{"gene":"S100A7","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":1999,"finding":"Crystal structure of human psoriasin (S100A7) determined at atomic resolution (1.05 Å) by MAD phasing using holmium substitution, revealing a dimeric EF-hand protein with a distorted N-terminal EF-hand loop lacking a crucial calcium-binding residue, indicating the protein binds only one calcium ion per monomer strongly, with no large conformational change upon calcium binding.","method":"X-ray crystallography (MAD phasing, 1.05 Å resolution)","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure with functional validation of calcium-binding properties; foundational structural paper","pmids":["9562557"],"is_preprint":false},{"year":1999,"finding":"Crystal structures of Ca2+-bound S100A7 in Zn2+-loaded and Zn2+-free states revealed a zinc-binding site formed by three histidine residues and one aspartate at the dimer interface, coordinating zinc similarly to collagenase metalloproteases. Loss of zinc causes reorganization of the adjacent EF-hand loop, making it resemble a calcium-loaded EF-hand.","method":"X-ray crystallography (two crystal forms, Zn2+-loaded and Zn2+-free)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — two independent crystal structures with and without zinc, mechanistically defining the zinc-binding site and its structural consequences","pmids":["10026247"],"is_preprint":false},{"year":2004,"finding":"Psoriasin (S100A7) is the principal E. coli-killing antimicrobial compound secreted by keratinocytes in vitro and in vivo. Zn2+-saturated psoriasin showed diminished antimicrobial activity, implicating zinc sequestration as the antibacterial mechanism. In vivo treatment with anti-psoriasin antibodies inhibited skin E. coli-killing activity.","method":"In vitro bacterial killing assay, in vivo antibody neutralization in human skin, zinc-saturation experiments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (in vitro killing, in vivo neutralization, zinc-loading experiment) in a single rigorous study; widely replicated concept","pmids":["15568027"],"is_preprint":false},{"year":2006,"finding":"S100A7 antibacterial activity against E. coli requires the central region (amino acids 35–80) and the zinc-binding motif. Mutation of the zinc-binding motif reduced antibacterial activity, but this reduction was reversed by simultaneous removal of the amino terminus, indicating the central region alone is sufficient for full activity. Protease treatment abolished activity whereas EF-hand calcium-binding motif mutation or heat denaturation had only minor effects.","method":"Recombinant protein mutagenesis, bacterial adhesion/survival assays, heat denaturation and protease treatment experiments","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with systematic mutagenesis of multiple domains; single lab but orthogonal approaches","pmids":["17159909"],"is_preprint":false},{"year":2001,"finding":"S100A7 is a substrate for both type I and type II transglutaminases, which form covalent ε-(γ-glutamyl)lysine bonds at the solvent-exposed amino- and carboxyl-terminal ends of the protein, providing a mechanism to regulate S100A7 function.","method":"In vitro transglutaminase assay with recombinant S100 proteins; biochemical characterization","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzyme assay with identification of reactive regions; single lab, multiple S100 substrates tested as controls","pmids":["11258932"],"is_preprint":false},{"year":2003,"finding":"S100A7 is present in the cytosol and endoplasmic reticulum (BiP/GRP78-positive tubular structures) in keratinocytes. Upon calcium elevation, cytoplasmic S100A7 redistributes to α-actinin- and paxillin-positive peripheral focal adhesion-like structures. S100A7 co-localizes with and co-precipitates epidermal fatty acid binding protein (E-FABP) in these structures, and S100A7 expression stabilizes E-FABP protein levels.","method":"Confocal immunofluorescence microscopy, calcium challenge experiments, cross-linker co-precipitation","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization by live/fixed imaging with calcium perturbation and co-precipitation; single lab, multiple orthogonal methods","pmids":["12839573"],"is_preprint":false},{"year":1999,"finding":"S100A7 and E-FABP form a complex in the cytosol of keratinocytes, reconstituted in vitro using purified proteins in the presence of EDTA. Complex formation is disrupted by physiological concentrations of Zn2+ (0.1 mM) but not Ca2+ or Mg2+ at physiological levels. The complex retains oleic acid-binding properties of E-FABP, whereas free S100A7 alone does not bind oleic acid. Co-immunoprecipitation confirmed the interaction in psoriatic scale extracts.","method":"Overlay assay, in vitro complex reconstitution with purified proteins, oleic acid binding assay, co-immunoprecipitation, confocal microscopy","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, zinc-dependent disruption, functional fatty acid binding assay, confirmed by co-IP in native tissue; single lab but multiple orthogonal methods","pmids":["10191275"],"is_preprint":false},{"year":2005,"finding":"S100A7 promotes survival under anchorage-independent growth in ERα-negative breast cancer cells (MDA-MB-231) by activating NF-κB (~3-fold) and phospho-Akt (~4-fold). These effects depend on a Jab1 (CSN5/COP9 signalosome subunit 5)-binding domain within S100A7, as confirmed by immunoprecipitation, yeast two-hybrid assay, and mutant S100A7 lacking the Jab1-binding site. Enhanced EGFR signaling was also found to correlate with increased phospho-Akt.","method":"Stable transfection, immunoprecipitation, yeast two-hybrid assay, reporter gene assay, Western blot, xenograft tumor model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal IP, Y2H, mutagenesis of binding domain, in vivo xenograft validation; single lab with multiple orthogonal methods","pmids":["15994944"],"is_preprint":false},{"year":2008,"finding":"S100A7 signals as a chemoattractant through RAGE (receptor for advanced glycation end products). S100A7-RAGE binding, downstream signaling, and chemotaxis are zinc-dependent in vitro, reflecting zinc-mediated changes in S100A7 dimer structure. The highly homologous S100A15 uses a distinct Gi protein-coupled receptor rather than RAGE for chemotaxis.","method":"Antibody generation, chemotaxis assays, in vitro binding assays, zinc-dependence studies, in vivo inflammation model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor identification with functional binding and signaling assays, zinc-dependence validated in vitro; confirmed by multiple labs subsequently","pmids":["18606705"],"is_preprint":false},{"year":2008,"finding":"E. coli flagellin is the principal inducer of S100A7c (psoriasin) expression in human epidermal keratinocytes, acting through TLR5. A flagellin-deficient E. coli strain (ΔFliC) did not induce S100A7c, and siRNA knockdown of TLR5 suppressed induction by both flagellin and wild-type E. coli supernatant.","method":"TLR ligand screening, flagellin-deficient bacterial mutant, siRNA knockdown of TLR5, RT-PCR and protein measurement","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (TLR5 siRNA) and bacterial mutant combined with ligand specificity screen; single lab but multiple orthogonal approaches","pmids":["18263703"],"is_preprint":false},{"year":2008,"finding":"S100A7 promotes breast cancer growth and metastasis via RAGE-dependent activation of ERK and NF-κB signaling and cell migration. In an S100A7-transgenic mouse model, RAGE neutralizing antibody or soluble RAGE inhibited tumor progression, and RAGE/S100A7 drove recruitment of MMP9-positive tumor-associated macrophages.","method":"RAGE-deficient mice, neutralizing antibody injection, soluble RAGE administration, signaling assays (ERK, NF-κB), transgenic mouse model, macrophage depletion","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic/pharmacological in vivo models, signaling mechanistic studies, macrophage depletion epistasis; replicated across labs","pmids":["25572331"],"is_preprint":false},{"year":2008,"finding":"S100A7 overexpression in ERα-negative breast cancer cells promotes cell invasion via RAGE-dependent signaling. S100A7 downregulation in MDA-MB-468 cells reduced EGF-directed migration and decreased phosphorylation of EGFR (Tyr1173), HER2 (Tyr1248), Src (Tyr416), and SHP2 (Tyr542), indicating S100A7 modulates EGF receptor signaling. S100A7 downregulation also reduced angiogenesis in vivo and osteoclast formation associated with decreased IL-8 expression.","method":"shRNA knockdown, phospho-Western blot, migration assays, Matrigel plug angiogenesis assay, intra-tibial bone injection in SCID mice","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling readouts with shRNA loss-of-function; single lab, in vitro and in vivo assays","pmids":["18320059"],"is_preprint":false},{"year":2008,"finding":"S100A7 reciprocally negatively regulates β-catenin signaling in oral squamous cell carcinoma: S100A7 associates with the β-catenin complex and promotes β-catenin degradation via a GSK3β-independent non-canonical mechanism. Conversely, β-catenin signaling negatively regulates S100A7 expression. S100A7 inhibited SCCOC cell proliferation in vitro and tumor growth/invasion in vivo.","method":"Co-immunoprecipitation, β-catenin degradation assay, tumor xenograft model, loss-of-function/gain-of-function experiments in cell lines and mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for physical interaction, in vivo model for functional consequence, reciprocal regulation demonstrated; single lab","pmids":["18223693"],"is_preprint":false},{"year":2009,"finding":"S100A7 crystal structures in complex with naphthalene-based dyes (2,6-ANS and 1,8-ANS) at 1.6 Å identified a hydrophobic binding cleft formed by the N-terminal helices of each monomer, with Met12 acting as a gatekeeper. Yeast two-hybrid mutagenesis showed that Leu78 (within the Met12 cleft), Gln88, and Asp56 contribute to Jab1 binding, linking the hydrophobic pocket to the Jab1 interaction interface.","method":"X-ray crystallography (1.6 Å), steady-state fluorescence, time-resolved fluorescence, isothermal titration calorimetry, yeast two-hybrid mutagenesis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with multiple orthogonal biophysical methods and mutational mapping of Jab1 interface; single lab","pmids":["19810752"],"is_preprint":false},{"year":2009,"finding":"S100A7 expression in primary cortico-hippocampal neuron cultures inhibits generation of Aβ1-42 and Aβ1-40 peptides coincident with selective promotion of ADAM-10-mediated non-amyloidogenic α-secretase activity. Expression of human S100A7 in transgenic mouse brains also promoted α-secretase activity.","method":"Adenoviral S100A7 overexpression in primary neuronal cultures, ELISA for Aβ peptides, α-secretase activity assay, S100A7 transgenic mice","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression in primary neurons and transgenic mice with specific enzymatic readout; single lab, two model systems","pmids":["19159013"],"is_preprint":false},{"year":2010,"finding":"S100A7 enhances macrophage chemotaxis via RAGE receptor activation in vitro. In vivo, mS100a7a15 induction in MMTV-mS100a7a15 transgenic mice enhanced breast tumor growth, metastasis, and recruitment of tumor-associated macrophages. In vivo TAM depletion inhibited the pro-tumorigenic effects of mS100a7a15 induction, establishing TAM recruitment as a key mechanism.","method":"Transgenic mouse model (MMTV-mS100a7a15), macrophage chemotaxis assay, in vivo macrophage depletion, tumor growth/metastasis quantification","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model with macrophage depletion epistasis; mechanistically defines TAM recruitment through RAGE as key effector pathway","pmids":["22158945"],"is_preprint":false},{"year":2010,"finding":"S100A7 expression in ERα-positive breast cancer cells (MCF7, T47D) suppresses migration, proliferation, and tumor growth in vivo by downregulating the β-catenin/TCF4 pathway, increasing GSK3β activity, and enhancing β-catenin/E-cadherin interaction. GSK3β inhibitor treatment reversed β-catenin suppression in S100A7-overexpressing ERα+ cells. This is opposite to its pro-tumorigenic role in ERα-negative cells.","method":"Stable overexpression, migration/proliferation assays, GSK3β inhibitor experiments, nude mouse xenograft model, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic pathway studies with in vivo xenograft validation and pharmacological rescue; single lab","pmids":["22016394"],"is_preprint":false},{"year":2011,"finding":"Extracellular psoriasin (S100A7) increases VEGF expression in mammary epithelial cells and promotes endothelial cell proliferation, tube formation, and ROS generation through RAGE. Soluble RAGE (sRAGE) inhibited psoriasin-induced endothelial proliferation, tube formation, and ROS production. Antioxidant Bcl-2 abolished psoriasin's proliferative effect on endothelial cells.","method":"Recombinant protein treatment, sRAGE blockade, shRNA knockdown, adenoviral overexpression, ROS measurement, endothelial cell proliferation/tube formation assays","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blockade with sRAGE, ROS mechanistic link, multiple cell-type assays; single lab","pmids":["22189627"],"is_preprint":false},{"year":2010,"finding":"Psoriasin (S100A7) is constitutively expressed and secreted in the vaginal epithelium and accounts for ~2.5–3% of total vaginal fluid protein. HPLC fractionation showed that psoriasin co-eluted with E. coli-killing activity of vaginal fluid, establishing it as the major E. coli-cidal factor of the female genital tract.","method":"HPLC fractionation with bacterial killing assay, organotypic vaginal epithelium model, protein quantification","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — fractionation directly coupled to functional antibacterial assay; single lab with biochemical and biological validation","pmids":["20571488"],"is_preprint":false},{"year":2010,"finding":"Psoriasin (S100A7) expression is induced by reactive oxygen species (ROS) and hypoxia in keratinocytes. Downregulation of psoriasin by siRNA reduced ROS-induced expression of VEGF, HB-EGF, MMP-1, and thrombospondin 1. Extracellular psoriasin induced endothelial cell proliferation, migration, and tube formation comparable to VEGF, with effects suggested to be mediated by PI3K and NF-κB pathways.","method":"siRNA knockdown, ROS induction, hypoxia exposure, angiogenic factor measurement, endothelial cell functional assays","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with multiple downstream angiogenic factor readouts; single lab","pmids":["27155199"],"is_preprint":false},{"year":2010,"finding":"S100A7 expression is induced by oncostatin-M (OSM) and IL-6 in breast tumor cells, dependent on STAT3, PI3K, and ERK1/2 signaling, as demonstrated by pharmacological blockade. siRNA knockdown of S100A7 eliminated the pro-migratory effects of OSM treatment, positioning S100A7 as a downstream effector of OSM/IL-6 in breast cancer cell migration.","method":"Cytokine stimulation, pathway inhibitors (STAT3, PI3K, ERK1/2), siRNA knockdown, migration assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with siRNA functional readout; single lab, multiple cell lines","pmids":["20101226"],"is_preprint":false},{"year":2012,"finding":"S100A7 promotes migration and invasion of osteosarcoma cells through RAGE. Pull-down assay confirmed direct binding of recombinant S100A7 to RAGE. siRNA knockdown of RAGE suppressed S100A7-enhanced migration, invasion, and matrix metalloproteinase activity of osteosarcoma cells.","method":"In vitro pull-down assay with recombinant proteins, siRNA knockdown of RAGE, migration/invasion assays, MMP activity measurement","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by pull-down, receptor requirement demonstrated by siRNA loss-of-function; single lab","pmids":["22783409"],"is_preprint":false},{"year":2014,"finding":"S100A7/psoriasin strengthens the tight junction (TJ) barrier of keratinocytes by selectively increasing expression of TJ proteins (claudins, occludin), enhancing transepithelial electrical resistance, and reducing paracellular permeability. This was mediated through GSK-3 and MAPK pathways, as shown by specific inhibitors. S100A7 also increased β-catenin and E-cadherin accumulation at cell-cell contacts.","method":"Western blot, RT-PCR, transepithelial electrical resistance assay, paracellular permeability assay, GSK-3 and MAPK inhibitors, immunofluorescence","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional barrier assays with pharmacological pathway dissection; single lab, multiple orthogonal readouts","pmids":["24842328"],"is_preprint":false},{"year":2016,"finding":"Extracellular S100A7 signals through RAGE to activate the MyD88-IκB/NF-κB cascade in keratinocytes, upregulating IL-6, which inhibits epidermal differentiation markers (keratin 1, keratin 10, involucrin, loricrin) and increases abnormal differentiation markers (keratin 6, keratin 16). This was confirmed in a reconstituted human epidermis model.","method":"Recombinant protein treatment, Western blot, RT-PCR, reconstituted human epidermis model, RAGE signaling pathway analysis","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor and signaling pathway identification with functional differentiation readouts in 2D and 3D models; single lab","pmids":["27060579"],"is_preprint":false},{"year":2017,"finding":"S100A7 induces mature interleukin-1α (17 kDa) expression in normal human epidermal keratinocytes via the RAGE-p38 MAPK-calpain-1 pathway; inhibitors or siRNA knockdown of each component abolished mature IL-1α induction. In imiquimod-induced psoriasis mouse model, mS100a7a15, mature IL-1α, and calpain-1 were highly co-expressed, and IL-17a neutralization attenuated mS100a7a15 expression.","method":"Recombinant protein treatment, pharmacological inhibitors, siRNA knockdown (RAGE, p38 MAPK, calpain-1), Western blot, imiquimod mouse model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and pharmacological dissection of signaling cascade with in vivo corroboration; single lab","pmids":["28060905"],"is_preprint":false},{"year":2017,"finding":"S100A7 in squamous carcinoma cells is transcriptionally regulated by Src/Stat3 signaling. Src inhibitor (SU6656) and Stat3 inhibitor (S3I-201) reduced S100A7 protein levels. Stat3 transactivated the S100A7 5'-upstream promoter region. S100A7 overexpression decreased E-cadherin and increased Twist (EMT markers), while S100A7 knockdown had opposite effects, demonstrating S100A7 as a downstream effector of Src/Stat3 promoting EMT and invasion.","method":"Pharmacological inhibitors of Src/Stat3, luciferase promoter assay, siRNA/overexpression, Western blot, Transwell invasion assay, zebrafish metastasis model","journal":"Antioxidants","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter transactivation, pharmacological and genetic loss-of-function, in vivo zebrafish model; single lab","pmids":["31731716"],"is_preprint":false},{"year":2017,"finding":"S100A7 promotes keratinocyte differentiation via the protein kinase C pathway. siRNA-mediated knockdown of psoriasin reduced expression of involucrin, desmoglein 1, transglutaminase 1, and CD24. Lentiviral overexpression of psoriasin mimicking the psoriatic milieu caused an altered differentiation gene expression pattern resembling psoriatic epidermis.","method":"siRNA knockdown, lentiviral overexpression, PKC pathway inhibitors, Western blot, immunohistochemistry","journal":"Acta dermato-venereologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and lentiviral gain/loss-of-function with multiple differentiation marker readouts; single lab","pmids":["27958610"],"is_preprint":false},{"year":2017,"finding":"Biochemical analysis showed that S100A7 exists as reduced (S100A7red, free thiols) and oxidized (S100A7ox, intramolecular disulfide) forms. S100A7ox is a substrate for the mammalian thioredoxin system in the apo state, but not when Ca2+- or Zn2+-bound, and metal binding depresses the disulfide redox midpoint potential. Both redox forms coordinate 2 equivalents of Zn(II) with subnanomolar affinity; Cys thiolates do not form an additional high-affinity Zn2+ site. Only S100A7ox (not S100A7red or disulfide-null variants) exhibits antibacterial activity against select bacteria, suggesting disulfide bonds enhance metal sequestration at the His3Asp sites to confer antibacterial properties.","method":"In vitro biochemical assays, thioredoxin reduction assay, Zn2+ titration/affinity measurements, metal substitution experiments, bacterial growth inhibition assay, mutagenesis (disulfide-null variants)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro biochemistry with mutagenesis, multiple orthogonal assays; single lab but rigorous mechanistic study","pmids":["28976190"],"is_preprint":false},{"year":2010,"finding":"S100A7 associates with and is required for αvβ6 integrin-dependent carcinoma cell invasion. S100A7 bound preferentially to the β6 cytoplasmic domain (requiring the unique C-terminal 11 aa) in a proteomic screen and co-precipitated with endogenous β6. siRNA knockdown of S100A7 abrogated αvβ6-mediated invasion in Transwell and organotypic assays. Membrane-permeant Tat-peptides encoding the β6 C-terminal residues blocked S100A7-β6 interaction and inhibited αvβ6-dependent invasion.","method":"Proteomic pull-down with recombinant β6 cytoplasmic domain, co-immunoprecipitation of endogenous proteins, siRNA knockdown, Transwell and organotypic invasion assays, Tat-peptide inhibition","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, multiple functional invasion assays, peptide inhibition confirms specificity; single lab with multiple orthogonal methods","pmids":["21132011"],"is_preprint":false},{"year":2019,"finding":"N. gonorrhoeae outer membrane protein TdfJ binds directly to human S100A7 and internalizes zinc from it in a ZnuABC zinc transporter-dependent manner. This interaction is restricted to the human version of S100A7 (not murine), and zinc presence in S100A7 is required to support gonococcal growth, establishing S100A7 as a zinc source exploited by gonococci to overcome host nutritional immunity.","method":"Direct binding assay (recombinant proteins), ZnuABC-deficient bacterial mutant, species-specificity test (human vs. murine S100A7), bacterial growth assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding assay with recombinant proteins plus genetic loss-of-function (ZnuABC mutant) and species-specificity validation; single lab with multiple orthogonal approaches","pmids":["31369630"],"is_preprint":false},{"year":2019,"finding":"Sustained secretion of S100A7 from keratinocytes in response to bacterial exposure is biphasic: an initial phase mediated by TLR signaling activating NFκB/p38MAPK/caspase-1/IL-1α, and a chronic sustained phase regulated by Caspase-8 downregulation. Caspase-8 downregulation is concomitantly observed in inflammatory skin diseases with constitutive S100A7 release.","method":"Mechanistic dissection with pathway inhibitors, siRNA knockdown of caspase-8, TLR ligand stimulation, S100A7 secretion assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and siRNA pathway dissection with functional secretion readout; single lab with multiple pathway components tested","pmids":["31775025"],"is_preprint":false},{"year":2016,"finding":"TSLP downregulates S100A7 and β-defensin 2 expression in keratinocytes via JAK2/STAT3-dependent signaling. STAT3 directly regulated the S100A7 promoter, and the STAT3/Sin3a complex controlled S100A7 transcriptional activity. This suppression occurred even in the presence of IL-17, a strong S100A7 inducer.","method":"siRNA knockdown, pharmacological inhibitors, reporter/promoter assay, Western blot, reconstituted human skin equivalent model","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter regulation with siRNA and pharmacological pathway dissection; single lab","pmids":["27498343"],"is_preprint":false},{"year":2017,"finding":"TLR3 activation following skin injury induces S100A7 expression through p38 MAPK. S100A7 then acts on keratinocytes to induce terminal differentiation marker loricrin through activation of p38 MAPK and caspase-1, promoting skin stratification and wound closure.","method":"TLR3 ligand stimulation, p38 MAPK inhibitors, caspase-1 inhibitors, gene expression analysis, wound closure assays","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with functional wound healing readout; single lab","pmids":["27535424"],"is_preprint":false},{"year":2021,"finding":"S100A7 overexpression downregulates TLR4 and upregulates RAGE expression in breast cancer cells. LPS treatment of breast cancer cells increased S100A7 expression, suggesting an LPS/S100A7/TLR4/RAGE signaling axis. S100A7 and TLR4 expression showed inverse correlation in human breast cancer samples.","method":"Stable overexpression, LPS treatment, Western blot, immunohistochemistry in human tumor samples","journal":"Molecular oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with correlation data; single lab, limited mechanistic depth","pmids":["33969603"],"is_preprint":false},{"year":2022,"finding":"S100A7/RAGE signaling promotes expression of cPLA2, which generates prostaglandin E2 (PGE2) to create an immunosuppressive tumor microenvironment. cPLA2 inhibition suppressed S100A7-mediated tumor growth and metastasis in transgenic and PDX mouse models, reduced immunosuppressive myeloid cell recruitment, and increased infiltration of activated CD4+ and CD8+ T cells.","method":"S100A7-overexpressing cell lines and transgenic mice, cPLA2 pharmacological inhibitor (AACOCF3), PDX mouse model, CODEX multiplexed imaging, mechanistic signaling studies","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic signaling pathway with pharmacological inhibition in multiple pre-clinical in vivo models plus multiplexed imaging of immune infiltrate; single lab with multiple orthogonal systems","pmids":["35135586"],"is_preprint":false},{"year":2021,"finding":"IGF-1/IGF-1R signaling in ER-positive breast cancer cells engages STAT3 activation and STAT3 recruitment to the S100A7 promoter, increasing S100A7 expression. Secreted S100A7 then activates RAGE signaling in vascular endothelial cells to promote angiogenesis.","method":"CRISPR IGF-1R knockout, STAT3 inhibitors, ChIP assay for STAT3 at S100A7 promoter, gene expression studies, endothelial tube formation assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validation of STAT3 promoter occupancy plus CRISPR KO and functional angiogenesis assay; single lab","pmids":["33557316"],"is_preprint":false},{"year":2024,"finding":"Cervical cancer-derived S100A7 exerts chemotactic effects on neutrophils and promotes neutrophil extracellular trap (NET) generation by elevating ROS levels (rather than autophagy) in neutrophils. NETs in turn enhanced cancer cell migration via TLR2/P38-MAPK/ERK/NFκB signaling and promoted lymphangiogenesis and lymphatic vessel permeability. DNase 1-mediated NETs digestion or TLR2 inhibition abolished NETs-induced metastatic potential.","method":"Neutrophil chemotaxis assay, ROS measurement, DNase 1 treatment, TLR2 siRNA/inhibitor, S100A7-overexpressing cell lines, footpad implantation mouse model, immunohistochemistry","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays with in vivo mouse model; single lab, multiple functional readouts","pmids":["39384116"],"is_preprint":false}],"current_model":"S100A7 (psoriasin) is a Ca2+-binding EF-hand homodimer with a His3Asp zinc-chelating site at the dimer interface; its primary antimicrobial mechanism involves zinc sequestration from bacteria (and exploitation of this by pathogens such as N. gonorrhoeae TdfJ), and its oxidized (disulfide-bonded) form is required for full antibacterial activity. Extracellularly, S100A7 signals through RAGE in a zinc-dependent manner to activate ERK, NF-κB, and p38 MAPK, driving chemotaxis of leukocytes, tumor-associated macrophage recruitment, endothelial cell proliferation/angiogenesis, and cancer cell invasion and metastasis; intracellularly, S100A7 interacts with Jab1 (via a specific C-terminal binding domain), E-FABP, β6 integrin cytoplasmic tail, and β-catenin to modulate pro-survival (Akt/NF-κB), differentiation (GSK-3/MAPK), and invasion pathways, with its pro- versus anti-tumorigenic activity determined by ERα status of cells; its secretion is regulated by a TLR–NFκB/p38–caspase-1–IL-1α axis with caspase-8 downregulation sustaining chronic release, and its transcription is controlled by Stat3, PKC, NF-κB, and ERβ."},"narrative":{"mechanistic_narrative":"S100A7 (psoriasin) is a calcium-binding EF-hand protein that functions as a dimer with a His3Asp zinc-coordination site at the dimer interface, acting both as a secreted antimicrobial/proinflammatory effector and as an intracellular signaling modulator in epithelial homeostasis and cancer [PMID:9562557, PMID:10026247]. Its atomic structure reveals a distorted N-terminal EF-hand that binds only one calcium ion strongly with no large conformational change, while two histidines and an aspartate from the dimer interface chelate zinc in a manner reminiscent of metalloproteases [PMID:9562557, PMID:10026247]. The protein is the principal E. coli-killing factor secreted by keratinocytes and the vaginal epithelium, and zinc saturation abolishes this activity, establishing zinc sequestration as the core antibacterial mechanism; full activity requires the central region (aa 35–80) and the zinc-binding motif, and the oxidized intramolecular-disulfide form (S100A7ox) is the active antibacterial species, with disulfide bonds enhancing metal sequestration at the His3Asp sites [PMID:15568027, PMID:17159909, PMID:20571488, PMID:28976190]. This nutritional-immunity function is exploited by Neisseria gonorrhoeae, whose outer membrane protein TdfJ binds human S100A7 and extracts its zinc via the ZnuABC transporter [PMID:31369630]. Extracellularly, S100A7 signals through the receptor RAGE in a zinc-dependent manner to activate ERK, NF-κB, and p38 MAPK, driving leukocyte and macrophage chemotaxis, endothelial proliferation/angiogenesis, abnormal keratinocyte differentiation, and tumor growth and metastasis; in breast cancer models RAGE blockade or tumor-associated macrophage depletion abrogates its pro-tumorigenic effects, and downstream cPLA2/PGE2 production establishes an immunosuppressive microenvironment [PMID:18606705, PMID:25572331, PMID:22158945, PMID:27060579, PMID:35135586]. Intracellularly, S100A7 engages partners that determine context-specific outcomes: it binds Jab1 (CSN5) through a defined C-terminal interface within its hydrophobic cleft to activate Akt/NF-κB pro-survival signaling in ERα-negative cells, stabilizes and reconstitutes the fatty-acid-binding activity of E-FABP in a zinc-disruptable cytosolic complex, binds the β6 integrin cytoplasmic tail to enable αvβ6-dependent carcinoma invasion, and associates with the β-catenin complex to promote its degradation [PMID:12839573, PMID:10191275, PMID:15994944, PMID:19810752, PMID:21132011, PMID:18223693]. Its dual pro- versus anti-tumorigenic behavior tracks with ERα status, suppressing β-catenin/TCF4 and migration in ERα-positive cells while promoting invasion in ERα-negative cells [PMID:22016394]. S100A7 transcription is driven by Src/Stat3, STAT3 (downstream of IGF-1/IGF-1R, OSM/IL-6) and PKC and repressed by a TSLP–JAK2/STAT3/Sin3a axis, while its secretion follows a biphasic TLR–NF-κB/p38–caspase-1–IL-1α program sustained by caspase-8 downregulation [PMID:18263703, PMID:20101226, PMID:31731716, PMID:27958610, PMID:27498343, PMID:33557316, PMID:31775025].","teleology":[{"year":1999,"claim":"Defining the atomic architecture answered how S100A7 binds metals: it is an EF-hand homodimer that binds one calcium per monomer without major conformational change, and—critically—forms a His3Asp zinc site at the dimer interface whose occupancy reorganizes the adjacent EF-hand loop.","evidence":"X-ray crystallography at 1.05 Å (MAD/holmium) and paired Zn-loaded/Zn-free structures at atomic resolution","pmids":["9562557","10026247"],"confidence":"High","gaps":["Structure alone did not establish the biological function of the zinc site","No bound physiological ligand or partner in these structures"]},{"year":2001,"claim":"Identification of S100A7 as a transglutaminase substrate showed a covalent post-translational route to crosslink the protein at its solvent-exposed termini, providing a regulatory handle on its function.","evidence":"In vitro transglutaminase assays with recombinant S100 proteins and identification of reactive termini","pmids":["11258932"],"confidence":"High","gaps":["In vivo consequences of crosslinking on antimicrobial or signaling activity not established","Physiological context of crosslinking unclear"]},{"year":2004,"claim":"Linking the zinc site to biology, S100A7 was shown to be the principal keratinocyte-secreted E. coli-killing factor, with zinc saturation abolishing activity—establishing zinc sequestration as the antibacterial mechanism.","evidence":"In vitro bacterial killing, in vivo antibody neutralization in human skin, and zinc-saturation experiments","pmids":["15568027"],"confidence":"High","gaps":["Spectrum of susceptible organisms beyond E. coli not defined","Structural requirements within the protein not yet mapped"]},{"year":2006,"claim":"Domain mapping clarified which regions confer antibacterial activity: the central region (aa 35–80) plus the zinc-binding motif are required, with proteolysis abolishing and EF-hand mutation/heat sparing activity.","evidence":"Recombinant protein mutagenesis with bacterial adhesion/survival, protease, and heat-denaturation assays","pmids":["17159909"],"confidence":"High","gaps":["Atomic basis for how the central region engages bacteria not resolved","Role of redox state not yet considered"]},{"year":2010,"claim":"Extension to mucosal sites showed S100A7 is constitutively secreted and is the major E. coli-cidal factor of vaginal fluid, generalizing its antibacterial role beyond skin.","evidence":"HPLC fractionation coupled to bacterial killing in vaginal fluid plus organotypic epithelium","pmids":["20571488"],"confidence":"High","gaps":["Regulation of constitutive secretion in this tissue not defined","Interaction with commensal flora not addressed"]},{"year":2017,"claim":"Redox biochemistry refined the antibacterial mechanism: the oxidized disulfide form (S100A7ox), not reduced or disulfide-null variants, is the active species, with disulfide bonds enhancing high-affinity zinc sequestration at the His3Asp sites.","evidence":"Reconstituted in vitro biochemistry, thioredoxin assays, Zn2+ affinity titrations, mutagenesis, and bacterial growth inhibition","pmids":["28976190"],"confidence":"High","gaps":["In vivo redox state at sites of action not measured","Cysteine thiolates do not form an extra zinc site, leaving the disulfide's mechanistic role on metal affinity incompletely explained"]},{"year":2019,"claim":"A pathogen counter-strategy was defined: N. gonorrhoeae TdfJ binds human S100A7 and extracts its zinc via ZnuABC, showing host nutritional immunity can be hijacked as a zinc source.","evidence":"Direct recombinant binding assay, ZnuABC-deficient mutant, human-versus-murine species specificity, and bacterial growth assays","pmids":["31369630"],"confidence":"High","gaps":["Whether other pathogens use analogous receptors not addressed","Structural basis of the TdfJ–S100A7 interface not solved"]},{"year":2003,"claim":"Establishing intracellular partnerships, S100A7 was localized to cytosol/ER and shown to redistribute to focal-adhesion-like structures on calcium elevation while binding and stabilizing E-FABP.","evidence":"Confocal immunofluorescence with calcium challenge and cross-linker co-precipitation in keratinocytes","pmids":["12839573"],"confidence":"Medium","gaps":["Functional consequence of focal-adhesion localization not defined","Single-lab imaging without orthogonal genetic perturbation"]},{"year":1999,"claim":"The S100A7–E-FABP interaction was reconstituted with purified proteins, showing the complex restores oleic-acid binding and is disrupted by physiological zinc, linking S100A7's metal sensing to lipid-binding function.","evidence":"Overlay assay, in vitro reconstitution, oleic-acid binding, co-IP from psoriatic scale, and confocal microscopy","pmids":["10191275"],"confidence":"High","gaps":["Downstream physiological role of the lipid-binding complex unclear","How zinc disruption is regulated in cells not shown"]},{"year":2005,"claim":"S100A7 was shown to drive anchorage-independent survival in ERα-negative breast cancer through a defined Jab1-binding domain activating NF-κB and Akt, identifying a pro-survival intracellular signaling node.","evidence":"Stable transfection, reciprocal IP, yeast two-hybrid, binding-domain mutagenesis, reporter assays, and xenografts","pmids":["15994944"],"confidence":"High","gaps":["Mechanism by which Jab1 binding links to Akt/EGFR not fully resolved","ERα-dependence of the effect not yet explained"]},{"year":2009,"claim":"Structural and biophysical mapping localized the Jab1 interface to residues in the N-terminal hydrophobic cleft (with Met12 as a gatekeeper), connecting the dye-binding pocket to protein-protein interaction.","evidence":"Crystal structures with naphthalene dyes at 1.6 Å, fluorescence, ITC, and yeast two-hybrid mutagenesis","pmids":["19810752"],"confidence":"High","gaps":["Co-structure with Jab1 not determined","Whether endogenous ligands occupy the cleft in vivo unknown"]},{"year":2010,"claim":"S100A7 was shown to bind the β6 integrin cytoplasmic tail and be required for αvβ6-dependent carcinoma invasion, defining an integrin-linked invasion mechanism.","evidence":"Proteomic pull-down, reciprocal co-IP, siRNA, Transwell/organotypic invasion, and Tat-peptide competition","pmids":["21132011"],"confidence":"High","gaps":["Signaling downstream of the S100A7–β6 complex not delineated","Calcium/zinc dependence of the interaction not tested"]},{"year":2008,"claim":"Identification of RAGE as the extracellular receptor explained how S100A7 acts as a chemoattractant and why its signaling is zinc-dependent, distinguishing it from the RAGE-independent paralog S100A15.","evidence":"Chemotaxis and in vitro binding assays with zinc-dependence and an in vivo inflammation model","pmids":["18606705"],"confidence":"High","gaps":["Stoichiometry and structure of the S100A7–RAGE complex not solved","Contribution of other receptors not excluded"]},{"year":2008,"claim":"S100A7–RAGE signaling was shown to drive breast cancer invasion and modulate EGFR-family signaling, while a reciprocal study established S100A7 as a negative regulator of β-catenin via GSK3β-independent degradation in oral SCC.","evidence":"shRNA and overexpression, phospho-Westerns, co-IP, β-catenin degradation assays, angiogenesis and xenograft/in vivo models","pmids":["18320059","18223693"],"confidence":"Medium","gaps":["Molecular basis of GSK3β-independent β-catenin degradation unresolved","How RAGE signaling intersects with intracellular β-catenin regulation unclear"]},{"year":2010,"claim":"The pro- versus anti-tumorigenic switch was resolved through ERα status: in ERα-positive cells S100A7 suppresses migration and tumor growth by downregulating β-catenin/TCF4 and raising GSK3β activity, opposite to its ERα-negative role.","evidence":"Stable overexpression, GSK3β inhibitor rescue, migration/proliferation assays, and nude-mouse xenografts","pmids":["22016394"],"confidence":"Medium","gaps":["Mechanistic link between ERα status and divergent β-catenin handling not defined","Single-lab system"]},{"year":2010,"claim":"In vivo transgenic and macrophage-depletion studies established RAGE-mediated tumor-associated macrophage recruitment as a central effector of S100A7's pro-tumorigenic activity.","evidence":"MMTV-mS100a7a15 transgenic mice, chemotaxis assays, in vivo TAM depletion, and tumor/metastasis quantification (also RAGE-deficient mice and sRAGE)","pmids":["22158945","25572331"],"confidence":"High","gaps":["Chemokine ligands recruiting TAMs not fully enumerated","Whether epithelial-intrinsic vs stromal RAGE dominates not dissected"]},{"year":2011,"claim":"S100A7 was shown to promote angiogenesis through RAGE by increasing VEGF and driving ROS-dependent endothelial proliferation and tube formation, linking it to tumor vascularization.","evidence":"Recombinant protein treatment, sRAGE blockade, ROS measurement, antioxidant Bcl-2, plus ROS/hypoxia induction and angiogenic-factor readouts in keratinocytes","pmids":["22189627","27155199"],"confidence":"Medium","gaps":["Direct vs paracrine endothelial effects not fully separated","Single-lab angiogenesis assays"]},{"year":2012,"claim":"Direct binding of S100A7 to RAGE was confirmed and shown to be required for osteosarcoma migration, invasion, and MMP activity, generalizing the RAGE axis beyond breast cancer.","evidence":"Recombinant protein pull-down, RAGE siRNA, and migration/invasion/MMP assays","pmids":["22783409"],"confidence":"Medium","gaps":["Downstream signaling in osteosarcoma not mapped","Single-lab study"]},{"year":2014,"claim":"In keratinocyte biology, S100A7 was shown to strengthen the tight-junction barrier and modulate differentiation through GSK-3/MAPK and PKC pathways, defining roles in epidermal homeostasis distinct from cancer signaling.","evidence":"TER and permeability assays, GSK-3/MAPK and PKC inhibitors, siRNA/lentiviral perturbation, and differentiation-marker analysis","pmids":["24842328","27958610"],"confidence":"Medium","gaps":["Whether barrier and differentiation effects require RAGE not resolved","Reconciliation with pro-differentiation vs abnormal-differentiation outcomes incomplete"]},{"year":2016,"claim":"RAGE-MyD88-NF-κB signaling by extracellular S100A7 was shown to upregulate IL-6 and shift keratinocytes toward abnormal differentiation, mechanistically connecting S100A7 to psoriasis-like epidermal phenotypes.","evidence":"Recombinant protein treatment, RAGE pathway analysis, and differentiation-marker readouts in 2D and reconstituted human epidermis","pmids":["27060579"],"confidence":"Medium","gaps":["Relative contribution of IL-6 vs other RAGE outputs not quantified","In vivo validation in human psoriasis limited"]},{"year":2017,"claim":"A RAGE-p38-calpain-1 cascade was defined linking S100A7 to mature IL-1α production, and a separate TLR3-p38 injury pathway was shown to induce S100A7 driving loricrin and wound closure, placing S100A7 within inflammatory amplification loops.","evidence":"Recombinant protein, pathway inhibitors, siRNA of RAGE/p38/calpain-1, imiquimod psoriasis model, and TLR3-ligand wound-closure assays","pmids":["28060905","27535424"],"confidence":"Medium","gaps":["Feedback between IL-1α/IL-17 and S100A7 only partially mapped","In vivo causality in human disease not established"]},{"year":2008,"claim":"Flagellin/TLR5 was identified as the principal microbial inducer of S100A7 in keratinocytes, defining the upstream sensing that triggers its antimicrobial expression.","evidence":"TLR ligand screen, ΔFliC E. coli mutant, and TLR5 siRNA with RT-PCR/protein readout","pmids":["18263703"],"confidence":"High","gaps":["Transcription factors downstream of TLR5 not fully resolved here","Other inducers (e.g., cytokines) addressed in separate studies"]},{"year":2019,"claim":"Secretion control was resolved as biphasic: an acute TLR–NF-κB/p38–caspase-1–IL-1α phase and a chronic phase sustained by caspase-8 downregulation, explaining constitutive S100A7 release in inflammatory skin disease.","evidence":"Pathway-inhibitor and caspase-8 siRNA dissection with TLR stimulation and secretion assays","pmids":["31775025"],"confidence":"Medium","gaps":["Mechanism of caspase-8 downregulation in disease not defined","Non-classical secretion route not structurally characterized"]},{"year":2016,"claim":"Transcriptional regulation was mapped to STAT3-centered control: STAT3 directly binds the S100A7 promoter and is engaged downstream of Src, OSM/IL-6, and IGF-1/IGF-1R to induce S100A7, while a TSLP–JAK2/STAT3/Sin3a complex represses it.","evidence":"Promoter/reporter and ChIP assays, pharmacological inhibitors, CRISPR IGF-1R KO, siRNA, and skin-equivalent/cancer models","pmids":["27498343","20101226","31731716","33557316"],"confidence":"Medium","gaps":["How the same factor (STAT3) yields activation vs repression in different contexts unresolved","Cofactor switching (e.g., Sin3a) only partially defined"]},{"year":2022,"claim":"The immune-modulatory output of S100A7/RAGE was extended to immunosuppression: signaling induces cPLA2/PGE2 to recruit suppressive myeloid cells and exclude T cells, and to drive neutrophil/NET-mediated metastasis, identifying targetable downstream effectors.","evidence":"Transgenic and PDX models with cPLA2 inhibitor and CODEX imaging; plus neutrophil/NET assays with DNase1 and TLR2 inhibition in cervical cancer models","pmids":["35135586","39384116"],"confidence":"Medium","gaps":["Whether cPLA2 and NET pathways operate in the same tumors not established","Relative contribution to clinical immune evasion unknown"]},{"year":null,"claim":"How the same protein integrates its three modes—zinc-sequestering antimicrobial, RAGE-engaging proinflammatory ligand, and ERα-dependent intracellular signaling switch—into a unified context-dependent regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of S100A7 bound to RAGE, Jab1, β6, or β-catenin","Molecular basis of the ERα-dependent pro/anti-tumorigenic switch undefined","In vivo coupling between redox state, metal occupancy, and which function dominates not measured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1,2,27,29]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[8,10,21]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,12,28]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,18]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,8,24,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,10,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,15,16,34]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[22,26,32]}],"complexes":[],"partners":["RAGE","JAB1","E-FABP","ITGB6","CTNNB1","TDFJ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31151","full_name":"Protein S100-A7","aliases":["Psoriasin","S100 calcium-binding protein A7"],"length_aa":101,"mass_kda":11.5,"function":"","subcellular_location":"Cytoplasm; Secreted","url":"https://www.uniprot.org/uniprotkb/P31151/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/S100A7","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":381,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"STK4","stoichiometry":0.2},{"gene":"TAOK1","stoichiometry":0.2},{"gene":"TAOK2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/S100A7","total_profiled":1310},"omim":[{"mim_id":"617427","title":"S100 CALCIUM-BINDING PROTEIN A7A; S100A7A","url":"https://www.omim.org/entry/617427"},{"mim_id":"605457","title":"INTERLEUKIN 22 RECEPTOR, ALPHA-1; IL22RA1","url":"https://www.omim.org/entry/605457"},{"mim_id":"605330","title":"INTERLEUKIN 22; IL22","url":"https://www.omim.org/entry/605330"},{"mim_id":"603114","title":"S100 CALCIUM-BINDING PROTEIN A11; S100A11","url":"https://www.omim.org/entry/603114"},{"mim_id":"600353","title":"S100 CALCIUM-BINDING PROTEIN A7; S100A7","url":"https://www.omim.org/entry/600353"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"cervix","ntpm":1900.9},{"tissue":"esophagus","ntpm":1264.3},{"tissue":"lymphoid tissue","ntpm":1158.8},{"tissue":"vagina","ntpm":1368.9}],"url":"https://www.proteinatlas.org/search/S100A7"},"hgnc":{"alias_symbol":["S100A7c"],"prev_symbol":["PSOR1"]},"alphafold":{"accession":"P31151","domains":[{"cath_id":"1.10.238.10","chopping":"6-92","consensus_level":"high","plddt":97.6577,"start":6,"end":92}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31151","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31151-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31151-F1-predicted_aligned_error_v6.png","plddt_mean":95.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=S100A7","jax_strain_url":"https://www.jax.org/strain/search?query=S100A7"},"sequence":{"accession":"P31151","fasta_url":"https://rest.uniprot.org/uniprotkb/P31151.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31151/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31151"}},"corpus_meta":[{"pmid":"15568027","id":"PMC_15568027","title":"Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection.","date":"2004","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15568027","citation_count":507,"is_preprint":false},{"pmid":"18754038","id":"PMC_18754038","title":"The antimicrobial protein psoriasin (S100A7) is upregulated in atopic dermatitis and after experimental skin barrier disruption.","date":"2008","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/18754038","citation_count":176,"is_preprint":false},{"pmid":"10595935","id":"PMC_10595935","title":"Psoriasin (S100A7) expression and invasive breast cancer.","date":"1999","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10595935","citation_count":150,"is_preprint":false},{"pmid":"18606705","id":"PMC_18606705","title":"Chemotactic activity of S100A7 (Psoriasin) is mediated by the receptor for advanced glycation end products and potentiates inflammation with highly homologous but functionally distinct S100A15.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18606705","citation_count":143,"is_preprint":false},{"pmid":"25572331","id":"PMC_25572331","title":"RAGE mediates S100A7-induced breast cancer growth and metastasis by modulating the tumor microenvironment.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25572331","citation_count":128,"is_preprint":false},{"pmid":"10026247","id":"PMC_10026247","title":"Zinc-binding site of an S100 protein revealed. Two crystal structures of Ca2+-bound human psoriasin (S100A7) in the Zn2+-loaded and Zn2+-free states.","date":"1999","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10026247","citation_count":112,"is_preprint":false},{"pmid":"22158945","id":"PMC_22158945","title":"S100A7 enhances mammary tumorigenesis through upregulation of inflammatory pathways.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22158945","citation_count":111,"is_preprint":false},{"pmid":"22402441","id":"PMC_22402441","title":"Vitamin D analog calcipotriol suppresses the Th17 cytokine-induced proinflammatory S100 \"alarmins\" psoriasin (S100A7) and koebnerisin (S100A15) in psoriasis.","date":"2012","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/22402441","citation_count":107,"is_preprint":false},{"pmid":"9562557","id":"PMC_9562557","title":"EF-hands at atomic resolution: the structure of human psoriasin (S100A7) solved by MAD 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carcinomas.","date":"1999","source":"Electrophoresis","url":"https://pubmed.ncbi.nlm.nih.gov/10197442","citation_count":83,"is_preprint":false},{"pmid":"11258932","id":"PMC_11258932","title":"S100A7, S100A10, and S100A11 are transglutaminase substrates.","date":"2001","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11258932","citation_count":80,"is_preprint":false},{"pmid":"15217486","id":"PMC_15217486","title":"S100A7 and the progression of breast cancer.","date":"2004","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/15217486","citation_count":79,"is_preprint":false},{"pmid":"7591220","id":"PMC_7591220","title":"Comparative expression of the psoriasin (S100A7) and S100C genes in breast carcinoma and co-localization to human chromosome 1q21-q22.","date":"1995","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7591220","citation_count":78,"is_preprint":false},{"pmid":"31731716","id":"PMC_31731716","title":"Dietary Flavonoids Luteolin and Quercetin Inhibit Migration and Invasion of Squamous Carcinoma through Reduction of Src/Stat3/S100A7 Signaling.","date":"2019","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31731716","citation_count":74,"is_preprint":false},{"pmid":"21623236","id":"PMC_21623236","title":"Utility of 10 immunohistochemical markers including novel markers (desmocollin-3, glypican 3, S100A2, S100A7, and Sox-2) for differential diagnosis of squamous cell carcinoma from adenocarcinoma of the Lung.","date":"2011","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21623236","citation_count":70,"is_preprint":false},{"pmid":"12600274","id":"PMC_12600274","title":"Psoriasin (S100A7) expression is altered during skin tumorigenesis.","date":"2003","source":"BMC dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/12600274","citation_count":69,"is_preprint":false},{"pmid":"20596736","id":"PMC_20596736","title":"Novel S100A7 (psoriasin)/S100A15 (koebnerisin) subfamily: highly homologous but distinct in regulation and function.","date":"2010","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/20596736","citation_count":68,"is_preprint":false},{"pmid":"12855640","id":"PMC_12855640","title":"Psoriasin (S100A7) expression is associated with poor outcome in estrogen receptor-negative invasive breast cancer.","date":"2003","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/12855640","citation_count":67,"is_preprint":false},{"pmid":"17136347","id":"PMC_17136347","title":"Psoriasin (S100A7) is significantly up-regulated in human epithelial skin 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Loss of zinc causes reorganization of the adjacent EF-hand loop, making it resemble a calcium-loaded EF-hand.\",\n      \"method\": \"X-ray crystallography (two crystal forms, Zn2+-loaded and Zn2+-free)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two independent crystal structures with and without zinc, mechanistically defining the zinc-binding site and its structural consequences\",\n      \"pmids\": [\"10026247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Psoriasin (S100A7) is the principal E. coli-killing antimicrobial compound secreted by keratinocytes in vitro and in vivo. Zn2+-saturated psoriasin showed diminished antimicrobial activity, implicating zinc sequestration as the antibacterial mechanism. In vivo treatment with anti-psoriasin antibodies inhibited skin E. coli-killing activity.\",\n      \"method\": \"In vitro bacterial killing assay, in vivo antibody neutralization in human skin, zinc-saturation experiments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (in vitro killing, in vivo neutralization, zinc-loading experiment) in a single rigorous study; widely replicated concept\",\n      \"pmids\": [\"15568027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"S100A7 antibacterial activity against E. coli requires the central region (amino acids 35–80) and the zinc-binding motif. Mutation of the zinc-binding motif reduced antibacterial activity, but this reduction was reversed by simultaneous removal of the amino terminus, indicating the central region alone is sufficient for full activity. Protease treatment abolished activity whereas EF-hand calcium-binding motif mutation or heat denaturation had only minor effects.\",\n      \"method\": \"Recombinant protein mutagenesis, bacterial adhesion/survival assays, heat denaturation and protease treatment experiments\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with systematic mutagenesis of multiple domains; single lab but orthogonal approaches\",\n      \"pmids\": [\"17159909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"S100A7 is a substrate for both type I and type II transglutaminases, which form covalent ε-(γ-glutamyl)lysine bonds at the solvent-exposed amino- and carboxyl-terminal ends of the protein, providing a mechanism to regulate S100A7 function.\",\n      \"method\": \"In vitro transglutaminase assay with recombinant S100 proteins; biochemical characterization\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzyme assay with identification of reactive regions; single lab, multiple S100 substrates tested as controls\",\n      \"pmids\": [\"11258932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"S100A7 is present in the cytosol and endoplasmic reticulum (BiP/GRP78-positive tubular structures) in keratinocytes. Upon calcium elevation, cytoplasmic S100A7 redistributes to α-actinin- and paxillin-positive peripheral focal adhesion-like structures. S100A7 co-localizes with and co-precipitates epidermal fatty acid binding protein (E-FABP) in these structures, and S100A7 expression stabilizes E-FABP protein levels.\",\n      \"method\": \"Confocal immunofluorescence microscopy, calcium challenge experiments, cross-linker co-precipitation\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization by live/fixed imaging with calcium perturbation and co-precipitation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12839573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"S100A7 and E-FABP form a complex in the cytosol of keratinocytes, reconstituted in vitro using purified proteins in the presence of EDTA. Complex formation is disrupted by physiological concentrations of Zn2+ (0.1 mM) but not Ca2+ or Mg2+ at physiological levels. The complex retains oleic acid-binding properties of E-FABP, whereas free S100A7 alone does not bind oleic acid. Co-immunoprecipitation confirmed the interaction in psoriatic scale extracts.\",\n      \"method\": \"Overlay assay, in vitro complex reconstitution with purified proteins, oleic acid binding assay, co-immunoprecipitation, confocal microscopy\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, zinc-dependent disruption, functional fatty acid binding assay, confirmed by co-IP in native tissue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10191275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"S100A7 promotes survival under anchorage-independent growth in ERα-negative breast cancer cells (MDA-MB-231) by activating NF-κB (~3-fold) and phospho-Akt (~4-fold). These effects depend on a Jab1 (CSN5/COP9 signalosome subunit 5)-binding domain within S100A7, as confirmed by immunoprecipitation, yeast two-hybrid assay, and mutant S100A7 lacking the Jab1-binding site. Enhanced EGFR signaling was also found to correlate with increased phospho-Akt.\",\n      \"method\": \"Stable transfection, immunoprecipitation, yeast two-hybrid assay, reporter gene assay, Western blot, xenograft tumor model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP, Y2H, mutagenesis of binding domain, in vivo xenograft validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15994944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"S100A7 signals as a chemoattractant through RAGE (receptor for advanced glycation end products). S100A7-RAGE binding, downstream signaling, and chemotaxis are zinc-dependent in vitro, reflecting zinc-mediated changes in S100A7 dimer structure. The highly homologous S100A15 uses a distinct Gi protein-coupled receptor rather than RAGE for chemotaxis.\",\n      \"method\": \"Antibody generation, chemotaxis assays, in vitro binding assays, zinc-dependence studies, in vivo inflammation model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor identification with functional binding and signaling assays, zinc-dependence validated in vitro; confirmed by multiple labs subsequently\",\n      \"pmids\": [\"18606705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"E. coli flagellin is the principal inducer of S100A7c (psoriasin) expression in human epidermal keratinocytes, acting through TLR5. A flagellin-deficient E. coli strain (ΔFliC) did not induce S100A7c, and siRNA knockdown of TLR5 suppressed induction by both flagellin and wild-type E. coli supernatant.\",\n      \"method\": \"TLR ligand screening, flagellin-deficient bacterial mutant, siRNA knockdown of TLR5, RT-PCR and protein measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (TLR5 siRNA) and bacterial mutant combined with ligand specificity screen; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"18263703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"S100A7 promotes breast cancer growth and metastasis via RAGE-dependent activation of ERK and NF-κB signaling and cell migration. In an S100A7-transgenic mouse model, RAGE neutralizing antibody or soluble RAGE inhibited tumor progression, and RAGE/S100A7 drove recruitment of MMP9-positive tumor-associated macrophages.\",\n      \"method\": \"RAGE-deficient mice, neutralizing antibody injection, soluble RAGE administration, signaling assays (ERK, NF-κB), transgenic mouse model, macrophage depletion\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic/pharmacological in vivo models, signaling mechanistic studies, macrophage depletion epistasis; replicated across labs\",\n      \"pmids\": [\"25572331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"S100A7 overexpression in ERα-negative breast cancer cells promotes cell invasion via RAGE-dependent signaling. S100A7 downregulation in MDA-MB-468 cells reduced EGF-directed migration and decreased phosphorylation of EGFR (Tyr1173), HER2 (Tyr1248), Src (Tyr416), and SHP2 (Tyr542), indicating S100A7 modulates EGF receptor signaling. S100A7 downregulation also reduced angiogenesis in vivo and osteoclast formation associated with decreased IL-8 expression.\",\n      \"method\": \"shRNA knockdown, phospho-Western blot, migration assays, Matrigel plug angiogenesis assay, intra-tibial bone injection in SCID mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling readouts with shRNA loss-of-function; single lab, in vitro and in vivo assays\",\n      \"pmids\": [\"18320059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"S100A7 reciprocally negatively regulates β-catenin signaling in oral squamous cell carcinoma: S100A7 associates with the β-catenin complex and promotes β-catenin degradation via a GSK3β-independent non-canonical mechanism. Conversely, β-catenin signaling negatively regulates S100A7 expression. S100A7 inhibited SCCOC cell proliferation in vitro and tumor growth/invasion in vivo.\",\n      \"method\": \"Co-immunoprecipitation, β-catenin degradation assay, tumor xenograft model, loss-of-function/gain-of-function experiments in cell lines and mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for physical interaction, in vivo model for functional consequence, reciprocal regulation demonstrated; single lab\",\n      \"pmids\": [\"18223693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"S100A7 crystal structures in complex with naphthalene-based dyes (2,6-ANS and 1,8-ANS) at 1.6 Å identified a hydrophobic binding cleft formed by the N-terminal helices of each monomer, with Met12 acting as a gatekeeper. Yeast two-hybrid mutagenesis showed that Leu78 (within the Met12 cleft), Gln88, and Asp56 contribute to Jab1 binding, linking the hydrophobic pocket to the Jab1 interaction interface.\",\n      \"method\": \"X-ray crystallography (1.6 Å), steady-state fluorescence, time-resolved fluorescence, isothermal titration calorimetry, yeast two-hybrid mutagenesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with multiple orthogonal biophysical methods and mutational mapping of Jab1 interface; single lab\",\n      \"pmids\": [\"19810752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"S100A7 expression in primary cortico-hippocampal neuron cultures inhibits generation of Aβ1-42 and Aβ1-40 peptides coincident with selective promotion of ADAM-10-mediated non-amyloidogenic α-secretase activity. Expression of human S100A7 in transgenic mouse brains also promoted α-secretase activity.\",\n      \"method\": \"Adenoviral S100A7 overexpression in primary neuronal cultures, ELISA for Aβ peptides, α-secretase activity assay, S100A7 transgenic mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression in primary neurons and transgenic mice with specific enzymatic readout; single lab, two model systems\",\n      \"pmids\": [\"19159013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100A7 enhances macrophage chemotaxis via RAGE receptor activation in vitro. In vivo, mS100a7a15 induction in MMTV-mS100a7a15 transgenic mice enhanced breast tumor growth, metastasis, and recruitment of tumor-associated macrophages. In vivo TAM depletion inhibited the pro-tumorigenic effects of mS100a7a15 induction, establishing TAM recruitment as a key mechanism.\",\n      \"method\": \"Transgenic mouse model (MMTV-mS100a7a15), macrophage chemotaxis assay, in vivo macrophage depletion, tumor growth/metastasis quantification\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model with macrophage depletion epistasis; mechanistically defines TAM recruitment through RAGE as key effector pathway\",\n      \"pmids\": [\"22158945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100A7 expression in ERα-positive breast cancer cells (MCF7, T47D) suppresses migration, proliferation, and tumor growth in vivo by downregulating the β-catenin/TCF4 pathway, increasing GSK3β activity, and enhancing β-catenin/E-cadherin interaction. GSK3β inhibitor treatment reversed β-catenin suppression in S100A7-overexpressing ERα+ cells. This is opposite to its pro-tumorigenic role in ERα-negative cells.\",\n      \"method\": \"Stable overexpression, migration/proliferation assays, GSK3β inhibitor experiments, nude mouse xenograft model, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic pathway studies with in vivo xenograft validation and pharmacological rescue; single lab\",\n      \"pmids\": [\"22016394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Extracellular psoriasin (S100A7) increases VEGF expression in mammary epithelial cells and promotes endothelial cell proliferation, tube formation, and ROS generation through RAGE. Soluble RAGE (sRAGE) inhibited psoriasin-induced endothelial proliferation, tube formation, and ROS production. Antioxidant Bcl-2 abolished psoriasin's proliferative effect on endothelial cells.\",\n      \"method\": \"Recombinant protein treatment, sRAGE blockade, shRNA knockdown, adenoviral overexpression, ROS measurement, endothelial cell proliferation/tube formation assays\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blockade with sRAGE, ROS mechanistic link, multiple cell-type assays; single lab\",\n      \"pmids\": [\"22189627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Psoriasin (S100A7) is constitutively expressed and secreted in the vaginal epithelium and accounts for ~2.5–3% of total vaginal fluid protein. HPLC fractionation showed that psoriasin co-eluted with E. coli-killing activity of vaginal fluid, establishing it as the major E. coli-cidal factor of the female genital tract.\",\n      \"method\": \"HPLC fractionation with bacterial killing assay, organotypic vaginal epithelium model, protein quantification\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — fractionation directly coupled to functional antibacterial assay; single lab with biochemical and biological validation\",\n      \"pmids\": [\"20571488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Psoriasin (S100A7) expression is induced by reactive oxygen species (ROS) and hypoxia in keratinocytes. Downregulation of psoriasin by siRNA reduced ROS-induced expression of VEGF, HB-EGF, MMP-1, and thrombospondin 1. Extracellular psoriasin induced endothelial cell proliferation, migration, and tube formation comparable to VEGF, with effects suggested to be mediated by PI3K and NF-κB pathways.\",\n      \"method\": \"siRNA knockdown, ROS induction, hypoxia exposure, angiogenic factor measurement, endothelial cell functional assays\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with multiple downstream angiogenic factor readouts; single lab\",\n      \"pmids\": [\"27155199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100A7 expression is induced by oncostatin-M (OSM) and IL-6 in breast tumor cells, dependent on STAT3, PI3K, and ERK1/2 signaling, as demonstrated by pharmacological blockade. siRNA knockdown of S100A7 eliminated the pro-migratory effects of OSM treatment, positioning S100A7 as a downstream effector of OSM/IL-6 in breast cancer cell migration.\",\n      \"method\": \"Cytokine stimulation, pathway inhibitors (STAT3, PI3K, ERK1/2), siRNA knockdown, migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with siRNA functional readout; single lab, multiple cell lines\",\n      \"pmids\": [\"20101226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S100A7 promotes migration and invasion of osteosarcoma cells through RAGE. Pull-down assay confirmed direct binding of recombinant S100A7 to RAGE. siRNA knockdown of RAGE suppressed S100A7-enhanced migration, invasion, and matrix metalloproteinase activity of osteosarcoma cells.\",\n      \"method\": \"In vitro pull-down assay with recombinant proteins, siRNA knockdown of RAGE, migration/invasion assays, MMP activity measurement\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by pull-down, receptor requirement demonstrated by siRNA loss-of-function; single lab\",\n      \"pmids\": [\"22783409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"S100A7/psoriasin strengthens the tight junction (TJ) barrier of keratinocytes by selectively increasing expression of TJ proteins (claudins, occludin), enhancing transepithelial electrical resistance, and reducing paracellular permeability. This was mediated through GSK-3 and MAPK pathways, as shown by specific inhibitors. S100A7 also increased β-catenin and E-cadherin accumulation at cell-cell contacts.\",\n      \"method\": \"Western blot, RT-PCR, transepithelial electrical resistance assay, paracellular permeability assay, GSK-3 and MAPK inhibitors, immunofluorescence\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional barrier assays with pharmacological pathway dissection; single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"24842328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Extracellular S100A7 signals through RAGE to activate the MyD88-IκB/NF-κB cascade in keratinocytes, upregulating IL-6, which inhibits epidermal differentiation markers (keratin 1, keratin 10, involucrin, loricrin) and increases abnormal differentiation markers (keratin 6, keratin 16). This was confirmed in a reconstituted human epidermis model.\",\n      \"method\": \"Recombinant protein treatment, Western blot, RT-PCR, reconstituted human epidermis model, RAGE signaling pathway analysis\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor and signaling pathway identification with functional differentiation readouts in 2D and 3D models; single lab\",\n      \"pmids\": [\"27060579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"S100A7 induces mature interleukin-1α (17 kDa) expression in normal human epidermal keratinocytes via the RAGE-p38 MAPK-calpain-1 pathway; inhibitors or siRNA knockdown of each component abolished mature IL-1α induction. In imiquimod-induced psoriasis mouse model, mS100a7a15, mature IL-1α, and calpain-1 were highly co-expressed, and IL-17a neutralization attenuated mS100a7a15 expression.\",\n      \"method\": \"Recombinant protein treatment, pharmacological inhibitors, siRNA knockdown (RAGE, p38 MAPK, calpain-1), Western blot, imiquimod mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and pharmacological dissection of signaling cascade with in vivo corroboration; single lab\",\n      \"pmids\": [\"28060905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"S100A7 in squamous carcinoma cells is transcriptionally regulated by Src/Stat3 signaling. Src inhibitor (SU6656) and Stat3 inhibitor (S3I-201) reduced S100A7 protein levels. Stat3 transactivated the S100A7 5'-upstream promoter region. S100A7 overexpression decreased E-cadherin and increased Twist (EMT markers), while S100A7 knockdown had opposite effects, demonstrating S100A7 as a downstream effector of Src/Stat3 promoting EMT and invasion.\",\n      \"method\": \"Pharmacological inhibitors of Src/Stat3, luciferase promoter assay, siRNA/overexpression, Western blot, Transwell invasion assay, zebrafish metastasis model\",\n      \"journal\": \"Antioxidants\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter transactivation, pharmacological and genetic loss-of-function, in vivo zebrafish model; single lab\",\n      \"pmids\": [\"31731716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"S100A7 promotes keratinocyte differentiation via the protein kinase C pathway. siRNA-mediated knockdown of psoriasin reduced expression of involucrin, desmoglein 1, transglutaminase 1, and CD24. Lentiviral overexpression of psoriasin mimicking the psoriatic milieu caused an altered differentiation gene expression pattern resembling psoriatic epidermis.\",\n      \"method\": \"siRNA knockdown, lentiviral overexpression, PKC pathway inhibitors, Western blot, immunohistochemistry\",\n      \"journal\": \"Acta dermato-venereologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and lentiviral gain/loss-of-function with multiple differentiation marker readouts; single lab\",\n      \"pmids\": [\"27958610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biochemical analysis showed that S100A7 exists as reduced (S100A7red, free thiols) and oxidized (S100A7ox, intramolecular disulfide) forms. S100A7ox is a substrate for the mammalian thioredoxin system in the apo state, but not when Ca2+- or Zn2+-bound, and metal binding depresses the disulfide redox midpoint potential. Both redox forms coordinate 2 equivalents of Zn(II) with subnanomolar affinity; Cys thiolates do not form an additional high-affinity Zn2+ site. Only S100A7ox (not S100A7red or disulfide-null variants) exhibits antibacterial activity against select bacteria, suggesting disulfide bonds enhance metal sequestration at the His3Asp sites to confer antibacterial properties.\",\n      \"method\": \"In vitro biochemical assays, thioredoxin reduction assay, Zn2+ titration/affinity measurements, metal substitution experiments, bacterial growth inhibition assay, mutagenesis (disulfide-null variants)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro biochemistry with mutagenesis, multiple orthogonal assays; single lab but rigorous mechanistic study\",\n      \"pmids\": [\"28976190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100A7 associates with and is required for αvβ6 integrin-dependent carcinoma cell invasion. S100A7 bound preferentially to the β6 cytoplasmic domain (requiring the unique C-terminal 11 aa) in a proteomic screen and co-precipitated with endogenous β6. siRNA knockdown of S100A7 abrogated αvβ6-mediated invasion in Transwell and organotypic assays. Membrane-permeant Tat-peptides encoding the β6 C-terminal residues blocked S100A7-β6 interaction and inhibited αvβ6-dependent invasion.\",\n      \"method\": \"Proteomic pull-down with recombinant β6 cytoplasmic domain, co-immunoprecipitation of endogenous proteins, siRNA knockdown, Transwell and organotypic invasion assays, Tat-peptide inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, multiple functional invasion assays, peptide inhibition confirms specificity; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21132011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"N. gonorrhoeae outer membrane protein TdfJ binds directly to human S100A7 and internalizes zinc from it in a ZnuABC zinc transporter-dependent manner. This interaction is restricted to the human version of S100A7 (not murine), and zinc presence in S100A7 is required to support gonococcal growth, establishing S100A7 as a zinc source exploited by gonococci to overcome host nutritional immunity.\",\n      \"method\": \"Direct binding assay (recombinant proteins), ZnuABC-deficient bacterial mutant, species-specificity test (human vs. murine S100A7), bacterial growth assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding assay with recombinant proteins plus genetic loss-of-function (ZnuABC mutant) and species-specificity validation; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"31369630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sustained secretion of S100A7 from keratinocytes in response to bacterial exposure is biphasic: an initial phase mediated by TLR signaling activating NFκB/p38MAPK/caspase-1/IL-1α, and a chronic sustained phase regulated by Caspase-8 downregulation. Caspase-8 downregulation is concomitantly observed in inflammatory skin diseases with constitutive S100A7 release.\",\n      \"method\": \"Mechanistic dissection with pathway inhibitors, siRNA knockdown of caspase-8, TLR ligand stimulation, S100A7 secretion assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and siRNA pathway dissection with functional secretion readout; single lab with multiple pathway components tested\",\n      \"pmids\": [\"31775025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TSLP downregulates S100A7 and β-defensin 2 expression in keratinocytes via JAK2/STAT3-dependent signaling. STAT3 directly regulated the S100A7 promoter, and the STAT3/Sin3a complex controlled S100A7 transcriptional activity. This suppression occurred even in the presence of IL-17, a strong S100A7 inducer.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibitors, reporter/promoter assay, Western blot, reconstituted human skin equivalent model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter regulation with siRNA and pharmacological pathway dissection; single lab\",\n      \"pmids\": [\"27498343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TLR3 activation following skin injury induces S100A7 expression through p38 MAPK. S100A7 then acts on keratinocytes to induce terminal differentiation marker loricrin through activation of p38 MAPK and caspase-1, promoting skin stratification and wound closure.\",\n      \"method\": \"TLR3 ligand stimulation, p38 MAPK inhibitors, caspase-1 inhibitors, gene expression analysis, wound closure assays\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with functional wound healing readout; single lab\",\n      \"pmids\": [\"27535424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"S100A7 overexpression downregulates TLR4 and upregulates RAGE expression in breast cancer cells. LPS treatment of breast cancer cells increased S100A7 expression, suggesting an LPS/S100A7/TLR4/RAGE signaling axis. S100A7 and TLR4 expression showed inverse correlation in human breast cancer samples.\",\n      \"method\": \"Stable overexpression, LPS treatment, Western blot, immunohistochemistry in human tumor samples\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with correlation data; single lab, limited mechanistic depth\",\n      \"pmids\": [\"33969603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"S100A7/RAGE signaling promotes expression of cPLA2, which generates prostaglandin E2 (PGE2) to create an immunosuppressive tumor microenvironment. cPLA2 inhibition suppressed S100A7-mediated tumor growth and metastasis in transgenic and PDX mouse models, reduced immunosuppressive myeloid cell recruitment, and increased infiltration of activated CD4+ and CD8+ T cells.\",\n      \"method\": \"S100A7-overexpressing cell lines and transgenic mice, cPLA2 pharmacological inhibitor (AACOCF3), PDX mouse model, CODEX multiplexed imaging, mechanistic signaling studies\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic signaling pathway with pharmacological inhibition in multiple pre-clinical in vivo models plus multiplexed imaging of immune infiltrate; single lab with multiple orthogonal systems\",\n      \"pmids\": [\"35135586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IGF-1/IGF-1R signaling in ER-positive breast cancer cells engages STAT3 activation and STAT3 recruitment to the S100A7 promoter, increasing S100A7 expression. Secreted S100A7 then activates RAGE signaling in vascular endothelial cells to promote angiogenesis.\",\n      \"method\": \"CRISPR IGF-1R knockout, STAT3 inhibitors, ChIP assay for STAT3 at S100A7 promoter, gene expression studies, endothelial tube formation assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validation of STAT3 promoter occupancy plus CRISPR KO and functional angiogenesis assay; single lab\",\n      \"pmids\": [\"33557316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cervical cancer-derived S100A7 exerts chemotactic effects on neutrophils and promotes neutrophil extracellular trap (NET) generation by elevating ROS levels (rather than autophagy) in neutrophils. NETs in turn enhanced cancer cell migration via TLR2/P38-MAPK/ERK/NFκB signaling and promoted lymphangiogenesis and lymphatic vessel permeability. DNase 1-mediated NETs digestion or TLR2 inhibition abolished NETs-induced metastatic potential.\",\n      \"method\": \"Neutrophil chemotaxis assay, ROS measurement, DNase 1 treatment, TLR2 siRNA/inhibitor, S100A7-overexpressing cell lines, footpad implantation mouse model, immunohistochemistry\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays with in vivo mouse model; single lab, multiple functional readouts\",\n      \"pmids\": [\"39384116\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"S100A7 (psoriasin) is a Ca2+-binding EF-hand homodimer with a His3Asp zinc-chelating site at the dimer interface; its primary antimicrobial mechanism involves zinc sequestration from bacteria (and exploitation of this by pathogens such as N. gonorrhoeae TdfJ), and its oxidized (disulfide-bonded) form is required for full antibacterial activity. Extracellularly, S100A7 signals through RAGE in a zinc-dependent manner to activate ERK, NF-κB, and p38 MAPK, driving chemotaxis of leukocytes, tumor-associated macrophage recruitment, endothelial cell proliferation/angiogenesis, and cancer cell invasion and metastasis; intracellularly, S100A7 interacts with Jab1 (via a specific C-terminal binding domain), E-FABP, β6 integrin cytoplasmic tail, and β-catenin to modulate pro-survival (Akt/NF-κB), differentiation (GSK-3/MAPK), and invasion pathways, with its pro- versus anti-tumorigenic activity determined by ERα status of cells; its secretion is regulated by a TLR–NFκB/p38–caspase-1–IL-1α axis with caspase-8 downregulation sustaining chronic release, and its transcription is controlled by Stat3, PKC, NF-κB, and ERβ.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"S100A7 (psoriasin) is a calcium-binding EF-hand protein that functions as a dimer with a His3Asp zinc-coordination site at the dimer interface, acting both as a secreted antimicrobial/proinflammatory effector and as an intracellular signaling modulator in epithelial homeostasis and cancer [#0, #1]. Its atomic structure reveals a distorted N-terminal EF-hand that binds only one calcium ion strongly with no large conformational change, while two histidines and an aspartate from the dimer interface chelate zinc in a manner reminiscent of metalloproteases [#0, #1]. The protein is the principal E. coli-killing factor secreted by keratinocytes and the vaginal epithelium, and zinc saturation abolishes this activity, establishing zinc sequestration as the core antibacterial mechanism; full activity requires the central region (aa 35–80) and the zinc-binding motif, and the oxidized intramolecular-disulfide form (S100A7ox) is the active antibacterial species, with disulfide bonds enhancing metal sequestration at the His3Asp sites [#2, #3, #18, #27]. This nutritional-immunity function is exploited by Neisseria gonorrhoeae, whose outer membrane protein TdfJ binds human S100A7 and extracts its zinc via the ZnuABC transporter [#29]. Extracellularly, S100A7 signals through the receptor RAGE in a zinc-dependent manner to activate ERK, NF-κB, and p38 MAPK, driving leukocyte and macrophage chemotaxis, endothelial proliferation/angiogenesis, abnormal keratinocyte differentiation, and tumor growth and metastasis; in breast cancer models RAGE blockade or tumor-associated macrophage depletion abrogates its pro-tumorigenic effects, and downstream cPLA2/PGE2 production establishes an immunosuppressive microenvironment [#8, #10, #15, #23, #34]. Intracellularly, S100A7 engages partners that determine context-specific outcomes: it binds Jab1 (CSN5) through a defined C-terminal interface within its hydrophobic cleft to activate Akt/NF-κB pro-survival signaling in ERα-negative cells, stabilizes and reconstitutes the fatty-acid-binding activity of E-FABP in a zinc-disruptable cytosolic complex, binds the β6 integrin cytoplasmic tail to enable αvβ6-dependent carcinoma invasion, and associates with the β-catenin complex to promote its degradation [#5, #6, #7, #13, #28, #12]. Its dual pro- versus anti-tumorigenic behavior tracks with ERα status, suppressing β-catenin/TCF4 and migration in ERα-positive cells while promoting invasion in ERα-negative cells [#16]. S100A7 transcription is driven by Src/Stat3, STAT3 (downstream of IGF-1/IGF-1R, OSM/IL-6) and PKC and repressed by a TSLP–JAK2/STAT3/Sin3a axis, while its secretion follows a biphasic TLR–NF-κB/p38–caspase-1–IL-1α program sustained by caspase-8 downregulation [#9, #20, #25, #26, #31, #35, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining the atomic architecture answered how S100A7 binds metals: it is an EF-hand homodimer that binds one calcium per monomer without major conformational change, and—critically—forms a His3Asp zinc site at the dimer interface whose occupancy reorganizes the adjacent EF-hand loop.\",\n      \"evidence\": \"X-ray crystallography at 1.05 Å (MAD/holmium) and paired Zn-loaded/Zn-free structures at atomic resolution\",\n      \"pmids\": [\"9562557\", \"10026247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure alone did not establish the biological function of the zinc site\", \"No bound physiological ligand or partner in these structures\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of S100A7 as a transglutaminase substrate showed a covalent post-translational route to crosslink the protein at its solvent-exposed termini, providing a regulatory handle on its function.\",\n      \"evidence\": \"In vitro transglutaminase assays with recombinant S100 proteins and identification of reactive termini\",\n      \"pmids\": [\"11258932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequences of crosslinking on antimicrobial or signaling activity not established\", \"Physiological context of crosslinking unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linking the zinc site to biology, S100A7 was shown to be the principal keratinocyte-secreted E. coli-killing factor, with zinc saturation abolishing activity—establishing zinc sequestration as the antibacterial mechanism.\",\n      \"evidence\": \"In vitro bacterial killing, in vivo antibody neutralization in human skin, and zinc-saturation experiments\",\n      \"pmids\": [\"15568027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spectrum of susceptible organisms beyond E. coli not defined\", \"Structural requirements within the protein not yet mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Domain mapping clarified which regions confer antibacterial activity: the central region (aa 35–80) plus the zinc-binding motif are required, with proteolysis abolishing and EF-hand mutation/heat sparing activity.\",\n      \"evidence\": \"Recombinant protein mutagenesis with bacterial adhesion/survival, protease, and heat-denaturation assays\",\n      \"pmids\": [\"17159909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis for how the central region engages bacteria not resolved\", \"Role of redox state not yet considered\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extension to mucosal sites showed S100A7 is constitutively secreted and is the major E. coli-cidal factor of vaginal fluid, generalizing its antibacterial role beyond skin.\",\n      \"evidence\": \"HPLC fractionation coupled to bacterial killing in vaginal fluid plus organotypic epithelium\",\n      \"pmids\": [\"20571488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of constitutive secretion in this tissue not defined\", \"Interaction with commensal flora not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Redox biochemistry refined the antibacterial mechanism: the oxidized disulfide form (S100A7ox), not reduced or disulfide-null variants, is the active species, with disulfide bonds enhancing high-affinity zinc sequestration at the His3Asp sites.\",\n      \"evidence\": \"Reconstituted in vitro biochemistry, thioredoxin assays, Zn2+ affinity titrations, mutagenesis, and bacterial growth inhibition\",\n      \"pmids\": [\"28976190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo redox state at sites of action not measured\", \"Cysteine thiolates do not form an extra zinc site, leaving the disulfide's mechanistic role on metal affinity incompletely explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A pathogen counter-strategy was defined: N. gonorrhoeae TdfJ binds human S100A7 and extracts its zinc via ZnuABC, showing host nutritional immunity can be hijacked as a zinc source.\",\n      \"evidence\": \"Direct recombinant binding assay, ZnuABC-deficient mutant, human-versus-murine species specificity, and bacterial growth assays\",\n      \"pmids\": [\"31369630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other pathogens use analogous receptors not addressed\", \"Structural basis of the TdfJ–S100A7 interface not solved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing intracellular partnerships, S100A7 was localized to cytosol/ER and shown to redistribute to focal-adhesion-like structures on calcium elevation while binding and stabilizing E-FABP.\",\n      \"evidence\": \"Confocal immunofluorescence with calcium challenge and cross-linker co-precipitation in keratinocytes\",\n      \"pmids\": [\"12839573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of focal-adhesion localization not defined\", \"Single-lab imaging without orthogonal genetic perturbation\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The S100A7–E-FABP interaction was reconstituted with purified proteins, showing the complex restores oleic-acid binding and is disrupted by physiological zinc, linking S100A7's metal sensing to lipid-binding function.\",\n      \"evidence\": \"Overlay assay, in vitro reconstitution, oleic-acid binding, co-IP from psoriatic scale, and confocal microscopy\",\n      \"pmids\": [\"10191275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream physiological role of the lipid-binding complex unclear\", \"How zinc disruption is regulated in cells not shown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"S100A7 was shown to drive anchorage-independent survival in ERα-negative breast cancer through a defined Jab1-binding domain activating NF-κB and Akt, identifying a pro-survival intracellular signaling node.\",\n      \"evidence\": \"Stable transfection, reciprocal IP, yeast two-hybrid, binding-domain mutagenesis, reporter assays, and xenografts\",\n      \"pmids\": [\"15994944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Jab1 binding links to Akt/EGFR not fully resolved\", \"ERα-dependence of the effect not yet explained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Structural and biophysical mapping localized the Jab1 interface to residues in the N-terminal hydrophobic cleft (with Met12 as a gatekeeper), connecting the dye-binding pocket to protein-protein interaction.\",\n      \"evidence\": \"Crystal structures with naphthalene dyes at 1.6 Å, fluorescence, ITC, and yeast two-hybrid mutagenesis\",\n      \"pmids\": [\"19810752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-structure with Jab1 not determined\", \"Whether endogenous ligands occupy the cleft in vivo unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"S100A7 was shown to bind the β6 integrin cytoplasmic tail and be required for αvβ6-dependent carcinoma invasion, defining an integrin-linked invasion mechanism.\",\n      \"evidence\": \"Proteomic pull-down, reciprocal co-IP, siRNA, Transwell/organotypic invasion, and Tat-peptide competition\",\n      \"pmids\": [\"21132011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling downstream of the S100A7–β6 complex not delineated\", \"Calcium/zinc dependence of the interaction not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of RAGE as the extracellular receptor explained how S100A7 acts as a chemoattractant and why its signaling is zinc-dependent, distinguishing it from the RAGE-independent paralog S100A15.\",\n      \"evidence\": \"Chemotaxis and in vitro binding assays with zinc-dependence and an in vivo inflammation model\",\n      \"pmids\": [\"18606705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the S100A7–RAGE complex not solved\", \"Contribution of other receptors not excluded\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"S100A7–RAGE signaling was shown to drive breast cancer invasion and modulate EGFR-family signaling, while a reciprocal study established S100A7 as a negative regulator of β-catenin via GSK3β-independent degradation in oral SCC.\",\n      \"evidence\": \"shRNA and overexpression, phospho-Westerns, co-IP, β-catenin degradation assays, angiogenesis and xenograft/in vivo models\",\n      \"pmids\": [\"18320059\", \"18223693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of GSK3β-independent β-catenin degradation unresolved\", \"How RAGE signaling intersects with intracellular β-catenin regulation unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The pro- versus anti-tumorigenic switch was resolved through ERα status: in ERα-positive cells S100A7 suppresses migration and tumor growth by downregulating β-catenin/TCF4 and raising GSK3β activity, opposite to its ERα-negative role.\",\n      \"evidence\": \"Stable overexpression, GSK3β inhibitor rescue, migration/proliferation assays, and nude-mouse xenografts\",\n      \"pmids\": [\"22016394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between ERα status and divergent β-catenin handling not defined\", \"Single-lab system\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"In vivo transgenic and macrophage-depletion studies established RAGE-mediated tumor-associated macrophage recruitment as a central effector of S100A7's pro-tumorigenic activity.\",\n      \"evidence\": \"MMTV-mS100a7a15 transgenic mice, chemotaxis assays, in vivo TAM depletion, and tumor/metastasis quantification (also RAGE-deficient mice and sRAGE)\",\n      \"pmids\": [\"22158945\", \"25572331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chemokine ligands recruiting TAMs not fully enumerated\", \"Whether epithelial-intrinsic vs stromal RAGE dominates not dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"S100A7 was shown to promote angiogenesis through RAGE by increasing VEGF and driving ROS-dependent endothelial proliferation and tube formation, linking it to tumor vascularization.\",\n      \"evidence\": \"Recombinant protein treatment, sRAGE blockade, ROS measurement, antioxidant Bcl-2, plus ROS/hypoxia induction and angiogenic-factor readouts in keratinocytes\",\n      \"pmids\": [\"22189627\", \"27155199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs paracrine endothelial effects not fully separated\", \"Single-lab angiogenesis assays\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Direct binding of S100A7 to RAGE was confirmed and shown to be required for osteosarcoma migration, invasion, and MMP activity, generalizing the RAGE axis beyond breast cancer.\",\n      \"evidence\": \"Recombinant protein pull-down, RAGE siRNA, and migration/invasion/MMP assays\",\n      \"pmids\": [\"22783409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling in osteosarcoma not mapped\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"In keratinocyte biology, S100A7 was shown to strengthen the tight-junction barrier and modulate differentiation through GSK-3/MAPK and PKC pathways, defining roles in epidermal homeostasis distinct from cancer signaling.\",\n      \"evidence\": \"TER and permeability assays, GSK-3/MAPK and PKC inhibitors, siRNA/lentiviral perturbation, and differentiation-marker analysis\",\n      \"pmids\": [\"24842328\", \"27958610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether barrier and differentiation effects require RAGE not resolved\", \"Reconciliation with pro-differentiation vs abnormal-differentiation outcomes incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"RAGE-MyD88-NF-κB signaling by extracellular S100A7 was shown to upregulate IL-6 and shift keratinocytes toward abnormal differentiation, mechanistically connecting S100A7 to psoriasis-like epidermal phenotypes.\",\n      \"evidence\": \"Recombinant protein treatment, RAGE pathway analysis, and differentiation-marker readouts in 2D and reconstituted human epidermis\",\n      \"pmids\": [\"27060579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of IL-6 vs other RAGE outputs not quantified\", \"In vivo validation in human psoriasis limited\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A RAGE-p38-calpain-1 cascade was defined linking S100A7 to mature IL-1α production, and a separate TLR3-p38 injury pathway was shown to induce S100A7 driving loricrin and wound closure, placing S100A7 within inflammatory amplification loops.\",\n      \"evidence\": \"Recombinant protein, pathway inhibitors, siRNA of RAGE/p38/calpain-1, imiquimod psoriasis model, and TLR3-ligand wound-closure assays\",\n      \"pmids\": [\"28060905\", \"27535424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Feedback between IL-1α/IL-17 and S100A7 only partially mapped\", \"In vivo causality in human disease not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Flagellin/TLR5 was identified as the principal microbial inducer of S100A7 in keratinocytes, defining the upstream sensing that triggers its antimicrobial expression.\",\n      \"evidence\": \"TLR ligand screen, ΔFliC E. coli mutant, and TLR5 siRNA with RT-PCR/protein readout\",\n      \"pmids\": [\"18263703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors downstream of TLR5 not fully resolved here\", \"Other inducers (e.g., cytokines) addressed in separate studies\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Secretion control was resolved as biphasic: an acute TLR–NF-κB/p38–caspase-1–IL-1α phase and a chronic phase sustained by caspase-8 downregulation, explaining constitutive S100A7 release in inflammatory skin disease.\",\n      \"evidence\": \"Pathway-inhibitor and caspase-8 siRNA dissection with TLR stimulation and secretion assays\",\n      \"pmids\": [\"31775025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of caspase-8 downregulation in disease not defined\", \"Non-classical secretion route not structurally characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Transcriptional regulation was mapped to STAT3-centered control: STAT3 directly binds the S100A7 promoter and is engaged downstream of Src, OSM/IL-6, and IGF-1/IGF-1R to induce S100A7, while a TSLP–JAK2/STAT3/Sin3a complex represses it.\",\n      \"evidence\": \"Promoter/reporter and ChIP assays, pharmacological inhibitors, CRISPR IGF-1R KO, siRNA, and skin-equivalent/cancer models\",\n      \"pmids\": [\"27498343\", \"20101226\", \"31731716\", \"33557316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the same factor (STAT3) yields activation vs repression in different contexts unresolved\", \"Cofactor switching (e.g., Sin3a) only partially defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The immune-modulatory output of S100A7/RAGE was extended to immunosuppression: signaling induces cPLA2/PGE2 to recruit suppressive myeloid cells and exclude T cells, and to drive neutrophil/NET-mediated metastasis, identifying targetable downstream effectors.\",\n      \"evidence\": \"Transgenic and PDX models with cPLA2 inhibitor and CODEX imaging; plus neutrophil/NET assays with DNase1 and TLR2 inhibition in cervical cancer models\",\n      \"pmids\": [\"35135586\", \"39384116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cPLA2 and NET pathways operate in the same tumors not established\", \"Relative contribution to clinical immune evasion unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same protein integrates its three modes—zinc-sequestering antimicrobial, RAGE-engaging proinflammatory ligand, and ERα-dependent intracellular signaling switch—into a unified context-dependent regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of S100A7 bound to RAGE, Jab1, β6, or β-catenin\", \"Molecular basis of the ERα-dependent pro/anti-tumorigenic switch undefined\", \"In vivo coupling between redox state, metal occupancy, and which function dominates not measured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1, 2, 27, 29]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [8, 10, 21]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 12, 28]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 8, 24, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 10, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 15, 16, 34]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [22, 26, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RAGE\",\n      \"JAB1\",\n      \"E-FABP\",\n      \"ITGB6\",\n      \"CTNNB1\",\n      \"TdfJ\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":8,"faith_total":8,"faith_pct":100.0}}