{"gene":"S100A14","run_date":"2026-04-28T20:42:06","timeline":{"discoveries":[{"year":2002,"finding":"S100A14 was identified as a new S100 family member with two EF-hand Ca2+-binding domains; epitope-tagged S100A14 localizes to the cytoplasm with association to the plasma membrane and perinuclear area in lung carcinoma and monkey cell lines.","method":"cDNA cloning, sequence analysis, epitope-tag transfection with immunofluorescence/subcellular fractionation","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment in multiple cell lines; single lab, initial characterization study","pmids":["11944983"],"is_preprint":false},{"year":2011,"finding":"Extracellular S100A14 binds to RAGE (receptor for advanced glycation end products) in esophageal squamous cell carcinoma cells, activating ERK1/2 MAPK and NF-κB signaling to stimulate cell proliferation at low doses; mutation of the N-EF hand (E39A, E45A) reduces S100A14-induced cell proliferation and ERK1/2 activation. At high doses, S100A14 induces apoptosis via the mitochondrial pathway (caspase-3, -9, PARP), partially RAGE-dependent.","method":"Co-immunoprecipitation, siRNA knockdown of RAGE, dominant-negative RAGE construct, RAGE antagonist peptide, EF-hand point mutagenesis, ERK1/2 and NF-κB activity assays, caspase activation assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including mutagenesis, dominant-negative, antagonist peptide, and Co-IP in same study","pmids":["21559403"],"is_preprint":false},{"year":2012,"finding":"S100A14 promotes cell motility and invasiveness of esophageal squamous cell carcinoma cells by upregulating MMP-2 expression through a p53-dependent mechanism: S100A14 affects p53 transactivity and stability, and p53 transrepresses MMP-2 transcription; MMP-2 inhibition partially reverses the invasive phenotype.","method":"Ectopic overexpression, MMP-2 inhibitor treatment, series of biochemical assays (reporter assays, Co-IP for p53 interaction), RT-qPCR in human breast cancer specimens","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing pathway epistasis between S100A14, p53, and MMP-2","pmids":["22451655"],"is_preprint":false},{"year":2012,"finding":"The solution structure of homodimeric human S100A14 in the apo state was solved by NMR, showing that S100A14 does not bind calcium ions and adopts a 'semi-open' conformation; lack of two canonical EF-hand ligands explains negligible Ca2+ affinity; exposed cysteines and histidine cause precipitation in the presence of zinc(II) or copper(II).","method":"NMR solution structure determination, metal-binding assays","journal":"Journal of biological inorganic chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structural determination with biochemical validation of metal-binding properties","pmids":["23197251"],"is_preprint":false},{"year":2013,"finding":"S100A14 directly binds to HER2 via co-immunoprecipitation and pull-down assays; the binding requires residues 956–1154 of the HER2 intracellular domain and residue 83 of S100A14; S100A14 silencing decreases HER2 phosphorylation and downstream PI3K/AKT and MAPK/ERK signaling and reduces HER2-stimulated cell proliferation.","method":"Co-immunoprecipitation, GST pull-down, deletion/point mutant mapping, siRNA knockdown, phosphorylation assays, proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP and pull-down with mutant mapping plus functional downstream signaling readouts","pmids":["24285542"],"is_preprint":false},{"year":2013,"finding":"S100A14 interacts with S100A16 as its single binding partner identified by yeast two-hybrid screen, confirmed by co-immunoprecipitation and co-immunofluorescence; overexpression of S100A14 leads to concomitant upregulation of S100A16 protein (but not mRNA), suggesting post-transcriptional regulation; the regulation is unidirectional (S100A16 overexpression does not affect S100A14).","method":"Yeast two-hybrid screen, co-immunoprecipitation, double indirect immunofluorescence, retroviral overexpression and knockdown, cycloheximide chase, qRT-PCR","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid plus reciprocal Co-IP plus functional validation with multiple cell lines and orthogonal approaches","pmids":["24086685"],"is_preprint":false},{"year":2013,"finding":"S100A14 is transcriptionally regulated by JunB, which binds the S100A14 promoter and controls expression during esophageal cancer cell differentiation; S100A14 mediates calcium-induced G1-phase cell cycle arrest and promotes expression of late differentiation markers involucrin (IVL) and filaggrin (FLG).","method":"ChIP, promoter reporter assays, overexpression and siRNA knockdown, cell cycle analysis, qRT-PCR for differentiation markers","journal":"Molecular cancer research","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus reporter assay plus KD/OE functional readouts in multiple systems","pmids":["24107296"],"is_preprint":false},{"year":2009,"finding":"The S100A14 gene contains a functional p53-binding site in its promoter; a SNP (461G>A) disrupts this p53-binding site and is associated with decreased S100A14 expression in vitro and in vivo, placing S100A14 downstream of p53 transcriptional regulation.","method":"DNA sequencing, p53-binding site mutagenesis, reporter assays, in vitro and in vivo expression analysis, case-control study","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — p53-binding site identified and functionally validated with mutagenesis and expression assays","pmids":["19351828"],"is_preprint":false},{"year":2011,"finding":"Overexpression of S100A14 in oral squamous carcinoma cells (harboring wild-type p53) induces G1-arrest with upregulation of p21; nuclear accumulation of p53 occurs upon S100A14 overexpression; shRNA-mediated p53 silencing partially suppresses S100A14-induced p21 upregulation, indicating functional linkage between S100A14 and the p53/p21 axis.","method":"Retroviral overexpression, shRNA knockdown of p53, cell cycle analysis, Western blot for p21 and nuclear p53","journal":"Oral oncology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD/KO with defined phenotype and epistasis experiment; single lab","pmids":["22032898"],"is_preprint":false},{"year":2010,"finding":"S100A14 regulates invasion of oral squamous cell carcinoma cells by modulating MMP1 and MMP9 expression: retroviral overexpression of S100A14 decreases invasive potential and downregulates MMP1 and MMP9 mRNA and MMP9 gelatinolytic activity, while siRNA knockdown increases invasion.","method":"Retroviral overexpression, siRNA knockdown, Matrigel invasion assay, PCR array, qRT-PCR, zymography","journal":"European journal of cancer","confidence":"High","confidence_rationale":"Tier 2 — bidirectional genetic manipulation (OE and KD) with multiple functional and mechanistic readouts in multiple cell lines","pmids":["21074410"],"is_preprint":false},{"year":2014,"finding":"KLF4 transcription factor directly binds two conserved GC-rich DNA segments within the S100A14 promoter, driving S100A14 transcriptional activation in response to TPA; stable silencing of KLF4 suppresses TPA-induced S100A14 upregulation and breast cancer cell migration.","method":"ChIP, promoter deletion/mutation analysis, reporter assays, stable shRNA knockdown, migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus reporter assay with functional KD readout; multiple orthogonal methods in single study","pmids":["24532790"],"is_preprint":false},{"year":2017,"finding":"S100A14 induces differentiation of gastric cancer cells by upregulating E-cadherin and PGII expression, and inhibits metastasis by blocking store-operated Ca2+ influx through suppression of Orai1 and STIM1 expression, leading to FAK activation, focal adhesion assembly, and MMP downregulation.","method":"Overexpression and knockdown, Western blot for E-cadherin/PGII/Orai1/STIM1/FAK/MMPs, Ca2+ influx assay, migration/invasion assays, in vivo mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple molecular readouts with in vitro and in vivo experiments; single lab","pmids":["28726786"],"is_preprint":false},{"year":2020,"finding":"S100A14 promotes breast cancer metastasis by upregulating expression and secretion of CCL2 and CXCL5 via RAGE-NF-κB-mediated transcription; NF-κB ChIP confirmed binding to CCL2/CXCL5 promoters; S100A14 knockout abolishes this effect.","method":"RNA-Seq, secreted proteomics, ChIP for NF-κB, ELISA, transwell assay, neutralizing antibodies, S100A14 knockout and overexpression, mouse metastasis experiments","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including ChIP, proteomics, KO/OE, and in vivo models across multiple systems","pmids":["32483412"],"is_preprint":false},{"year":2020,"finding":"S100A14 suppresses NPC metastasis by promoting ubiquitin-proteasome-mediated degradation of IRAK1, thereby inhibiting NF-κB signaling and reversing EMT; S100A14 and IRAK1 form a feedback loop that can be disrupted by the IRAK1 inhibitor T2457.","method":"Gain- and loss-of-function studies, ubiquitination assays, Western blot for IRAK1 and NF-κB pathway, in vitro and in vivo motility assays, IHC of 202 NPC samples","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — bidirectional genetic manipulation with mechanistic ubiquitination assay and pathway epistasis; validated in vivo","pmids":["32555330"],"is_preprint":false},{"year":2022,"finding":"S100A14 inhibits PD-L1 expression in colorectal cancer by directly interacting with STAT3 and inducing its proteasome-mediated degradation; gain-of-S100A14 reduces STAT3-driven PD-L1 transcription, while loss-of-S100A14 increases PD-L1, cancer stem cell phenotypes, and chemoresistance.","method":"Co-IP of S100A14-STAT3, proteasome inhibitor rescue, PD-L1 expression assays, gain/loss-of-function in vitro and in vivo, chemoresistant CRC subline models","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 2 — Co-IP for direct interaction plus proteasome inhibitor validation plus bidirectional functional assays in vitro and in vivo","pmids":["35858011"],"is_preprint":false},{"year":2016,"finding":"SOX2 binds the 3'-UTR of S100A14 mRNA via a stem-loop structure, stabilizing S100A14 mRNA and enhancing its expression; depletion of SOX2 decreases S100A14 mRNA and protein levels, and knockdown of S100A14 phenocopies SOX2 depletion in increasing cell mobility in urothelial carcinoma.","method":"Oligomer-directed RNase H digestion, CLIP (cross-linking immunoprecipitation), EGFP-3'UTR reporter assay, mobility shift assay, siRNA knockdown, cell growth and migration assays","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 2 — CLIP plus reporter assay plus functional epistasis; single lab","pmids":["28955911"],"is_preprint":false},{"year":2015,"finding":"S100A14 overexpression in cervical cancer cells promotes EMT by increasing N-cadherin and Vimentin while decreasing E-cadherin; S100A14 overexpression increases G2/M phase proportion, proliferation, migration, and invasion, while knockdown reverses these effects.","method":"Lentiviral overexpression and knockdown, cell cycle analysis, transwell migration and invasion assays, Western blot for EMT markers","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional genetic manipulation with multiple phenotypic readouts; single lab","pmids":["26101712"],"is_preprint":false},{"year":2019,"finding":"Extracellular S100A14 protein activates NK cells in a PBMC co-culture system (but not purified NK cells alone); treatment of purified monocytes with recombinant S100A14 induces TNF-alpha secretion and promotes NK cell CD69 activation via a TLR4-dependent interaction in co-culture.","method":"Recombinant protein treatment, PBMC/purified NK/monocyte co-culture, TLR4 blocking, ELISA for TNF-alpha, flow cytometry for CD69","journal":"Journal of acquired immune deficiency syndromes","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro functional assay with TLR4 blocking control; single lab","pmids":["30422902"],"is_preprint":false},{"year":2022,"finding":"ZHX2 transcriptionally inhibits S100A14 by binding to the S100A14 promoter; ZHX2 knockdown promotes thyroid cancer cell migration, an effect attenuated by S100A14 inhibition, placing S100A14 downstream of ZHX2 in this pro-metastatic axis.","method":"ChIP for ZHX2 at S100A14 promoter, ZHX2 and S100A14 knockdown, migration assay, wound healing, in vivo lung metastasis model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus epistasis (rescue experiment) with in vivo validation; single lab","pmids":["35151335"],"is_preprint":false},{"year":2022,"finding":"TP63 transcriptionally activates S100A14 expression by occupying its enhancer region together with SOX2 and EP300; disruption of this enhancer reduces S100A14 expression and dramatically promotes 4NQO-induced ESCC tumorigenesis in mice.","method":"ChIP for TP63/SOX2/EP300 at S100A14 enhancer, enhancer disruption (CRISPR or deletion), 4NQO mouse tumorigenesis model, survival analysis","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 — ChIP with multiple factors plus in vivo genetic loss-of-function model with survival readout","pmids":["35917972"],"is_preprint":false},{"year":2024,"finding":"CTBP1-AS lncRNA blocks TP63-mediated transcriptional activation of S100A14, thereby reducing S100A14 expression; CTBP1-AS silencing suppresses proliferation, migration, invasion and tumorigenicity of prostate cancer cells, while TP63 overexpression further weakens malignant phenotype unless S100A14 is artificially silenced.","method":"Bioinformatics, qRT-PCR, Western blot, lentiviral overexpression/silencing, transcriptional activation assays, proliferation/apoptosis/migration/invasion assays, epistasis rescue experiment","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis rescue experiment establishing CTBP1-AS→TP63→S100A14 regulatory axis; single lab","pmids":["38476086"],"is_preprint":false},{"year":2025,"finding":"S100A14 binds to glutaminase (GLS) and blocks its phosphorylation at Y308 and S314, which inhibits GLS ubiquitination and subsequent proteasomal degradation, thereby stabilizing GLS; this reduces oxidative stress in HCC cells and antagonizes sorafenib-induced apoptosis.","method":"Co-immunoprecipitation, mass spectrometry to identify GLS as S100A14 binding partner, phosphorylation site mapping, ubiquitination assays, cell viability assays, in vivo xenograft experiments","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP with MS identification, phosphorylation site mapping, ubiquitination assay, and in vivo validation; multiple orthogonal methods","pmids":["40217256"],"is_preprint":false},{"year":2025,"finding":"Mfsd2a interacts with S100A14 (identified by Co-IP and mass spectrometry), enhancing S100A14 expression and thereby inhibiting STAT3 phosphorylation; this suppresses CRC cell proliferation, migration, invasion, EMT, and liver metastasis.","method":"Co-immunoprecipitation, mass spectrometry, immunofluorescence, Western blot for p-STAT3, in vitro functional assays, in vivo tumor growth and liver metastasis models, STAT3 activator rescue","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus MS with functional epistasis (colivelin rescue); single lab","pmids":["39806334"],"is_preprint":false},{"year":2026,"finding":"S100A14 in tumor-derived extracellular vesicles (EVs) directly targets PIAS3 in astrocytes to activate STAT3 signaling, reprogramming astrocytes to secrete pro-inflammatory chemokines (CCL2/CCL5/CXCL5) that recruit immunosuppressive MDSCs and promote brain metastasis; the natural compound germacrone disrupts the S100A14-PIAS3 interaction to suppress this pathway.","method":"DIA-based proteomics of EVs, intracardiac injection mouse model, non-contact co-culture, multiplex cytokine profiling, MDSCs recruitment transwell assay, Co-IP for S100A14-PIAS3 interaction, Western blot for STAT3, CETSA/DARTS for germacrone binding","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP for direct binding plus in vivo model plus mechanistic pathway; single lab, preprint-era publication","pmids":["41961478"],"is_preprint":false},{"year":2026,"finding":"Extracellular S100A14 from tumor-derived EVs targets astrocytic TLR4, activating NF-κB signaling and reprogramming astrocytes to secrete IL-6, CCL2, and CXCL1, thereby recruiting polymorphonuclear and monocytic MDSCs and establishing an immunosuppressive brain niche promoting metastasis.","method":"TMT-based quantitative proteomics, intracardiac mouse model, non-contact co-culture with primary astrocytes, multiplex cytokine profiling, MDSCs transwell recruitment assay, CETSA/DARTS for curdione binding to S100A14","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — proteomics plus in vivo model plus mechanistic co-culture assay; single lab","pmids":["41691987"],"is_preprint":false},{"year":2026,"finding":"S100A14 directly interacts with S100A16 (confirmed by Co-IP); S100A14 stabilizes S100A16 protein through post-translational modification without transcriptional regulation; the S100A14/S100A16 axis reduces p53 protein stability and inhibits p53 transcriptional activity and downstream p21 expression in pancreatic cancer.","method":"Co-immunoprecipitation, CHX chase assay, dual-luciferase reporter assay for p53 transcriptional activity, Western blot, qRT-PCR, CCK-8, Transwell, apoptosis assays","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus CHX chase plus reporter assay establishing the S100A14→S100A16→p53 axis; single lab","pmids":["41799516"],"is_preprint":false},{"year":2021,"finding":"S100A14 promotes cell growth and inhibits EMT in prostate cancer through activating FAT1 expression and the downstream Hippo pathway; S100A14 suppresses proliferation and motility of prostate cancer cells, confirmed in vivo in mouse xenograft models.","method":"Overexpression and knockdown of S100A14, Western blot for FAT1 and Hippo pathway components, proliferation/apoptosis/migration/invasion assays, mouse xenograft experiments","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional manipulation with pathway readout and in vivo validation; single lab","pmids":["33890248"],"is_preprint":false}],"current_model":"S100A14 is an EF-hand calcium-binding protein (which paradoxically does not bind Ca2+ in solution and adopts a semi-open apo conformation) that functions as a context-dependent regulator of cancer cell behavior: extracellularly it signals through RAGE to activate ERK1/2 and NF-κB, promotes metastasis via NF-κB-driven CCL2/CXCL5 secretion, and activates TLR4 on innate immune cells; intracellularly it modulates p53 stability and transcription, suppresses IRAK1 and STAT3 via proteasomal degradation, forms functional heterodimers with S100A16 (stabilizing it post-translationally to suppress p53/p21), binds and stabilizes glutaminase to reduce oxidative stress, directly interacts with HER2 to potentiate its downstream signaling, and is transcriptionally controlled by p53, JunB, KLF4, TP63, SOX2 (as an RNA-binding protein at the 3'-UTR), and enhancer-associated factors (TP63/SOX2/EP300)."},"narrative":{"teleology":[{"year":2002,"claim":"Identification of S100A14 as a new S100 family member with cytoplasmic and plasma membrane localization established its basic molecular identity and subcellular context.","evidence":"cDNA cloning with epitope-tag immunofluorescence and subcellular fractionation in lung carcinoma and COS cells","pmids":["11944983"],"confidence":"Medium","gaps":["No endogenous antibody validation at this stage","Functional role entirely unknown","Metal-binding properties not tested"]},{"year":2009,"claim":"Discovery of a functional p53-binding site in the S100A14 promoter placed S100A14 as a direct p53 transcriptional target, establishing the first regulatory link to a major tumor suppressor.","evidence":"Promoter mutagenesis, reporter assays, and SNP (461G>A) expression analysis in vitro and in vivo","pmids":["19351828"],"confidence":"High","gaps":["Whether p53 activation or repression of S100A14 is context-dependent was not resolved","Downstream effectors of S100A14 were unknown"]},{"year":2010,"claim":"Bidirectional manipulation of S100A14 in oral cancer cells revealed it suppresses invasion by downregulating MMP1/MMP9, providing the first direct evidence for a functional role in invasion regulation.","evidence":"Retroviral overexpression, siRNA knockdown, Matrigel invasion assay, zymography","pmids":["21074410"],"confidence":"High","gaps":["Mechanism connecting S100A14 to MMP transcription was not established","Generalizability to other cancer types unclear"]},{"year":2011,"claim":"Demonstration that extracellular S100A14 binds RAGE and activates ERK1/2 and NF-κB revealed a receptor-mediated extracellular signaling function, with EF-hand mutagenesis confirming structural requirements for activity; concurrently, intracellular S100A14 was shown to activate the p53/p21 axis and induce G1 arrest.","evidence":"Co-IP, dominant-negative RAGE, RAGE antagonist peptide, EF-hand mutants, caspase assays (PMID:21559403); retroviral overexpression with p53 shRNA epistasis (PMID:22032898)","pmids":["21559403","22032898"],"confidence":"High","gaps":["Whether RAGE and p53 pathways converge or represent independent S100A14 functions was unresolved","Dose-dependent switch between proliferation and apoptosis mechanism unclear"]},{"year":2012,"claim":"NMR structure of apo S100A14 revealed it does not bind Ca²⁺ and adopts a semi-open conformation, fundamentally distinguishing it from canonical S100 proteins and resolving the paradox of its classification as a calcium-binding protein.","evidence":"NMR solution structure determination with metal-binding assays","pmids":["23197251"],"confidence":"High","gaps":["How S100A14 achieves ligand recognition without calcium-induced conformational change was not explained","No structure of S100A14 in complex with any partner"]},{"year":2012,"claim":"Mechanistic epistasis experiments connected S100A14 to p53 transactivity and stability, with p53-dependent transrepression of MMP-2 explaining S100A14's pro-invasive phenotype in esophageal cancer.","evidence":"Reporter assays, Co-IP for p53, MMP-2 inhibitor rescue in esophageal and breast cancer cells","pmids":["22451655"],"confidence":"High","gaps":["Whether S100A14 directly binds p53 or acts through an intermediary was not definitively resolved","Context dependency (pro-invasive in esophageal vs. anti-invasive in oral cancer) unexplained"]},{"year":2013,"claim":"Identification of S100A16 as the sole direct binding partner of S100A14 by yeast two-hybrid, with unidirectional post-translational stabilization, established a functional heterodimerization axis; simultaneously, direct binding to HER2 and JunB-driven transcription were established.","evidence":"Yeast two-hybrid, reciprocal Co-IP, cycloheximide chase (PMID:24086685); Co-IP, GST pull-down, mutant mapping for HER2 (PMID:24285542); ChIP and reporter assay for JunB (PMID:24107296)","pmids":["24086685","24285542","24107296"],"confidence":"High","gaps":["How the S100A14-S100A16 heterodimer differs structurally from the S100A14 homodimer was unknown","Whether HER2 and S100A16 binding are mutually exclusive was untested","Functional consequences of S100A14-S100A16 interaction beyond protein stability were unclear"]},{"year":2014,"claim":"KLF4 was identified as a direct transcriptional activator of S100A14 through GC-rich promoter elements, adding to the growing network of transcription factors (p53, JunB, KLF4) controlling S100A14 expression.","evidence":"ChIP, promoter deletion/mutation reporter assays, stable shRNA knockdown with migration readout","pmids":["24532790"],"confidence":"High","gaps":["Integration of multiple transcription factor inputs at the S100A14 promoter was not modeled","Chromatin context of KLF4 binding not explored"]},{"year":2016,"claim":"SOX2 was found to bind the 3'-UTR of S100A14 mRNA as an RNA-binding protein, stabilizing the transcript post-transcriptionally — an unusual mechanism for a transcription factor.","evidence":"CLIP, RNase H mapping, EGFP-3'UTR reporter assay, siRNA epistasis in urothelial carcinoma","pmids":["28955911"],"confidence":"Medium","gaps":["SOX2 RNA-binding specificity determinants and generalizability to other mRNAs not established","Single lab finding","Structural basis of SOX2-S100A14 mRNA interaction unknown"]},{"year":2020,"claim":"Two studies resolved opposing S100A14 roles in NF-κB signaling: extracellular S100A14 activates RAGE-NF-κB to drive CCL2/CXCL5-dependent breast cancer metastasis, while intracellular S100A14 suppresses NF-κB in nasopharyngeal cancer by promoting IRAK1 proteasomal degradation.","evidence":"RNA-Seq, secreted proteomics, NF-κB ChIP, S100A14 KO, mouse metastasis (PMID:32483412); ubiquitination assays, bidirectional genetic manipulation, in vivo motility (PMID:32555330)","pmids":["32483412","32555330"],"confidence":"High","gaps":["How context (intracellular vs. extracellular, cell type) determines opposing NF-κB outcomes is not mechanistically resolved","E3 ligase recruited by S100A14 for IRAK1 ubiquitination not identified"]},{"year":2022,"claim":"S100A14 was shown to directly interact with STAT3 and promote its proteasomal degradation, suppressing PD-L1 expression in colorectal cancer; separately, TP63/SOX2/EP300 were found to co-occupy an S100A14 enhancer whose disruption promotes esophageal tumorigenesis.","evidence":"Co-IP of S100A14-STAT3, proteasome inhibitor rescue (PMID:35858011); ChIP for TP63/SOX2/EP300, enhancer CRISPR disruption, 4NQO mouse model (PMID:35917972)","pmids":["35858011","35917972"],"confidence":"High","gaps":["E3 ligase mediating STAT3 degradation not identified","Whether enhancer disruption effects are solely S100A14-dependent or involve neighboring genes not fully excluded"]},{"year":2025,"claim":"S100A14 was found to bind glutaminase (GLS), blocking phosphorylation at Y308/S314 and subsequent ubiquitination, thereby stabilizing GLS and reducing oxidative stress in hepatocellular carcinoma; additionally, Mfsd2a was identified as a physical partner that enhances S100A14 expression to inhibit STAT3.","evidence":"Co-IP with MS identification, phosphosite mapping, ubiquitination assay, xenograft (PMID:40217256); Co-IP/MS and STAT3 activator rescue (PMID:39806334)","pmids":["40217256","39806334"],"confidence":"High","gaps":["Kinase phosphorylating GLS at Y308/S314 not identified","Mechanism by which Mfsd2a enhances S100A14 expression unknown","Whether GLS stabilization occurs in non-cancer contexts untested"]},{"year":2026,"claim":"Extracellular vesicle-delivered S100A14 was shown to reprogram brain astrocytes by targeting PIAS3 (activating STAT3) and TLR4 (activating NF-κB), establishing S100A14 as a key mediator of immunosuppressive brain pre-metastatic niche formation; the S100A14-S100A16 axis was further shown to destabilize p53 in pancreatic cancer.","evidence":"DIA proteomics, intracardiac mouse model, Co-IP for PIAS3, CETSA/DARTS (PMID:41961478); TMT proteomics, TLR4-dependent astrocyte co-culture (PMID:41691987); Co-IP, CHX chase, p53 reporter assay (PMID:41799516)","pmids":["41961478","41691987","41799516"],"confidence":"Medium","gaps":["All three findings from single labs; independent replication needed","How S100A14 is selectively loaded into EVs is unknown","Whether PIAS3 and TLR4 engagement by S100A14 occurs simultaneously or in distinct EV subpopulations is unresolved","Structural basis of S100A14-PIAS3 interaction not determined"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of S100A14's calcium-independent partner recognition; identification of E3 ligases it recruits for IRAK1 and STAT3 degradation; the mechanism determining whether S100A14 activates or suppresses NF-κB/STAT3 in different cell types; and whether its EV-mediated extracellular functions are relevant in normal physiology.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal or cryo-EM structure of S100A14 with any partner","No unifying model for context-dependent pro- vs. anti-metastatic activity","Normal physiological role outside cancer poorly studied"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,13,14,21]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5,23]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,12,17,23,24]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[23,24]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,12,13,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,23,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13,14,21]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,10,19]}],"complexes":["S100A14-S100A16 heterodimer"],"partners":["S100A16","ERBB2","AGER","TP53","IRAK1","STAT3","GLS","PIAS3"],"other_free_text":[]},"mechanistic_narrative":"S100A14 is an EF-hand-containing S100 family member that functions as a context-dependent signaling scaffold linking calcium-independent protein-protein interactions to transcriptional and post-translational control of cell proliferation, differentiation, invasion, and immune modulation. Structurally, S100A14 homodimerizes but does not bind calcium, adopting a semi-open apo conformation due to loss of canonical EF-hand ligands [PMID:23197251]. Extracellularly, S100A14 signals through RAGE to activate ERK1/2 and NF-κB, driving chemokine secretion (CCL2, CXCL5) that promotes metastasis, and engages TLR4 on monocytes and astrocytes to stimulate innate immune activation and immunosuppressive niche formation [PMID:21559403, PMID:32483412, PMID:30422902, PMID:41691987]. Intracellularly, S100A14 directly binds HER2 to potentiate PI3K/AKT and MAPK signaling [PMID:24285542], heterodimerizes with S100A16 to destabilize p53 and suppress p21 [PMID:24086685, PMID:41799516], promotes proteasomal degradation of IRAK1 and STAT3 to inhibit NF-κB and PD-L1 expression [PMID:32555330, PMID:35858011], and stabilizes glutaminase by blocking its phosphorylation-dependent ubiquitination to reduce oxidative stress [PMID:40217256]."},"prefetch_data":{"uniprot":{"accession":"Q9HCY8","full_name":"Protein S100-A14","aliases":["S100 calcium-binding protein A14","S114"],"length_aa":104,"mass_kda":11.7,"function":"Modulates P53/TP53 protein levels, and thereby plays a role in the regulation of cell survival and apoptosis. Depending on the context, it can promote cell proliferation or apoptosis. Plays a role in the regulation of cell migration by modulating the levels of MMP2, a matrix protease that is under transcriptional control of P53/TP53. Does not bind calcium","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9HCY8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/S100A14","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/S100A14","total_profiled":1310},"omim":[{"mim_id":"617437","title":"S100 CALCIUM-BINDING PROTEIN A16; S100A16","url":"https://www.omim.org/entry/617437"},{"mim_id":"607986","title":"S100 CALCIUM-BINDING PROTEIN A14; S100A14","url":"https://www.omim.org/entry/607986"},{"mim_id":"133239","title":"ESOPHAGEAL CANCER","url":"https://www.omim.org/entry/133239"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":3629.8},{"tissue":"vagina","ntpm":1167.7}],"url":"https://www.proteinatlas.org/search/S100A14"},"hgnc":{"alias_symbol":["S100A15","BCMP84"],"prev_symbol":[]},"alphafold":{"accession":"Q9HCY8","domains":[{"cath_id":"1.10.238.10","chopping":"19-94","consensus_level":"high","plddt":82.1454,"start":19,"end":94}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCY8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCY8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCY8-F1-predicted_aligned_error_v6.png","plddt_mean":76.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=S100A14","jax_strain_url":"https://www.jax.org/strain/search?query=S100A14"},"sequence":{"accession":"Q9HCY8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCY8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCY8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCY8"}},"corpus_meta":[{"pmid":"18606705","id":"PMC_18606705","title":"Chemotactic 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epitope-tagged S100A14 localizes to the cytoplasm with association to the plasma membrane and perinuclear area in lung carcinoma and monkey cell lines.\",\n      \"method\": \"cDNA cloning, sequence analysis, epitope-tag transfection with immunofluorescence/subcellular fractionation\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment in multiple cell lines; single lab, initial characterization study\",\n      \"pmids\": [\"11944983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Extracellular S100A14 binds to RAGE (receptor for advanced glycation end products) in esophageal squamous cell carcinoma cells, activating ERK1/2 MAPK and NF-κB signaling to stimulate cell proliferation at low doses; mutation of the N-EF hand (E39A, E45A) reduces S100A14-induced cell proliferation and ERK1/2 activation. At high doses, S100A14 induces apoptosis via the mitochondrial pathway (caspase-3, -9, PARP), partially RAGE-dependent.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of RAGE, dominant-negative RAGE construct, RAGE antagonist peptide, EF-hand point mutagenesis, ERK1/2 and NF-κB activity assays, caspase activation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including mutagenesis, dominant-negative, antagonist peptide, and Co-IP in same study\",\n      \"pmids\": [\"21559403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S100A14 promotes cell motility and invasiveness of esophageal squamous cell carcinoma cells by upregulating MMP-2 expression through a p53-dependent mechanism: S100A14 affects p53 transactivity and stability, and p53 transrepresses MMP-2 transcription; MMP-2 inhibition partially reverses the invasive phenotype.\",\n      \"method\": \"Ectopic overexpression, MMP-2 inhibitor treatment, series of biochemical assays (reporter assays, Co-IP for p53 interaction), RT-qPCR in human breast cancer specimens\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing pathway epistasis between S100A14, p53, and MMP-2\",\n      \"pmids\": [\"22451655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The solution structure of homodimeric human S100A14 in the apo state was solved by NMR, showing that S100A14 does not bind calcium ions and adopts a 'semi-open' conformation; lack of two canonical EF-hand ligands explains negligible Ca2+ affinity; exposed cysteines and histidine cause precipitation in the presence of zinc(II) or copper(II).\",\n      \"method\": \"NMR solution structure determination, metal-binding assays\",\n      \"journal\": \"Journal of biological inorganic chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural determination with biochemical validation of metal-binding properties\",\n      \"pmids\": [\"23197251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S100A14 directly binds to HER2 via co-immunoprecipitation and pull-down assays; the binding requires residues 956–1154 of the HER2 intracellular domain and residue 83 of S100A14; S100A14 silencing decreases HER2 phosphorylation and downstream PI3K/AKT and MAPK/ERK signaling and reduces HER2-stimulated cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, deletion/point mutant mapping, siRNA knockdown, phosphorylation assays, proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP and pull-down with mutant mapping plus functional downstream signaling readouts\",\n      \"pmids\": [\"24285542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S100A14 interacts with S100A16 as its single binding partner identified by yeast two-hybrid screen, confirmed by co-immunoprecipitation and co-immunofluorescence; overexpression of S100A14 leads to concomitant upregulation of S100A16 protein (but not mRNA), suggesting post-transcriptional regulation; the regulation is unidirectional (S100A16 overexpression does not affect S100A14).\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, double indirect immunofluorescence, retroviral overexpression and knockdown, cycloheximide chase, qRT-PCR\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus reciprocal Co-IP plus functional validation with multiple cell lines and orthogonal approaches\",\n      \"pmids\": [\"24086685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S100A14 is transcriptionally regulated by JunB, which binds the S100A14 promoter and controls expression during esophageal cancer cell differentiation; S100A14 mediates calcium-induced G1-phase cell cycle arrest and promotes expression of late differentiation markers involucrin (IVL) and filaggrin (FLG).\",\n      \"method\": \"ChIP, promoter reporter assays, overexpression and siRNA knockdown, cell cycle analysis, qRT-PCR for differentiation markers\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assay plus KD/OE functional readouts in multiple systems\",\n      \"pmids\": [\"24107296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The S100A14 gene contains a functional p53-binding site in its promoter; a SNP (461G>A) disrupts this p53-binding site and is associated with decreased S100A14 expression in vitro and in vivo, placing S100A14 downstream of p53 transcriptional regulation.\",\n      \"method\": \"DNA sequencing, p53-binding site mutagenesis, reporter assays, in vitro and in vivo expression analysis, case-control study\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — p53-binding site identified and functionally validated with mutagenesis and expression assays\",\n      \"pmids\": [\"19351828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of S100A14 in oral squamous carcinoma cells (harboring wild-type p53) induces G1-arrest with upregulation of p21; nuclear accumulation of p53 occurs upon S100A14 overexpression; shRNA-mediated p53 silencing partially suppresses S100A14-induced p21 upregulation, indicating functional linkage between S100A14 and the p53/p21 axis.\",\n      \"method\": \"Retroviral overexpression, shRNA knockdown of p53, cell cycle analysis, Western blot for p21 and nuclear p53\",\n      \"journal\": \"Oral oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD/KO with defined phenotype and epistasis experiment; single lab\",\n      \"pmids\": [\"22032898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100A14 regulates invasion of oral squamous cell carcinoma cells by modulating MMP1 and MMP9 expression: retroviral overexpression of S100A14 decreases invasive potential and downregulates MMP1 and MMP9 mRNA and MMP9 gelatinolytic activity, while siRNA knockdown increases invasion.\",\n      \"method\": \"Retroviral overexpression, siRNA knockdown, Matrigel invasion assay, PCR array, qRT-PCR, zymography\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation (OE and KD) with multiple functional and mechanistic readouts in multiple cell lines\",\n      \"pmids\": [\"21074410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLF4 transcription factor directly binds two conserved GC-rich DNA segments within the S100A14 promoter, driving S100A14 transcriptional activation in response to TPA; stable silencing of KLF4 suppresses TPA-induced S100A14 upregulation and breast cancer cell migration.\",\n      \"method\": \"ChIP, promoter deletion/mutation analysis, reporter assays, stable shRNA knockdown, migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assay with functional KD readout; multiple orthogonal methods in single study\",\n      \"pmids\": [\"24532790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"S100A14 induces differentiation of gastric cancer cells by upregulating E-cadherin and PGII expression, and inhibits metastasis by blocking store-operated Ca2+ influx through suppression of Orai1 and STIM1 expression, leading to FAK activation, focal adhesion assembly, and MMP downregulation.\",\n      \"method\": \"Overexpression and knockdown, Western blot for E-cadherin/PGII/Orai1/STIM1/FAK/MMPs, Ca2+ influx assay, migration/invasion assays, in vivo mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular readouts with in vitro and in vivo experiments; single lab\",\n      \"pmids\": [\"28726786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S100A14 promotes breast cancer metastasis by upregulating expression and secretion of CCL2 and CXCL5 via RAGE-NF-κB-mediated transcription; NF-κB ChIP confirmed binding to CCL2/CXCL5 promoters; S100A14 knockout abolishes this effect.\",\n      \"method\": \"RNA-Seq, secreted proteomics, ChIP for NF-κB, ELISA, transwell assay, neutralizing antibodies, S100A14 knockout and overexpression, mouse metastasis experiments\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including ChIP, proteomics, KO/OE, and in vivo models across multiple systems\",\n      \"pmids\": [\"32483412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S100A14 suppresses NPC metastasis by promoting ubiquitin-proteasome-mediated degradation of IRAK1, thereby inhibiting NF-κB signaling and reversing EMT; S100A14 and IRAK1 form a feedback loop that can be disrupted by the IRAK1 inhibitor T2457.\",\n      \"method\": \"Gain- and loss-of-function studies, ubiquitination assays, Western blot for IRAK1 and NF-κB pathway, in vitro and in vivo motility assays, IHC of 202 NPC samples\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation with mechanistic ubiquitination assay and pathway epistasis; validated in vivo\",\n      \"pmids\": [\"32555330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"S100A14 inhibits PD-L1 expression in colorectal cancer by directly interacting with STAT3 and inducing its proteasome-mediated degradation; gain-of-S100A14 reduces STAT3-driven PD-L1 transcription, while loss-of-S100A14 increases PD-L1, cancer stem cell phenotypes, and chemoresistance.\",\n      \"method\": \"Co-IP of S100A14-STAT3, proteasome inhibitor rescue, PD-L1 expression assays, gain/loss-of-function in vitro and in vivo, chemoresistant CRC subline models\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for direct interaction plus proteasome inhibitor validation plus bidirectional functional assays in vitro and in vivo\",\n      \"pmids\": [\"35858011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SOX2 binds the 3'-UTR of S100A14 mRNA via a stem-loop structure, stabilizing S100A14 mRNA and enhancing its expression; depletion of SOX2 decreases S100A14 mRNA and protein levels, and knockdown of S100A14 phenocopies SOX2 depletion in increasing cell mobility in urothelial carcinoma.\",\n      \"method\": \"Oligomer-directed RNase H digestion, CLIP (cross-linking immunoprecipitation), EGFP-3'UTR reporter assay, mobility shift assay, siRNA knockdown, cell growth and migration assays\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CLIP plus reporter assay plus functional epistasis; single lab\",\n      \"pmids\": [\"28955911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"S100A14 overexpression in cervical cancer cells promotes EMT by increasing N-cadherin and Vimentin while decreasing E-cadherin; S100A14 overexpression increases G2/M phase proportion, proliferation, migration, and invasion, while knockdown reverses these effects.\",\n      \"method\": \"Lentiviral overexpression and knockdown, cell cycle analysis, transwell migration and invasion assays, Western blot for EMT markers\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation with multiple phenotypic readouts; single lab\",\n      \"pmids\": [\"26101712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Extracellular S100A14 protein activates NK cells in a PBMC co-culture system (but not purified NK cells alone); treatment of purified monocytes with recombinant S100A14 induces TNF-alpha secretion and promotes NK cell CD69 activation via a TLR4-dependent interaction in co-culture.\",\n      \"method\": \"Recombinant protein treatment, PBMC/purified NK/monocyte co-culture, TLR4 blocking, ELISA for TNF-alpha, flow cytometry for CD69\",\n      \"journal\": \"Journal of acquired immune deficiency syndromes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional assay with TLR4 blocking control; single lab\",\n      \"pmids\": [\"30422902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZHX2 transcriptionally inhibits S100A14 by binding to the S100A14 promoter; ZHX2 knockdown promotes thyroid cancer cell migration, an effect attenuated by S100A14 inhibition, placing S100A14 downstream of ZHX2 in this pro-metastatic axis.\",\n      \"method\": \"ChIP for ZHX2 at S100A14 promoter, ZHX2 and S100A14 knockdown, migration assay, wound healing, in vivo lung metastasis model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus epistasis (rescue experiment) with in vivo validation; single lab\",\n      \"pmids\": [\"35151335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TP63 transcriptionally activates S100A14 expression by occupying its enhancer region together with SOX2 and EP300; disruption of this enhancer reduces S100A14 expression and dramatically promotes 4NQO-induced ESCC tumorigenesis in mice.\",\n      \"method\": \"ChIP for TP63/SOX2/EP300 at S100A14 enhancer, enhancer disruption (CRISPR or deletion), 4NQO mouse tumorigenesis model, survival analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with multiple factors plus in vivo genetic loss-of-function model with survival readout\",\n      \"pmids\": [\"35917972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CTBP1-AS lncRNA blocks TP63-mediated transcriptional activation of S100A14, thereby reducing S100A14 expression; CTBP1-AS silencing suppresses proliferation, migration, invasion and tumorigenicity of prostate cancer cells, while TP63 overexpression further weakens malignant phenotype unless S100A14 is artificially silenced.\",\n      \"method\": \"Bioinformatics, qRT-PCR, Western blot, lentiviral overexpression/silencing, transcriptional activation assays, proliferation/apoptosis/migration/invasion assays, epistasis rescue experiment\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis rescue experiment establishing CTBP1-AS→TP63→S100A14 regulatory axis; single lab\",\n      \"pmids\": [\"38476086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"S100A14 binds to glutaminase (GLS) and blocks its phosphorylation at Y308 and S314, which inhibits GLS ubiquitination and subsequent proteasomal degradation, thereby stabilizing GLS; this reduces oxidative stress in HCC cells and antagonizes sorafenib-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry to identify GLS as S100A14 binding partner, phosphorylation site mapping, ubiquitination assays, cell viability assays, in vivo xenograft experiments\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP with MS identification, phosphorylation site mapping, ubiquitination assay, and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"40217256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mfsd2a interacts with S100A14 (identified by Co-IP and mass spectrometry), enhancing S100A14 expression and thereby inhibiting STAT3 phosphorylation; this suppresses CRC cell proliferation, migration, invasion, EMT, and liver metastasis.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunofluorescence, Western blot for p-STAT3, in vitro functional assays, in vivo tumor growth and liver metastasis models, STAT3 activator rescue\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus MS with functional epistasis (colivelin rescue); single lab\",\n      \"pmids\": [\"39806334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"S100A14 in tumor-derived extracellular vesicles (EVs) directly targets PIAS3 in astrocytes to activate STAT3 signaling, reprogramming astrocytes to secrete pro-inflammatory chemokines (CCL2/CCL5/CXCL5) that recruit immunosuppressive MDSCs and promote brain metastasis; the natural compound germacrone disrupts the S100A14-PIAS3 interaction to suppress this pathway.\",\n      \"method\": \"DIA-based proteomics of EVs, intracardiac injection mouse model, non-contact co-culture, multiplex cytokine profiling, MDSCs recruitment transwell assay, Co-IP for S100A14-PIAS3 interaction, Western blot for STAT3, CETSA/DARTS for germacrone binding\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for direct binding plus in vivo model plus mechanistic pathway; single lab, preprint-era publication\",\n      \"pmids\": [\"41961478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Extracellular S100A14 from tumor-derived EVs targets astrocytic TLR4, activating NF-κB signaling and reprogramming astrocytes to secrete IL-6, CCL2, and CXCL1, thereby recruiting polymorphonuclear and monocytic MDSCs and establishing an immunosuppressive brain niche promoting metastasis.\",\n      \"method\": \"TMT-based quantitative proteomics, intracardiac mouse model, non-contact co-culture with primary astrocytes, multiplex cytokine profiling, MDSCs transwell recruitment assay, CETSA/DARTS for curdione binding to S100A14\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics plus in vivo model plus mechanistic co-culture assay; single lab\",\n      \"pmids\": [\"41691987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"S100A14 directly interacts with S100A16 (confirmed by Co-IP); S100A14 stabilizes S100A16 protein through post-translational modification without transcriptional regulation; the S100A14/S100A16 axis reduces p53 protein stability and inhibits p53 transcriptional activity and downstream p21 expression in pancreatic cancer.\",\n      \"method\": \"Co-immunoprecipitation, CHX chase assay, dual-luciferase reporter assay for p53 transcriptional activity, Western blot, qRT-PCR, CCK-8, Transwell, apoptosis assays\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus CHX chase plus reporter assay establishing the S100A14→S100A16→p53 axis; single lab\",\n      \"pmids\": [\"41799516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"S100A14 promotes cell growth and inhibits EMT in prostate cancer through activating FAT1 expression and the downstream Hippo pathway; S100A14 suppresses proliferation and motility of prostate cancer cells, confirmed in vivo in mouse xenograft models.\",\n      \"method\": \"Overexpression and knockdown of S100A14, Western blot for FAT1 and Hippo pathway components, proliferation/apoptosis/migration/invasion assays, mouse xenograft experiments\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation with pathway readout and in vivo validation; single lab\",\n      \"pmids\": [\"33890248\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"S100A14 is an EF-hand calcium-binding protein (which paradoxically does not bind Ca2+ in solution and adopts a semi-open apo conformation) that functions as a context-dependent regulator of cancer cell behavior: extracellularly it signals through RAGE to activate ERK1/2 and NF-κB, promotes metastasis via NF-κB-driven CCL2/CXCL5 secretion, and activates TLR4 on innate immune cells; intracellularly it modulates p53 stability and transcription, suppresses IRAK1 and STAT3 via proteasomal degradation, forms functional heterodimers with S100A16 (stabilizing it post-translationally to suppress p53/p21), binds and stabilizes glutaminase to reduce oxidative stress, directly interacts with HER2 to potentiate its downstream signaling, and is transcriptionally controlled by p53, JunB, KLF4, TP63, SOX2 (as an RNA-binding protein at the 3'-UTR), and enhancer-associated factors (TP63/SOX2/EP300).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"S100A14 is an EF-hand-containing S100 family member that functions as a context-dependent signaling scaffold linking calcium-independent protein-protein interactions to transcriptional and post-translational control of cell proliferation, differentiation, invasion, and immune modulation. Structurally, S100A14 homodimerizes but does not bind calcium, adopting a semi-open apo conformation due to loss of canonical EF-hand ligands [PMID:23197251]. Extracellularly, S100A14 signals through RAGE to activate ERK1/2 and NF-κB, driving chemokine secretion (CCL2, CXCL5) that promotes metastasis, and engages TLR4 on monocytes and astrocytes to stimulate innate immune activation and immunosuppressive niche formation [PMID:21559403, PMID:32483412, PMID:30422902, PMID:41691987]. Intracellularly, S100A14 directly binds HER2 to potentiate PI3K/AKT and MAPK signaling [PMID:24285542], heterodimerizes with S100A16 to destabilize p53 and suppress p21 [PMID:24086685, PMID:41799516], promotes proteasomal degradation of IRAK1 and STAT3 to inhibit NF-κB and PD-L1 expression [PMID:32555330, PMID:35858011], and stabilizes glutaminase by blocking its phosphorylation-dependent ubiquitination to reduce oxidative stress [PMID:40217256].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of S100A14 as a new S100 family member with cytoplasmic and plasma membrane localization established its basic molecular identity and subcellular context.\",\n      \"evidence\": \"cDNA cloning with epitope-tag immunofluorescence and subcellular fractionation in lung carcinoma and COS cells\",\n      \"pmids\": [\"11944983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous antibody validation at this stage\", \"Functional role entirely unknown\", \"Metal-binding properties not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery of a functional p53-binding site in the S100A14 promoter placed S100A14 as a direct p53 transcriptional target, establishing the first regulatory link to a major tumor suppressor.\",\n      \"evidence\": \"Promoter mutagenesis, reporter assays, and SNP (461G>A) expression analysis in vitro and in vivo\",\n      \"pmids\": [\"19351828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p53 activation or repression of S100A14 is context-dependent was not resolved\", \"Downstream effectors of S100A14 were unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Bidirectional manipulation of S100A14 in oral cancer cells revealed it suppresses invasion by downregulating MMP1/MMP9, providing the first direct evidence for a functional role in invasion regulation.\",\n      \"evidence\": \"Retroviral overexpression, siRNA knockdown, Matrigel invasion assay, zymography\",\n      \"pmids\": [\"21074410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting S100A14 to MMP transcription was not established\", \"Generalizability to other cancer types unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that extracellular S100A14 binds RAGE and activates ERK1/2 and NF-κB revealed a receptor-mediated extracellular signaling function, with EF-hand mutagenesis confirming structural requirements for activity; concurrently, intracellular S100A14 was shown to activate the p53/p21 axis and induce G1 arrest.\",\n      \"evidence\": \"Co-IP, dominant-negative RAGE, RAGE antagonist peptide, EF-hand mutants, caspase assays (PMID:21559403); retroviral overexpression with p53 shRNA epistasis (PMID:22032898)\",\n      \"pmids\": [\"21559403\", \"22032898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAGE and p53 pathways converge or represent independent S100A14 functions was unresolved\", \"Dose-dependent switch between proliferation and apoptosis mechanism unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"NMR structure of apo S100A14 revealed it does not bind Ca²⁺ and adopts a semi-open conformation, fundamentally distinguishing it from canonical S100 proteins and resolving the paradox of its classification as a calcium-binding protein.\",\n      \"evidence\": \"NMR solution structure determination with metal-binding assays\",\n      \"pmids\": [\"23197251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How S100A14 achieves ligand recognition without calcium-induced conformational change was not explained\", \"No structure of S100A14 in complex with any partner\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mechanistic epistasis experiments connected S100A14 to p53 transactivity and stability, with p53-dependent transrepression of MMP-2 explaining S100A14's pro-invasive phenotype in esophageal cancer.\",\n      \"evidence\": \"Reporter assays, Co-IP for p53, MMP-2 inhibitor rescue in esophageal and breast cancer cells\",\n      \"pmids\": [\"22451655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether S100A14 directly binds p53 or acts through an intermediary was not definitively resolved\", \"Context dependency (pro-invasive in esophageal vs. anti-invasive in oral cancer) unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of S100A16 as the sole direct binding partner of S100A14 by yeast two-hybrid, with unidirectional post-translational stabilization, established a functional heterodimerization axis; simultaneously, direct binding to HER2 and JunB-driven transcription were established.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, cycloheximide chase (PMID:24086685); Co-IP, GST pull-down, mutant mapping for HER2 (PMID:24285542); ChIP and reporter assay for JunB (PMID:24107296)\",\n      \"pmids\": [\"24086685\", \"24285542\", \"24107296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the S100A14-S100A16 heterodimer differs structurally from the S100A14 homodimer was unknown\", \"Whether HER2 and S100A16 binding are mutually exclusive was untested\", \"Functional consequences of S100A14-S100A16 interaction beyond protein stability were unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"KLF4 was identified as a direct transcriptional activator of S100A14 through GC-rich promoter elements, adding to the growing network of transcription factors (p53, JunB, KLF4) controlling S100A14 expression.\",\n      \"evidence\": \"ChIP, promoter deletion/mutation reporter assays, stable shRNA knockdown with migration readout\",\n      \"pmids\": [\"24532790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of multiple transcription factor inputs at the S100A14 promoter was not modeled\", \"Chromatin context of KLF4 binding not explored\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"SOX2 was found to bind the 3'-UTR of S100A14 mRNA as an RNA-binding protein, stabilizing the transcript post-transcriptionally — an unusual mechanism for a transcription factor.\",\n      \"evidence\": \"CLIP, RNase H mapping, EGFP-3'UTR reporter assay, siRNA epistasis in urothelial carcinoma\",\n      \"pmids\": [\"28955911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SOX2 RNA-binding specificity determinants and generalizability to other mRNAs not established\", \"Single lab finding\", \"Structural basis of SOX2-S100A14 mRNA interaction unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two studies resolved opposing S100A14 roles in NF-κB signaling: extracellular S100A14 activates RAGE-NF-κB to drive CCL2/CXCL5-dependent breast cancer metastasis, while intracellular S100A14 suppresses NF-κB in nasopharyngeal cancer by promoting IRAK1 proteasomal degradation.\",\n      \"evidence\": \"RNA-Seq, secreted proteomics, NF-κB ChIP, S100A14 KO, mouse metastasis (PMID:32483412); ubiquitination assays, bidirectional genetic manipulation, in vivo motility (PMID:32555330)\",\n      \"pmids\": [\"32483412\", \"32555330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How context (intracellular vs. extracellular, cell type) determines opposing NF-κB outcomes is not mechanistically resolved\", \"E3 ligase recruited by S100A14 for IRAK1 ubiquitination not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"S100A14 was shown to directly interact with STAT3 and promote its proteasomal degradation, suppressing PD-L1 expression in colorectal cancer; separately, TP63/SOX2/EP300 were found to co-occupy an S100A14 enhancer whose disruption promotes esophageal tumorigenesis.\",\n      \"evidence\": \"Co-IP of S100A14-STAT3, proteasome inhibitor rescue (PMID:35858011); ChIP for TP63/SOX2/EP300, enhancer CRISPR disruption, 4NQO mouse model (PMID:35917972)\",\n      \"pmids\": [\"35858011\", \"35917972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating STAT3 degradation not identified\", \"Whether enhancer disruption effects are solely S100A14-dependent or involve neighboring genes not fully excluded\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"S100A14 was found to bind glutaminase (GLS), blocking phosphorylation at Y308/S314 and subsequent ubiquitination, thereby stabilizing GLS and reducing oxidative stress in hepatocellular carcinoma; additionally, Mfsd2a was identified as a physical partner that enhances S100A14 expression to inhibit STAT3.\",\n      \"evidence\": \"Co-IP with MS identification, phosphosite mapping, ubiquitination assay, xenograft (PMID:40217256); Co-IP/MS and STAT3 activator rescue (PMID:39806334)\",\n      \"pmids\": [\"40217256\", \"39806334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase phosphorylating GLS at Y308/S314 not identified\", \"Mechanism by which Mfsd2a enhances S100A14 expression unknown\", \"Whether GLS stabilization occurs in non-cancer contexts untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extracellular vesicle-delivered S100A14 was shown to reprogram brain astrocytes by targeting PIAS3 (activating STAT3) and TLR4 (activating NF-κB), establishing S100A14 as a key mediator of immunosuppressive brain pre-metastatic niche formation; the S100A14-S100A16 axis was further shown to destabilize p53 in pancreatic cancer.\",\n      \"evidence\": \"DIA proteomics, intracardiac mouse model, Co-IP for PIAS3, CETSA/DARTS (PMID:41961478); TMT proteomics, TLR4-dependent astrocyte co-culture (PMID:41691987); Co-IP, CHX chase, p53 reporter assay (PMID:41799516)\",\n      \"pmids\": [\"41961478\", \"41691987\", \"41799516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"All three findings from single labs; independent replication needed\", \"How S100A14 is selectively loaded into EVs is unknown\", \"Whether PIAS3 and TLR4 engagement by S100A14 occurs simultaneously or in distinct EV subpopulations is unresolved\", \"Structural basis of S100A14-PIAS3 interaction not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of S100A14's calcium-independent partner recognition; identification of E3 ligases it recruits for IRAK1 and STAT3 degradation; the mechanism determining whether S100A14 activates or suppresses NF-κB/STAT3 in different cell types; and whether its EV-mediated extracellular functions are relevant in normal physiology.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-crystal or cryo-EM structure of S100A14 with any partner\", \"No unifying model for context-dependent pro- vs. anti-metastatic activity\", \"Normal physiological role outside cancer poorly studied\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 13, 14, 21]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 12, 17, 23, 24]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [23, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 12, 13, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 23, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13, 14, 21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 10, 19]}\n    ],\n    \"complexes\": [\n      \"S100A14-S100A16 heterodimer\"\n    ],\n    \"partners\": [\n      \"S100A16\",\n      \"ERBB2\",\n      \"AGER\",\n      \"TP53\",\n      \"IRAK1\",\n      \"STAT3\",\n      \"GLS\",\n      \"PIAS3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}