{"gene":"S100A14","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2002,"finding":"S100A14 protein localizes predominantly to the cytoplasm with association with the plasma membrane and perinuclear area in human lung carcinoma cell lines, as determined by epitope-tagged protein imaging. The protein contains two EF-hand Ca2+-binding domains and is encoded by a gene on chromosome 1q21.","method":"Epitope-tagged protein immunofluorescence/localization in cell lines; molecular cloning and sequence analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization by tagged-protein imaging in multiple cell lines, but no functional consequence linked to localization","pmids":["11944983"],"is_preprint":false},{"year":2011,"finding":"Extracellular S100A14 binds directly to RAGE (receptor for advanced glycation end products), activating ERK1/2 MAPK and NF-κB signaling to promote cell proliferation at low doses and apoptosis via the mitochondrial pathway (caspase-3, caspase-9, PARP activation) at high doses. Mutation of the N-EF hand (E39A, E45A) reduced S100A14-induced proliferation and ERK1/2 activation. RAGE inhibition (siRNA, dominant-negative construct, or antagonist peptide) blocked S100A14-induced effects.","method":"Co-immunoprecipitation, siRNA knockdown, dominant-negative overexpression, EF-hand point mutagenesis, RAGE antagonist peptide, ERK1/2 phosphorylation assay, caspase activity assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of EF-hand, multiple orthogonal RAGE-inhibition approaches, and downstream signaling readouts in a single study","pmids":["21559403"],"is_preprint":false},{"year":2012,"finding":"S100A14 promotes cell motility and invasion by increasing MMP-2 expression and activity in a p53-dependent manner: S100A14 affects p53 transactivity and stability, and p53 in turn transrepresses MMP-2 transcription. Functional p53 is required for S100A14 to modulate MMP2 levels.","method":"Ectopic overexpression, MMP2-specific inhibitor rescue, reporter/transactivation assays, RT-qPCR, Western blot, Matrigel invasion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (overexpression, inhibitor rescue, transcription assays, clinical correlation) establishing pathway position via p53","pmids":["22451655"],"is_preprint":false},{"year":2012,"finding":"Solution structure of homodimeric human S100A14 in the apo state was solved by NMR at physiological temperature. The protein does not bind Ca2+ ions and adopts a 'semi-open' conformation. Absence of two Ca2+-coordinating ligands in the canonical EF-hand site explains negligible Ca2+ affinity. Exposed cysteines and histidine cause precipitation in the presence of Zn2+ or Cu2+ ions.","method":"NMR solution structure determination; metal-binding assays","journal":"Journal of biological inorganic chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional validation of metal-binding properties, single lab but high-resolution structural method","pmids":["23197251"],"is_preprint":false},{"year":2010,"finding":"S100A14 overexpression decreases invasive potential of oral squamous cell carcinoma cells and is associated with downregulation of MMP1 and MMP9 mRNA and suppression of MMP9 gelatinolytic activity; siRNA-mediated knockdown increases invasiveness. S100A14 protein undergoes membrane-to-cytoplasm translocation in invading tumor islands.","method":"Retroviral overexpression, siRNA knockdown, Matrigel invasion assay, PCR array, qRT-PCR, gelatin zymography, immunohistochemistry","journal":"European journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional loss/gain-of-function with multiple orthogonal readouts (invasion, mRNA, enzymatic activity) replicated across two cell lines","pmids":["21074410"],"is_preprint":false},{"year":2011,"finding":"S100A14 overexpression induces G1-phase cell cycle arrest and inhibits proliferation in oral carcinoma cells harboring wild-type p53, correlating with upregulation of p21. Nuclear accumulation of p53 occurs upon S100A14 overexpression. shRNA-mediated p53 silencing partially suppresses S100A14-induced p21 upregulation, indicating that p21 induction is at least partly p53-dependent.","method":"Retroviral overexpression, shRNA knockdown, cell cycle analysis (flow cytometry), Western blot, immunofluorescence","journal":"Oral oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell lines, p53 epistasis via shRNA rescue, cell cycle and protein-level readouts","pmids":["22032898"],"is_preprint":false},{"year":2013,"finding":"S100A14 directly binds HER2 via co-immunoprecipitation and pull-down assays. The interaction requires residues 956–1154 of the HER2 intracellular domain and residue 83 of S100A14. S100A14 silencing reduces HER2 phosphorylation and downstream PI3K/AKT and MAPK/ERK signaling and decreases HER2-stimulated cell proliferation.","method":"Co-immunoprecipitation, pull-down assay, domain-mapping mutagenesis, siRNA knockdown, phosphorylation assays, proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP and pull-down with domain mutagenesis identifying binding residues, combined with functional signaling readouts","pmids":["24285542"],"is_preprint":false},{"year":2013,"finding":"S100A14 interacts with S100A16 (identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation and co-immunofluorescence). S100A14 overexpression upregulates S100A16 protein without increasing S100A16 mRNA, indicating post-transcriptional regulation. Regulation is unidirectional: S100A16 overexpression does not upregulate S100A14. The degradation of both proteins is independent of classical proteasomal and lysosomal pathways.","method":"Yeast two-hybrid screen, co-immunoprecipitation, double indirect immunofluorescence, retroviral overexpression/knockdown, cycloheximide chase assay, proteasome/lysosome inhibitor treatment","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction identified by Y2H and confirmed by Co-IP plus co-localization, directionality established by bidirectional manipulation","pmids":["24086685"],"is_preprint":false},{"year":2013,"finding":"S100A14 expression is transcriptionally regulated by JunB, which binds directly to the S100A14 promoter. S100A14 promotes terminal differentiation of esophageal cancer cells and calcium-induced G1 arrest, and modulates expression of late differentiation markers involucrin (IVL) and filaggrin (FLG).","method":"Overexpression/knockdown, ChIP (JunB binding to S100A14 promoter), immunohistochemistry, RT-PCR, Western blot, cell cycle analysis","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes transcriptional regulation by JunB, functional differentiation phenotype confirmed by loss/gain-of-function, single lab","pmids":["24107296"],"is_preprint":false},{"year":2014,"finding":"KLF4 transcriptionally activates S100A14 expression by binding directly to two conserved GC-rich elements in the S100A14 promoter in response to TPA treatment. KLF4 silencing suppresses TPA-induced breast cancer cell migration, demonstrating that TPA promotes cell motility through the KLF4–S100A14 axis.","method":"ChIP (KLF4 binding to S100A14 promoter), promoter reporter assays, stable KLF4 silencing, cell migration assay, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP with promoter reporter validation, epistasis rescue experiment, multiple orthogonal methods in single study","pmids":["24532790"],"is_preprint":false},{"year":2014,"finding":"S100A14 overexpression in epithelial ovarian cancer cells promotes cell proliferation, tumorigenesis, migration, and invasion through the PI3K/Akt pathway; knockdown inhibits these properties and reduces xenograft tumor growth.","method":"Lentiviral overexpression/knockdown, proliferation assay, migration/invasion assay, xenograft mouse model, PI3K/Akt pathway inhibition","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional loss/gain-of-function with in vivo validation, PI3K/Akt pathway assignment by pharmacological inhibition, single lab","pmids":["24939856"],"is_preprint":false},{"year":2017,"finding":"S100A14 induces differentiation of gastric cancer cells, upregulating E-cadherin and PGII. S100A14 blocks store-operated Ca2+ influx by suppressing Orai1 and STIM1 expression, leading to FAK expression activation, focal adhesion assembly, and MMP downregulation, thereby suppressing metastasis.","method":"Overexpression/knockdown, Western blot, Ca2+ imaging/store-operated Ca2+ entry assay, FAK/focal adhesion analysis, invasion assay, in vivo metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic readouts linking S100A14 to Orai1/STIM1/Ca2+ and FAK signaling, but single lab","pmids":["28726786"],"is_preprint":false},{"year":2016,"finding":"SOX2 binds directly to the 3'-UTR of S100A14 mRNA (identified as a stem-loop structure) and stabilizes S100A14 mRNA, increasing its expression. SOX2 depletion reduces S100A14 mRNA and protein; loss of either SOX2 or S100A14 increases cell growth and mobility in urothelial carcinoma cells.","method":"CLIP (cross-linking and immunoprecipitation), oligomer-directed RNase H digestion, EGFP-3'UTR reporter, RNA mobility shift assay, siRNA knockdown, cell migration and growth assays","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP and RNase H mapping define binding site, reporter and mobility shift assays confirm interaction, functional epistasis demonstrated, single lab","pmids":["28955911"],"is_preprint":false},{"year":2019,"finding":"Extracellular recombinant S100A14 activates NK cells indirectly by first activating monocytes through a TLR4-dependent interaction to secrete TNF-alpha, which then activates NK cells (increased CD69) in co-culture. S100A14 does not activate purified NK cells alone.","method":"Recombinant protein treatment, co-culture assay, TLR4 inhibition, ELISA (TNF-alpha), flow cytometry (NK CD69)","journal":"Journal of acquired immune deficiency syndromes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TLR4 dependence confirmed pharmacologically, co-culture vs purified cell experiments distinguish direct vs indirect effect, single lab","pmids":["30422902"],"is_preprint":false},{"year":2020,"finding":"S100A14 promotes breast cancer metastasis by upregulating the expression and secretion of chemokines CCL2 and CXCL5 via RAGE-NF-κB–mediated transcription, as demonstrated by RNA-Seq, secreted proteomics, ChIP (NF-κB binding to CCL2/CXCL5 promoters), and neutralizing antibody experiments.","method":"S100A14 knockout/overexpression, RNA-Seq, secreted proteomics, ChIP, ELISA, transwell assay, neutralizing antibody, mouse metastasis model","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA-Seq, proteomics, ChIP, in vivo metastasis, antibody rescue) establishing mechanistic pathway, single lab but comprehensive","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 regulatory loop that can be disrupted by the IRAK1 inhibitor T2457.","method":"Gain/loss-of-function experiments, ubiquitin-proteasome pathway assays, NF-κB reporter, EMT marker analysis, IRAK1 inhibitor treatment, in vivo motility assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteasome-mediated degradation mechanism identified, feedback loop confirmed pharmacologically, in vitro and in vivo validation","pmids":["32555330"],"is_preprint":false},{"year":2022,"finding":"S100A14 directly interacts with STAT3 and induces its proteasome-mediated degradation, thereby inhibiting PD-L1 expression in colorectal cancer cells and suppressing cancer stem-like cell phenotypes and chemoresistance.","method":"Co-immunoprecipitation (S100A14–STAT3 interaction), proteasome inhibitor treatment, Western blot, PD-L1 reporter, gain/loss-of-function, in vivo tumor model, recombinant S100A14 protein treatment","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishes direct interaction, proteasome dependence confirmed, functional rescue with recombinant protein, in vivo validation","pmids":["35858011"],"is_preprint":false},{"year":2022,"finding":"ZHX2 transcription factor binds to the S100A14 promoter to suppress its transcription, thereby inhibiting S100A14-mediated thyroid cancer metastasis. ZHX2 knockdown-induced enhanced metastasis was attenuated by S100A14 inhibition.","method":"ChIP (ZHX2 binding to S100A14 promoter), ZHX2/S100A14 knockdown, migration assay, wound healing assay, in vivo lung metastasis model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding, epistasis rescue links ZHX2 to S100A14 in metastasis, single lab","pmids":["35151335"],"is_preprint":false},{"year":2022,"finding":"Disruption of an enhancer element (occupied by TP63, SOX2, and EP300) decreases S100A14 expression in ESCC. S100A14 deficiency promotes 4NQO-induced esophageal tumorigenesis and triggers an aberrant differentiation program in vivo.","method":"ChIP (TP63, SOX2, EP300 occupancy at S100A14 enhancer), enhancer deletion/disruption, 4NQO mouse carcinogenesis model, survival analysis, Western blot","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes transcription factor occupancy, in vivo carcinogenesis model confirms functional relevance, single lab","pmids":["35917972"],"is_preprint":false},{"year":2021,"finding":"S100A14 promotes prostate cancer cell growth and EMT by upregulating FAT1, which activates the Hippo signaling pathway. S100A14 knockdown suppresses tumor growth in vivo through the FAT1-Hippo axis.","method":"Overexpression/knockdown, Western blot (Hippo pathway components), proliferation/apoptosis assays, EMT marker analysis, xenograft mouse model","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FAT1-Hippo pathway placement via overexpression/knockdown with in vivo confirmation, single lab, pathway assignment relies on Western blot without direct epistasis rescue","pmids":["33890248"],"is_preprint":false},{"year":2025,"finding":"S100A14 binds directly to glutaminase (GLS) and blocks GLS phosphorylation at residues Y308 and S314, thereby inhibiting its ubiquitination and degradation. This GLS stabilization reduces oxidative stress in hepatocellular carcinoma cells and antagonizes sorafenib-induced apoptosis, conferring primary sorafenib resistance.","method":"Co-immunoprecipitation and mass spectrometry (S100A14–GLS interaction), GLS phosphorylation site mapping, ubiquitination assay, cell viability assay, xenograft mouse model, S100A14/GLS knockdown","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP with mass spectrometry identifies binding partner, phosphorylation/ubiquitination mechanism defined, in vivo validation, multiple orthogonal methods","pmids":["40217256"],"is_preprint":false},{"year":2025,"finding":"Mfsd2a interacts with S100A14 (confirmed by Co-IP and mass spectrometry) and enhances S100A14 expression, leading to inhibition of STAT3 phosphorylation and suppression of colorectal cancer progression and liver metastasis. STAT3 activator colivelin partially reverses the inhibitory effects of Mfsd2a overexpression.","method":"Co-immunoprecipitation, mass spectrometry, immunofluorescence, Western blot (p-STAT3), colivelin rescue experiment, in vitro and in vivo tumor models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and MS confirm interaction, epistasis via STAT3 activator rescue, single lab","pmids":["39806334"],"is_preprint":false},{"year":2026,"finding":"S100A14 stabilizes S100A16 protein through post-translational modification (without transcriptional regulation); the S100A14/S100A16 complex then reduces p53 protein stability and inhibits p53 transcriptional activity and downstream p21 expression, promoting pancreatic cancer progression. Co-IP confirms the S100A14–S100A16 physical interaction.","method":"Co-immunoprecipitation (S100A14–S100A16), CHX chase assay (protein stability), dual-luciferase assay (p53 transcriptional activity), gain/loss-of-function, Western blot","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, CHX chase, and transcriptional assay establish mechanism, but single lab and no in vivo validation reported","pmids":["41799516"],"is_preprint":false},{"year":2026,"finding":"Tumor-derived S100A14 in extracellular vesicles (EVs) directly targets PIAS3 in astrocytes to activate STAT3 signaling and promote secretion of CCL2, CCL5, and CXCL5, recruiting immunosuppressive MDSCs and establishing a brain immunosuppressive niche that promotes brain metastasis. The natural compound germacrone disrupts the S100A14–PIAS3 interaction to reverse this pathway.","method":"DIA-based proteomics, intracardiac injection brain metastasis mouse model, EV isolation and overexpression, non-contact co-culture, STAT3 signaling assays, MDSC recruitment transwell assay, CELTS/DARTS assays (germacrone binding to S100A14)","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo EV model with proteomics and mechanistic rescue by germacrone, but PIAS3 direct binding evidence from DARTS is indirect; single lab","pmids":["41961478"],"is_preprint":false},{"year":2026,"finding":"Tumor-derived extracellular S100A14 targets astrocytic TLR4 to activate NF-κB signaling, reprogramming astrocytes to secrete IL-6, CCL2, and CXCL1, which recruit both polymorphonuclear and monocytic MDSCs and establish a brain immunosuppressive niche promoting brain metastasis. Curdione directly binds S100A14 to reverse this cascade.","method":"TMT-based quantitative proteomics, intracardiac injection brain metastasis mouse model, non-contact co-culture with primary astrocytes, multiplex cytokine profiling, MDSC recruitment transwell assay, CELTS/DARTS assays (curdione–S100A14 binding), ELISA","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with mechanistic validation (TLR4 pathway) and direct binding evidence by DARTS; note partial overlap with another 2026 paper from same group with slightly different mechanism (PIAS3 vs TLR4)","pmids":["41691987"],"is_preprint":false},{"year":2024,"finding":"The lncRNA CTBP1-AS blocks TP63-mediated transcriptional activation of S100A14 without affecting TP63 expression itself, thereby reducing S100A14 levels and promoting prostate cancer progression. TP63 overexpression partially rescues the malignant phenotype induced by CTBP1-AS, and this rescue is reversed by S100A14 silencing.","method":"Overexpression/knockdown of CTBP1-AS and TP63, Western blot, RT-qPCR, cell proliferation/migration/invasion assays, epistasis rescue experiments","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiments with TP63/S100A14 rescue define pathway order, single lab without direct promoter binding confirmation for TP63–S100A14 in this study","pmids":["38476086"],"is_preprint":false},{"year":2009,"finding":"A single nucleotide polymorphism (461G>A) in the S100A14 locus disrupts a p53-binding site in the S100A14 regulatory region, resulting in decreased S100A14 expression in vitro and in vivo, placing S100A14 as a transcriptional target of p53.","method":"DNA sequencing, functional reporter assays (p53-binding site), RT-PCR, in vivo expression analysis, case-control genetics","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay links p53-binding site to S100A14 transcription, supported by in vivo expression data; genetics is association-level but mechanism is functionally validated","pmids":["19351828"],"is_preprint":false}],"current_model":"S100A14 is an EF-hand-containing calcium-binding protein that, unusually, does not bind Ca2+ and adopts a semi-open homodimeric conformation; extracellularly it signals through RAGE (and TLR4) to activate ERK1/2/NF-κB and modulate cell survival, while intracellularly it acts as a context-dependent regulator of invasion and metastasis by (i) binding HER2 to potentiate its phosphorylation and downstream PI3K/AKT/MAPK signaling, (ii) promoting MMP-2 expression via a p53-dependent transcriptional axis, (iii) suppressing NF-κB by driving ubiquitin-proteasome degradation of IRAK1, (iv) inhibiting STAT3 phosphorylation through direct interaction and proteasome-mediated STAT3 degradation, (v) stabilizing glutaminase (GLS) by blocking its phosphorylation and ubiquitination to confer sorafenib resistance, (vi) forming a heterodimer with S100A16 that is unidirectionally regulated at the post-translational level, (vii) functioning as a transcriptional target of p53, JunB, KLF4, TP63, and an enhancer complex containing TP63/SOX2/EP300, and (viii) promoting terminal differentiation and G1 arrest through p53/p21 nuclear accumulation."},"narrative":{"mechanistic_narrative":"S100A14 is an EF-hand family calcium-binding protein that paradoxically does not bind Ca2+: its apo NMR solution structure reveals a semi-open homodimer in which the loss of two coordinating ligands in the canonical EF-hand abolishes Ca2+ affinity [PMID:23197251]. It functions both as a secreted signaling ligand and as an intracellular regulator of cancer cell behavior. Extracellularly, S100A14 binds directly to RAGE to activate ERK1/2 and NF-κB, driving proliferation at low doses and mitochondrial apoptosis at high doses [PMID:21559403]; this RAGE–NF-κB axis transcriptionally induces secreted chemokines (CCL2, CXCL5) that promote metastasis [PMID:32483412], and tumor-derived extracellular S100A14 reprograms astrocytes through TLR4–NF-κB and PIAS3–STAT3 to recruit immunosuppressive MDSCs and establish a brain metastatic niche [PMID:41961478, PMID:41691987]. Intracellularly, S100A14 binds HER2 to potentiate its phosphorylation and downstream PI3K/AKT and MAPK/ERK signaling [PMID:24285542], and acts as a context-dependent regulator of invasion: it modulates MMP expression through a p53-dependent transcriptional axis [PMID:22451655, PMID:21074410] and induces G1 arrest and terminal differentiation via nuclear p53/p21 accumulation [PMID:22032898, PMID:24107296]. S100A14 also suppresses oncogenic signaling by directing ubiquitin-proteasome degradation of IRAK1 to inhibit NF-κB [PMID:32555330] and of STAT3 to limit PD-L1 expression and stemness [PMID:35858011]. It binds and stabilizes glutaminase by blocking its phosphorylation and ubiquitination, conferring sorafenib resistance [PMID:40217256], and forms a post-translationally regulated heterodimer with S100A16 [PMID:24086685, PMID:41799516]. S100A14 is itself a downstream transcriptional target, regulated by p53 [PMID:19351828], JunB [PMID:24107296], KLF4 [PMID:24532790], and a TP63/SOX2/EP300 enhancer complex [PMID:35917972].","teleology":[{"year":2002,"claim":"Establishing that S100A14 is a cytoplasmic, membrane-associated EF-hand protein gave the first structural and localization framework for an uncharacterized S100 family member.","evidence":"Epitope-tagged protein immunofluorescence and molecular cloning in lung carcinoma cell lines","pmids":["11944983"],"confidence":"Medium","gaps":["No functional consequence linked to localization","Ca2+-binding capacity not tested"]},{"year":2009,"claim":"Identification of a p53-binding site disrupted by a SNP placed S100A14 transcriptionally downstream of p53, anchoring it within tumor-suppressor circuitry.","evidence":"Functional reporter assays of a 461G>A variant, RT-PCR, and case-control genetics","pmids":["19351828"],"confidence":"Medium","gaps":["Direct promoter occupancy by p53 not shown in this study","Genetics is association-level"]},{"year":2012,"claim":"The apo NMR structure resolved the paradox of an EF-hand protein that cannot bind Ca2+, explaining its non-canonical semi-open conformation.","evidence":"NMR solution structure determination and metal-binding assays","pmids":["23197251"],"confidence":"High","gaps":["Functional role of the semi-open conformation not defined","Physiological metal/ligand interactions not mapped"]},{"year":2011,"claim":"Demonstrating direct S100A14–RAGE binding identified the extracellular receptor through which S100A14 controls a dose-dependent proliferation/apoptosis switch.","evidence":"Reciprocal Co-IP, EF-hand mutagenesis, multiple RAGE-inhibition approaches, ERK/caspase readouts","pmids":["21559403"],"confidence":"High","gaps":["Threshold determining proliferation versus apoptosis not defined","Did not establish secreted source in vivo"]},{"year":2012,"claim":"Connecting S100A14 to MMP regulation through p53 defined a transcriptional axis controlling invasion, while context dictated direction.","evidence":"Overexpression, inhibitor rescue, transactivation reporters, Matrigel invasion (JBC); contrasted with OSCC loss/gain-of-function and zymography","pmids":["22451655","21074410"],"confidence":"High","gaps":["Opposing pro- and anti-invasive effects across cell types not mechanistically reconciled","p53-dependence varies with p53 status"]},{"year":2011,"claim":"Linking S100A14 to G1 arrest, p21 induction, and terminal differentiation established its tumor-suppressive, differentiation-promoting role in wild-type p53 contexts.","evidence":"Retroviral overexpression, shRNA p53 silencing, flow cytometry, differentiation marker analysis (Oral Oncol; Mol Cancer Res)","pmids":["22032898","24107296"],"confidence":"Medium","gaps":["How nuclear p53 accumulation is triggered is unresolved","p21 induction only partly p53-dependent"]},{"year":2013,"claim":"Mapping a direct S100A14–HER2 interaction identified an intracellular mechanism by which S100A14 amplifies receptor tyrosine kinase signaling.","evidence":"Reciprocal Co-IP, pull-down, domain-mapping mutagenesis, phosphorylation and proliferation assays","pmids":["24285542"],"confidence":"High","gaps":["Whether binding directly alters HER2 kinase activity versus stability not separated","Ca2+-independence of the interaction not tested"]},{"year":2013,"claim":"Discovery of the S100A14–S100A16 heterodimer and its unidirectional post-translational regulation revealed cross-talk within the S100 family.","evidence":"Yeast two-hybrid, Co-IP, co-immunofluorescence, cycloheximide chase, proteasome/lysosome inhibitor treatment","pmids":["24086685"],"confidence":"High","gaps":["Degradation pathway stabilizing S100A16 not identified (proteasome/lysosome-independent)","Functional output of the heterodimer not defined here"]},{"year":2014,"claim":"Identifying JunB and KLF4 as direct promoter-binding activators placed S100A14 downstream of stress- and TPA-responsive transcription, linking its expression to motility programs.","evidence":"ChIP, promoter reporter assays, KLF4 silencing epistasis, migration assays","pmids":["24532790"],"confidence":"High","gaps":["Interplay between the multiple upstream transcription factors not integrated","Signals selecting activator usage unknown"]},{"year":2014,"claim":"Demonstrating PI3K/Akt-dependent pro-tumorigenic effects in ovarian cancer established a context where S100A14 acts as a metastasis promoter, contrasting with its suppressive roles elsewhere.","evidence":"Lentiviral overexpression/knockdown, xenograft, PI3K/Akt pharmacological inhibition","pmids":["24939856"],"confidence":"Medium","gaps":["Pathway assignment by inhibitor without direct epistasis","Upstream link to PI3K/Akt not molecularly defined"]},{"year":2017,"claim":"Linking S100A14 to suppression of Orai1/STIM1 store-operated Ca2+ entry and FAK activation provided a mechanism for its anti-metastatic, pro-differentiation effect in gastric cancer.","evidence":"Overexpression/knockdown, Ca2+ imaging, FAK/focal adhesion analysis, in vivo metastasis model","pmids":["28726786"],"confidence":"Medium","gaps":["How a non-Ca2+-binding protein regulates Ca2+ channels is unexplained","Single lab"]},{"year":2020,"claim":"Defining a RAGE–NF-κB chemokine output (CCL2/CXCL5) and a counterbalancing IRAK1-degradation mechanism clarified how S100A14 both activates and restrains NF-κB depending on context.","evidence":"RNA-Seq, secreted proteomics, ChIP, neutralizing antibody, metastasis models; separately ubiquitin-proteasome and NF-κB reporter assays for IRAK1","pmids":["32483412","32555330"],"confidence":"High","gaps":["What determines pro- versus anti-NF-κB outcome across tumor types not resolved","E3 ligase for IRAK1 degradation not identified"]},{"year":2022,"claim":"Discovery that S100A14 directly binds STAT3 to drive its proteasomal degradation linked S100A14 to immune evasion via PD-L1 and to stemness/chemoresistance.","evidence":"Co-IP, proteasome inhibitor treatment, PD-L1 reporter, recombinant protein rescue, in vivo model","pmids":["35858011"],"confidence":"High","gaps":["E3 ligase mediating STAT3 degradation not identified","Reconciliation with STAT3-activating roles in other contexts unaddressed"]},{"year":2022,"claim":"Identifying ZHX2 as a repressor and a TP63/SOX2/EP300 enhancer as an activator extended the transcriptional control map and confirmed tumor-suppressive function in vivo.","evidence":"ChIP, enhancer disruption, 4NQO carcinogenesis model, knockdown migration assays","pmids":["35151335","35917972"],"confidence":"Medium","gaps":["Coordination among the many transcriptional regulators not integrated","Single labs"]},{"year":2025,"claim":"Showing that S100A14 binds glutaminase and blocks its phosphorylation/ubiquitination defined a metabolic stabilization mechanism conferring sorafenib resistance.","evidence":"Co-IP/mass spectrometry, phosphosite mapping, ubiquitination assay, xenograft","pmids":["40217256"],"confidence":"High","gaps":["Kinase/E3 ligase normally targeting GLS not identified","Generality beyond hepatocellular carcinoma untested"]},{"year":2026,"claim":"Demonstrating that EV-delivered S100A14 reprograms astrocytes via TLR4-NF-κB and PIAS3-STAT3 to recruit MDSCs established a non-cell-autonomous role in building a brain metastatic immunosuppressive niche.","evidence":"Quantitative proteomics, intracardiac brain metastasis models, astrocyte co-culture, MDSC recruitment assays, DARTS-based compound binding","pmids":["41961478","41691987"],"confidence":"Medium","gaps":["PIAS3 versus TLR4 mechanisms from the same group not reconciled","Direct PIAS3 binding inferred from DARTS rather than reconstitution"]},{"year":2026,"claim":"Refining the S100A14–S100A16 axis showed the heterodimer destabilizes p53 to inhibit p21, providing a molecular basis for context-dependent pro-tumorigenic activity.","evidence":"Co-IP, CHX chase, dual-luciferase p53 activity assay, gain/loss-of-function","pmids":["41799516"],"confidence":"Medium","gaps":["Mechanism of p53 destabilization not defined","No in vivo validation"]},{"year":null,"claim":"How a single non-Ca2+-binding protein switches between tumor-suppressive (p53/p21, IRAK1/STAT3 degradation, differentiation) and pro-metastatic (RAGE/NF-κB chemokine, PI3K/Akt, GLS stabilization, astrocyte reprogramming) programs across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking conformation to opposing activities","E3 ligases for IRAK1/STAT3/GLS degradation unidentified","In vivo source and regulation of secreted versus intracellular pools unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[15,16,20]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,20,22]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,23]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,15,20,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,23,24]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,16,20]}],"complexes":["S100A14/S100A16 heterodimer"],"partners":["RAGE","HER2","S100A16","STAT3","IRAK1","GLS","TLR4","PIAS3"],"other_free_text":[]}},"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. 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suppressor cells promoting brain metastasis and Curdione reversal effect.","date":"2026","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41691987","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":27694,"output_tokens":7136,"usd":0.095061,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16322,"output_tokens":5360,"usd":0.107805,"stage2_stop_reason":"end_turn"},"total_usd":0.202866,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"S100A14 protein localizes predominantly to the cytoplasm with association with the plasma membrane and perinuclear area in human lung carcinoma cell lines, as determined by epitope-tagged protein imaging. The protein contains two EF-hand Ca2+-binding domains and is encoded by a gene on chromosome 1q21.\",\n      \"method\": \"Epitope-tagged protein immunofluorescence/localization in cell lines; molecular cloning and sequence analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization by tagged-protein imaging in multiple cell lines, but no functional consequence linked to localization\",\n      \"pmids\": [\"11944983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Extracellular S100A14 binds directly to RAGE (receptor for advanced glycation end products), activating ERK1/2 MAPK and NF-κB signaling to promote cell proliferation at low doses and apoptosis via the mitochondrial pathway (caspase-3, caspase-9, PARP activation) at high doses. Mutation of the N-EF hand (E39A, E45A) reduced S100A14-induced proliferation and ERK1/2 activation. RAGE inhibition (siRNA, dominant-negative construct, or antagonist peptide) blocked S100A14-induced effects.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, dominant-negative overexpression, EF-hand point mutagenesis, RAGE antagonist peptide, ERK1/2 phosphorylation assay, caspase activity assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis of EF-hand, multiple orthogonal RAGE-inhibition approaches, and downstream signaling readouts in a single study\",\n      \"pmids\": [\"21559403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S100A14 promotes cell motility and invasion by increasing MMP-2 expression and activity in a p53-dependent manner: S100A14 affects p53 transactivity and stability, and p53 in turn transrepresses MMP-2 transcription. Functional p53 is required for S100A14 to modulate MMP2 levels.\",\n      \"method\": \"Ectopic overexpression, MMP2-specific inhibitor rescue, reporter/transactivation assays, RT-qPCR, Western blot, Matrigel invasion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (overexpression, inhibitor rescue, transcription assays, clinical correlation) establishing pathway position via p53\",\n      \"pmids\": [\"22451655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Solution structure of homodimeric human S100A14 in the apo state was solved by NMR at physiological temperature. The protein does not bind Ca2+ ions and adopts a 'semi-open' conformation. Absence of two Ca2+-coordinating ligands in the canonical EF-hand site explains negligible Ca2+ affinity. Exposed cysteines and histidine cause precipitation in the presence of Zn2+ or Cu2+ ions.\",\n      \"method\": \"NMR solution structure determination; metal-binding assays\",\n      \"journal\": \"Journal of biological inorganic chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional validation of metal-binding properties, single lab but high-resolution structural method\",\n      \"pmids\": [\"23197251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100A14 overexpression decreases invasive potential of oral squamous cell carcinoma cells and is associated with downregulation of MMP1 and MMP9 mRNA and suppression of MMP9 gelatinolytic activity; siRNA-mediated knockdown increases invasiveness. S100A14 protein undergoes membrane-to-cytoplasm translocation in invading tumor islands.\",\n      \"method\": \"Retroviral overexpression, siRNA knockdown, Matrigel invasion assay, PCR array, qRT-PCR, gelatin zymography, immunohistochemistry\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional loss/gain-of-function with multiple orthogonal readouts (invasion, mRNA, enzymatic activity) replicated across two cell lines\",\n      \"pmids\": [\"21074410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"S100A14 overexpression induces G1-phase cell cycle arrest and inhibits proliferation in oral carcinoma cells harboring wild-type p53, correlating with upregulation of p21. Nuclear accumulation of p53 occurs upon S100A14 overexpression. shRNA-mediated p53 silencing partially suppresses S100A14-induced p21 upregulation, indicating that p21 induction is at least partly p53-dependent.\",\n      \"method\": \"Retroviral overexpression, shRNA knockdown, cell cycle analysis (flow cytometry), Western blot, immunofluorescence\",\n      \"journal\": \"Oral oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell lines, p53 epistasis via shRNA rescue, cell cycle and protein-level readouts\",\n      \"pmids\": [\"22032898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S100A14 directly binds HER2 via co-immunoprecipitation and pull-down assays. The interaction requires residues 956–1154 of the HER2 intracellular domain and residue 83 of S100A14. S100A14 silencing reduces HER2 phosphorylation and downstream PI3K/AKT and MAPK/ERK signaling and decreases HER2-stimulated cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assay, domain-mapping mutagenesis, siRNA knockdown, phosphorylation assays, proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP and pull-down with domain mutagenesis identifying binding residues, combined with functional signaling readouts\",\n      \"pmids\": [\"24285542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S100A14 interacts with S100A16 (identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation and co-immunofluorescence). S100A14 overexpression upregulates S100A16 protein without increasing S100A16 mRNA, indicating post-transcriptional regulation. Regulation is unidirectional: S100A16 overexpression does not upregulate S100A14. The degradation of both proteins is independent of classical proteasomal and lysosomal pathways.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, double indirect immunofluorescence, retroviral overexpression/knockdown, cycloheximide chase assay, proteasome/lysosome inhibitor treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction identified by Y2H and confirmed by Co-IP plus co-localization, directionality established by bidirectional manipulation\",\n      \"pmids\": [\"24086685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S100A14 expression is transcriptionally regulated by JunB, which binds directly to the S100A14 promoter. S100A14 promotes terminal differentiation of esophageal cancer cells and calcium-induced G1 arrest, and modulates expression of late differentiation markers involucrin (IVL) and filaggrin (FLG).\",\n      \"method\": \"Overexpression/knockdown, ChIP (JunB binding to S100A14 promoter), immunohistochemistry, RT-PCR, Western blot, cell cycle analysis\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes transcriptional regulation by JunB, functional differentiation phenotype confirmed by loss/gain-of-function, single lab\",\n      \"pmids\": [\"24107296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLF4 transcriptionally activates S100A14 expression by binding directly to two conserved GC-rich elements in the S100A14 promoter in response to TPA treatment. KLF4 silencing suppresses TPA-induced breast cancer cell migration, demonstrating that TPA promotes cell motility through the KLF4–S100A14 axis.\",\n      \"method\": \"ChIP (KLF4 binding to S100A14 promoter), promoter reporter assays, stable KLF4 silencing, cell migration assay, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP with promoter reporter validation, epistasis rescue experiment, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24532790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"S100A14 overexpression in epithelial ovarian cancer cells promotes cell proliferation, tumorigenesis, migration, and invasion through the PI3K/Akt pathway; knockdown inhibits these properties and reduces xenograft tumor growth.\",\n      \"method\": \"Lentiviral overexpression/knockdown, proliferation assay, migration/invasion assay, xenograft mouse model, PI3K/Akt pathway inhibition\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional loss/gain-of-function with in vivo validation, PI3K/Akt pathway assignment by pharmacological inhibition, single lab\",\n      \"pmids\": [\"24939856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"S100A14 induces differentiation of gastric cancer cells, upregulating E-cadherin and PGII. S100A14 blocks store-operated Ca2+ influx by suppressing Orai1 and STIM1 expression, leading to FAK expression activation, focal adhesion assembly, and MMP downregulation, thereby suppressing metastasis.\",\n      \"method\": \"Overexpression/knockdown, Western blot, Ca2+ imaging/store-operated Ca2+ entry assay, FAK/focal adhesion analysis, invasion assay, in vivo metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic readouts linking S100A14 to Orai1/STIM1/Ca2+ and FAK signaling, but single lab\",\n      \"pmids\": [\"28726786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SOX2 binds directly to the 3'-UTR of S100A14 mRNA (identified as a stem-loop structure) and stabilizes S100A14 mRNA, increasing its expression. SOX2 depletion reduces S100A14 mRNA and protein; loss of either SOX2 or S100A14 increases cell growth and mobility in urothelial carcinoma cells.\",\n      \"method\": \"CLIP (cross-linking and immunoprecipitation), oligomer-directed RNase H digestion, EGFP-3'UTR reporter, RNA mobility shift assay, siRNA knockdown, cell migration and growth assays\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP and RNase H mapping define binding site, reporter and mobility shift assays confirm interaction, functional epistasis demonstrated, single lab\",\n      \"pmids\": [\"28955911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Extracellular recombinant S100A14 activates NK cells indirectly by first activating monocytes through a TLR4-dependent interaction to secrete TNF-alpha, which then activates NK cells (increased CD69) in co-culture. S100A14 does not activate purified NK cells alone.\",\n      \"method\": \"Recombinant protein treatment, co-culture assay, TLR4 inhibition, ELISA (TNF-alpha), flow cytometry (NK CD69)\",\n      \"journal\": \"Journal of acquired immune deficiency syndromes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TLR4 dependence confirmed pharmacologically, co-culture vs purified cell experiments distinguish direct vs indirect effect, single lab\",\n      \"pmids\": [\"30422902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S100A14 promotes breast cancer metastasis by upregulating the expression and secretion of chemokines CCL2 and CXCL5 via RAGE-NF-κB–mediated transcription, as demonstrated by RNA-Seq, secreted proteomics, ChIP (NF-κB binding to CCL2/CXCL5 promoters), and neutralizing antibody experiments.\",\n      \"method\": \"S100A14 knockout/overexpression, RNA-Seq, secreted proteomics, ChIP, ELISA, transwell assay, neutralizing antibody, mouse metastasis model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA-Seq, proteomics, ChIP, in vivo metastasis, antibody rescue) establishing mechanistic pathway, single lab but comprehensive\",\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 regulatory loop that can be disrupted by the IRAK1 inhibitor T2457.\",\n      \"method\": \"Gain/loss-of-function experiments, ubiquitin-proteasome pathway assays, NF-κB reporter, EMT marker analysis, IRAK1 inhibitor treatment, in vivo motility assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteasome-mediated degradation mechanism identified, feedback loop confirmed pharmacologically, in vitro and in vivo validation\",\n      \"pmids\": [\"32555330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"S100A14 directly interacts with STAT3 and induces its proteasome-mediated degradation, thereby inhibiting PD-L1 expression in colorectal cancer cells and suppressing cancer stem-like cell phenotypes and chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation (S100A14–STAT3 interaction), proteasome inhibitor treatment, Western blot, PD-L1 reporter, gain/loss-of-function, in vivo tumor model, recombinant S100A14 protein treatment\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishes direct interaction, proteasome dependence confirmed, functional rescue with recombinant protein, in vivo validation\",\n      \"pmids\": [\"35858011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZHX2 transcription factor binds to the S100A14 promoter to suppress its transcription, thereby inhibiting S100A14-mediated thyroid cancer metastasis. ZHX2 knockdown-induced enhanced metastasis was attenuated by S100A14 inhibition.\",\n      \"method\": \"ChIP (ZHX2 binding to S100A14 promoter), ZHX2/S100A14 knockdown, migration assay, wound healing assay, in vivo lung metastasis model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding, epistasis rescue links ZHX2 to S100A14 in metastasis, single lab\",\n      \"pmids\": [\"35151335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Disruption of an enhancer element (occupied by TP63, SOX2, and EP300) decreases S100A14 expression in ESCC. S100A14 deficiency promotes 4NQO-induced esophageal tumorigenesis and triggers an aberrant differentiation program in vivo.\",\n      \"method\": \"ChIP (TP63, SOX2, EP300 occupancy at S100A14 enhancer), enhancer deletion/disruption, 4NQO mouse carcinogenesis model, survival analysis, Western blot\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes transcription factor occupancy, in vivo carcinogenesis model confirms functional relevance, single lab\",\n      \"pmids\": [\"35917972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"S100A14 promotes prostate cancer cell growth and EMT by upregulating FAT1, which activates the Hippo signaling pathway. S100A14 knockdown suppresses tumor growth in vivo through the FAT1-Hippo axis.\",\n      \"method\": \"Overexpression/knockdown, Western blot (Hippo pathway components), proliferation/apoptosis assays, EMT marker analysis, xenograft mouse model\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FAT1-Hippo pathway placement via overexpression/knockdown with in vivo confirmation, single lab, pathway assignment relies on Western blot without direct epistasis rescue\",\n      \"pmids\": [\"33890248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"S100A14 binds directly to glutaminase (GLS) and blocks GLS phosphorylation at residues Y308 and S314, thereby inhibiting its ubiquitination and degradation. This GLS stabilization reduces oxidative stress in hepatocellular carcinoma cells and antagonizes sorafenib-induced apoptosis, conferring primary sorafenib resistance.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry (S100A14–GLS interaction), GLS phosphorylation site mapping, ubiquitination assay, cell viability assay, xenograft mouse model, S100A14/GLS knockdown\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP with mass spectrometry identifies binding partner, phosphorylation/ubiquitination mechanism defined, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"40217256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mfsd2a interacts with S100A14 (confirmed by Co-IP and mass spectrometry) and enhances S100A14 expression, leading to inhibition of STAT3 phosphorylation and suppression of colorectal cancer progression and liver metastasis. STAT3 activator colivelin partially reverses the inhibitory effects of Mfsd2a overexpression.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunofluorescence, Western blot (p-STAT3), colivelin rescue experiment, in vitro and in vivo tumor models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and MS confirm interaction, epistasis via STAT3 activator rescue, single lab\",\n      \"pmids\": [\"39806334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"S100A14 stabilizes S100A16 protein through post-translational modification (without transcriptional regulation); the S100A14/S100A16 complex then reduces p53 protein stability and inhibits p53 transcriptional activity and downstream p21 expression, promoting pancreatic cancer progression. Co-IP confirms the S100A14–S100A16 physical interaction.\",\n      \"method\": \"Co-immunoprecipitation (S100A14–S100A16), CHX chase assay (protein stability), dual-luciferase assay (p53 transcriptional activity), gain/loss-of-function, Western blot\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, CHX chase, and transcriptional assay establish mechanism, but single lab and no in vivo validation reported\",\n      \"pmids\": [\"41799516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Tumor-derived S100A14 in extracellular vesicles (EVs) directly targets PIAS3 in astrocytes to activate STAT3 signaling and promote secretion of CCL2, CCL5, and CXCL5, recruiting immunosuppressive MDSCs and establishing a brain immunosuppressive niche that promotes brain metastasis. The natural compound germacrone disrupts the S100A14–PIAS3 interaction to reverse this pathway.\",\n      \"method\": \"DIA-based proteomics, intracardiac injection brain metastasis mouse model, EV isolation and overexpression, non-contact co-culture, STAT3 signaling assays, MDSC recruitment transwell assay, CELTS/DARTS assays (germacrone binding to S100A14)\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo EV model with proteomics and mechanistic rescue by germacrone, but PIAS3 direct binding evidence from DARTS is indirect; single lab\",\n      \"pmids\": [\"41961478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Tumor-derived extracellular S100A14 targets astrocytic TLR4 to activate NF-κB signaling, reprogramming astrocytes to secrete IL-6, CCL2, and CXCL1, which recruit both polymorphonuclear and monocytic MDSCs and establish a brain immunosuppressive niche promoting brain metastasis. Curdione directly binds S100A14 to reverse this cascade.\",\n      \"method\": \"TMT-based quantitative proteomics, intracardiac injection brain metastasis mouse model, non-contact co-culture with primary astrocytes, multiplex cytokine profiling, MDSC recruitment transwell assay, CELTS/DARTS assays (curdione–S100A14 binding), ELISA\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with mechanistic validation (TLR4 pathway) and direct binding evidence by DARTS; note partial overlap with another 2026 paper from same group with slightly different mechanism (PIAS3 vs TLR4)\",\n      \"pmids\": [\"41691987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The lncRNA CTBP1-AS blocks TP63-mediated transcriptional activation of S100A14 without affecting TP63 expression itself, thereby reducing S100A14 levels and promoting prostate cancer progression. TP63 overexpression partially rescues the malignant phenotype induced by CTBP1-AS, and this rescue is reversed by S100A14 silencing.\",\n      \"method\": \"Overexpression/knockdown of CTBP1-AS and TP63, Western blot, RT-qPCR, cell proliferation/migration/invasion assays, epistasis rescue experiments\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiments with TP63/S100A14 rescue define pathway order, single lab without direct promoter binding confirmation for TP63–S100A14 in this study\",\n      \"pmids\": [\"38476086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A single nucleotide polymorphism (461G>A) in the S100A14 locus disrupts a p53-binding site in the S100A14 regulatory region, resulting in decreased S100A14 expression in vitro and in vivo, placing S100A14 as a transcriptional target of p53.\",\n      \"method\": \"DNA sequencing, functional reporter assays (p53-binding site), RT-PCR, in vivo expression analysis, case-control genetics\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay links p53-binding site to S100A14 transcription, supported by in vivo expression data; genetics is association-level but mechanism is functionally validated\",\n      \"pmids\": [\"19351828\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"S100A14 is an EF-hand-containing calcium-binding protein that, unusually, does not bind Ca2+ and adopts a semi-open homodimeric conformation; extracellularly it signals through RAGE (and TLR4) to activate ERK1/2/NF-κB and modulate cell survival, while intracellularly it acts as a context-dependent regulator of invasion and metastasis by (i) binding HER2 to potentiate its phosphorylation and downstream PI3K/AKT/MAPK signaling, (ii) promoting MMP-2 expression via a p53-dependent transcriptional axis, (iii) suppressing NF-κB by driving ubiquitin-proteasome degradation of IRAK1, (iv) inhibiting STAT3 phosphorylation through direct interaction and proteasome-mediated STAT3 degradation, (v) stabilizing glutaminase (GLS) by blocking its phosphorylation and ubiquitination to confer sorafenib resistance, (vi) forming a heterodimer with S100A16 that is unidirectionally regulated at the post-translational level, (vii) functioning as a transcriptional target of p53, JunB, KLF4, TP63, and an enhancer complex containing TP63/SOX2/EP300, and (viii) promoting terminal differentiation and G1 arrest through p53/p21 nuclear accumulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"S100A14 is an EF-hand family calcium-binding protein that paradoxically does not bind Ca2+: its apo NMR solution structure reveals a semi-open homodimer in which the loss of two coordinating ligands in the canonical EF-hand abolishes Ca2+ affinity [#3]. It functions both as a secreted signaling ligand and as an intracellular regulator of cancer cell behavior. Extracellularly, S100A14 binds directly to RAGE to activate ERK1/2 and NF-\\u03baB, driving proliferation at low doses and mitochondrial apoptosis at high doses [#1]; this RAGE\\u2013NF-\\u03baB axis transcriptionally induces secreted chemokines (CCL2, CXCL5) that promote metastasis [#14], and tumor-derived extracellular S100A14 reprograms astrocytes through TLR4\\u2013NF-\\u03baB and PIAS3\\u2013STAT3 to recruit immunosuppressive MDSCs and establish a brain metastatic niche [#23, #24]. Intracellularly, S100A14 binds HER2 to potentiate its phosphorylation and downstream PI3K/AKT and MAPK/ERK signaling [#6], and acts as a context-dependent regulator of invasion: it modulates MMP expression through a p53-dependent transcriptional axis [#2, #4] and induces G1 arrest and terminal differentiation via nuclear p53/p21 accumulation [#5, #8]. S100A14 also suppresses oncogenic signaling by directing ubiquitin-proteasome degradation of IRAK1 to inhibit NF-\\u03baB [#15] and of STAT3 to limit PD-L1 expression and stemness [#16]. It binds and stabilizes glutaminase by blocking its phosphorylation and ubiquitination, conferring sorafenib resistance [#20], and forms a post-translationally regulated heterodimer with S100A16 [#7, #22]. S100A14 is itself a downstream transcriptional target, regulated by p53 [#26], JunB [#8], KLF4 [#9], and a TP63/SOX2/EP300 enhancer complex [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that S100A14 is a cytoplasmic, membrane-associated EF-hand protein gave the first structural and localization framework for an uncharacterized S100 family member.\",\n      \"evidence\": \"Epitope-tagged protein immunofluorescence and molecular cloning in lung carcinoma cell lines\",\n      \"pmids\": [\"11944983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence linked to localization\", \"Ca2+-binding capacity not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of a p53-binding site disrupted by a SNP placed S100A14 transcriptionally downstream of p53, anchoring it within tumor-suppressor circuitry.\",\n      \"evidence\": \"Functional reporter assays of a 461G>A variant, RT-PCR, and case-control genetics\",\n      \"pmids\": [\"19351828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy by p53 not shown in this study\", \"Genetics is association-level\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The apo NMR structure resolved the paradox of an EF-hand protein that cannot bind Ca2+, explaining its non-canonical semi-open conformation.\",\n      \"evidence\": \"NMR solution structure determination and metal-binding assays\",\n      \"pmids\": [\"23197251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of the semi-open conformation not defined\", \"Physiological metal/ligand interactions not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating direct S100A14\\u2013RAGE binding identified the extracellular receptor through which S100A14 controls a dose-dependent proliferation/apoptosis switch.\",\n      \"evidence\": \"Reciprocal Co-IP, EF-hand mutagenesis, multiple RAGE-inhibition approaches, ERK/caspase readouts\",\n      \"pmids\": [\"21559403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Threshold determining proliferation versus apoptosis not defined\", \"Did not establish secreted source in vivo\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connecting S100A14 to MMP regulation through p53 defined a transcriptional axis controlling invasion, while context dictated direction.\",\n      \"evidence\": \"Overexpression, inhibitor rescue, transactivation reporters, Matrigel invasion (JBC); contrasted with OSCC loss/gain-of-function and zymography\",\n      \"pmids\": [\"22451655\", \"21074410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Opposing pro- and anti-invasive effects across cell types not mechanistically reconciled\", \"p53-dependence varies with p53 status\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking S100A14 to G1 arrest, p21 induction, and terminal differentiation established its tumor-suppressive, differentiation-promoting role in wild-type p53 contexts.\",\n      \"evidence\": \"Retroviral overexpression, shRNA p53 silencing, flow cytometry, differentiation marker analysis (Oral Oncol; Mol Cancer Res)\",\n      \"pmids\": [\"22032898\", \"24107296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How nuclear p53 accumulation is triggered is unresolved\", \"p21 induction only partly p53-dependent\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping a direct S100A14\\u2013HER2 interaction identified an intracellular mechanism by which S100A14 amplifies receptor tyrosine kinase signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, pull-down, domain-mapping mutagenesis, phosphorylation and proliferation assays\",\n      \"pmids\": [\"24285542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether binding directly alters HER2 kinase activity versus stability not separated\", \"Ca2+-independence of the interaction not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of the S100A14\\u2013S100A16 heterodimer and its unidirectional post-translational regulation revealed cross-talk within the S100 family.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, co-immunofluorescence, cycloheximide chase, proteasome/lysosome inhibitor treatment\",\n      \"pmids\": [\"24086685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation pathway stabilizing S100A16 not identified (proteasome/lysosome-independent)\", \"Functional output of the heterodimer not defined here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying JunB and KLF4 as direct promoter-binding activators placed S100A14 downstream of stress- and TPA-responsive transcription, linking its expression to motility programs.\",\n      \"evidence\": \"ChIP, promoter reporter assays, KLF4 silencing epistasis, migration assays\",\n      \"pmids\": [\"24532790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between the multiple upstream transcription factors not integrated\", \"Signals selecting activator usage unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating PI3K/Akt-dependent pro-tumorigenic effects in ovarian cancer established a context where S100A14 acts as a metastasis promoter, contrasting with its suppressive roles elsewhere.\",\n      \"evidence\": \"Lentiviral overexpression/knockdown, xenograft, PI3K/Akt pharmacological inhibition\",\n      \"pmids\": [\"24939856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway assignment by inhibitor without direct epistasis\", \"Upstream link to PI3K/Akt not molecularly defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking S100A14 to suppression of Orai1/STIM1 store-operated Ca2+ entry and FAK activation provided a mechanism for its anti-metastatic, pro-differentiation effect in gastric cancer.\",\n      \"evidence\": \"Overexpression/knockdown, Ca2+ imaging, FAK/focal adhesion analysis, in vivo metastasis model\",\n      \"pmids\": [\"28726786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a non-Ca2+-binding protein regulates Ca2+ channels is unexplained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining a RAGE\\u2013NF-\\u03baB chemokine output (CCL2/CXCL5) and a counterbalancing IRAK1-degradation mechanism clarified how S100A14 both activates and restrains NF-\\u03baB depending on context.\",\n      \"evidence\": \"RNA-Seq, secreted proteomics, ChIP, neutralizing antibody, metastasis models; separately ubiquitin-proteasome and NF-\\u03baB reporter assays for IRAK1\",\n      \"pmids\": [\"32483412\", \"32555330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines pro- versus anti-NF-\\u03baB outcome across tumor types not resolved\", \"E3 ligase for IRAK1 degradation not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that S100A14 directly binds STAT3 to drive its proteasomal degradation linked S100A14 to immune evasion via PD-L1 and to stemness/chemoresistance.\",\n      \"evidence\": \"Co-IP, proteasome inhibitor treatment, PD-L1 reporter, recombinant protein rescue, in vivo model\",\n      \"pmids\": [\"35858011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating STAT3 degradation not identified\", \"Reconciliation with STAT3-activating roles in other contexts unaddressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying ZHX2 as a repressor and a TP63/SOX2/EP300 enhancer as an activator extended the transcriptional control map and confirmed tumor-suppressive function in vivo.\",\n      \"evidence\": \"ChIP, enhancer disruption, 4NQO carcinogenesis model, knockdown migration assays\",\n      \"pmids\": [\"35151335\", \"35917972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coordination among the many transcriptional regulators not integrated\", \"Single labs\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that S100A14 binds glutaminase and blocks its phosphorylation/ubiquitination defined a metabolic stabilization mechanism conferring sorafenib resistance.\",\n      \"evidence\": \"Co-IP/mass spectrometry, phosphosite mapping, ubiquitination assay, xenograft\",\n      \"pmids\": [\"40217256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase/E3 ligase normally targeting GLS not identified\", \"Generality beyond hepatocellular carcinoma untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrating that EV-delivered S100A14 reprograms astrocytes via TLR4-NF-\\u03baB and PIAS3-STAT3 to recruit MDSCs established a non-cell-autonomous role in building a brain metastatic immunosuppressive niche.\",\n      \"evidence\": \"Quantitative proteomics, intracardiac brain metastasis models, astrocyte co-culture, MDSC recruitment assays, DARTS-based compound binding\",\n      \"pmids\": [\"41961478\", \"41691987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PIAS3 versus TLR4 mechanisms from the same group not reconciled\", \"Direct PIAS3 binding inferred from DARTS rather than reconstitution\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Refining the S100A14\\u2013S100A16 axis showed the heterodimer destabilizes p53 to inhibit p21, providing a molecular basis for context-dependent pro-tumorigenic activity.\",\n      \"evidence\": \"Co-IP, CHX chase, dual-luciferase p53 activity assay, gain/loss-of-function\",\n      \"pmids\": [\"41799516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of p53 destabilization not defined\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single non-Ca2+-binding protein switches between tumor-suppressive (p53/p21, IRAK1/STAT3 degradation, differentiation) and pro-metastatic (RAGE/NF-\\u03baB chemokine, PI3K/Akt, GLS stabilization, astrocyte reprogramming) programs across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking conformation to opposing activities\", \"E3 ligases for IRAK1/STAT3/GLS degradation unidentified\", \"In vivo source and regulation of secreted versus intracellular pools unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [15, 16, 20]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 20, 22]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 23]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 15, 20, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 23, 24]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 16, 20]}\n    ],\n    \"complexes\": [\n      \"S100A14/S100A16 heterodimer\"\n    ],\n    \"partners\": [\n      \"RAGE\",\n      \"HER2\",\n      \"S100A16\",\n      \"STAT3\",\n      \"IRAK1\",\n      \"GLS\",\n      \"TLR4\",\n      \"PIAS3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}