{"gene":"STRN3","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2001,"finding":"PP2A catalytic subunit methylation at Leu309 is NOT required for SG2NA binding to the PP2A A/C heterodimer; unmethylated C subunit mutants showed enhanced binding to SG2NA, whereas Balpha subunit binding is critically dependent on C subunit methylation.","method":"Genetic (C subunit mutants) and biochemical (co-immunoprecipitation with methylation-selective monoclonal antibodies, recombinant methylesterase demethylation assay)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (13 C-subunit mutants, selective antibodies, recombinant methylesterase), rigorous controls, in-cell and cell-lysate experiments","pmids":["11160832"],"is_preprint":false},{"year":2000,"finding":"SG2NA (STRN3) binds calmodulin in a Ca2+-dependent manner through its calmodulin-binding domain, and localizes to both cytosolic and membrane-bound fractions; it is expressed in soma and dendrites of neurons, suggesting a scaffolding role.","method":"Calmodulin-binding assay, subcellular fractionation, immunohistochemistry/immunofluorescence with domain-specific antibodies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct calmodulin-binding and fractionation experiments in single study with specific antibodies","pmids":["10748158"],"is_preprint":false},{"year":2001,"finding":"The N-terminal region of SG2NA (aa 1–391) functions as a transcriptional activator in both yeast and mammalian cells, while its C-terminal WD-40 repeats inhibit this transcription activation activity; WD-40 repeats from yeast Met30 and Cdc4 can substitute for SG2NA WD-40 repeats in mediating transcription repression.","method":"Yeast and mammalian transcription activation assays, domain-swap (molecular swapping of WD-40 regions), GAL4-VP16 chimera repression assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional domain dissection with molecular swapping and reporter assays in two cell systems, single lab","pmids":["11570823"],"is_preprint":false},{"year":2014,"finding":"SG2NA associates with antioxidant protein DJ-1 and survival kinase Akt, forming a trimeric complex; the C-terminal WD-40 domain of SG2NA is required for Akt interaction, while DJ-1 binds a region upstream. The complex co-localizes to mitochondria and plasma membrane, and cells depleted of SG2NA are susceptible to oxidative stress-induced apoptosis while overexpressors are resistant. DJ-1 mutants associated with familial Parkinsonism are not recruited by SG2NA.","method":"Co-immunoprecipitation, domain-deletion mutants, subcellular fractionation/co-localization (immunofluorescence), knockdown/overexpression with apoptosis assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal co-IP, domain mapping, functional rescue experiments, single lab with multiple orthogonal methods","pmids":["25035075"],"is_preprint":false},{"year":2015,"finding":"SG2NA protects DJ-1 from proteasomal degradation in cancer cells; loss of SG2NA reduces DJ-1/Akt co-localization and decreases anchorage-dependent and -independent growth. Reactive oxygen species enhance SG2NA–DJ-1–Akt trimerization.","method":"shRNA knockdown, proteasome inhibitor assay, co-localization/co-IP, cell proliferation and colony formation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple functional readouts (degradation, co-localization, growth assays) in single lab","pmids":["26022125"],"is_preprint":false},{"year":2020,"finding":"STRN3 acts as a regulatory subunit of PP2A that recruits MST1/2 kinases and promotes their dephosphorylation, thereby inactivating the Hippo pathway and activating YAP. A structure-guided peptide inhibitor (SHAP) that disrupts the STRN3–PP2Aa interaction reactivates Hippo signaling, inhibits YAP, and suppresses tumor growth in vivo.","method":"Co-immunoprecipitation (STRN3–PP2A and STRN3–MST1/2), in vitro phosphatase assay, structure-guided peptide design, in vivo tumor xenograft, genetic gain- and loss-of-function","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, in vitro phosphatase assay, structure-guided inhibitor with in vivo validation), mechanistic dissection of STRN3–PP2A–MST1/2–YAP pathway","pmids":["32589942"],"is_preprint":false},{"year":2017,"finding":"GSK3β promotes SG2NA protein stability (phospho-SG2NA is more stable than dephosphorylated form), while ERK indirectly decreases phospho-SG2NA levels by inhibiting GSK3β. PP2A inhibition by okadaic acid increases SG2NA levels. Knockdown of SG2NA reduces pGSK3β and pERK levels, indicating mutual regulation. Loss of SG2NA extends G1 phase; overexpression extends G2/M phase.","method":"Pharmacological kinase/phosphatase inhibition (LiCl, PD98059, okadaic acid), shRNA knockdown, proteasome inhibition, cell cycle analysis, western blot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple pharmacological and genetic perturbations with functional cell cycle readouts, single lab","pmids":["28790387"],"is_preprint":false},{"year":2017,"finding":"Depletion of SG2NA (78 kDa isoform) in NIH3T3 cells triggers ER stress; conversely, ER stressors (thapsigargin, tunicamycin) increase SG2NA expression and relocalize it to mitochondria and microsomes. Loss of SG2NA reduces cyclin D1 and causes G1 arrest, and concurrent ER stress then promotes cell death.","method":"shRNA knockdown, proteome analysis, ER stressor treatment, subcellular fractionation, cell cycle analysis, in vivo mouse injection","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — knockdown with proteomic readout plus functional cell cycle analysis and in vivo validation, single lab","pmids":["28634818"],"is_preprint":false},{"year":2018,"finding":"The 87 kDa and 78 kDa isoforms of SG2NA differ in secondary structure composition, thermal stability, and binding affinity to DJ-1 and calmodulin in vitro, demonstrating that alternative splicing generates functionally distinct protein variants.","method":"Biophysical characterization (circular dichroism, thermal denaturation), in vitro binding assays with purified isoforms","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 1–3 / Moderate — direct in vitro biophysical and binding assays on purified isoforms, single lab","pmids":["30132185"],"is_preprint":false},{"year":2008,"finding":"SG2NA was identified as encoding two major protein isoforms (alpha and beta) that function as regulatory subunits of PP2A, with the alpha isoform differentially expressed across tissues and developmental stages.","method":"Molecular cloning, RT-PCR, western blot across tissues and developmental stages","journal":"Gene regulation and systems biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — characterization of isoforms by expression profiling only; PP2A subunit function inferred by homology without direct biochemical demonstration in this paper","pmids":["19838339"],"is_preprint":false},{"year":2023,"finding":"STRN3 fused to PDGFRB (via t(5;14)(q32;q12)) produces a chimeric protein containing the coiled-coil domain of STRN3 and the transmembrane/kinase domains of PDGFRB; this fusion protein localizes to the cytoplasm, transforms Ba/F3 cells to growth factor independence, and causes MDS/MPN-like disease in mice.","method":"RT-PCR/Sanger sequencing of fusion transcript, Ba/F3 transformation assay, mouse transplantation model, subcellular localization by imaging","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro transformation assay and in vivo mouse model confirm leukemogenic activity of the fusion protein, with biochemical confirmation of fusion structure","pmids":["37550570"],"is_preprint":false}],"current_model":"STRN3 (SG2NA) is a scaffold/regulatory subunit of PP2A that binds the PP2A A/C heterodimer independently of C-subunit methylation; through its WD-40 domain it recruits substrates including MST1/2 kinases (promoting their dephosphorylation and YAP activation via Hippo pathway suppression), and also scaffolds a trimeric complex with DJ-1 and Akt at mitochondria/plasma membrane to protect against oxidative stress; its stability is regulated by GSK3β-mediated phosphorylation (counteracted by ERK) and proteasomal degradation, and its multiple splice isoforms differ in binding partners, subcellular localization, and cell-cycle effects."},"narrative":{"mechanistic_narrative":"STRN3 (SG2NA) is a striatin-family scaffold and regulatory subunit of protein phosphatase 2A (PP2A) that couples the phosphatase to specific substrates and signaling outputs [PMID:11160832, PMID:32589942]. It binds the PP2A A/C heterodimer in a manner independent of catalytic-subunit methylation at Leu309, with unmethylated C subunit favoring the interaction [PMID:11160832]. Through its C-terminal WD-40 domain, STRN3 recruits MST1/2 kinases to PP2A and promotes their dephosphorylation, thereby inactivating Hippo signaling and activating YAP; a structure-guided peptide that disrupts the STRN3–PP2A interface reactivates Hippo signaling and suppresses tumor growth in vivo [PMID:32589942]. STRN3 also assembles a trimeric complex with the antioxidant protein DJ-1 and the kinase Akt at mitochondria and the plasma membrane—the WD-40 domain engaging Akt and a region upstream binding DJ-1—where it protects DJ-1 from proteasomal degradation and shields cells from oxidative stress-induced apoptosis [PMID:25035075, PMID:26022125]. Its own abundance is controlled by GSK3β-mediated phosphorylation that stabilizes the protein, counteracted by ERK, and STRN3 levels in turn influence cell-cycle progression and the ER stress response [PMID:28790387, PMID:28634818]. Alternative splicing generates isoforms that differ in structure, stability, and binding affinity for DJ-1 and calmodulin, and STRN3 binds calmodulin in a Ca2+-dependent manner [PMID:10748158, PMID:30132185]. A recurrent STRN3–PDGFRB fusion that retains the STRN3 coiled-coil domain produces a transforming chimeric kinase causing MDS/MPN-like disease in mice [PMID:37550570].","teleology":[{"year":2000,"claim":"Established STRN3/SG2NA as a Ca2+-responsive scaffold by demonstrating Ca2+-dependent calmodulin binding and dual cytosolic/membrane localization in neurons.","evidence":"Calmodulin-binding assay, subcellular fractionation, and immunostaining with domain-specific antibodies","pmids":["10748158"],"confidence":"Medium","gaps":["Functional consequence of calmodulin binding not defined","No link to phosphatase activity established at this stage"]},{"year":2001,"claim":"Defined how STRN3 docks onto PP2A, showing binding to the A/C heterodimer does not require C-subunit methylation—distinguishing it from methylation-dependent B subunits and clarifying the assembly logic of striatin-containing PP2A.","evidence":"PP2A C-subunit mutant panel with methylation-selective antibodies and recombinant methylesterase demethylation assay","pmids":["11160832"],"confidence":"High","gaps":["Substrates of the STRN3-PP2A complex not yet identified","Structural basis of methylation-independent binding not resolved"]},{"year":2001,"claim":"Mapped intramolecular functional architecture, showing the N-terminus can activate transcription while the WD-40 repeats are repressive and interchangeable with other WD-40 modules.","evidence":"Yeast and mammalian reporter assays with WD-40 domain swaps and GAL4-VP16 chimeras","pmids":["11570823"],"confidence":"Medium","gaps":["Physiological relevance of transcriptional activity unclear","No endogenous target genes identified"]},{"year":2008,"claim":"Catalogued STRN3 isoforms (alpha/beta) and their tissue/developmental expression, framing them as PP2A regulatory subunits.","evidence":"Molecular cloning, RT-PCR, and western blot across tissues and developmental stages","pmids":["19838339"],"confidence":"Low","gaps":["PP2A subunit role inferred by homology rather than demonstrated biochemically here","Functional differences between isoforms not tested"]},{"year":2014,"claim":"Revealed a cytoprotective scaffolding role by identifying a STRN3–DJ-1–Akt trimeric complex at mitochondria/membrane that defends against oxidative stress.","evidence":"Reciprocal co-IP, domain-deletion mapping, co-localization imaging, and knockdown/overexpression apoptosis assays","pmids":["25035075"],"confidence":"Medium","gaps":["Whether PP2A activity is involved in this complex untested","Mechanism linking complex to apoptosis resistance not detailed"]},{"year":2015,"claim":"Extended the cytoprotective role, showing STRN3 stabilizes DJ-1 against proteasomal degradation and supports cancer cell growth, with ROS enhancing complex assembly.","evidence":"shRNA knockdown, proteasome inhibition, co-IP/co-localization, and proliferation/colony-formation assays","pmids":["26022125"],"confidence":"Medium","gaps":["Direct E3 ligase or degradation pathway for DJ-1 not identified","In vivo relevance to tumor growth not tested here"]},{"year":2017,"claim":"Defined regulation of STRN3 stability and its reciprocal influence on signaling, showing GSK3β phosphorylation stabilizes it, ERK opposes this via GSK3β, and STRN3 levels feed back on pERK/pGSK3β and cell-cycle phase.","evidence":"Pharmacological kinase/phosphatase inhibition, shRNA knockdown, proteasome inhibition, and cell-cycle analysis","pmids":["28790387"],"confidence":"Medium","gaps":["Direct phosphosites on STRN3 not mapped","Mechanism of feedback on ERK/GSK3β unresolved"]},{"year":2017,"claim":"Connected STRN3 to ER stress and cell-cycle control, showing depletion triggers ER stress and G1 arrest while ER stressors upregulate and relocalize STRN3.","evidence":"shRNA knockdown with proteome analysis, ER stressor treatment, fractionation, cell-cycle analysis, and in vivo mouse injection","pmids":["28634818"],"confidence":"Medium","gaps":["Molecular link between STRN3 loss and ER stress induction unknown","Isoform-specific contribution not dissected beyond 78 kDa form"]},{"year":2018,"claim":"Demonstrated that alternative splicing yields biophysically and functionally distinct STRN3 isoforms differing in stability and partner affinity.","evidence":"Circular dichroism, thermal denaturation, and in vitro binding assays with purified 87 and 78 kDa isoforms","pmids":["30132185"],"confidence":"Medium","gaps":["In vivo functional divergence of isoforms not established","Structural basis for affinity differences unresolved"]},{"year":2020,"claim":"Established the core oncogenic mechanism: STRN3-PP2A recruits and dephosphorylates MST1/2 to inactivate Hippo and activate YAP, and showed this interface is druggable.","evidence":"Co-IP, in vitro phosphatase assay, structure-guided peptide inhibitor (SHAP), and in vivo tumor xenografts with gain/loss of function","pmids":["32589942"],"confidence":"High","gaps":["How STRN3 selects MST1/2 over other substrates not fully defined","Relationship between Hippo regulation and the DJ-1/Akt scaffold role unexplored"]},{"year":2023,"claim":"Implicated STRN3 in leukemogenesis via a STRN3-PDGFRB fusion whose coiled-coil drives constitutive kinase activation.","evidence":"RT-PCR/sequencing of fusion transcript, Ba/F3 transformation assay, mouse transplantation model, and imaging","pmids":["37550570"],"confidence":"Medium","gaps":["Contribution of STRN3 domains beyond oligomerization not dissected","Whether endogenous STRN3 functions are perturbed by the fusion unknown"]},{"year":null,"claim":"How STRN3's distinct roles—Hippo/YAP regulation via PP2A, DJ-1/Akt cytoprotection, and cell-cycle/ER-stress control—are integrated, and how isoform identity and localization partition these functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural or spatial model linking the substrate-recruitment functions","Isoform-specific in vivo roles not defined","Physiological substrate repertoire of STRN3-PP2A incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,7]}],"complexes":["PP2A (STRN3-PP2A A/C holoenzyme)","STRN3-DJ-1-Akt trimeric complex"],"partners":["PPP2CA","MST1","MST2","DJ-1","AKT","CALMODULIN","GSK3B","PDGFRB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13033","full_name":"Striatin-3","aliases":["Cell cycle autoantigen SG2NA","S/G2 antigen"],"length_aa":797,"mass_kda":87.2,"function":"Calmodulin-binding scaffolding protein which is the center of the striatin-interacting phosphatase and kinase (STRIPAK) complexes (PubMed:18782753, PubMed:30622739, PubMed:33633399). STRIPAK complexes have critical roles in protein (de)phosphorylation and are regulators of multiple signaling pathways including Hippo, MAPK, nuclear receptor and cytoskeleton remodeling. Different types of STRIPAK complexes are involved in a variety of biological processes such as cell growth, differentiation, apoptosis, metabolism and immune regulation (Probable)","subcellular_location":"Cytoplasm; Membrane","url":"https://www.uniprot.org/uniprotkb/Q13033/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STRN3","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000196792","cell_line_id":"CID001233","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"cytoskeleton","grade":3}],"interactors":[{"gene":"DYNLL1","stoichiometry":10.0},{"gene":"DYNLL2","stoichiometry":10.0},{"gene":"PPP2CA","stoichiometry":10.0},{"gene":"PPP2CB","stoichiometry":10.0},{"gene":"STK24","stoichiometry":10.0},{"gene":"STK26","stoichiometry":10.0},{"gene":"STRN4","stoichiometry":10.0},{"gene":"STK25","stoichiometry":4.0},{"gene":"PPP2R1A","stoichiometry":4.0},{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001233","total_profiled":1310},"omim":[{"mim_id":"617919","title":"STRIATIN-INTERACTING PROTEIN 2; STRIP2","url":"https://www.omim.org/entry/617919"},{"mim_id":"617918","title":"STRIATIN-INTERACTING PROTEIN 1; STRIP1","url":"https://www.omim.org/entry/617918"},{"mim_id":"614767","title":"STRIATIN, CALMODULIN-BINDING PROTEIN 4; STRN4","url":"https://www.omim.org/entry/614767"},{"mim_id":"614766","title":"STRIATIN, CALMODULIN-BINDING PROTEIN 3; STRN3","url":"https://www.omim.org/entry/614766"},{"mim_id":"614765","title":"STRIATIN, CALMODULIN-BINDING PROTEIN; STRN","url":"https://www.omim.org/entry/614765"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STRN3"},"hgnc":{"alias_symbol":["SG2NA","PPP2R6B","S/G2NA"],"prev_symbol":[]},"alphafold":{"accession":"Q13033","domains":[{"cath_id":"2.130.10.10","chopping":"473-674_681-797","consensus_level":"high","plddt":93.7271,"start":473,"end":797},{"cath_id":"1.20.5","chopping":"73-139","consensus_level":"medium","plddt":86.6012,"start":73,"end":139}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13033","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13033-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13033-F1-predicted_aligned_error_v6.png","plddt_mean":67.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STRN3","jax_strain_url":"https://www.jax.org/strain/search?query=STRN3"},"sequence":{"accession":"Q13033","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13033.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13033/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13033"}},"corpus_meta":[{"pmid":"11160832","id":"PMC_11160832","title":"Methylation 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STRN3.","date":"2024","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/39148682","citation_count":2,"is_preprint":false},{"pmid":"30559394","id":"PMC_30559394","title":"Author Correction: GSK3β and ERK regulate the expression of 78 kDa SG2NA and ectopic modulation of its level affects phases of cell cycle.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30559394","citation_count":1,"is_preprint":false},{"pmid":"40692742","id":"PMC_40692742","title":"Alectinib efficacy in advanced lung adenocarcinoma with coexistence of a novel ALK-MTUS2 and STRN3-ALK double fusion: A case report and literature review.","date":"2025","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/40692742","citation_count":0,"is_preprint":false},{"pmid":"41297092","id":"PMC_41297092","title":"Striatin-3 is a human autoantigen but it is not associated with the S-phase G2 nuclear antigen (SG2NA) staining pattern.","date":"2025","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/41297092","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13803,"output_tokens":2842,"usd":0.04202,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10209,"output_tokens":3887,"usd":0.07411,"stage2_stop_reason":"end_turn"},"total_usd":0.11613,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"PP2A catalytic subunit methylation at Leu309 is NOT required for SG2NA binding to the PP2A A/C heterodimer; unmethylated C subunit mutants showed enhanced binding to SG2NA, whereas Balpha subunit binding is critically dependent on C subunit methylation.\",\n      \"method\": \"Genetic (C subunit mutants) and biochemical (co-immunoprecipitation with methylation-selective monoclonal antibodies, recombinant methylesterase demethylation assay)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (13 C-subunit mutants, selective antibodies, recombinant methylesterase), rigorous controls, in-cell and cell-lysate experiments\",\n      \"pmids\": [\"11160832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SG2NA (STRN3) binds calmodulin in a Ca2+-dependent manner through its calmodulin-binding domain, and localizes to both cytosolic and membrane-bound fractions; it is expressed in soma and dendrites of neurons, suggesting a scaffolding role.\",\n      \"method\": \"Calmodulin-binding assay, subcellular fractionation, immunohistochemistry/immunofluorescence with domain-specific antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct calmodulin-binding and fractionation experiments in single study with specific antibodies\",\n      \"pmids\": [\"10748158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The N-terminal region of SG2NA (aa 1–391) functions as a transcriptional activator in both yeast and mammalian cells, while its C-terminal WD-40 repeats inhibit this transcription activation activity; WD-40 repeats from yeast Met30 and Cdc4 can substitute for SG2NA WD-40 repeats in mediating transcription repression.\",\n      \"method\": \"Yeast and mammalian transcription activation assays, domain-swap (molecular swapping of WD-40 regions), GAL4-VP16 chimera repression assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional domain dissection with molecular swapping and reporter assays in two cell systems, single lab\",\n      \"pmids\": [\"11570823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SG2NA associates with antioxidant protein DJ-1 and survival kinase Akt, forming a trimeric complex; the C-terminal WD-40 domain of SG2NA is required for Akt interaction, while DJ-1 binds a region upstream. The complex co-localizes to mitochondria and plasma membrane, and cells depleted of SG2NA are susceptible to oxidative stress-induced apoptosis while overexpressors are resistant. DJ-1 mutants associated with familial Parkinsonism are not recruited by SG2NA.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion mutants, subcellular fractionation/co-localization (immunofluorescence), knockdown/overexpression with apoptosis assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal co-IP, domain mapping, functional rescue experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25035075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SG2NA protects DJ-1 from proteasomal degradation in cancer cells; loss of SG2NA reduces DJ-1/Akt co-localization and decreases anchorage-dependent and -independent growth. Reactive oxygen species enhance SG2NA–DJ-1–Akt trimerization.\",\n      \"method\": \"shRNA knockdown, proteasome inhibitor assay, co-localization/co-IP, cell proliferation and colony formation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple functional readouts (degradation, co-localization, growth assays) in single lab\",\n      \"pmids\": [\"26022125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STRN3 acts as a regulatory subunit of PP2A that recruits MST1/2 kinases and promotes their dephosphorylation, thereby inactivating the Hippo pathway and activating YAP. A structure-guided peptide inhibitor (SHAP) that disrupts the STRN3–PP2Aa interaction reactivates Hippo signaling, inhibits YAP, and suppresses tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation (STRN3–PP2A and STRN3–MST1/2), in vitro phosphatase assay, structure-guided peptide design, in vivo tumor xenograft, genetic gain- and loss-of-function\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, in vitro phosphatase assay, structure-guided inhibitor with in vivo validation), mechanistic dissection of STRN3–PP2A–MST1/2–YAP pathway\",\n      \"pmids\": [\"32589942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GSK3β promotes SG2NA protein stability (phospho-SG2NA is more stable than dephosphorylated form), while ERK indirectly decreases phospho-SG2NA levels by inhibiting GSK3β. PP2A inhibition by okadaic acid increases SG2NA levels. Knockdown of SG2NA reduces pGSK3β and pERK levels, indicating mutual regulation. Loss of SG2NA extends G1 phase; overexpression extends G2/M phase.\",\n      \"method\": \"Pharmacological kinase/phosphatase inhibition (LiCl, PD98059, okadaic acid), shRNA knockdown, proteasome inhibition, cell cycle analysis, western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple pharmacological and genetic perturbations with functional cell cycle readouts, single lab\",\n      \"pmids\": [\"28790387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Depletion of SG2NA (78 kDa isoform) in NIH3T3 cells triggers ER stress; conversely, ER stressors (thapsigargin, tunicamycin) increase SG2NA expression and relocalize it to mitochondria and microsomes. Loss of SG2NA reduces cyclin D1 and causes G1 arrest, and concurrent ER stress then promotes cell death.\",\n      \"method\": \"shRNA knockdown, proteome analysis, ER stressor treatment, subcellular fractionation, cell cycle analysis, in vivo mouse injection\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — knockdown with proteomic readout plus functional cell cycle analysis and in vivo validation, single lab\",\n      \"pmids\": [\"28634818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The 87 kDa and 78 kDa isoforms of SG2NA differ in secondary structure composition, thermal stability, and binding affinity to DJ-1 and calmodulin in vitro, demonstrating that alternative splicing generates functionally distinct protein variants.\",\n      \"method\": \"Biophysical characterization (circular dichroism, thermal denaturation), in vitro binding assays with purified isoforms\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–3 / Moderate — direct in vitro biophysical and binding assays on purified isoforms, single lab\",\n      \"pmids\": [\"30132185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SG2NA was identified as encoding two major protein isoforms (alpha and beta) that function as regulatory subunits of PP2A, with the alpha isoform differentially expressed across tissues and developmental stages.\",\n      \"method\": \"Molecular cloning, RT-PCR, western blot across tissues and developmental stages\",\n      \"journal\": \"Gene regulation and systems biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — characterization of isoforms by expression profiling only; PP2A subunit function inferred by homology without direct biochemical demonstration in this paper\",\n      \"pmids\": [\"19838339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STRN3 fused to PDGFRB (via t(5;14)(q32;q12)) produces a chimeric protein containing the coiled-coil domain of STRN3 and the transmembrane/kinase domains of PDGFRB; this fusion protein localizes to the cytoplasm, transforms Ba/F3 cells to growth factor independence, and causes MDS/MPN-like disease in mice.\",\n      \"method\": \"RT-PCR/Sanger sequencing of fusion transcript, Ba/F3 transformation assay, mouse transplantation model, subcellular localization by imaging\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro transformation assay and in vivo mouse model confirm leukemogenic activity of the fusion protein, with biochemical confirmation of fusion structure\",\n      \"pmids\": [\"37550570\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STRN3 (SG2NA) is a scaffold/regulatory subunit of PP2A that binds the PP2A A/C heterodimer independently of C-subunit methylation; through its WD-40 domain it recruits substrates including MST1/2 kinases (promoting their dephosphorylation and YAP activation via Hippo pathway suppression), and also scaffolds a trimeric complex with DJ-1 and Akt at mitochondria/plasma membrane to protect against oxidative stress; its stability is regulated by GSK3β-mediated phosphorylation (counteracted by ERK) and proteasomal degradation, and its multiple splice isoforms differ in binding partners, subcellular localization, and cell-cycle effects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STRN3 (SG2NA) is a striatin-family scaffold and regulatory subunit of protein phosphatase 2A (PP2A) that couples the phosphatase to specific substrates and signaling outputs [#0, #5]. It binds the PP2A A/C heterodimer in a manner independent of catalytic-subunit methylation at Leu309, with unmethylated C subunit favoring the interaction [#0]. Through its C-terminal WD-40 domain, STRN3 recruits MST1/2 kinases to PP2A and promotes their dephosphorylation, thereby inactivating Hippo signaling and activating YAP; a structure-guided peptide that disrupts the STRN3\\u2013PP2A interface reactivates Hippo signaling and suppresses tumor growth in vivo [#5]. STRN3 also assembles a trimeric complex with the antioxidant protein DJ-1 and the kinase Akt at mitochondria and the plasma membrane\\u2014the WD-40 domain engaging Akt and a region upstream binding DJ-1\\u2014where it protects DJ-1 from proteasomal degradation and shields cells from oxidative stress-induced apoptosis [#3, #4]. Its own abundance is controlled by GSK3\\u03b2-mediated phosphorylation that stabilizes the protein, counteracted by ERK, and STRN3 levels in turn influence cell-cycle progression and the ER stress response [#6, #7]. Alternative splicing generates isoforms that differ in structure, stability, and binding affinity for DJ-1 and calmodulin, and STRN3 binds calmodulin in a Ca2+-dependent manner [#1, #8]. A recurrent STRN3\\u2013PDGFRB fusion that retains the STRN3 coiled-coil domain produces a transforming chimeric kinase causing MDS/MPN-like disease in mice [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established STRN3/SG2NA as a Ca2+-responsive scaffold by demonstrating Ca2+-dependent calmodulin binding and dual cytosolic/membrane localization in neurons.\",\n      \"evidence\": \"Calmodulin-binding assay, subcellular fractionation, and immunostaining with domain-specific antibodies\",\n      \"pmids\": [\"10748158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of calmodulin binding not defined\", \"No link to phosphatase activity established at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined how STRN3 docks onto PP2A, showing binding to the A/C heterodimer does not require C-subunit methylation\\u2014distinguishing it from methylation-dependent B subunits and clarifying the assembly logic of striatin-containing PP2A.\",\n      \"evidence\": \"PP2A C-subunit mutant panel with methylation-selective antibodies and recombinant methylesterase demethylation assay\",\n      \"pmids\": [\"11160832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates of the STRN3-PP2A complex not yet identified\", \"Structural basis of methylation-independent binding not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapped intramolecular functional architecture, showing the N-terminus can activate transcription while the WD-40 repeats are repressive and interchangeable with other WD-40 modules.\",\n      \"evidence\": \"Yeast and mammalian reporter assays with WD-40 domain swaps and GAL4-VP16 chimeras\",\n      \"pmids\": [\"11570823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of transcriptional activity unclear\", \"No endogenous target genes identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Catalogued STRN3 isoforms (alpha/beta) and their tissue/developmental expression, framing them as PP2A regulatory subunits.\",\n      \"evidence\": \"Molecular cloning, RT-PCR, and western blot across tissues and developmental stages\",\n      \"pmids\": [\"19838339\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"PP2A subunit role inferred by homology rather than demonstrated biochemically here\", \"Functional differences between isoforms not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a cytoprotective scaffolding role by identifying a STRN3\\u2013DJ-1\\u2013Akt trimeric complex at mitochondria/membrane that defends against oxidative stress.\",\n      \"evidence\": \"Reciprocal co-IP, domain-deletion mapping, co-localization imaging, and knockdown/overexpression apoptosis assays\",\n      \"pmids\": [\"25035075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PP2A activity is involved in this complex untested\", \"Mechanism linking complex to apoptosis resistance not detailed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the cytoprotective role, showing STRN3 stabilizes DJ-1 against proteasomal degradation and supports cancer cell growth, with ROS enhancing complex assembly.\",\n      \"evidence\": \"shRNA knockdown, proteasome inhibition, co-IP/co-localization, and proliferation/colony-formation assays\",\n      \"pmids\": [\"26022125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct E3 ligase or degradation pathway for DJ-1 not identified\", \"In vivo relevance to tumor growth not tested here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined regulation of STRN3 stability and its reciprocal influence on signaling, showing GSK3\\u03b2 phosphorylation stabilizes it, ERK opposes this via GSK3\\u03b2, and STRN3 levels feed back on pERK/pGSK3\\u03b2 and cell-cycle phase.\",\n      \"evidence\": \"Pharmacological kinase/phosphatase inhibition, shRNA knockdown, proteasome inhibition, and cell-cycle analysis\",\n      \"pmids\": [\"28790387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphosites on STRN3 not mapped\", \"Mechanism of feedback on ERK/GSK3\\u03b2 unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected STRN3 to ER stress and cell-cycle control, showing depletion triggers ER stress and G1 arrest while ER stressors upregulate and relocalize STRN3.\",\n      \"evidence\": \"shRNA knockdown with proteome analysis, ER stressor treatment, fractionation, cell-cycle analysis, and in vivo mouse injection\",\n      \"pmids\": [\"28634818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between STRN3 loss and ER stress induction unknown\", \"Isoform-specific contribution not dissected beyond 78 kDa form\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that alternative splicing yields biophysically and functionally distinct STRN3 isoforms differing in stability and partner affinity.\",\n      \"evidence\": \"Circular dichroism, thermal denaturation, and in vitro binding assays with purified 87 and 78 kDa isoforms\",\n      \"pmids\": [\"30132185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo functional divergence of isoforms not established\", \"Structural basis for affinity differences unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the core oncogenic mechanism: STRN3-PP2A recruits and dephosphorylates MST1/2 to inactivate Hippo and activate YAP, and showed this interface is druggable.\",\n      \"evidence\": \"Co-IP, in vitro phosphatase assay, structure-guided peptide inhibitor (SHAP), and in vivo tumor xenografts with gain/loss of function\",\n      \"pmids\": [\"32589942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How STRN3 selects MST1/2 over other substrates not fully defined\", \"Relationship between Hippo regulation and the DJ-1/Akt scaffold role unexplored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated STRN3 in leukemogenesis via a STRN3-PDGFRB fusion whose coiled-coil drives constitutive kinase activation.\",\n      \"evidence\": \"RT-PCR/sequencing of fusion transcript, Ba/F3 transformation assay, mouse transplantation model, and imaging\",\n      \"pmids\": [\"37550570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of STRN3 domains beyond oligomerization not dissected\", \"Whether endogenous STRN3 functions are perturbed by the fusion unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How STRN3's distinct roles\\u2014Hippo/YAP regulation via PP2A, DJ-1/Akt cytoprotection, and cell-cycle/ER-stress control\\u2014are integrated, and how isoform identity and localization partition these functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural or spatial model linking the substrate-recruitment functions\", \"Isoform-specific in vivo roles not defined\", \"Physiological substrate repertoire of STRN3-PP2A incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\n      \"PP2A (STRN3-PP2A A/C holoenzyme)\",\n      \"STRN3-DJ-1-Akt trimeric complex\"\n    ],\n    \"partners\": [\n      \"PPP2CA\",\n      \"MST1\",\n      \"MST2\",\n      \"DJ-1\",\n      \"AKT\",\n      \"calmodulin\",\n      \"GSK3B\",\n      \"PDGFRB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}