{"gene":"SCIN","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2013,"finding":"Knockdown of SCIN (scinderin) in PC3 prostate cancer cells inhibits proliferation and colony formation, and induces G0/G1 cell cycle arrest with upregulation of p21Waf1/Cip1 and CDKN2A (p16Ink4A) and altered cyclin A2 expression, demonstrating SCIN's role in cell cycle progression.","method":"Lentivirus-mediated RNAi knockdown, cell cycle analysis (flow cytometry), colony formation assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype (cell cycle arrest) and molecular readouts, but single lab, single cell line focus, no rescue experiment","pmids":["24212916"],"is_preprint":false},{"year":2014,"finding":"Knockdown of SCIN in lung carcinoma cell lines A549 and H1299 inhibits proliferation and colony formation, induces G0/G1 arrest and sub-G1 accumulation, and alters expression of Cyclin B1, Cyclin D1, p21, and PARP, establishing SCIN's role in lung carcinoma cell proliferation and cell cycle regulation.","method":"Lentivirus-mediated RNAi knockdown, flow cytometry cell cycle analysis, western blot","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype across two cell lines, molecular readouts, but single lab","pmids":["25303873"],"is_preprint":false},{"year":2023,"finding":"PIK3C3 (VPS34) kinase activity and autophagy regulation in Sertoli cells negatively regulates SCIN (scinderin): loss of PIK3C3 causes accumulation of SCIN via failure of autophagy-lysosome pathway degradation. HDAC6, phosphorylated at S59 by PIK3C3, deacetylates SCIN at K189 when it accumulates in PIK3C3-null Sertoli cells, leading to F-actin cytoskeleton disassembly and disruption of Sertoli cell polarity.","method":"Conditional knockout mouse model (Pik3c3 Sertoli-cell-specific deletion), proteomics/phosphoproteomics, autophagy-lysosome pathway inhibition, ubiquitin-proteasome pathway analysis, site-specific mutagenesis (HDAC6 S59, SCIN K189)","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo cKO model with proteomics, phosphoproteomics, and site-specific mutagenesis identifying the HDAC6-SCIN deacetylation axis; multiple orthogonal methods in single study","pmids":["37450577"],"is_preprint":false},{"year":2021,"finding":"miR-301a-5p directly targets SCIN mRNA (validated by dual-luciferase reporter assay); knockdown of SCIN phenocopies miR-301a-5p overexpression by promoting gastric cancer cell proliferation and motility via STAT3 and NF-κB signaling and epithelial-mesenchymal transition.","method":"Dual-luciferase reporter assay, qRT-PCR, western blot, CCK-8/colony formation/Transwell assays, pathway inhibition","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — dual-luciferase validates direct targeting; functional rescue experiments link SCIN to STAT3/NF-κB signaling; single lab","pmids":["34405002"],"is_preprint":false},{"year":2022,"finding":"MEX3A promotes NPC progression via a miR-3163/SCIN axis: MEX3A depletion reduces SCIN expression, and SCIN depletion reverses MEX3A-driven oncogenic effects; NF-κB signaling inhibition reverses effects of both SCIN and MEX3A overexpression, placing SCIN downstream of MEX3A/miR-3163 and upstream of NF-κB signaling in NPC.","method":"Whole-transcript expression arrays, bioinformatic analysis, rescue experiments (siRNA/overexpression), NF-κB signaling inhibition, in vitro cell function assays, in vivo tumor growth","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — epistasis via rescue experiments placing SCIN in MEX3A/miR-3163/NF-κB pathway; single lab, no direct binding shown for MEX3A-SCIN","pmids":["35490173"],"is_preprint":false},{"year":2023,"finding":"RSRC2 transcriptionally suppresses SCIN expression in triple-negative breast cancer cells; SCIN re-expression in RSRC2-overexpressing cells reverses the suppression of cell adhesion, proliferation, migration, and invasion caused by RSRC2, establishing SCIN as a direct downstream transcriptional target of RSRC2 that mediates TNBC cell functions.","method":"ChIP-seq, ChIP-qPCR, Human Transcriptome Array, RT-qPCR, western blot, cell function assays in vitro, metastatic mouse model in vivo, rescue experiments","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and ChIP-qPCR establish transcriptional regulation; rescue experiments confirm functional epistasis; multiple orthogonal methods, single lab","pmids":["38201443"],"is_preprint":false},{"year":2025,"finding":"PDGF-BB suppresses F-actin formation and chondrocyte dedifferentiation in osteoarthritis through oxygen-dependent regulation of HIF-1α/SCIN signaling and inhibition of the RhoA/ROCK pathway, placing SCIN downstream of HIF-1α in controlling F-actin cytoskeleton dynamics in chondrocytes.","method":"3D chondrogenic organoid model, in vitro and in vivo OA models, pharmacological pathway manipulation (RhoA/ROCK inhibition), HIF-1α/SCIN pathway analysis","journal":"European journal of pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement inferred from pharmacological manipulation with limited direct mechanistic validation of HIF-1α→SCIN axis; single study, abstract-level detail","pmids":["41135736"],"is_preprint":false},{"year":2016,"finding":"Genetic interaction analysis identified a statistically significant epistatic interaction between CDC42 and SCIN SNPs in melanoma Breslow thickness, consistent with their known opposing roles in actin cytoskeleton organization—CDC42 promotes actin polymerization while SCIN (scinderin) severs and caps F-actin.","method":"GWAS epistasis analysis (genome-wide interaction study), replication in independent cohort","journal":"International journal of cancer","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genetic association/epistasis only; no direct experiment on SCIN protein function performed in this study","pmids":["27347659"],"is_preprint":false}],"current_model":"SCIN (scinderin) is a calcium-regulated F-actin severing and capping protein whose abundance is controlled post-translationally by autophagy-lysosome degradation (regulated by PIK3C3) and by HDAC6-mediated deacetylation at K189; transcriptionally, SCIN is suppressed by RSRC2 and targeted post-transcriptionally by miR-301a-5p and miR-3163 downstream of MEX3A; elevated SCIN promotes cell proliferation, migration, and invasion via STAT3 and NF-κB signaling, while loss of SCIN induces G0/G1 cell cycle arrest through upregulation of p21 and CDKN2A, and in Sertoli cells SCIN accumulation disrupts F-actin cytoskeleton organization and cell polarity."},"narrative":{"mechanistic_narrative":"SCIN (scinderin) is an actin-cytoskeleton regulatory protein that controls F-actin organization and, through it, cell proliferation, migration, and invasion across multiple cell types [PMID:24212916, PMID:37450577]. Its abundance is set post-translationally by the autophagy-lysosome pathway: PIK3C3 (VPS34) kinase activity drives SCIN turnover, and loss of PIK3C3 causes SCIN accumulation; the kinase also phosphorylates HDAC6 at S59, which then deacetylates accumulated SCIN at K189, leading to F-actin disassembly and disruption of Sertoli cell polarity [PMID:37450577]. SCIN is further constrained at the transcriptional level by RSRC2, which directly suppresses its expression in triple-negative breast cancer, and post-transcriptionally by miR-301a-5p and by the MEX3A/miR-3163 axis [PMID:34405002, PMID:35490173, PMID:38201443]. When SCIN is elevated it promotes proliferation, motility, and epithelial-mesenchymal transition through STAT3 and NF-κB signaling, whereas SCIN loss arrests cells in G0/G1 with upregulation of p21 and CDKN2A, linking its actin function to cell cycle control [PMID:24212916, PMID:25303873, PMID:34405002, PMID:35490173].","teleology":[{"year":2013,"claim":"Established that SCIN is required for cancer cell cycle progression, moving it from an actin-regulatory protein to a driver of proliferation.","evidence":"Lentiviral RNAi knockdown in PC3 prostate cancer cells with flow-cytometry cell cycle analysis and colony formation","pmids":["24212916"],"confidence":"Medium","gaps":["No rescue experiment to confirm specificity","Mechanism linking SCIN actin activity to p21/CDKN2A induction not defined","Single cell line"]},{"year":2014,"claim":"Generalized SCIN's proliferative role beyond prostate cancer by showing it controls G0/G1 transition and cyclin expression in lung carcinoma.","evidence":"Lentiviral RNAi knockdown in A549 and H1299 lung carcinoma cells with cell cycle analysis and western blot","pmids":["25303873"],"confidence":"Medium","gaps":["No rescue","Causal link between SCIN and cyclin/PARP changes not mechanistically resolved","Single lab"]},{"year":2016,"claim":"Provided genetic evidence that SCIN functions in opposition to CDC42 in actin organization, contextualizing its severing/capping role in tumor phenotype.","evidence":"Genome-wide epistasis analysis of CDC42 and SCIN SNPs with melanoma Breslow thickness, replicated in an independent cohort","pmids":["27347659"],"confidence":"Low","gaps":["Genetic association only, no direct protein-level experiment","Opposing actin roles inferred, not tested here"]},{"year":2021,"claim":"Identified SCIN as a direct target of miR-301a-5p and connected its activity to STAT3/NF-κB-driven proliferation, motility, and EMT in gastric cancer.","evidence":"Dual-luciferase reporter assay, qRT-PCR, functional assays, and pathway inhibition in gastric cancer cells","pmids":["34405002"],"confidence":"Medium","gaps":["Whether SCIN acts directly on STAT3/NF-κB or indirectly via actin remodeling unresolved","Single lab"]},{"year":2022,"claim":"Placed SCIN within an oncogenic regulatory hierarchy downstream of MEX3A/miR-3163 and upstream of NF-κB in nasopharyngeal carcinoma.","evidence":"Expression arrays, rescue experiments, NF-κB inhibition, and in vivo tumor growth in NPC models","pmids":["35490173"],"confidence":"Medium","gaps":["No direct MEX3A-SCIN binding shown","Mechanism by which SCIN activates NF-κB not defined"]},{"year":2023,"claim":"Defined the post-translational control of SCIN abundance, showing PIK3C3-dependent autophagy degrades SCIN and an HDAC6-mediated K189 deacetylation event governs its effect on F-actin and cell polarity.","evidence":"Sertoli-cell-specific Pik3c3 conditional knockout mouse with proteomics, phosphoproteomics, autophagy/proteasome pathway analysis, and site-specific mutagenesis of HDAC6 S59 and SCIN K189","pmids":["37450577"],"confidence":"High","gaps":["Direct demonstration of K189 acetylation altering SCIN severing/capping activity in vitro not shown","How deacetylated SCIN drives F-actin disassembly mechanistically incomplete"]},{"year":2023,"claim":"Established RSRC2 as a direct transcriptional repressor of SCIN whose tumor-suppressive effects in TNBC are mediated by keeping SCIN low.","evidence":"ChIP-seq, ChIP-qPCR, transcriptome arrays, rescue experiments, and a metastatic mouse model in triple-negative breast cancer cells","pmids":["38201443"],"confidence":"Medium","gaps":["Downstream effectors of SCIN in TNBC adhesion/invasion not fully resolved","Single lab"]},{"year":2025,"claim":"Connected SCIN to oxygen-sensitive signaling by placing it downstream of HIF-1α in controlling chondrocyte F-actin dynamics and dedifferentiation.","evidence":"3D chondrogenic organoid and in vivo osteoarthritis models with pharmacological RhoA/ROCK and HIF-1α/SCIN pathway manipulation","pmids":["41135736"],"confidence":"Low","gaps":["HIF-1α→SCIN axis inferred pharmacologically, not directly validated","Abstract-level mechanistic detail only"]},{"year":null,"claim":"How SCIN's calcium-regulated actin severing/capping activity is biochemically coupled to its downstream effects on STAT3/NF-κB signaling and cell cycle arrest remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vitro reconstitution linking acetylation state to actin-severing activity","Direct molecular bridge between SCIN actin remodeling and transcriptional/cell cycle outputs not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]}],"complexes":[],"partners":["HDAC6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6U3","full_name":"Scinderin","aliases":["Adseverin"],"length_aa":715,"mass_kda":80.5,"function":"Ca(2+)-dependent actin filament-severing protein that has a regulatory function in exocytosis by affecting the organization of the microfilament network underneath the plasma membrane (PubMed:26365202, PubMed:8547642). Severing activity is inhibited by phosphatidylinositol 4,5-bis-phosphate (PIP2) (By similarity). In vitro, also has barbed end capping and nucleating activities in the presence of Ca(2+). Required for megakaryocyte differentiation, maturation, polyploidization and apoptosis with the release of platelet-like particles (PubMed:11568009). Plays a role in osteoclastogenesis (OCG) and actin cytoskeletal organization in osteoclasts (By similarity). Regulates chondrocyte proliferation and differentiation (By similarity). Inhibits cell proliferation and tumorigenesis. Signaling is mediated by MAPK, p38 and JNK pathways (PubMed:11568009)","subcellular_location":"Cytoplasm, cytoskeleton; Cell projection, podosome","url":"https://www.uniprot.org/uniprotkb/Q9Y6U3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCIN","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"SLC30A5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SCIN","total_profiled":1310},"omim":[{"mim_id":"613416","title":"SCINDERIN; SCIN","url":"https://www.omim.org/entry/613416"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":43.6},{"tissue":"kidney","ntpm":44.0},{"tissue":"placenta","ntpm":73.1}],"url":"https://www.proteinatlas.org/search/SCIN"},"hgnc":{"alias_symbol":["KIAA1905"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6U3","domains":[{"cath_id":"3.40.20.10","chopping":"9-119","consensus_level":"medium","plddt":87.0595,"start":9,"end":119},{"cath_id":"3.40.20.10","chopping":"139-231","consensus_level":"high","plddt":82.052,"start":139,"end":231},{"cath_id":"3.40.20.10","chopping":"246-343","consensus_level":"medium","plddt":80.9121,"start":246,"end":343},{"cath_id":"3.40.20.10","chopping":"398-495","consensus_level":"high","plddt":90.3072,"start":398,"end":495},{"cath_id":"3.40.20.10","chopping":"512-516_536-607","consensus_level":"high","plddt":92.6405,"start":512,"end":607},{"cath_id":"3.40.20.10","chopping":"616-706","consensus_level":"high","plddt":87.6601,"start":616,"end":706}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6U3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6U3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6U3-F1-predicted_aligned_error_v6.png","plddt_mean":83.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCIN","jax_strain_url":"https://www.jax.org/strain/search?query=SCIN"},"sequence":{"accession":"Q9Y6U3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6U3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6U3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6U3"}},"corpus_meta":[{"pmid":"18805985","id":"PMC_18805985","title":"SciN is an outer membrane lipoprotein required for type VI secretion in enteroaggregative Escherichia coli.","date":"2008","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/18805985","citation_count":182,"is_preprint":false},{"pmid":"16882032","id":"PMC_16882032","title":"Early expression of SCIN and CHIPS drives instant immune evasion by Staphylococcus aureus.","date":"2006","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16882032","citation_count":120,"is_preprint":false},{"pmid":"24212916","id":"PMC_24212916","title":"Suppression of SCIN inhibits human prostate cancer cell proliferation and induces G0/G1 phase arrest.","date":"2013","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24212916","citation_count":42,"is_preprint":false},{"pmid":"20654625","id":"PMC_20654625","title":"Molecular basis for complement recognition and inhibition determined by crystallographic studies of the staphylococcal complement inhibitor (SCIN) bound to C3c and C3b.","date":"2010","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20654625","citation_count":35,"is_preprint":false},{"pmid":"21948365","id":"PMC_21948365","title":"Advances in understanding the structure, function, and mechanism of the SCIN and Efb families of Staphylococcal immune evasion proteins.","date":"2012","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/21948365","citation_count":34,"is_preprint":false},{"pmid":"29784858","id":"PMC_29784858","title":"Production of Staphylococcal Complement Inhibitor (SCIN) and Other Immune Modulators during the Early Stages of Staphylococcus aureus Biofilm Formation in a Mammalian Cell Culture Medium.","date":"2018","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/29784858","citation_count":28,"is_preprint":false},{"pmid":"22086928","id":"PMC_22086928","title":"Diversity in the C3b [corrected] contact residues and tertiary structures of the staphylococcal complement inhibitor (SCIN) protein family.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22086928","citation_count":26,"is_preprint":false},{"pmid":"25303873","id":"PMC_25303873","title":"Lentivirus-mediated silencing of SCIN inhibits proliferation of human lung carcinoma cells.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/25303873","citation_count":22,"is_preprint":false},{"pmid":"34405002","id":"PMC_34405002","title":"MiR-301a-5p/SCIN promotes gastric cancer progression via regulating STAT3 and NF-κB signaling.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34405002","citation_count":20,"is_preprint":false},{"pmid":"38201443","id":"PMC_38201443","title":"RSRC2 Expression Inhibits Malignant Progression of Triple-Negative Breast Cancer by Transcriptionally Regulating SCIN Expression.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38201443","citation_count":16,"is_preprint":false},{"pmid":"35490173","id":"PMC_35490173","title":"MEX3A promotes nasopharyngeal carcinoma progression via the miR-3163/SCIN axis by regulating NF-κB signaling pathway.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35490173","citation_count":16,"is_preprint":false},{"pmid":"23233676","id":"PMC_23233676","title":"A structurally dynamic N-terminal helix is a key functional determinant in staphylococcal complement inhibitor (SCIN) proteins.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23233676","citation_count":16,"is_preprint":false},{"pmid":"37450577","id":"PMC_37450577","title":"Autophagy regulation and protein kinase activity of PIK3C3 controls sertoli cell polarity through its negative regulation on SCIN (scinderin).","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37450577","citation_count":15,"is_preprint":false},{"pmid":"28277903","id":"PMC_28277903","title":"A human monoclonal antibody that specifically binds and inhibits the staphylococcal complement inhibitor protein SCIN.","date":"2017","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/28277903","citation_count":12,"is_preprint":false},{"pmid":"27347659","id":"PMC_27347659","title":"A comprehensive genome-wide analysis of melanoma Breslow thickness identifies interaction between CDC42 and SCIN genetic variants.","date":"2016","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27347659","citation_count":11,"is_preprint":false},{"pmid":"26052070","id":"PMC_26052070","title":"Identification of peptidic inhibitors of the alternative complement pathway based on Staphylococcus aureus SCIN proteins.","date":"2015","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26052070","citation_count":10,"is_preprint":false},{"pmid":"19407382","id":"PMC_19407382","title":"Crystallization of human complement component C3b in the presence of a staphylococcal complement-inhibitor protein (SCIN).","date":"2009","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/19407382","citation_count":9,"is_preprint":false},{"pmid":"40856525","id":"PMC_40856525","title":"sCIN: a contrastive learning framework for single-cell multi-omics data integration.","date":"2025","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/40856525","citation_count":2,"is_preprint":false},{"pmid":"31204912","id":"PMC_31204912","title":"[Clinical Study of SCIN Expression and Dromoter Methylation in Patients with Chronic Myeloid Leukemia].","date":"2019","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/31204912","citation_count":1,"is_preprint":false},{"pmid":"38411940","id":"PMC_38411940","title":"Comprehensive Analysis Based on the TCGA Database Identified SCIN as a Key DNA Methylation-Driver Gene in Epstein-Barr Virus-Associated Gastric Cancer.","date":"2024","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38411940","citation_count":1,"is_preprint":false},{"pmid":"41135736","id":"PMC_41135736","title":"PDGF-BB inhibits F-actin formation and chondrocyte dedifferentiation in osteoarthritis via oxygen-dependent HIF-1α/SCIN regulation and RhoA/ROCK signaling inhibition.","date":"2025","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41135736","citation_count":1,"is_preprint":false},{"pmid":"42080107","id":"PMC_42080107","title":"In vitro and In silico Analysis of SCIN rs376349889 as a Potential Biomarker for Gastric and Colorectal Cancers.","date":"2026","source":"Avicenna journal of medical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/42080107","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.07.669115","title":"Structural insights into C3 convertase activity of the classical pathway of complement","date":"2025-08-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.07.669115","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.11.617544","title":"HDAC Inhibitors recapitulate Human Disease-Associated Microglia Signatures  <i>in vitro</i>","date":"2024-10-12","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.11.617544","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14637,"output_tokens":2274,"usd":0.03901,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9370,"output_tokens":2722,"usd":0.05745,"stage2_stop_reason":"end_turn"},"total_usd":0.09646,"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\": 2013,\n      \"finding\": \"Knockdown of SCIN (scinderin) in PC3 prostate cancer cells inhibits proliferation and colony formation, and induces G0/G1 cell cycle arrest with upregulation of p21Waf1/Cip1 and CDKN2A (p16Ink4A) and altered cyclin A2 expression, demonstrating SCIN's role in cell cycle progression.\",\n      \"method\": \"Lentivirus-mediated RNAi knockdown, cell cycle analysis (flow cytometry), colony formation assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype (cell cycle arrest) and molecular readouts, but single lab, single cell line focus, no rescue experiment\",\n      \"pmids\": [\"24212916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Knockdown of SCIN in lung carcinoma cell lines A549 and H1299 inhibits proliferation and colony formation, induces G0/G1 arrest and sub-G1 accumulation, and alters expression of Cyclin B1, Cyclin D1, p21, and PARP, establishing SCIN's role in lung carcinoma cell proliferation and cell cycle regulation.\",\n      \"method\": \"Lentivirus-mediated RNAi knockdown, flow cytometry cell cycle analysis, western blot\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype across two cell lines, molecular readouts, but single lab\",\n      \"pmids\": [\"25303873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIK3C3 (VPS34) kinase activity and autophagy regulation in Sertoli cells negatively regulates SCIN (scinderin): loss of PIK3C3 causes accumulation of SCIN via failure of autophagy-lysosome pathway degradation. HDAC6, phosphorylated at S59 by PIK3C3, deacetylates SCIN at K189 when it accumulates in PIK3C3-null Sertoli cells, leading to F-actin cytoskeleton disassembly and disruption of Sertoli cell polarity.\",\n      \"method\": \"Conditional knockout mouse model (Pik3c3 Sertoli-cell-specific deletion), proteomics/phosphoproteomics, autophagy-lysosome pathway inhibition, ubiquitin-proteasome pathway analysis, site-specific mutagenesis (HDAC6 S59, SCIN K189)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo cKO model with proteomics, phosphoproteomics, and site-specific mutagenesis identifying the HDAC6-SCIN deacetylation axis; multiple orthogonal methods in single study\",\n      \"pmids\": [\"37450577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-301a-5p directly targets SCIN mRNA (validated by dual-luciferase reporter assay); knockdown of SCIN phenocopies miR-301a-5p overexpression by promoting gastric cancer cell proliferation and motility via STAT3 and NF-κB signaling and epithelial-mesenchymal transition.\",\n      \"method\": \"Dual-luciferase reporter assay, qRT-PCR, western blot, CCK-8/colony formation/Transwell assays, pathway inhibition\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — dual-luciferase validates direct targeting; functional rescue experiments link SCIN to STAT3/NF-κB signaling; single lab\",\n      \"pmids\": [\"34405002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MEX3A promotes NPC progression via a miR-3163/SCIN axis: MEX3A depletion reduces SCIN expression, and SCIN depletion reverses MEX3A-driven oncogenic effects; NF-κB signaling inhibition reverses effects of both SCIN and MEX3A overexpression, placing SCIN downstream of MEX3A/miR-3163 and upstream of NF-κB signaling in NPC.\",\n      \"method\": \"Whole-transcript expression arrays, bioinformatic analysis, rescue experiments (siRNA/overexpression), NF-κB signaling inhibition, in vitro cell function assays, in vivo tumor growth\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — epistasis via rescue experiments placing SCIN in MEX3A/miR-3163/NF-κB pathway; single lab, no direct binding shown for MEX3A-SCIN\",\n      \"pmids\": [\"35490173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RSRC2 transcriptionally suppresses SCIN expression in triple-negative breast cancer cells; SCIN re-expression in RSRC2-overexpressing cells reverses the suppression of cell adhesion, proliferation, migration, and invasion caused by RSRC2, establishing SCIN as a direct downstream transcriptional target of RSRC2 that mediates TNBC cell functions.\",\n      \"method\": \"ChIP-seq, ChIP-qPCR, Human Transcriptome Array, RT-qPCR, western blot, cell function assays in vitro, metastatic mouse model in vivo, rescue experiments\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and ChIP-qPCR establish transcriptional regulation; rescue experiments confirm functional epistasis; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38201443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PDGF-BB suppresses F-actin formation and chondrocyte dedifferentiation in osteoarthritis through oxygen-dependent regulation of HIF-1α/SCIN signaling and inhibition of the RhoA/ROCK pathway, placing SCIN downstream of HIF-1α in controlling F-actin cytoskeleton dynamics in chondrocytes.\",\n      \"method\": \"3D chondrogenic organoid model, in vitro and in vivo OA models, pharmacological pathway manipulation (RhoA/ROCK inhibition), HIF-1α/SCIN pathway analysis\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement inferred from pharmacological manipulation with limited direct mechanistic validation of HIF-1α→SCIN axis; single study, abstract-level detail\",\n      \"pmids\": [\"41135736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic interaction analysis identified a statistically significant epistatic interaction between CDC42 and SCIN SNPs in melanoma Breslow thickness, consistent with their known opposing roles in actin cytoskeleton organization—CDC42 promotes actin polymerization while SCIN (scinderin) severs and caps F-actin.\",\n      \"method\": \"GWAS epistasis analysis (genome-wide interaction study), replication in independent cohort\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genetic association/epistasis only; no direct experiment on SCIN protein function performed in this study\",\n      \"pmids\": [\"27347659\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCIN (scinderin) is a calcium-regulated F-actin severing and capping protein whose abundance is controlled post-translationally by autophagy-lysosome degradation (regulated by PIK3C3) and by HDAC6-mediated deacetylation at K189; transcriptionally, SCIN is suppressed by RSRC2 and targeted post-transcriptionally by miR-301a-5p and miR-3163 downstream of MEX3A; elevated SCIN promotes cell proliferation, migration, and invasion via STAT3 and NF-κB signaling, while loss of SCIN induces G0/G1 cell cycle arrest through upregulation of p21 and CDKN2A, and in Sertoli cells SCIN accumulation disrupts F-actin cytoskeleton organization and cell polarity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCIN (scinderin) is an actin-cytoskeleton regulatory protein that controls F-actin organization and, through it, cell proliferation, migration, and invasion across multiple cell types [#0, #2]. Its abundance is set post-translationally by the autophagy-lysosome pathway: PIK3C3 (VPS34) kinase activity drives SCIN turnover, and loss of PIK3C3 causes SCIN accumulation; the kinase also phosphorylates HDAC6 at S59, which then deacetylates accumulated SCIN at K189, leading to F-actin disassembly and disruption of Sertoli cell polarity [#2]. SCIN is further constrained at the transcriptional level by RSRC2, which directly suppresses its expression in triple-negative breast cancer, and post-transcriptionally by miR-301a-5p and by the MEX3A/miR-3163 axis [#3, #4, #5]. When SCIN is elevated it promotes proliferation, motility, and epithelial-mesenchymal transition through STAT3 and NF-\\u03baB signaling, whereas SCIN loss arrests cells in G0/G1 with upregulation of p21 and CDKN2A, linking its actin function to cell cycle control [#0, #1, #3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that SCIN is required for cancer cell cycle progression, moving it from an actin-regulatory protein to a driver of proliferation.\",\n      \"evidence\": \"Lentiviral RNAi knockdown in PC3 prostate cancer cells with flow-cytometry cell cycle analysis and colony formation\",\n      \"pmids\": [\"24212916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue experiment to confirm specificity\", \"Mechanism linking SCIN actin activity to p21/CDKN2A induction not defined\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Generalized SCIN's proliferative role beyond prostate cancer by showing it controls G0/G1 transition and cyclin expression in lung carcinoma.\",\n      \"evidence\": \"Lentiviral RNAi knockdown in A549 and H1299 lung carcinoma cells with cell cycle analysis and western blot\",\n      \"pmids\": [\"25303873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue\", \"Causal link between SCIN and cyclin/PARP changes not mechanistically resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided genetic evidence that SCIN functions in opposition to CDC42 in actin organization, contextualizing its severing/capping role in tumor phenotype.\",\n      \"evidence\": \"Genome-wide epistasis analysis of CDC42 and SCIN SNPs with melanoma Breslow thickness, replicated in an independent cohort\",\n      \"pmids\": [\"27347659\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Genetic association only, no direct protein-level experiment\", \"Opposing actin roles inferred, not tested here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified SCIN as a direct target of miR-301a-5p and connected its activity to STAT3/NF-\\u03baB-driven proliferation, motility, and EMT in gastric cancer.\",\n      \"evidence\": \"Dual-luciferase reporter assay, qRT-PCR, functional assays, and pathway inhibition in gastric cancer cells\",\n      \"pmids\": [\"34405002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SCIN acts directly on STAT3/NF-\\u03baB or indirectly via actin remodeling unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed SCIN within an oncogenic regulatory hierarchy downstream of MEX3A/miR-3163 and upstream of NF-\\u03baB in nasopharyngeal carcinoma.\",\n      \"evidence\": \"Expression arrays, rescue experiments, NF-\\u03baB inhibition, and in vivo tumor growth in NPC models\",\n      \"pmids\": [\"35490173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct MEX3A-SCIN binding shown\", \"Mechanism by which SCIN activates NF-\\u03baB not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the post-translational control of SCIN abundance, showing PIK3C3-dependent autophagy degrades SCIN and an HDAC6-mediated K189 deacetylation event governs its effect on F-actin and cell polarity.\",\n      \"evidence\": \"Sertoli-cell-specific Pik3c3 conditional knockout mouse with proteomics, phosphoproteomics, autophagy/proteasome pathway analysis, and site-specific mutagenesis of HDAC6 S59 and SCIN K189\",\n      \"pmids\": [\"37450577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of K189 acetylation altering SCIN severing/capping activity in vitro not shown\", \"How deacetylated SCIN drives F-actin disassembly mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established RSRC2 as a direct transcriptional repressor of SCIN whose tumor-suppressive effects in TNBC are mediated by keeping SCIN low.\",\n      \"evidence\": \"ChIP-seq, ChIP-qPCR, transcriptome arrays, rescue experiments, and a metastatic mouse model in triple-negative breast cancer cells\",\n      \"pmids\": [\"38201443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of SCIN in TNBC adhesion/invasion not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected SCIN to oxygen-sensitive signaling by placing it downstream of HIF-1\\u03b1 in controlling chondrocyte F-actin dynamics and dedifferentiation.\",\n      \"evidence\": \"3D chondrogenic organoid and in vivo osteoarthritis models with pharmacological RhoA/ROCK and HIF-1\\u03b1/SCIN pathway manipulation\",\n      \"pmids\": [\"41135736\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"HIF-1\\u03b1\\u2192SCIN axis inferred pharmacologically, not directly validated\", \"Abstract-level mechanistic detail only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SCIN's calcium-regulated actin severing/capping activity is biochemically coupled to its downstream effects on STAT3/NF-\\u03baB signaling and cell cycle arrest remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution linking acetylation state to actin-severing activity\", \"Direct molecular bridge between SCIN actin remodeling and transcriptional/cell cycle outputs not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HDAC6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}