology and applied neurobiology 33 7898625
1994 Expression of a calcium binding protein pEL98 (mts1) during differentiation of human promyelocytic leukemia HL-60 cells. Biochemical and biophysical research communications 33 8037774
2020 S100A4 promotes hepatocellular carcinogenesis by intensifying fibrosis-associated cancer cell stemness. Oncoimmunology 32 32117590
2014 S100A4 and uric acid promote mesenchymal stromal cell induction of IL-10+/IDO+ lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 32 24795458
2000 Localisation by in situ hybridisation of S100A4 (p9Ka) mRNA in primary human breast tumour specimens. International journal of cancer 31 10738249
2018 S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis. Oncoimmunology 30 30221056
2017 Smad3 and Bmal1 regulate p21 and S100A4 expression in myocardial stromal fibroblasts via TNF-α. Histochemistry and cell biology 30 28721450
2018 S100A4 Protects Myeloid-Derived Suppressor Cells from Intrinsic Apoptosis via TLR4-ERK1/2 Signaling. Frontiers in immunology 29 29556233
2016 Extracellular S100A4 affects endothelial cell integrity and stimulates transmigration of A375 melanoma cells. Biochemical and biophysical research communications 29 27387233
2006 Expression of calcium-binding proteins S100A2 and S100A4 in Barrett's adenocarcinomas. Neoplasia (New York, N.Y.) 29 17032501
2016 S100A4 protects the myocardium against ischemic stress. Journal of molecular and cellular cardiology 28 27721024
2015 Functional profile of S100A4-deficient T cells. Immunity, inflammation and disease 28 26734465
1997 Elevated expression of calcium-binding protein p9Ka is associated with increasing malignant characteristics of rat prostate carcinoma cells. International journal of cancer 28 9180153
2024 S100A4 a classical DAMP as a therapeutic target in fibrosis. Matrix biology : journal of the International Society for Matrix Biology 27 38219976
2020 Overexpression of S100A4 protects retinal ganglion cells against retinal ischemia-reperfusion injury in mice. Experimental eye research 27 33031790
2022 Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis. Cells 26 36078170
2021 Targeting S100A4 with niclosamide attenuates inflammatory and profibrotic pathways in models of amyotrophic lateral sclerosis. Journal of neuroinflammation 26 34118929
2022 Neutralization of S100A4 induces stabilization of atherosclerotic plaques: role of smooth muscle cells. Cardiovascular research 25 33135065
2016 S100A4 Elevation Empowers Expression of Metastasis Effector Molecules in Human Breast Cancer. Cancer research 25 27927689
2020 S100A4+ macrophages facilitate zika virus invasion and persistence in the seminiferous tubules via interferon-gamma mediation. PLoS pathogens 24 33315931
2017 S100A4 regulates macrophage invasion by distinct myosin-dependent and myosin-independent mechanisms. Molecular biology of the cell 24 29282275
2016 S100A4 accelerates the proliferation and invasion of endometrioid carcinoma and is associated with the "MELF" pattern. Cancer science 24 27348205
2013 Expression of metastasin S100A4 is essential for bone resorption and regulates osteoclast function. Biochimica et biophysica acta 24 23830916
2010 Small interfering RNA-directed knockdown of S100A4 decreases proliferation and invasiveness of osteosarcoma cells. Cancer letters 24 20855150
2005 S100A4 (Mts1): is there any relation to the pathogenesis of rheumatoid arthritis? Autoimmunity reviews 24 16431343
1998 Interleukin-1 alpha and basic fibroblast growth factor induction of matrix metalloproteinases and their inhibitors in osteosarcoma cells is modulated by the metastasis associated protein CAPL. Anticancer research 23 9858899
2020 The protein S100A4 as a novel marker of insulin resistance in prepubertal and pubertal children with obesity. Metabolism: clinical and experimental 22 32084430
2020 Calcium-Binding Protein S100A4 Is Upregulated in Carotid Atherosclerotic Plaques and Contributes to Expansive Remodeling. Journal of the American Heart Association 21 32914661
1994 Purification and primary structure of Capl, an S-100-related calcium-binding protein isolated from bovine retina. The Journal of biological chemistry 21 8119967
2024 ANXA9 facilitates S100A4 and promotes breast cancer progression through modulating STAT3 pathway. Cell death & disease 20 38609357
2018 Osterix promotes the migration and angiogenesis of breast cancer by upregulation of S100A4 expression. Journal of cellular and molecular medicine 20 30450809
2009 Different expression and clinical role of S100A4 in serous ovarian carcinoma at different anatomic sites. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 20 19194111
1997 Transcriptional down-regulation of the metastasis-inducing S100A4 (p9Ka) in benign but not in malignant rat mammary epithelial cells by GC-factor. The Journal of biological chemistry 20 9242709

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