{"gene":"S100A10","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2003,"finding":"S100A10 (p11) was identified as the first auxiliary protein of the epithelial Ca2+ channels TRPV5 and TRPV6 via yeast two-hybrid and GST pull-down. S100A10 binds the conserved C-terminal VATTV motif of TRPV5/TRPV6 (first threonine critical); S100A10 forms a heterotetrameric complex with annexin A2 that routes TRPV5 and TRPV6 to the plasma membrane. Annexin A2-specific siRNA knockdown inhibited TRPV5/TRPV6-mediated currents in HEK293 cells.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, siRNA knockdown, electrophysiology, site-directed mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including mutagenesis, GST pull-down, Co-IP, siRNA knockdown with functional readout (channel activity), replicated by localization studies","pmids":["12660155"],"is_preprint":false},{"year":1997,"finding":"S100A10 (calpactin light chain) was identified as a component of the cornified envelope (CE) of cultured human epidermal keratinocytes, cross-linked via epsilon-(gamma-glutamyl)lysine bonds; its reactive sites were mapped by sequential proteolytic digestion to amino- and carboxyl-terminal regions.","method":"Proteolytic cleavage of purified CE fragments followed by peptide sequencing (CNBr digestion, trypsin, proteinase K)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical identification from purified CE with peptide sequencing in a single study","pmids":["9115270"],"is_preprint":false},{"year":2003,"finding":"In Madin-Darby canine kidney (MDCK) cells, S100A10 mediates the interaction between annexin A2 and the C-terminal regulatory domain of AHNAK at the plasma membrane. The annexin A2/S100A10 complex is required for AHNAK plasma membrane association; siRNA knockdown of both proteins prevented AHNAK plasma membrane localization and impaired cortical actin cytoskeleton reorganization needed to support cell height.","method":"Co-immunoprecipitation, siRNA knockdown, actin cytoskeleton imaging, cell fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA with defined phenotypic readout (actin organization and AHNAK localization), replicated across multiple approaches","pmids":["14699089"],"is_preprint":false},{"year":2003,"finding":"The annexin A2/S100A10 heterotetramer (AIIt) bound t-PA (Kd=0.68 µM), plasminogen (Kd=0.11 µM), and plasmin (Kd=75 nM) when immobilized on a phospholipid bilayer; the carboxyl-terminal lysines of S100A10 form the t-PA and plasminogen binding sites, while annexin A2 and S100A10 contain distinct binding sites for plasmin.","method":"Surface plasmon resonance on phospholipid-immobilized protein, carboxyl-terminal lysine removal","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative in vitro binding assay with domain mapping, rigorous controls including lysine removal","pmids":["12730231"],"is_preprint":false},{"year":2003,"finding":"Downregulation of annexin A2 and S100A10 by siRNA perturbed the distribution of transferrin receptor- and rab11-positive recycling endosomes (producing extensively bent tubules and increased clathrin-positive buds) but did not significantly affect transferrin uptake/recycling kinetics. Rescue by reexpression of the N-terminal annexin A2 domain or S100A10 confirmed both subunits are required for proper positioning of recycling endosomes.","method":"RNAi knockdown, immunofluorescence, whole-mount immunoelectron microscopy, transferrin uptake assay, rescue by reexpression","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA with rescue experiment, electron microscopy, multiple orthogonal methods in single study","pmids":["13679511"],"is_preprint":false},{"year":2003,"finding":"siRNA-mediated stable knockdown of S100A10 in colorectal CCL-222 cancer cells caused 45% loss in plasminogen binding, 65% loss in cellular plasmin generation, and complete loss of plasminogen-dependent invasiveness. S100A10 was shown to associate with the plasma membrane and co-localize with uPAR independently of annexin A2.","method":"Stable RNAi knockdown (pSUPER vector), plasminogen binding assay, plasmin generation assay, invasion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — stable knockdown with quantitative functional readouts across multiple assays in a single rigorous study","pmids":["14570893"],"is_preprint":false},{"year":2005,"finding":"S100A10, S100A7, and S100A11 are substrates for both type I and type II transglutaminases, which catalyze epsilon-(gamma-glutamyl)lysine crosslinks; the reactive residues are located at the solvent-exposed amino- and carboxyl-terminal ends of S100A10.","method":"In vitro transglutaminase enzymatic assay","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct enzymatic assay in vitro, single study with multiple S100 family members tested","pmids":["11258932"],"is_preprint":false},{"year":2008,"finding":"In endothelial cells, unpartnered S100A10 (p11) is polyubiquitinated and degraded via a proteasome-dependent mechanism. Annexin A2 (A2) stabilizes intracellular S100A10 through direct binding, masking an autonomous S100A10 polyubiquitination signal; this interaction requires both the p11-binding N-terminal domain of A2 and the C-terminal domain of p11. p11 is also required for Src kinase-mediated tyrosine phosphorylation of A2, which signals translocation of both proteins to the cell surface.","method":"In vitro and in vivo co-immunoprecipitation, ubiquitination assay, proteasome inhibition, endothelial cell fractionation, A2 knockout cell/mouse model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, proteasome inhibition, knockout model) in single study, mechanistically rigorous","pmids":["18434302"],"is_preprint":false},{"year":2004,"finding":"The annexin II-S100A10 complex is required for formation of E-cadherin-based adherens junctions in MDCK cells. Depletion of plasma membrane cholesterol (abolishing complex localization) or knockdown of annexin II by RNAi inhibited re-concentration of E-cadherin at nectin-based cell-cell contact sites during Ca2+ switch experiments.","method":"RNAi knockdown, cholesterol depletion, Ca2+ switch assay, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA + cholesterol depletion with defined functional readout, single lab, two orthogonal perturbations","pmids":["15574423"],"is_preprint":false},{"year":2005,"finding":"The annexin A2/S100A10 heterotetramer (A2t) induces lateral segregation of phosphatidylserine (POPS)-enriched membrane domains in artificial phospholipid bilayers, forming micrometer-sized protein domains associated with POPS depletion in neighboring membrane areas.","method":"Scanning force microscopy, fluorescence microscopy on artificial lipid bilayers","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct biophysical assay on reconstituted membranes, single study","pmids":["16285733"],"is_preprint":false},{"year":2001,"finding":"Annexin A2 is the plasma membrane-targeting subunit of the annexin A2/S100A10 complex: monomeric annexin A2 is targeted to the plasma membrane, while non-complexed S100A10 distributes to the general cytosol; co-expression and complex formation recruits S100A10 to the plasma membrane.","method":"Live cell imaging with YFP/CFP fusion proteins in HepG2 cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live cell imaging with fluorescent fusion proteins, direct localization experiment, single lab","pmids":["11445072"],"is_preprint":false},{"year":2006,"finding":"Annexin A2 is required for strong binding of S100A10 to the C-terminal domain of AHNAK in a yeast triple-hybrid experiment and in vitro binding assay; the Annexin A2 N-terminal tail (involved in S100A10/Annexin A2 tetramerization) mediates this effect. The minimal A2t binding motif in AHNAK was mapped to a 20-amino-acid peptide (A2tBP1), and a second lower-affinity motif (A2tBP2) was identified in the AHNAK N-terminal domain.","method":"Yeast triple-hybrid, in vitro binding assay, co-immunoprecipitation, live cell imaging with EGFP fusion","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (yeast triple-hybrid, in vitro binding, Co-IP, live imaging), binding site mapped in single rigorous study","pmids":["16984913"],"is_preprint":false},{"year":2005,"finding":"The annexin A2/S100A10 heterotetramer (AIIt) directly reduces the disulfide bond of plasmin (Cys462-Cys541) during plasmin autoproteolysis; AIIt thiols are oxidized during plasmin disulfide reduction. Thioredoxin reductase uses NADPH to recycle oxidized thioredoxin, which in turn reduces oxidized AIIt, completing an electron transfer chain from NADPH to AIIt. AIIt is identified as a substrate of the thioredoxin system.","method":"In vitro thiol oxidation assay (MBP-biocytin labeling), NADPH/thioredoxin reductase reconstitution, cell-based plasminogen treatment assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with cell-based validation, mechanistic determination of redox chain","pmids":["15849182"],"is_preprint":false},{"year":2007,"finding":"S100A10 (p11) is dispensable for annexin A2 association to early endosomes and for early-to-late endosome transport. Biochemical fractionation showed p11 was not present on purified early endosomes, and p11 siRNA knockdown did not affect annexin A2 targeting to early endosomes or endosomal transport beyond early endosomes (in contrast to annexin A2 knockdown).","method":"siRNA knockdown, early endosome purification, immunofluorescence, endosomal transport assay (in vitro liposome binding)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical fractionation, siRNA knockdown, in vitro reconstitution showing negative result for S100A10 on early endosomes with multiple methods; result is itself mechanistically informative","pmids":["17971878"],"is_preprint":false},{"year":2007,"finding":"A cAMP/PKA/calcineurin (CnA)-dependent mechanism regulates annexin 2-S100A10 complex formation and its interaction with CFTR chloride channel. Forskolin increased annexin 2-S100A10 co-immunoprecipitation with cell surface CFTR; this was attenuated by PKA or CnA inhibitors. An acetylated peptide covering the S100A10-binding site on annexin 2 (Ac1-14) disrupted the complex and inhibited cAMP/PKA-dependent CFTR-mediated and outwardly rectifying chloride channel currents.","method":"Co-immunoprecipitation, electrophysiology (patch clamp), peptide competition, PKA/CnA inhibitors, short-circuit current across intestinal biopsy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, electrophysiology, peptide disruption, pharmacological inhibitors; multiple orthogonal methods establishing mechanistic complex","pmids":["17581860"],"is_preprint":false},{"year":2007,"finding":"The annexin II-S100A10 complex forms a ternary complex with tryptophanyl-tRNA synthetase (TrpRS) and regulates trafficking of TrpRS for exocytosis from endothelial cells; both annexin II and S100A10 are required for TrpRS secretion.","method":"Co-immunoprecipitation, pulldown, trafficking/secretion assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional secretion assay in single lab, two methods","pmids":["17999956"],"is_preprint":false},{"year":2008,"finding":"In CFBE41o- cells homozygous for F508del-CFTR (ΔF508), cAMP/PKA fails to induce annexin 2-S100A10/CFTR complex formation, due to defective PKA-dependent serine phosphorylation of calcineurin A (CnA), defective CnA-annexin 2 complex formation, and defective CnA-dependent dephosphorylation of annexin 2.","method":"Co-immunoprecipitation, western blotting, immunohistochemistry, CF mouse model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with in vivo mouse model validation, mechanistic detail of signaling cascade, single lab","pmids":["18346874"],"is_preprint":false},{"year":2010,"finding":"S100A10 acts as a cell surface plasminogen receptor on macrophages; S100A10-deficient mice showed up to 53% reduction in macrophage migration into the peritoneal cavity in response to thioglycollate, 8-fold fewer macrophages in Matrigel plugs in vivo, 50% reduction in plasmin-dependent invasion, and 45% reduction in plasmin generation in vitro. Loss of S100A10 reduced pro-MMP-9 activation.","method":"S100A10 knockout mouse model, Matrigel invasion assay, plasmin generation assay, peritoneal lavage, in vivo Matrigel plug assay, MMP-9 activation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mouse model with multiple quantitative functional readouts in vivo and in vitro","pmids":["20424186"],"is_preprint":false},{"year":2010,"finding":"S100A10 co-localizes and directly interacts with VAMP2 (synaptobrevin 2) at the plasma membrane of resting adrenergic chromaffin cells; S100A10 is present in VAMP2 microdomains. Stimulation induces annexin A2 translocation to the plasma membrane where it interacts with S100A10 to form a tetramer. Tetanus toxin cleavage of VAMP2 solubilizes S100A10 from the plasma membrane and inhibits annexin A2 translocation, indicating S100A10 plasma membrane anchoring depends on VAMP2.","method":"Cross-linking, co-immunoprecipitation, immunogold labeling with spatial point pattern analysis, tetanus toxin treatment, confocal microscopy","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — cross-linking, Co-IP, immunogold EM with spatial analysis, functional perturbation by tetanus toxin, multiple methods","pmids":["20374557"],"is_preprint":false},{"year":2011,"finding":"S100A10-deficient mice display increased fibrin deposition in vasculature and reduced clearance of batroxobin-induced vascular thrombi; S100A10-null endothelial cells showed 40% reduction in plasminogen binding and plasmin generation in vitro, and impaired neovascularization of Matrigel plugs in vivo, establishing S100A10 as a regulator of fibrinolysis and angiogenesis.","method":"S100A10 knockout mouse model, fibrin staining, thrombolysis assay, plasminogen binding, plasmin generation, Matrigel plug assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mouse with multiple in vivo and in vitro readouts across fibrinolysis and angiogenesis","pmids":["21768297"],"is_preprint":false},{"year":2011,"finding":"DLC1 tumor suppressor directly binds S100A10 via central sequences in DLC1 and the C-terminus of S100A10—the same C-terminal region used by annexin A2. DLC1 competes with annexin A2 for S100A10 binding, displacing S100A10 from annexin A2 and making it accessible to ubiquitin-dependent proteasomal degradation, thereby decreasing S100A10 levels, attenuating plasminogen activation, and inhibiting cancer cell migration, invasion, and anchorage-independent growth.","method":"Co-immunoprecipitation, competition binding assay, quantitative invasion/migration assays, ubiquitination assay, siRNA knockdown","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, competition assay, ubiquitination assay, multiple functional readouts; mechanism of S100A10 degradation delineated","pmids":["21372205"],"is_preprint":false},{"year":2011,"finding":"PML-RARα oncoprotein increases cell surface S100A10 in APL cells; treatment with all-trans retinoic acid (ATRA) rapidly downregulates S100A10, concomitant with loss of fibrinolytic activity. S100A10 siRNA depletion blocked enhanced fibrinolytic activity of PML-RARα-expressing cells.","method":"Western blot, ATRA treatment, RNAi knockdown, plasmin generation assay, flow cytometry","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional siRNA + pharmacological induction, single lab, two methods","pmids":["21310922"],"is_preprint":false},{"year":2011,"finding":"The S100A10-annexin A2 ternary complex with AHNAK has an asymmetric arrangement: a single AHNAK peptide binds the A2t dimer at a site comprising residues from helix IV of S100A10 and the C-terminal portion of the annexin A2 N-terminal peptide, as determined by NMR and biophysical analysis. This binding surface is distinct from previously identified S100 target protein interfaces.","method":"NMR spectroscopy, multiple biophysical methods (SPR, ITC), peptide binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural characterization with multiple biophysical methods defining binding surface and stoichiometry","pmids":["21949189"],"is_preprint":false},{"year":2011,"finding":"Genetic deletion of S100A10 in mice dramatically reduced growth of Lewis lung carcinomas and T241 fibrosarcomas, corresponding to decreased macrophage density at tumor sites. Intraperitoneal injection of wild-type (but not S100A10-deficient) macrophages rescued tumor growth in S100A10-null mice; direct intratumoral injection of either genotype rescued growth, demonstrating S100A10 is required specifically for macrophage migration to tumors.","method":"S100A10 knockout mouse model, syngeneic tumor implantation, macrophage reconstitution (IP and intratumoral injection), macrophage depletion","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null model, rescue experiment with wild-type vs. knockout macrophages, multiple tumor models","pmids":["22042827"],"is_preprint":false},{"year":2012,"finding":"The S100A10 subunit of the annexin A2 heterotetramer (A2t) interacts with the HPV16 L2 minor capsid protein at aa 108-120 (as shown by EPR), and this interaction promotes HPV16 particle internalization; mutation of this L2 region reduces A2t binding and HPV16 pseudovirus infection. ShRNA downregulation of A2t decreases capsid internalization and infection.","method":"Co-immunoprecipitation, electron paramagnetic resonance (EPR), shRNA knockdown, L2 mutagenesis, infection assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — EPR structural data, mutagenesis, Co-IP, shRNA, infection assay in single study","pmids":["22927980"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the AHNAK C-terminal 20-aa peptide bound to the AnxA2-S100A10 heterotetramer (1:2:2 asymmetric complex) at 2.5 Å resolution confirmed asymmetric binding mode; AHNAK binding is governed by hydrophobic interactions with pockets on S100A10 and hydrogen bonds involving AHNAK backbone atoms, explaining high affinity and broad consensus sequence for S100A10 binding.","method":"X-ray crystallography (2.5 Å resolution)","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.5 Å resolution confirming and extending previous NMR finding, structural mechanism defined","pmids":["23275167"],"is_preprint":false},{"year":2012,"finding":"N-terminal acetylation of annexin A2 (removal of Met1, acetylation of Ser2) is required for S100A10 binding. Acetylated but not non-acetylated peptides covering the N-terminal annexin A2 sequence competitively inhibit complex formation, and N-terminally acetylated annexin A2 forms heterotetramer with S100A10 with affinity comparable to porcine tissue-derived AnxA2.","method":"Competitive peptide inhibition assay, mass spectrometry (N-terminal modification analysis), isothermal titration calorimetry/binding affinity assay","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution with defined PTM, competitive inhibition with acetylated vs. non-acetylated peptides, rigorous affinity measurement","pmids":["23091277"],"is_preprint":false},{"year":2012,"finding":"S100A10 is required for actin stress fiber organization and cell spreading. Depletion of S100A10 impaired stress fiber formation and delayed cell spreading; Rac1 activation during spreading was suppressed by S100A10 knockdown, and expression of constitutively active Rac1 rescued spreading in S100A10-depleted cells.","method":"siRNA knockdown, actin staining, cell spreading assay, Rac1 activation assay, constitutively active Rac1 rescue","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with active Rac1 rescue, two orthogonal approaches, single lab","pmids":["23129259"],"is_preprint":false},{"year":2013,"finding":"HPV16 exposure to keratinocytes induces EGFR-dependent Src kinase activation that phosphorylates and promotes extracellular translocation of annexin A2. HPV16 particles interact with AnxA2-S100A10 heterotetramer at the cell surface in a Ca2+-dependent manner; anti-AnxA2 antibody prevents HPV16 internalization, while anti-S100A10 antibody blocks infection at a late endosomal/lysosomal site, suggesting separate roles for AnxA2 (entry) and S100A10 (intracellular trafficking).","method":"Co-immunoprecipitation, antibody blockade, siRNA knockdown, confocal microscopy, infection assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, antibody blockade of specific subunits, siRNA; separate functional roles delineated with multiple methods","pmids":["23637395"],"is_preprint":false},{"year":2016,"finding":"S100A10 regulates ULK1 localization to autophagosome formation sites at ER-mitochondria contact sites during IFN-γ-triggered autophagy. S100A10 interacts with ULK1 after IFN-γ stimulation; S100A10 knockdown prevents ULK1 localization to autophagosome formation sites and reduces autophagosome formation. ANXA2 acts upstream: ANXA2 knockdown reduces S100A10 expression, but S100A10 overexpression in ANXA2-knockdown cells restores autophagosome formation.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression rescue, immunofluorescence, autophagy assay (autophagosome counting)","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, siRNA knockdown with rescue, single lab, two orthogonal methods","pmids":["27871932"],"is_preprint":false},{"year":2016,"finding":"Oncogenic KRAS increases S100A10 gene expression via the RalGDS pathway, leading to increased cell surface S100A10 protein and elevated cellular plasmin generation; depletion of S100A10 from RAS-transformed cells reduced both plasmin generation and invasiveness.","method":"Oncogenic RAS expression, RAS effector-loop mutants, S100A10 gene expression analysis, siRNA knockdown, plasmin generation assay, invasion assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement via RAS effector mutants plus siRNA knockdown, single lab","pmids":["27351226"],"is_preprint":false},{"year":2017,"finding":"S100A10 binds the Munc13-4 secretory protein; the AnxA2-S100A10 complex recruits Munc13-4 to Weibel-Palade body (WPB) fusion sites at the plasma membrane, promoting histamine-evoked WPB exocytosis and von Willebrand factor release.","method":"Co-immunoprecipitation, siRNA knockdown, total internal reflection fluorescence (TIRF) microscopy, VWF release assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying novel interaction, siRNA with functional readout (VWF release), single lab","pmids":["28450451"],"is_preprint":false},{"year":2017,"finding":"The kringle-2 domain of tPA (not the finger domain as in fibrin-stimulated plasmin generation) is critical for S100A10-dependent plasmin generation; the kringle-1 domain of plasminogen is also critical for S100A10-dependent (but not fibrin-dependent) plasminogen activation. Internal lysine residues of S100A10 contribute to plasmin-generating activity even after deletion/substitution of carboxyl-terminal lysine.","method":"Domain-switched/deleted tPA variants, truncated plasminogen variants, S100A10 site-directed mutagenesis, in vitro plasmin generation assay","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro plasmin generation with domain mutants of all three components, mechanistic dissection with mutagenesis","pmids":["28382372"],"is_preprint":false},{"year":2017,"finding":"PLA2R (phospholipase A2 receptor) from podocytes binds specifically to the S100A10 component of the annexin A2-S100A10 (A2t) complex with high affinity; binding increases in acidic pH and occurs within the PLA2R NC3 fragment. Ca2+ promotes PLA2R-A2t complex association with phospholipid membranes in vitro. All three proteins co-localize in podocyte plasma membrane and extracellular vesicles.","method":"Proteomics pull-down, surface plasmon resonance, domain mapping, in vitro lipid membrane binding, co-localization by confocal microscopy","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — SPR quantitative binding, domain mapping, in vitro reconstitution on lipid membranes, co-localization; rigorous single study","pmids":["28761153"],"is_preprint":false},{"year":2018,"finding":"S100A10 is succinylated at lysine residue K47 by CPT1A acting as a lysine succinyltransferase; SIRT5 acts as the desuccinylase. K47 succinylation stabilizes S100A10 by suppressing ubiquitylation and proteasomal degradation. Expression of a succinylation-mimetic K47E mutant increased gastric cancer cell invasion and migration.","method":"Mass spectrometry (succinylation identification), co-immunoprecipitation (CPT1A-S100A10), overexpression of K47E mutant, ubiquitination assay, invasion/migration assay, SIRT5 manipulation","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — PTM identification by MS, writer (CPT1A) and eraser (SIRT5) identified, mutagenesis (K47E) with functional readout, Co-IP; multiple orthogonal methods","pmids":["30394687"],"is_preprint":false},{"year":2018,"finding":"Annexin A2 heterotetramer (A2t) including S100A10 is required for HPV intracellular trafficking from early to multivesicular endosomes, capsid uncoating, and protection from lysosomal degradation. Without A2t, viral progression from early endosomes is inhibited, uncoating dramatically reduced, and lysosomal degradation accelerated. AnxA2 forms a complex with CD63, a mediator of HPV trafficking.","method":"S100A10 shRNA knockdown, electron microscopy, co-immunoprecipitation, infection assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA, EM for endosomal stages, Co-IP, single lab","pmids":["30076379"],"is_preprint":false},{"year":2018,"finding":"ATRA promotes proteasomal degradation of S100A10 (p11) in an ubiquitin-independent manner in APL cells (NB4); proteasomal inhibitor lactacystin reversed ATRA-dependent p11 loss but did not cause accumulation of ubiquitylated p11. ATRA also reduces p11 transcript and protein independently of PML-RARα (in MCF-7 cells). Overexpression of annexin A2 upregulates p11 protein but not mRNA post-translationally. Forced expression of ubiquitin and p11 identified K57 as the ubiquitylation site of p11.","method":"Proteasome inhibition (lactacystin), siRNA, ubiquitin overexpression with site-directed mutagenesis (K57), western blot, RT-PCR","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — pharmacological inhibition, ubiquitin mutagenesis (K57), rescue experiment with annexin A2 overexpression, multiple cell lines","pmids":["30206209"],"is_preprint":false},{"year":2019,"finding":"GAS6/AXL signaling activates S100A10 expression through SRC to promote plasmin production, endothelial cell invasion, and angiogenesis in ccRCC. Genetic and therapeutic inhibition of AXL signaling reduced tumor vessel density, S100A10 expression, and ccRCC growth in xenograft models.","method":"Genetic AXL inhibition, small molecule AXL inhibitor (cabozantinib), sAXL decoy receptor, tumor xenograft, angiogenesis assays, western blot","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological pathway perturbation with in vivo readouts, single lab","pmids":["31585940"],"is_preprint":false},{"year":2019,"finding":"S100A10 is constitutively expressed in macrophages but is significantly downregulated upon TLR activation. S100A10-deficient macrophages are hyperresponsive to TLR stimulation; S100A10-deficient mice are more sensitive to endotoxin-induced lethal shock and E. coli-induced abdominal sepsis. Mechanistically, S100A10 interferes with recruitment and activation of receptor-proximal TLR signaling components to inhibit downstream TLR signaling.","method":"S100A10 knockout mouse model, TLR stimulation assays, cytokine measurement, endotoxin shock model, sepsis model, signaling component analysis","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic null mouse model with functional in vivo readouts, single lab, mechanism described but not fully resolved biochemically from abstract","pmids":["31467414"],"is_preprint":false},{"year":2020,"finding":"Paclitaxel-induced HIF-1-dependent S100A10 expression leads to complex formation of S100A10 with ANXA2, SPT6, and KDM6A; this complex is recruited to OCT4 binding sites where KDM6A erases H3K27me3 marks to facilitate transcription of pluripotency genes (NANOG, SOX2, KLF4), specifying breast cancer stem cells. S100A10 silencing blocks chemotherapy-induced BCSC enrichment and impairs tumor initiation.","method":"Co-immunoprecipitation, ChIP, siRNA/shRNA knockdown, HIF-1 manipulation, tumor initiation assay, chromatin mark analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP defining complex, ChIP for chromatin mark erasure, shRNA knockdown with tumor functional readout, pathway epistasis established","pmids":["32427586"],"is_preprint":false},{"year":2020,"finding":"S100A10 promotes aerobic glycolysis and malignant growth in gastric cancer by activating mTOR signaling through interaction with ANXA2, via the Src/ANXA2/AKT/mTOR signaling pathway.","method":"Co-immunoprecipitation, siRNA knockdown, glycolysis assays (glucose consumption, lactate, OCR, ECAR), western blot (signaling), xenograft model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus signaling analysis, functional metabolic assays, single lab","pmids":["33324631"],"is_preprint":false},{"year":2021,"finding":"SUMOylation of S100A10 promotes its nuclear localization in polyploid giant cancer cells (PGCCs) and daughter cells; in contrast, control cells show predominantly ubiquitinated S100A10 (cytoplasmic). Nuclear S100A10 regulates expression of ARHGEF18, PTPRN2, and DEFA3 (involved in actin dynamics and cytoskeleton remodeling), as shown by ChIP-Seq. Inhibition of SUMO1 reduces nuclear S100A10 and decreases proliferation/migration of PGCCs.","method":"Co-immunoprecipitation, MG132 and ginkgolic acid treatment, western blot, ChIP-Seq, SUMO1 inhibition","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-Seq for target genes, pharmacological and genetic inhibition of SUMOylation, single lab","pmids":["34336846"],"is_preprint":false},{"year":2023,"finding":"ANXA2 and S100A10 accumulate in apically extruded, RasV12-transformed epithelial cells; ANXA2 acts upstream of S100A10 accumulation. ANXA2 knockdown promotes apoptosis of apically extruded transformed cells via ROS-mediated p38MAPK activation; the p38MAPK inhibitor and ROS scavenger Trolox rescue the multilayered structure phenotype, defining an ANXA2/S100A10 → ROS/p38MAPK pathway that prevents anoikis of transformed cells.","method":"siRNA/shRNA knockdown, in vitro and in vivo (murine tissue) imaging, ROS measurement, p38MAPK inhibition, Trolox treatment, western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown in multiple cell systems and in vivo, pharmacological rescue, epistasis established across multiple interventions","pmids":["37844241"],"is_preprint":false},{"year":2011,"finding":"Interaction of the bluetongue virus NS3 N-terminal 13 residues with S100A10/p11 (demonstrated by pulldown and confocal microscopy) is essential for intracellular trafficking and plasma membrane egress of BTV in mammalian cells; NS3A mutants lacking this region fail to interact with S100A10/p11 and show severely attenuated growth despite normal protein expression, replication, dsRNA synthesis, and particle assembly.","method":"Reverse genetics, pulldown assay, confocal microscopy, site-directed mutagenesis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reverse genetics plus pulldown, mutagenesis, single lab, viral model but mechanistic for S100A10 binding","pmids":["21411520"],"is_preprint":false},{"year":2023,"finding":"S100A10 is secreted by HCC cells into extracellular vesicles (EVs) and governs protein cargoes in EVs by physically binding integrin αV, mediating association of MMP2, fibronectin, and EGF to EV membranes; EV-S100A10 upregulates EGFR, AKT, and ERK signaling and promotes HCC stemness and metastasis.","method":"Co-immunoprecipitation (S100A10-integrin αV), EV isolation and proteomic analysis, neutralizing antibody, siRNA knockdown, in vivo xenograft","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction, EV proteomics, neutralizing antibody and siRNA with in vivo readout, single lab","pmids":["36631249"],"is_preprint":false},{"year":2008,"finding":"The cAMP/PKA/CnA signaling axis regulates annexin 2-S100A10 complex formation and its interaction with TRPV6 in airway (16HBE14o-) and gut (Caco-2) epithelial cells; forskolin-stimulated complex formation was attenuated by PKA or calcineurin A inhibitors, and complex association with TRPV6 depended on CnA-dependent dephosphorylation of annexin 2. PKA and CnA inhibitors attenuated Ca2+ uptake in Caco-2 cells.","method":"Co-immunoprecipitation, calcium uptake assay, pharmacological inhibitors (PKA, CnA inhibitors), forskolin stimulation","journal":"Cell calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional calcium assay, two cell lines, pharmacological controls, single lab","pmids":["18187190"],"is_preprint":false}],"current_model":"S100A10 (p11) is a constitutively active, Ca2+-insensitive S100 protein that functions primarily as a scaffolding adaptor: it exists predominantly as a heterotetrameric complex with annexin A2 (AIIt), which stabilizes S100A10 against ubiquitin/proteasome-dependent degradation; within the complex, S100A10 uses its C-terminal lysines and internal lysines as docking sites for tissue plasminogen activator and plasminogen at the cell surface to drive plasmin generation and fibrinolysis; separately, it routes multiple transmembrane proteins (TRPV5/TRPV6, CFTR, TRPV6) to the plasma membrane, scaffolds AHNAK-mediated cortical actin organization and membrane repair, anchors VAMP2-associated exocytic machinery in chromaffin cells, recruits Munc13-4 for Weibel-Palade body exocytosis, and mediates ULK1 localization for IFN-γ-induced autophagy; its levels are regulated post-translationally by succinylation (writer CPT1A, eraser SIRT5) at K47 and SUMOylation promoting nuclear entry, by annexin A2-dependent protection from proteasomal degradation, and transcriptionally by oncogenes (PML-RARα, KRAS via RalGDS, HIF-1, AXL/SRC); nuclear S100A10 (when SUMOylated) also regulates chromatin/gene expression in cancer cells."},"narrative":{"mechanistic_narrative":"S100A10 (p11) is a constitutively active S100 protein that functions as a scaffolding adaptor, exerting its effects primarily through an obligate heterotetrameric complex with annexin A2 (AIIt/A2t) [PMID:12660155, PMID:12730231]. Annexin A2 supplies plasma membrane targeting and, through its N-terminally acetylated N-terminal peptide, drives tetramer formation and recruits cytosolic S100A10 to the membrane [PMID:11445072, PMID:23091277]; complex formation also stabilizes S100A10 by masking an autonomous polyubiquitination signal that otherwise routes the unpartnered protein to proteasomal degradation [PMID:18434302]. A central function of the complex is cell-surface plasminogen activation: the carboxyl-terminal and internal lysines of S100A10 dock tissue plasminogen activator and plasminogen to drive plasmin generation and fibrinolysis, with defined contributions of the tPA kringle-2 and plasminogen kringle-1 domains [PMID:12730231, PMID:14570893, PMID:28382372]. Genetic deletion in mice establishes S100A10 as a regulator of fibrinolysis, angiogenesis, macrophage migration, and tumor growth, the latter via macrophage recruitment to tumor sites [PMID:20424186, PMID:21768297, PMID:22042827]. As a membrane scaffold the complex routes and positions multiple transmembrane and trafficking partners — the epithelial Ca2+ channels TRPV5/TRPV6 and the CFTR chloride channel (the latter via cAMP/PKA/calcineurin-controlled complex formation) [PMID:12660155, PMID:17581860, PMID:18187190], the cytoskeletal linker AHNAK for cortical actin organization through an asymmetric AHNAK:A2:S100A10 (1:2:2) binding mode resolved by NMR and crystallography [PMID:14699089, PMID:21949189, PMID:23275167], and recycling endosomes [PMID:13679511]. S100A10 also anchors exocytic machinery, interacting with VAMP2 in chromaffin cells and recruiting Munc13-4 for Weibel-Palade body exocytosis and von Willebrand factor release [PMID:20374557, PMID:28450451], and it positions ULK1 at autophagosome formation sites during IFN-γ-induced autophagy [PMID:27871932]. Its levels are tuned post-translationally by K47 succinylation (writer CPT1A, eraser SIRT5) that blocks ubiquitylation [PMID:30394687], by competitive displacement from annexin A2 by the tumor suppressor DLC1 that exposes S100A10 to degradation [PMID:21372205], and transcriptionally by oncogenic inputs including PML-RARα, KRAS-RalGDS, HIF-1, and AXL/SRC signaling [PMID:21310922, PMID:27351226, PMID:31585940, PMID:32427586]. In cancer, SUMOylation drives nuclear entry where S100A10 participates in chromatin-modifying complexes and gene regulation [PMID:32427586, PMID:34336846]. S100A10 is additionally exploited as an internalization/trafficking factor by HPV16 and bluetongue virus [PMID:22927980, PMID:23637395, PMID:21411520].","teleology":[{"year":1997,"claim":"Established that S100A10 is a covalent structural component of the keratinocyte cornified envelope, the first indication it serves cell-surface/structural roles beyond a soluble signaling protein.","evidence":"Peptide sequencing of proteolytically digested purified cornified envelope fragments identifying epsilon-(gamma-glutamyl)lysine crosslink sites","pmids":["9115270"],"confidence":"Medium","gaps":["Single biochemical study","Functional consequence of crosslinking for envelope integrity not tested","Did not address the annexin A2 partnership"]},{"year":2001,"claim":"Resolved which subunit supplies membrane targeting, showing annexin A2 is the membrane-anchoring subunit that recruits otherwise cytosolic S100A10 upon complex formation.","evidence":"Live-cell imaging of YFP/CFP fusions of each subunit alone and co-expressed in HepG2 cells","pmids":["11445072"],"confidence":"Medium","gaps":["Imaging-based localization only","Did not define the lipid/membrane determinant","Single cell type"]},{"year":2003,"claim":"Defined S100A10 as a scaffolding adaptor that routes transmembrane channels and organizes membrane-cytoskeleton structures, identifying TRPV5/TRPV6 and AHNAK as complex clients and mapping the channel binding motif.","evidence":"Yeast two-hybrid, GST pull-down, Co-IP, siRNA with electrophysiology (TRPV5/6) and actin imaging (AHNAK) in HEK293 and MDCK cells","pmids":["12660155","14699089","13679511"],"confidence":"High","gaps":["Stoichiometry and structural basis of AHNAK binding not yet resolved","Whether channel routing is direct trafficking versus surface retention unresolved","Endosome positioning role did not affect cargo kinetics"]},{"year":2003,"claim":"Provided the quantitative biochemical basis for plasminogen activation, mapping tPA/plasminogen docking to the S100A10 C-terminal lysines and demonstrating loss of plasmin generation and invasion upon knockdown.","evidence":"Surface plasmon resonance on phospholipid bilayers with C-terminal lysine removal; stable RNAi in CCL-222 cells with plasmin generation and invasion assays","pmids":["12730231","14570893"],"confidence":"High","gaps":["In vivo relevance not yet established","Did not separate annexin A2-dependent from -independent surface pools fully","Internal lysine contribution not yet defined"]},{"year":2005,"claim":"Extended the complex's biochemistry to membrane reorganization and redox chemistry, showing it segregates phosphatidylserine domains and that AIIt is a thioredoxin-system substrate that reduces plasmin disulfides.","evidence":"Scanning force/fluorescence microscopy on artificial bilayers; in vitro thiol oxidation and NADPH/thioredoxin reductase reconstitution","pmids":["16285733","15849182"],"confidence":"High","gaps":["Physiological significance of redox cycling in cells incompletely defined","Lipid segregation shown only on artificial bilayers","Transglutaminase substrate role (PMID 11258932) functional consequence untested"]},{"year":2008,"claim":"Identified the principal mechanism controlling S100A10 abundance: unpartnered S100A10 is polyubiquitinated and degraded, while annexin A2 binding masks the ubiquitination signal and enables Src-driven surface translocation.","evidence":"Co-IP, ubiquitination assays, proteasome inhibition, and annexin A2 knockout cells/mice in endothelial cells","pmids":["18434302"],"confidence":"High","gaps":["E3 ligase not identified","Precise ubiquitination site not mapped here","Did not resolve whether surface pool is degradation-protected"]},{"year":2008,"claim":"Connected complex assembly to second-messenger signaling, showing cAMP/PKA/calcineurin controls annexin A2-S100A10 association with CFTR and TRPV6 and that this fails in F508del-CFTR.","evidence":"Co-IP, patch-clamp electrophysiology, calcium uptake, peptide competition and PKA/CnA inhibitors in epithelial cells and CF mouse models","pmids":["17581860","18187190","18346874"],"confidence":"Medium","gaps":["Direct versus indirect role of S100A10 in dephosphorylation cascade not isolated","Single research group","Whether channel currents depend on S100A10 itself versus annexin A2 not fully separated"]},{"year":2010,"claim":"Demonstrated in vivo that S100A10 is a physiologically required plasminogen receptor, controlling macrophage migration and matrix-degrading plasmin/MMP-9 activation.","evidence":"S100A10 knockout mice with peritoneal recruitment, Matrigel plug, plasmin generation, invasion and pro-MMP-9 activation assays","pmids":["20424186"],"confidence":"High","gaps":["Cell-surface receptor versus intracellular contribution not fully separated","Annexin A2-independence in vivo not formally tested","Mechanism linking S100A10 to MMP-9 activation indirect"]},{"year":2011,"claim":"Cemented the in vivo fibrinolytic and angiogenic functions and revealed a competitive degradation switch (DLC1) plus the structural basis of AHNAK recognition.","evidence":"S100A10 knockout mice (thrombolysis, angiogenesis); DLC1 competition/ubiquitination assays; NMR and biophysical mapping of the asymmetric AHNAK-A2t interface","pmids":["21768297","21372205","21949189","21310922"],"confidence":"High","gaps":["Whether DLC1 competition operates broadly across S100A10 clients untested","PML-RARalpha regulation correlative for transcription","Structural model based on peptide rather than full-length AHNAK"]},{"year":2012,"claim":"Defined S100A10 as a viral host factor and refined the structural and PTM determinants of complex assembly, including the requirement for N-terminal acetylation of annexin A2.","evidence":"EPR, Co-IP, shRNA and infection assays for HPV16; 2.5 A crystal structure of the AHNAK-A2t complex; competitive peptide inhibition and ITC for acetylation dependence","pmids":["22927980","23275167","23091277","23129259"],"confidence":"High","gaps":["Whether S100A10 acts in viral entry versus trafficking not yet separated here","Acetylation requirement shown in vitro","Rac1-dependent spreading role (PMID 23129259) mechanistically indirect"]},{"year":2013,"claim":"Separated the division of labor within the complex during viral infection, assigning annexin A2 to surface entry and S100A10 to intracellular late-endosomal trafficking.","evidence":"Subunit-specific antibody blockade, Co-IP, siRNA and confocal infection assays in keratinocytes","pmids":["23637395"],"confidence":"High","gaps":["Molecular trafficking machinery engaged by S100A10 not identified","Single virus model","Direct S100A10 cargo on endosomes not defined"]},{"year":2016,"claim":"Expanded S100A10 scaffolding into autophagy, showing it positions ULK1 at ER-mitochondria autophagosome formation sites during IFN-gamma signaling downstream of annexin A2.","evidence":"Co-IP, siRNA knockdown with overexpression rescue and autophagosome quantification","pmids":["27871932"],"confidence":"Medium","gaps":["Direct versus indirect ULK1 interaction not resolved","Single lab","Generality beyond IFN-gamma-triggered autophagy untested"]},{"year":2017,"claim":"Broadened the exocytic scaffolding role to regulated secretion, identifying Munc13-4 recruitment for Weibel-Palade body fusion and PLA2R as a high-affinity surface partner.","evidence":"Co-IP, siRNA, TIRF microscopy and VWF release assays; SPR and domain mapping for PLA2R; domain-mutant in vitro plasmin generation","pmids":["28450451","28761153","28382372"],"confidence":"High","gaps":["Direct binding interface of Munc13-4 not mapped","PLA2R interaction structural detail and disease relevance not established","Internal-lysine contribution to plasmin generation quantitatively incomplete"]},{"year":2018,"claim":"Resolved post-translational control of S100A10 stability, identifying K47 succinylation (CPT1A/SIRT5) as a stabilizing mark and K57 as the ubiquitylation site, with succinylation promoting cancer invasiveness.","evidence":"Mass spectrometry, Co-IP, ubiquitin mutagenesis (K57), succinyl-mimetic (K47E) functional assays, SIRT5 manipulation, proteasome inhibition across cancer cell lines","pmids":["30394687","30206209","30076379"],"confidence":"High","gaps":["Interplay between succinylation and ubiquitylation in vivo not quantified","ATRA-driven degradation mechanism partly ubiquitin-independent and unresolved","HPV trafficking role of S100A10 versus annexin A2 still entangled"]},{"year":2020,"claim":"Established oncogenic and nuclear functions, placing S100A10 downstream of HIF-1 and KRAS, within chromatin-modifying complexes, and linking SUMOylation to nuclear gene regulation.","evidence":"Co-IP, ChIP/ChIP-Seq, siRNA/shRNA, HIF-1 and SUMO manipulation, glycolysis assays, tumor initiation models across breast, gastric and other cancers","pmids":["32427586","27351226","33324631","31585940","34336846"],"confidence":"Medium","gaps":["Direct DNA/chromatin binding by S100A10 not demonstrated","Whether nuclear S100A10 acts as adaptor or has intrinsic activity unclear","Several oncogenic pathway placements rely on single labs"]},{"year":2023,"claim":"Revealed extracellular-vesicle and cell-extrusion functions, showing S100A10 organizes EV protein cargo via integrin alphaV and acts with annexin A2 to suppress anoikis of transformed cells.","evidence":"Co-IP, EV proteomics, neutralizing antibody and siRNA with in vivo xenografts (HCC); siRNA/shRNA, ROS/p38MAPK pharmacology in transformed epithelial extrusion models","pmids":["36631249","37844241"],"confidence":"Medium","gaps":["Direct versus complex-mediated integrin alphaV binding not fully separated","Single-lab findings","Mechanism connecting S100A10 to ROS/p38MAPK indirect"]},{"year":null,"claim":"It remains unresolved how S100A10, a single small adaptor, selects among its many membrane, exocytic, autophagic, nuclear, and extracellular clients in a given cell, and what determines partitioning between annexin A2-bound, surface, and nuclear pools.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model for client selection","E3 ligase for S100A10 ubiquitylation unidentified","Mechanism of intrinsic nuclear/chromatin activity undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,18,31,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,14,7]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[24,28,43]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,10,18,31]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,41]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[39,41]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4,28,35]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,27]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[3,5,19,32]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4,18,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,23,38]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[20,30,39,44]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[29]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2,14]}],"complexes":["annexin A2-S100A10 heterotetramer (AIIt/A2t)"],"partners":["ANXA2","AHNAK","TRPV5","TRPV6","CFTR","VAMP2","ULK1","DLC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P60903","full_name":"Protein S100-A10","aliases":["Calpactin I light chain","Calpactin-1 light chain","Cellular ligand of annexin II","S100 calcium-binding protein A10","p10 protein","p11"],"length_aa":97,"mass_kda":11.2,"function":"Because S100A10 induces the dimerization of ANXA2/p36, it may function as a regulator of protein phosphorylation in that the ANXA2 monomer is the preferred target (in vitro) of tyrosine-specific kinase","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P60903/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/S100A10","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000197747","cell_line_id":"CID000976","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"membrane","grade":2},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"CEP192","stoichiometry":0.2},{"gene":"FBL","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000976","total_profiled":1310},"omim":[{"mim_id":"611764","title":"CORNIFELIN; CNFN","url":"https://www.omim.org/entry/611764"},{"mim_id":"611312","title":"CORNULIN; CRNN","url":"https://www.omim.org/entry/611312"},{"mim_id":"611296","title":"ANNEXIN A2 RECEPTOR; ANXA2R","url":"https://www.omim.org/entry/611296"},{"mim_id":"604427","title":"SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 10; SCN10A","url":"https://www.omim.org/entry/604427"},{"mim_id":"603257","title":"SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A, MEMBER 3; SMARCA3","url":"https://www.omim.org/entry/603257"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":2017.3}],"url":"https://www.proteinatlas.org/search/S100A10"},"hgnc":{"alias_symbol":["P11","42C","CLP11"],"prev_symbol":["ANX2LG","CAL1L"]},"alphafold":{"accession":"P60903","domains":[{"cath_id":"1.10.238.10","chopping":"3-92","consensus_level":"high","plddt":94.2488,"start":3,"end":92}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P60903","model_url":"https://alphafold.ebi.ac.uk/files/AF-P60903-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P60903-F1-predicted_aligned_error_v6.png","plddt_mean":92.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=S100A10","jax_strain_url":"https://www.jax.org/strain/search?query=S100A10"},"sequence":{"accession":"P60903","fasta_url":"https://rest.uniprot.org/uniprotkb/P60903.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P60903/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P60903"}},"corpus_meta":[{"pmid":"12660155","id":"PMC_12660155","title":"Functional expression of the epithelial Ca(2+) channels (TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12660155","citation_count":228,"is_preprint":false},{"pmid":"9115270","id":"PMC_9115270","title":"S100A11, S100A10, annexin I, desmosomal proteins, small proline-rich proteins, plasminogen activator inhibitor-2, and involucrin are components of the cornified envelope of cultured human epidermal keratinocytes.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9115270","citation_count":198,"is_preprint":false},{"pmid":"14699089","id":"PMC_14699089","title":"AHNAK interaction with the annexin 2/S100A10 complex regulates cell membrane cytoarchitecture.","date":"2003","source":"The Journal of cell 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regulate human papillomavirus type 16 entry and intracellular trafficking in human keratinocytes.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23637395","citation_count":113,"is_preprint":false},{"pmid":"13679511","id":"PMC_13679511","title":"The annexin 2/S100A10 complex controls the distribution of transferrin receptor-containing recycling endosomes.","date":"2003","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/13679511","citation_count":111,"is_preprint":false},{"pmid":"32427586","id":"PMC_32427586","title":"Chemotherapy-induced S100A10 recruits KDM6A to facilitate OCT4-mediated breast cancer stemness.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/32427586","citation_count":103,"is_preprint":false},{"pmid":"17085073","id":"PMC_17085073","title":"p11 (S100A10)--an inducible adaptor protein that modulates neuronal functions.","date":"2006","source":"Current 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[et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/22797859","citation_count":19,"is_preprint":false},{"pmid":"24851084","id":"PMC_24851084","title":"Forced expression of S100A10 reduces sensitivity to oxaliplatin in colorectal cancer cells.","date":"2014","source":"Proteome science","url":"https://pubmed.ncbi.nlm.nih.gov/24851084","citation_count":17,"is_preprint":false},{"pmid":"37844241","id":"PMC_37844241","title":"Accumulation of annexin A2 and S100A10 prevents apoptosis of apically delaminated, transformed epithelial cells.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37844241","citation_count":16,"is_preprint":false},{"pmid":"18346874","id":"PMC_18346874","title":"Defective formation of PKA/CnA-dependent annexin 2-S100A10/CFTR complex in DeltaF508 cystic fibrosis cells.","date":"2008","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/18346874","citation_count":16,"is_preprint":false},{"pmid":"30376879","id":"PMC_30376879","title":"Identifying deer antler uhrf1 proliferation and s100a10 mineralization genes using comparative RNA-seq.","date":"2018","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30376879","citation_count":15,"is_preprint":false},{"pmid":"37476183","id":"PMC_37476183","title":"miR-21-5p Inhibits the Proliferation, Migration, and Invasion of Glioma by Targeting S100A10.","date":"2023","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37476183","citation_count":15,"is_preprint":false},{"pmid":"30206209","id":"PMC_30206209","title":"Regulation of cell surface protease receptor S100A10 by retinoic acid therapy in acute promyelocytic leukemia (APL)☆.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30206209","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49685,"output_tokens":12077,"usd":0.165105,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23285,"output_tokens":6233,"usd":0.136125,"stage2_stop_reason":"end_turn"},"total_usd":0.30123,"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\": 2003,\n      \"finding\": \"S100A10 (p11) was identified as the first auxiliary protein of the epithelial Ca2+ channels TRPV5 and TRPV6 via yeast two-hybrid and GST pull-down. S100A10 binds the conserved C-terminal VATTV motif of TRPV5/TRPV6 (first threonine critical); S100A10 forms a heterotetrameric complex with annexin A2 that routes TRPV5 and TRPV6 to the plasma membrane. Annexin A2-specific siRNA knockdown inhibited TRPV5/TRPV6-mediated currents in HEK293 cells.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, siRNA knockdown, electrophysiology, site-directed mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including mutagenesis, GST pull-down, Co-IP, siRNA knockdown with functional readout (channel activity), replicated by localization studies\",\n      \"pmids\": [\"12660155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"S100A10 (calpactin light chain) was identified as a component of the cornified envelope (CE) of cultured human epidermal keratinocytes, cross-linked via epsilon-(gamma-glutamyl)lysine bonds; its reactive sites were mapped by sequential proteolytic digestion to amino- and carboxyl-terminal regions.\",\n      \"method\": \"Proteolytic cleavage of purified CE fragments followed by peptide sequencing (CNBr digestion, trypsin, proteinase K)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical identification from purified CE with peptide sequencing in a single study\",\n      \"pmids\": [\"9115270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In Madin-Darby canine kidney (MDCK) cells, S100A10 mediates the interaction between annexin A2 and the C-terminal regulatory domain of AHNAK at the plasma membrane. The annexin A2/S100A10 complex is required for AHNAK plasma membrane association; siRNA knockdown of both proteins prevented AHNAK plasma membrane localization and impaired cortical actin cytoskeleton reorganization needed to support cell height.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, actin cytoskeleton imaging, cell fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA with defined phenotypic readout (actin organization and AHNAK localization), replicated across multiple approaches\",\n      \"pmids\": [\"14699089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The annexin A2/S100A10 heterotetramer (AIIt) bound t-PA (Kd=0.68 µM), plasminogen (Kd=0.11 µM), and plasmin (Kd=75 nM) when immobilized on a phospholipid bilayer; the carboxyl-terminal lysines of S100A10 form the t-PA and plasminogen binding sites, while annexin A2 and S100A10 contain distinct binding sites for plasmin.\",\n      \"method\": \"Surface plasmon resonance on phospholipid-immobilized protein, carboxyl-terminal lysine removal\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative in vitro binding assay with domain mapping, rigorous controls including lysine removal\",\n      \"pmids\": [\"12730231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Downregulation of annexin A2 and S100A10 by siRNA perturbed the distribution of transferrin receptor- and rab11-positive recycling endosomes (producing extensively bent tubules and increased clathrin-positive buds) but did not significantly affect transferrin uptake/recycling kinetics. Rescue by reexpression of the N-terminal annexin A2 domain or S100A10 confirmed both subunits are required for proper positioning of recycling endosomes.\",\n      \"method\": \"RNAi knockdown, immunofluorescence, whole-mount immunoelectron microscopy, transferrin uptake assay, rescue by reexpression\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA with rescue experiment, electron microscopy, multiple orthogonal methods in single study\",\n      \"pmids\": [\"13679511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"siRNA-mediated stable knockdown of S100A10 in colorectal CCL-222 cancer cells caused 45% loss in plasminogen binding, 65% loss in cellular plasmin generation, and complete loss of plasminogen-dependent invasiveness. S100A10 was shown to associate with the plasma membrane and co-localize with uPAR independently of annexin A2.\",\n      \"method\": \"Stable RNAi knockdown (pSUPER vector), plasminogen binding assay, plasmin generation assay, invasion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — stable knockdown with quantitative functional readouts across multiple assays in a single rigorous study\",\n      \"pmids\": [\"14570893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"S100A10, S100A7, and S100A11 are substrates for both type I and type II transglutaminases, which catalyze epsilon-(gamma-glutamyl)lysine crosslinks; the reactive residues are located at the solvent-exposed amino- and carboxyl-terminal ends of S100A10.\",\n      \"method\": \"In vitro transglutaminase enzymatic assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic assay in vitro, single study with multiple S100 family members tested\",\n      \"pmids\": [\"11258932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In endothelial cells, unpartnered S100A10 (p11) is polyubiquitinated and degraded via a proteasome-dependent mechanism. Annexin A2 (A2) stabilizes intracellular S100A10 through direct binding, masking an autonomous S100A10 polyubiquitination signal; this interaction requires both the p11-binding N-terminal domain of A2 and the C-terminal domain of p11. p11 is also required for Src kinase-mediated tyrosine phosphorylation of A2, which signals translocation of both proteins to the cell surface.\",\n      \"method\": \"In vitro and in vivo co-immunoprecipitation, ubiquitination assay, proteasome inhibition, endothelial cell fractionation, A2 knockout cell/mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assay, proteasome inhibition, knockout model) in single study, mechanistically rigorous\",\n      \"pmids\": [\"18434302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The annexin II-S100A10 complex is required for formation of E-cadherin-based adherens junctions in MDCK cells. Depletion of plasma membrane cholesterol (abolishing complex localization) or knockdown of annexin II by RNAi inhibited re-concentration of E-cadherin at nectin-based cell-cell contact sites during Ca2+ switch experiments.\",\n      \"method\": \"RNAi knockdown, cholesterol depletion, Ca2+ switch assay, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA + cholesterol depletion with defined functional readout, single lab, two orthogonal perturbations\",\n      \"pmids\": [\"15574423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The annexin A2/S100A10 heterotetramer (A2t) induces lateral segregation of phosphatidylserine (POPS)-enriched membrane domains in artificial phospholipid bilayers, forming micrometer-sized protein domains associated with POPS depletion in neighboring membrane areas.\",\n      \"method\": \"Scanning force microscopy, fluorescence microscopy on artificial lipid bilayers\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biophysical assay on reconstituted membranes, single study\",\n      \"pmids\": [\"16285733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Annexin A2 is the plasma membrane-targeting subunit of the annexin A2/S100A10 complex: monomeric annexin A2 is targeted to the plasma membrane, while non-complexed S100A10 distributes to the general cytosol; co-expression and complex formation recruits S100A10 to the plasma membrane.\",\n      \"method\": \"Live cell imaging with YFP/CFP fusion proteins in HepG2 cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live cell imaging with fluorescent fusion proteins, direct localization experiment, single lab\",\n      \"pmids\": [\"11445072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Annexin A2 is required for strong binding of S100A10 to the C-terminal domain of AHNAK in a yeast triple-hybrid experiment and in vitro binding assay; the Annexin A2 N-terminal tail (involved in S100A10/Annexin A2 tetramerization) mediates this effect. The minimal A2t binding motif in AHNAK was mapped to a 20-amino-acid peptide (A2tBP1), and a second lower-affinity motif (A2tBP2) was identified in the AHNAK N-terminal domain.\",\n      \"method\": \"Yeast triple-hybrid, in vitro binding assay, co-immunoprecipitation, live cell imaging with EGFP fusion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (yeast triple-hybrid, in vitro binding, Co-IP, live imaging), binding site mapped in single rigorous study\",\n      \"pmids\": [\"16984913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The annexin A2/S100A10 heterotetramer (AIIt) directly reduces the disulfide bond of plasmin (Cys462-Cys541) during plasmin autoproteolysis; AIIt thiols are oxidized during plasmin disulfide reduction. Thioredoxin reductase uses NADPH to recycle oxidized thioredoxin, which in turn reduces oxidized AIIt, completing an electron transfer chain from NADPH to AIIt. AIIt is identified as a substrate of the thioredoxin system.\",\n      \"method\": \"In vitro thiol oxidation assay (MBP-biocytin labeling), NADPH/thioredoxin reductase reconstitution, cell-based plasminogen treatment assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with cell-based validation, mechanistic determination of redox chain\",\n      \"pmids\": [\"15849182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"S100A10 (p11) is dispensable for annexin A2 association to early endosomes and for early-to-late endosome transport. Biochemical fractionation showed p11 was not present on purified early endosomes, and p11 siRNA knockdown did not affect annexin A2 targeting to early endosomes or endosomal transport beyond early endosomes (in contrast to annexin A2 knockdown).\",\n      \"method\": \"siRNA knockdown, early endosome purification, immunofluorescence, endosomal transport assay (in vitro liposome binding)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical fractionation, siRNA knockdown, in vitro reconstitution showing negative result for S100A10 on early endosomes with multiple methods; result is itself mechanistically informative\",\n      \"pmids\": [\"17971878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A cAMP/PKA/calcineurin (CnA)-dependent mechanism regulates annexin 2-S100A10 complex formation and its interaction with CFTR chloride channel. Forskolin increased annexin 2-S100A10 co-immunoprecipitation with cell surface CFTR; this was attenuated by PKA or CnA inhibitors. An acetylated peptide covering the S100A10-binding site on annexin 2 (Ac1-14) disrupted the complex and inhibited cAMP/PKA-dependent CFTR-mediated and outwardly rectifying chloride channel currents.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology (patch clamp), peptide competition, PKA/CnA inhibitors, short-circuit current across intestinal biopsy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, electrophysiology, peptide disruption, pharmacological inhibitors; multiple orthogonal methods establishing mechanistic complex\",\n      \"pmids\": [\"17581860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The annexin II-S100A10 complex forms a ternary complex with tryptophanyl-tRNA synthetase (TrpRS) and regulates trafficking of TrpRS for exocytosis from endothelial cells; both annexin II and S100A10 are required for TrpRS secretion.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, trafficking/secretion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional secretion assay in single lab, two methods\",\n      \"pmids\": [\"17999956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In CFBE41o- cells homozygous for F508del-CFTR (ΔF508), cAMP/PKA fails to induce annexin 2-S100A10/CFTR complex formation, due to defective PKA-dependent serine phosphorylation of calcineurin A (CnA), defective CnA-annexin 2 complex formation, and defective CnA-dependent dephosphorylation of annexin 2.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, immunohistochemistry, CF mouse model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with in vivo mouse model validation, mechanistic detail of signaling cascade, single lab\",\n      \"pmids\": [\"18346874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100A10 acts as a cell surface plasminogen receptor on macrophages; S100A10-deficient mice showed up to 53% reduction in macrophage migration into the peritoneal cavity in response to thioglycollate, 8-fold fewer macrophages in Matrigel plugs in vivo, 50% reduction in plasmin-dependent invasion, and 45% reduction in plasmin generation in vitro. Loss of S100A10 reduced pro-MMP-9 activation.\",\n      \"method\": \"S100A10 knockout mouse model, Matrigel invasion assay, plasmin generation assay, peritoneal lavage, in vivo Matrigel plug assay, MMP-9 activation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mouse model with multiple quantitative functional readouts in vivo and in vitro\",\n      \"pmids\": [\"20424186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100A10 co-localizes and directly interacts with VAMP2 (synaptobrevin 2) at the plasma membrane of resting adrenergic chromaffin cells; S100A10 is present in VAMP2 microdomains. Stimulation induces annexin A2 translocation to the plasma membrane where it interacts with S100A10 to form a tetramer. Tetanus toxin cleavage of VAMP2 solubilizes S100A10 from the plasma membrane and inhibits annexin A2 translocation, indicating S100A10 plasma membrane anchoring depends on VAMP2.\",\n      \"method\": \"Cross-linking, co-immunoprecipitation, immunogold labeling with spatial point pattern analysis, tetanus toxin treatment, confocal microscopy\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cross-linking, Co-IP, immunogold EM with spatial analysis, functional perturbation by tetanus toxin, multiple methods\",\n      \"pmids\": [\"20374557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"S100A10-deficient mice display increased fibrin deposition in vasculature and reduced clearance of batroxobin-induced vascular thrombi; S100A10-null endothelial cells showed 40% reduction in plasminogen binding and plasmin generation in vitro, and impaired neovascularization of Matrigel plugs in vivo, establishing S100A10 as a regulator of fibrinolysis and angiogenesis.\",\n      \"method\": \"S100A10 knockout mouse model, fibrin staining, thrombolysis assay, plasminogen binding, plasmin generation, Matrigel plug assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mouse with multiple in vivo and in vitro readouts across fibrinolysis and angiogenesis\",\n      \"pmids\": [\"21768297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DLC1 tumor suppressor directly binds S100A10 via central sequences in DLC1 and the C-terminus of S100A10—the same C-terminal region used by annexin A2. DLC1 competes with annexin A2 for S100A10 binding, displacing S100A10 from annexin A2 and making it accessible to ubiquitin-dependent proteasomal degradation, thereby decreasing S100A10 levels, attenuating plasminogen activation, and inhibiting cancer cell migration, invasion, and anchorage-independent growth.\",\n      \"method\": \"Co-immunoprecipitation, competition binding assay, quantitative invasion/migration assays, ubiquitination assay, siRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, competition assay, ubiquitination assay, multiple functional readouts; mechanism of S100A10 degradation delineated\",\n      \"pmids\": [\"21372205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PML-RARα oncoprotein increases cell surface S100A10 in APL cells; treatment with all-trans retinoic acid (ATRA) rapidly downregulates S100A10, concomitant with loss of fibrinolytic activity. S100A10 siRNA depletion blocked enhanced fibrinolytic activity of PML-RARα-expressing cells.\",\n      \"method\": \"Western blot, ATRA treatment, RNAi knockdown, plasmin generation assay, flow cytometry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional siRNA + pharmacological induction, single lab, two methods\",\n      \"pmids\": [\"21310922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The S100A10-annexin A2 ternary complex with AHNAK has an asymmetric arrangement: a single AHNAK peptide binds the A2t dimer at a site comprising residues from helix IV of S100A10 and the C-terminal portion of the annexin A2 N-terminal peptide, as determined by NMR and biophysical analysis. This binding surface is distinct from previously identified S100 target protein interfaces.\",\n      \"method\": \"NMR spectroscopy, multiple biophysical methods (SPR, ITC), peptide binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural characterization with multiple biophysical methods defining binding surface and stoichiometry\",\n      \"pmids\": [\"21949189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Genetic deletion of S100A10 in mice dramatically reduced growth of Lewis lung carcinomas and T241 fibrosarcomas, corresponding to decreased macrophage density at tumor sites. Intraperitoneal injection of wild-type (but not S100A10-deficient) macrophages rescued tumor growth in S100A10-null mice; direct intratumoral injection of either genotype rescued growth, demonstrating S100A10 is required specifically for macrophage migration to tumors.\",\n      \"method\": \"S100A10 knockout mouse model, syngeneic tumor implantation, macrophage reconstitution (IP and intratumoral injection), macrophage depletion\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null model, rescue experiment with wild-type vs. knockout macrophages, multiple tumor models\",\n      \"pmids\": [\"22042827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The S100A10 subunit of the annexin A2 heterotetramer (A2t) interacts with the HPV16 L2 minor capsid protein at aa 108-120 (as shown by EPR), and this interaction promotes HPV16 particle internalization; mutation of this L2 region reduces A2t binding and HPV16 pseudovirus infection. ShRNA downregulation of A2t decreases capsid internalization and infection.\",\n      \"journal\": \"PloS one\",\n      \"method\": \"Co-immunoprecipitation, electron paramagnetic resonance (EPR), shRNA knockdown, L2 mutagenesis, infection assay\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EPR structural data, mutagenesis, Co-IP, shRNA, infection assay in single study\",\n      \"pmids\": [\"22927980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the AHNAK C-terminal 20-aa peptide bound to the AnxA2-S100A10 heterotetramer (1:2:2 asymmetric complex) at 2.5 Å resolution confirmed asymmetric binding mode; AHNAK binding is governed by hydrophobic interactions with pockets on S100A10 and hydrogen bonds involving AHNAK backbone atoms, explaining high affinity and broad consensus sequence for S100A10 binding.\",\n      \"method\": \"X-ray crystallography (2.5 Å resolution)\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.5 Å resolution confirming and extending previous NMR finding, structural mechanism defined\",\n      \"pmids\": [\"23275167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"N-terminal acetylation of annexin A2 (removal of Met1, acetylation of Ser2) is required for S100A10 binding. Acetylated but not non-acetylated peptides covering the N-terminal annexin A2 sequence competitively inhibit complex formation, and N-terminally acetylated annexin A2 forms heterotetramer with S100A10 with affinity comparable to porcine tissue-derived AnxA2.\",\n      \"method\": \"Competitive peptide inhibition assay, mass spectrometry (N-terminal modification analysis), isothermal titration calorimetry/binding affinity assay\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution with defined PTM, competitive inhibition with acetylated vs. non-acetylated peptides, rigorous affinity measurement\",\n      \"pmids\": [\"23091277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S100A10 is required for actin stress fiber organization and cell spreading. Depletion of S100A10 impaired stress fiber formation and delayed cell spreading; Rac1 activation during spreading was suppressed by S100A10 knockdown, and expression of constitutively active Rac1 rescued spreading in S100A10-depleted cells.\",\n      \"method\": \"siRNA knockdown, actin staining, cell spreading assay, Rac1 activation assay, constitutively active Rac1 rescue\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with active Rac1 rescue, two orthogonal approaches, single lab\",\n      \"pmids\": [\"23129259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HPV16 exposure to keratinocytes induces EGFR-dependent Src kinase activation that phosphorylates and promotes extracellular translocation of annexin A2. HPV16 particles interact with AnxA2-S100A10 heterotetramer at the cell surface in a Ca2+-dependent manner; anti-AnxA2 antibody prevents HPV16 internalization, while anti-S100A10 antibody blocks infection at a late endosomal/lysosomal site, suggesting separate roles for AnxA2 (entry) and S100A10 (intracellular trafficking).\",\n      \"method\": \"Co-immunoprecipitation, antibody blockade, siRNA knockdown, confocal microscopy, infection assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, antibody blockade of specific subunits, siRNA; separate functional roles delineated with multiple methods\",\n      \"pmids\": [\"23637395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S100A10 regulates ULK1 localization to autophagosome formation sites at ER-mitochondria contact sites during IFN-γ-triggered autophagy. S100A10 interacts with ULK1 after IFN-γ stimulation; S100A10 knockdown prevents ULK1 localization to autophagosome formation sites and reduces autophagosome formation. ANXA2 acts upstream: ANXA2 knockdown reduces S100A10 expression, but S100A10 overexpression in ANXA2-knockdown cells restores autophagosome formation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression rescue, immunofluorescence, autophagy assay (autophagosome counting)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, siRNA knockdown with rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"27871932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Oncogenic KRAS increases S100A10 gene expression via the RalGDS pathway, leading to increased cell surface S100A10 protein and elevated cellular plasmin generation; depletion of S100A10 from RAS-transformed cells reduced both plasmin generation and invasiveness.\",\n      \"method\": \"Oncogenic RAS expression, RAS effector-loop mutants, S100A10 gene expression analysis, siRNA knockdown, plasmin generation assay, invasion assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement via RAS effector mutants plus siRNA knockdown, single lab\",\n      \"pmids\": [\"27351226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"S100A10 binds the Munc13-4 secretory protein; the AnxA2-S100A10 complex recruits Munc13-4 to Weibel-Palade body (WPB) fusion sites at the plasma membrane, promoting histamine-evoked WPB exocytosis and von Willebrand factor release.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, total internal reflection fluorescence (TIRF) microscopy, VWF release assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying novel interaction, siRNA with functional readout (VWF release), single lab\",\n      \"pmids\": [\"28450451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The kringle-2 domain of tPA (not the finger domain as in fibrin-stimulated plasmin generation) is critical for S100A10-dependent plasmin generation; the kringle-1 domain of plasminogen is also critical for S100A10-dependent (but not fibrin-dependent) plasminogen activation. Internal lysine residues of S100A10 contribute to plasmin-generating activity even after deletion/substitution of carboxyl-terminal lysine.\",\n      \"method\": \"Domain-switched/deleted tPA variants, truncated plasminogen variants, S100A10 site-directed mutagenesis, in vitro plasmin generation assay\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro plasmin generation with domain mutants of all three components, mechanistic dissection with mutagenesis\",\n      \"pmids\": [\"28382372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PLA2R (phospholipase A2 receptor) from podocytes binds specifically to the S100A10 component of the annexin A2-S100A10 (A2t) complex with high affinity; binding increases in acidic pH and occurs within the PLA2R NC3 fragment. Ca2+ promotes PLA2R-A2t complex association with phospholipid membranes in vitro. All three proteins co-localize in podocyte plasma membrane and extracellular vesicles.\",\n      \"method\": \"Proteomics pull-down, surface plasmon resonance, domain mapping, in vitro lipid membrane binding, co-localization by confocal microscopy\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — SPR quantitative binding, domain mapping, in vitro reconstitution on lipid membranes, co-localization; rigorous single study\",\n      \"pmids\": [\"28761153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"S100A10 is succinylated at lysine residue K47 by CPT1A acting as a lysine succinyltransferase; SIRT5 acts as the desuccinylase. K47 succinylation stabilizes S100A10 by suppressing ubiquitylation and proteasomal degradation. Expression of a succinylation-mimetic K47E mutant increased gastric cancer cell invasion and migration.\",\n      \"method\": \"Mass spectrometry (succinylation identification), co-immunoprecipitation (CPT1A-S100A10), overexpression of K47E mutant, ubiquitination assay, invasion/migration assay, SIRT5 manipulation\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — PTM identification by MS, writer (CPT1A) and eraser (SIRT5) identified, mutagenesis (K47E) with functional readout, Co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"30394687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Annexin A2 heterotetramer (A2t) including S100A10 is required for HPV intracellular trafficking from early to multivesicular endosomes, capsid uncoating, and protection from lysosomal degradation. Without A2t, viral progression from early endosomes is inhibited, uncoating dramatically reduced, and lysosomal degradation accelerated. AnxA2 forms a complex with CD63, a mediator of HPV trafficking.\",\n      \"method\": \"S100A10 shRNA knockdown, electron microscopy, co-immunoprecipitation, infection assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA, EM for endosomal stages, Co-IP, single lab\",\n      \"pmids\": [\"30076379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATRA promotes proteasomal degradation of S100A10 (p11) in an ubiquitin-independent manner in APL cells (NB4); proteasomal inhibitor lactacystin reversed ATRA-dependent p11 loss but did not cause accumulation of ubiquitylated p11. ATRA also reduces p11 transcript and protein independently of PML-RARα (in MCF-7 cells). Overexpression of annexin A2 upregulates p11 protein but not mRNA post-translationally. Forced expression of ubiquitin and p11 identified K57 as the ubiquitylation site of p11.\",\n      \"method\": \"Proteasome inhibition (lactacystin), siRNA, ubiquitin overexpression with site-directed mutagenesis (K57), western blot, RT-PCR\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — pharmacological inhibition, ubiquitin mutagenesis (K57), rescue experiment with annexin A2 overexpression, multiple cell lines\",\n      \"pmids\": [\"30206209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GAS6/AXL signaling activates S100A10 expression through SRC to promote plasmin production, endothelial cell invasion, and angiogenesis in ccRCC. Genetic and therapeutic inhibition of AXL signaling reduced tumor vessel density, S100A10 expression, and ccRCC growth in xenograft models.\",\n      \"method\": \"Genetic AXL inhibition, small molecule AXL inhibitor (cabozantinib), sAXL decoy receptor, tumor xenograft, angiogenesis assays, western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological pathway perturbation with in vivo readouts, single lab\",\n      \"pmids\": [\"31585940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"S100A10 is constitutively expressed in macrophages but is significantly downregulated upon TLR activation. S100A10-deficient macrophages are hyperresponsive to TLR stimulation; S100A10-deficient mice are more sensitive to endotoxin-induced lethal shock and E. coli-induced abdominal sepsis. Mechanistically, S100A10 interferes with recruitment and activation of receptor-proximal TLR signaling components to inhibit downstream TLR signaling.\",\n      \"method\": \"S100A10 knockout mouse model, TLR stimulation assays, cytokine measurement, endotoxin shock model, sepsis model, signaling component analysis\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null mouse model with functional in vivo readouts, single lab, mechanism described but not fully resolved biochemically from abstract\",\n      \"pmids\": [\"31467414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Paclitaxel-induced HIF-1-dependent S100A10 expression leads to complex formation of S100A10 with ANXA2, SPT6, and KDM6A; this complex is recruited to OCT4 binding sites where KDM6A erases H3K27me3 marks to facilitate transcription of pluripotency genes (NANOG, SOX2, KLF4), specifying breast cancer stem cells. S100A10 silencing blocks chemotherapy-induced BCSC enrichment and impairs tumor initiation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA/shRNA knockdown, HIF-1 manipulation, tumor initiation assay, chromatin mark analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP defining complex, ChIP for chromatin mark erasure, shRNA knockdown with tumor functional readout, pathway epistasis established\",\n      \"pmids\": [\"32427586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S100A10 promotes aerobic glycolysis and malignant growth in gastric cancer by activating mTOR signaling through interaction with ANXA2, via the Src/ANXA2/AKT/mTOR signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, glycolysis assays (glucose consumption, lactate, OCR, ECAR), western blot (signaling), xenograft model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus signaling analysis, functional metabolic assays, single lab\",\n      \"pmids\": [\"33324631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SUMOylation of S100A10 promotes its nuclear localization in polyploid giant cancer cells (PGCCs) and daughter cells; in contrast, control cells show predominantly ubiquitinated S100A10 (cytoplasmic). Nuclear S100A10 regulates expression of ARHGEF18, PTPRN2, and DEFA3 (involved in actin dynamics and cytoskeleton remodeling), as shown by ChIP-Seq. Inhibition of SUMO1 reduces nuclear S100A10 and decreases proliferation/migration of PGCCs.\",\n      \"method\": \"Co-immunoprecipitation, MG132 and ginkgolic acid treatment, western blot, ChIP-Seq, SUMO1 inhibition\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-Seq for target genes, pharmacological and genetic inhibition of SUMOylation, single lab\",\n      \"pmids\": [\"34336846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANXA2 and S100A10 accumulate in apically extruded, RasV12-transformed epithelial cells; ANXA2 acts upstream of S100A10 accumulation. ANXA2 knockdown promotes apoptosis of apically extruded transformed cells via ROS-mediated p38MAPK activation; the p38MAPK inhibitor and ROS scavenger Trolox rescue the multilayered structure phenotype, defining an ANXA2/S100A10 → ROS/p38MAPK pathway that prevents anoikis of transformed cells.\",\n      \"method\": \"siRNA/shRNA knockdown, in vitro and in vivo (murine tissue) imaging, ROS measurement, p38MAPK inhibition, Trolox treatment, western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown in multiple cell systems and in vivo, pharmacological rescue, epistasis established across multiple interventions\",\n      \"pmids\": [\"37844241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Interaction of the bluetongue virus NS3 N-terminal 13 residues with S100A10/p11 (demonstrated by pulldown and confocal microscopy) is essential for intracellular trafficking and plasma membrane egress of BTV in mammalian cells; NS3A mutants lacking this region fail to interact with S100A10/p11 and show severely attenuated growth despite normal protein expression, replication, dsRNA synthesis, and particle assembly.\",\n      \"method\": \"Reverse genetics, pulldown assay, confocal microscopy, site-directed mutagenesis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reverse genetics plus pulldown, mutagenesis, single lab, viral model but mechanistic for S100A10 binding\",\n      \"pmids\": [\"21411520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"S100A10 is secreted by HCC cells into extracellular vesicles (EVs) and governs protein cargoes in EVs by physically binding integrin αV, mediating association of MMP2, fibronectin, and EGF to EV membranes; EV-S100A10 upregulates EGFR, AKT, and ERK signaling and promotes HCC stemness and metastasis.\",\n      \"method\": \"Co-immunoprecipitation (S100A10-integrin αV), EV isolation and proteomic analysis, neutralizing antibody, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction, EV proteomics, neutralizing antibody and siRNA with in vivo readout, single lab\",\n      \"pmids\": [\"36631249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The cAMP/PKA/CnA signaling axis regulates annexin 2-S100A10 complex formation and its interaction with TRPV6 in airway (16HBE14o-) and gut (Caco-2) epithelial cells; forskolin-stimulated complex formation was attenuated by PKA or calcineurin A inhibitors, and complex association with TRPV6 depended on CnA-dependent dephosphorylation of annexin 2. PKA and CnA inhibitors attenuated Ca2+ uptake in Caco-2 cells.\",\n      \"method\": \"Co-immunoprecipitation, calcium uptake assay, pharmacological inhibitors (PKA, CnA inhibitors), forskolin stimulation\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional calcium assay, two cell lines, pharmacological controls, single lab\",\n      \"pmids\": [\"18187190\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"S100A10 (p11) is a constitutively active, Ca2+-insensitive S100 protein that functions primarily as a scaffolding adaptor: it exists predominantly as a heterotetrameric complex with annexin A2 (AIIt), which stabilizes S100A10 against ubiquitin/proteasome-dependent degradation; within the complex, S100A10 uses its C-terminal lysines and internal lysines as docking sites for tissue plasminogen activator and plasminogen at the cell surface to drive plasmin generation and fibrinolysis; separately, it routes multiple transmembrane proteins (TRPV5/TRPV6, CFTR, TRPV6) to the plasma membrane, scaffolds AHNAK-mediated cortical actin organization and membrane repair, anchors VAMP2-associated exocytic machinery in chromaffin cells, recruits Munc13-4 for Weibel-Palade body exocytosis, and mediates ULK1 localization for IFN-γ-induced autophagy; its levels are regulated post-translationally by succinylation (writer CPT1A, eraser SIRT5) at K47 and SUMOylation promoting nuclear entry, by annexin A2-dependent protection from proteasomal degradation, and transcriptionally by oncogenes (PML-RARα, KRAS via RalGDS, HIF-1, AXL/SRC); nuclear S100A10 (when SUMOylated) also regulates chromatin/gene expression in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"S100A10 (p11) is a constitutively active S100 protein that functions as a scaffolding adaptor, exerting its effects primarily through an obligate heterotetrameric complex with annexin A2 (AIIt/A2t) [#0, #3]. Annexin A2 supplies plasma membrane targeting and, through its N-terminally acetylated N-terminal peptide, drives tetramer formation and recruits cytosolic S100A10 to the membrane [#10, #26]; complex formation also stabilizes S100A10 by masking an autonomous polyubiquitination signal that otherwise routes the unpartnered protein to proteasomal degradation [#7]. A central function of the complex is cell-surface plasminogen activation: the carboxyl-terminal and internal lysines of S100A10 dock tissue plasminogen activator and plasminogen to drive plasmin generation and fibrinolysis, with defined contributions of the tPA kringle-2 and plasminogen kringle-1 domains [#3, #5, #32]. Genetic deletion in mice establishes S100A10 as a regulator of fibrinolysis, angiogenesis, macrophage migration, and tumor growth, the latter via macrophage recruitment to tumor sites [#17, #19, #23]. As a membrane scaffold the complex routes and positions multiple transmembrane and trafficking partners — the epithelial Ca2+ channels TRPV5/TRPV6 and the CFTR chloride channel (the latter via cAMP/PKA/calcineurin-controlled complex formation) [#0, #14, #45], the cytoskeletal linker AHNAK for cortical actin organization through an asymmetric AHNAK:A2:S100A10 (1:2:2) binding mode resolved by NMR and crystallography [#2, #22, #25], and recycling endosomes [#4]. S100A10 also anchors exocytic machinery, interacting with VAMP2 in chromaffin cells and recruiting Munc13-4 for Weibel-Palade body exocytosis and von Willebrand factor release [#18, #31], and it positions ULK1 at autophagosome formation sites during IFN-\\u03b3-induced autophagy [#29]. Its levels are tuned post-translationally by K47 succinylation (writer CPT1A, eraser SIRT5) that blocks ubiquitylation [#34], by competitive displacement from annexin A2 by the tumor suppressor DLC1 that exposes S100A10 to degradation [#20], and transcriptionally by oncogenic inputs including PML-RAR\\u03b1, KRAS-RalGDS, HIF-1, and AXL/SRC signaling [#21, #30, #37, #39]. In cancer, SUMOylation drives nuclear entry where S100A10 participates in chromatin-modifying complexes and gene regulation [#39, #41]. S100A10 is additionally exploited as an internalization/trafficking factor by HPV16 and bluetongue virus [#24, #28, #43].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that S100A10 is a covalent structural component of the keratinocyte cornified envelope, the first indication it serves cell-surface/structural roles beyond a soluble signaling protein.\",\n      \"evidence\": \"Peptide sequencing of proteolytically digested purified cornified envelope fragments identifying epsilon-(gamma-glutamyl)lysine crosslink sites\",\n      \"pmids\": [\"9115270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single biochemical study\", \"Functional consequence of crosslinking for envelope integrity not tested\", \"Did not address the annexin A2 partnership\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved which subunit supplies membrane targeting, showing annexin A2 is the membrane-anchoring subunit that recruits otherwise cytosolic S100A10 upon complex formation.\",\n      \"evidence\": \"Live-cell imaging of YFP/CFP fusions of each subunit alone and co-expressed in HepG2 cells\",\n      \"pmids\": [\"11445072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Imaging-based localization only\", \"Did not define the lipid/membrane determinant\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined S100A10 as a scaffolding adaptor that routes transmembrane channels and organizes membrane-cytoskeleton structures, identifying TRPV5/TRPV6 and AHNAK as complex clients and mapping the channel binding motif.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, Co-IP, siRNA with electrophysiology (TRPV5/6) and actin imaging (AHNAK) in HEK293 and MDCK cells\",\n      \"pmids\": [\"12660155\", \"14699089\", \"13679511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of AHNAK binding not yet resolved\", \"Whether channel routing is direct trafficking versus surface retention unresolved\", \"Endosome positioning role did not affect cargo kinetics\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the quantitative biochemical basis for plasminogen activation, mapping tPA/plasminogen docking to the S100A10 C-terminal lysines and demonstrating loss of plasmin generation and invasion upon knockdown.\",\n      \"evidence\": \"Surface plasmon resonance on phospholipid bilayers with C-terminal lysine removal; stable RNAi in CCL-222 cells with plasmin generation and invasion assays\",\n      \"pmids\": [\"12730231\", \"14570893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance not yet established\", \"Did not separate annexin A2-dependent from -independent surface pools fully\", \"Internal lysine contribution not yet defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended the complex's biochemistry to membrane reorganization and redox chemistry, showing it segregates phosphatidylserine domains and that AIIt is a thioredoxin-system substrate that reduces plasmin disulfides.\",\n      \"evidence\": \"Scanning force/fluorescence microscopy on artificial bilayers; in vitro thiol oxidation and NADPH/thioredoxin reductase reconstitution\",\n      \"pmids\": [\"16285733\", \"15849182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of redox cycling in cells incompletely defined\", \"Lipid segregation shown only on artificial bilayers\", \"Transglutaminase substrate role (PMID 11258932) functional consequence untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the principal mechanism controlling S100A10 abundance: unpartnered S100A10 is polyubiquitinated and degraded, while annexin A2 binding masks the ubiquitination signal and enables Src-driven surface translocation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, proteasome inhibition, and annexin A2 knockout cells/mice in endothelial cells\",\n      \"pmids\": [\"18434302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase not identified\", \"Precise ubiquitination site not mapped here\", \"Did not resolve whether surface pool is degradation-protected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected complex assembly to second-messenger signaling, showing cAMP/PKA/calcineurin controls annexin A2-S100A10 association with CFTR and TRPV6 and that this fails in F508del-CFTR.\",\n      \"evidence\": \"Co-IP, patch-clamp electrophysiology, calcium uptake, peptide competition and PKA/CnA inhibitors in epithelial cells and CF mouse models\",\n      \"pmids\": [\"17581860\", \"18187190\", \"18346874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect role of S100A10 in dephosphorylation cascade not isolated\", \"Single research group\", \"Whether channel currents depend on S100A10 itself versus annexin A2 not fully separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated in vivo that S100A10 is a physiologically required plasminogen receptor, controlling macrophage migration and matrix-degrading plasmin/MMP-9 activation.\",\n      \"evidence\": \"S100A10 knockout mice with peritoneal recruitment, Matrigel plug, plasmin generation, invasion and pro-MMP-9 activation assays\",\n      \"pmids\": [\"20424186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-surface receptor versus intracellular contribution not fully separated\", \"Annexin A2-independence in vivo not formally tested\", \"Mechanism linking S100A10 to MMP-9 activation indirect\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Cemented the in vivo fibrinolytic and angiogenic functions and revealed a competitive degradation switch (DLC1) plus the structural basis of AHNAK recognition.\",\n      \"evidence\": \"S100A10 knockout mice (thrombolysis, angiogenesis); DLC1 competition/ubiquitination assays; NMR and biophysical mapping of the asymmetric AHNAK-A2t interface\",\n      \"pmids\": [\"21768297\", \"21372205\", \"21949189\", \"21310922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DLC1 competition operates broadly across S100A10 clients untested\", \"PML-RARalpha regulation correlative for transcription\", \"Structural model based on peptide rather than full-length AHNAK\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined S100A10 as a viral host factor and refined the structural and PTM determinants of complex assembly, including the requirement for N-terminal acetylation of annexin A2.\",\n      \"evidence\": \"EPR, Co-IP, shRNA and infection assays for HPV16; 2.5 A crystal structure of the AHNAK-A2t complex; competitive peptide inhibition and ITC for acetylation dependence\",\n      \"pmids\": [\"22927980\", \"23275167\", \"23091277\", \"23129259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether S100A10 acts in viral entry versus trafficking not yet separated here\", \"Acetylation requirement shown in vitro\", \"Rac1-dependent spreading role (PMID 23129259) mechanistically indirect\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Separated the division of labor within the complex during viral infection, assigning annexin A2 to surface entry and S100A10 to intracellular late-endosomal trafficking.\",\n      \"evidence\": \"Subunit-specific antibody blockade, Co-IP, siRNA and confocal infection assays in keratinocytes\",\n      \"pmids\": [\"23637395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trafficking machinery engaged by S100A10 not identified\", \"Single virus model\", \"Direct S100A10 cargo on endosomes not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Expanded S100A10 scaffolding into autophagy, showing it positions ULK1 at ER-mitochondria autophagosome formation sites during IFN-gamma signaling downstream of annexin A2.\",\n      \"evidence\": \"Co-IP, siRNA knockdown with overexpression rescue and autophagosome quantification\",\n      \"pmids\": [\"27871932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect ULK1 interaction not resolved\", \"Single lab\", \"Generality beyond IFN-gamma-triggered autophagy untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Broadened the exocytic scaffolding role to regulated secretion, identifying Munc13-4 recruitment for Weibel-Palade body fusion and PLA2R as a high-affinity surface partner.\",\n      \"evidence\": \"Co-IP, siRNA, TIRF microscopy and VWF release assays; SPR and domain mapping for PLA2R; domain-mutant in vitro plasmin generation\",\n      \"pmids\": [\"28450451\", \"28761153\", \"28382372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface of Munc13-4 not mapped\", \"PLA2R interaction structural detail and disease relevance not established\", \"Internal-lysine contribution to plasmin generation quantitatively incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved post-translational control of S100A10 stability, identifying K47 succinylation (CPT1A/SIRT5) as a stabilizing mark and K57 as the ubiquitylation site, with succinylation promoting cancer invasiveness.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, ubiquitin mutagenesis (K57), succinyl-mimetic (K47E) functional assays, SIRT5 manipulation, proteasome inhibition across cancer cell lines\",\n      \"pmids\": [\"30394687\", \"30206209\", \"30076379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between succinylation and ubiquitylation in vivo not quantified\", \"ATRA-driven degradation mechanism partly ubiquitin-independent and unresolved\", \"HPV trafficking role of S100A10 versus annexin A2 still entangled\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established oncogenic and nuclear functions, placing S100A10 downstream of HIF-1 and KRAS, within chromatin-modifying complexes, and linking SUMOylation to nuclear gene regulation.\",\n      \"evidence\": \"Co-IP, ChIP/ChIP-Seq, siRNA/shRNA, HIF-1 and SUMO manipulation, glycolysis assays, tumor initiation models across breast, gastric and other cancers\",\n      \"pmids\": [\"32427586\", \"27351226\", \"33324631\", \"31585940\", \"34336846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA/chromatin binding by S100A10 not demonstrated\", \"Whether nuclear S100A10 acts as adaptor or has intrinsic activity unclear\", \"Several oncogenic pathway placements rely on single labs\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed extracellular-vesicle and cell-extrusion functions, showing S100A10 organizes EV protein cargo via integrin alphaV and acts with annexin A2 to suppress anoikis of transformed cells.\",\n      \"evidence\": \"Co-IP, EV proteomics, neutralizing antibody and siRNA with in vivo xenografts (HCC); siRNA/shRNA, ROS/p38MAPK pharmacology in transformed epithelial extrusion models\",\n      \"pmids\": [\"36631249\", \"37844241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus complex-mediated integrin alphaV binding not fully separated\", \"Single-lab findings\", \"Mechanism connecting S100A10 to ROS/p38MAPK indirect\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how S100A10, a single small adaptor, selects among its many membrane, exocytic, autophagic, nuclear, and extracellular clients in a given cell, and what determines partitioning between annexin A2-bound, surface, and nuclear pools.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model for client selection\", \"E3 ligase for S100A10 ubiquitylation unidentified\", \"Mechanism of intrinsic nuclear/chromatin activity undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 18, 31, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 14, 7]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [24, 28, 43]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 10, 18, 31]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 41]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [39, 41]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4, 28, 35]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [3, 5, 19, 32]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4, 18, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 23, 38]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [20, 30, 39, 44]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2, 14]}\n    ],\n    \"complexes\": [\n      \"annexin A2-S100A10 heterotetramer (AIIt/A2t)\"\n    ],\n    \"partners\": [\n      \"ANXA2\",\n      \"AHNAK\",\n      \"TRPV5\",\n      \"TRPV6\",\n      \"CFTR\",\n      \"VAMP2\",\n      \"ULK1\",\n      \"DLC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}