{"gene":"STRN4","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2020,"finding":"STRN4 is a generic binding partner for MAP4K family kinases and a key component of the STRIPAK complex that regulates MAP4Ks in the Hippo pathway; identified through proteomic (AP-MS) interactome analysis of MAP4K family kinases in endometrial cancer.","method":"Proteomic/AP-MS protein-protein interaction network (MAP4K interactome screen)","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass-spectrometry-based interactome with functional follow-up in cancer context, single lab","pmids":["32640226"],"is_preprint":false},{"year":2023,"finding":"STRN4 mediates PP2A binding to and dephosphorylation of Hippo kinases MST1/2, resulting in stabilization of YAP/TAZ, which antagonizes STING-type I IFN signaling in macrophages; PP2A/STRN4 deficiency increased MST1/2 activity and STING-driven IFN responses in tumor-associated macrophages.","method":"Genetic knockdown/knockout of PP2A and STRN4 in macrophages, phosphorylation assays of MST1/2, co-immunoprecipitation, mouse tumor models with macrophage-specific PP2A deficiency","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, dephosphorylation assay, in vivo mouse models, multiple orthogonal methods establishing mechanism","pmids":["36757811"],"is_preprint":false},{"year":2017,"finding":"STRN4 is preferentially expressed in mushroom-type dendritic spines, and specifically maintains mushroom spine morphology (but not thin spines or filopodia) through its interaction with the phosphatase PP2A; local STRN4 expression in dendrites depends on NMDA receptor activation.","method":"Immunofluorescence/spine morphology analysis, STRN4 knockdown in neurons, PP2A interaction assays, NMDA receptor blockade experiments, dendritic mRNA localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (KD phenotype in spine morphology) and PP2A interaction, single lab with multiple methods","pmids":["28442576"],"is_preprint":false},{"year":2025,"finding":"DHHC9 palmitoylates STRN4 at cysteine 701; this palmitoylation reduces YAP phosphorylation, promotes nuclear translocation of YAP, and activates downstream Hippo pathway transcriptional targets (CCN1, CCN2, ANKRD1), thereby driving cancer cell migration.","method":"Proteomic identification of palmitoylation site, site-directed mutagenesis (C701), YAP phosphorylation assay, nuclear fractionation/translocation assay, DHHC9 knockdown, in vitro migration and in vivo metastasis assays","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — palmitoylation site identified with mutagenesis, phosphorylation and localization assays, in vivo validation; single lab but multiple orthogonal methods","pmids":["40903842"],"is_preprint":false},{"year":2014,"finding":"STRN4 directly associates with protein kinases MINK1, TNIK, and MAP4K4 as part of a large protein complex; depletion of STRN4 suppresses cancer cell proliferation, migration, invasion, anchorage-independent growth, and in vivo metastasis.","method":"Co-immunoprecipitation (STRN4 with kinases), siRNA/shRNA knockdown, proliferation/migration/invasion assays, mouse xenograft models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding partners confirmed, loss-of-function with defined cellular phenotypes in vitro and in vivo, single lab","pmids":["25250919"],"is_preprint":false},{"year":2019,"finding":"The transcription factor Pokemon (LRF) binds to the STRN4 promoter and induces STRN4 expression, promoting prostate cancer cell proliferation and suppressing apoptosis via a Pokemon/STRN4 axis.","method":"Chromatin immunoprecipitation (ChIP) showing Pokemon binding to STRN4 promoter, Pokemon knockdown with measurement of STRN4 expression levels, proliferation and apoptosis assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP establishes direct promoter binding, downstream functional readout, single lab single study","pmids":["31205540"],"is_preprint":false}],"current_model":"STRN4 is a scaffold protein and core STRIPAK complex component that acts as a regulatory B subunit directing PP2A phosphatase activity toward Hippo kinases MST1/2 (promoting YAP/TAZ stabilization and Hippo pathway suppression), interacts with MAP4K family kinases to regulate the Hippo pathway, is palmitoylated by DHHC9 at Cys701 to reduce YAP phosphorylation and drive nuclear YAP activity, and in neurons localizes to mushroom dendritic spines where it maintains their morphology via PP2A in an NMDA receptor-dependent manner."},"narrative":{"mechanistic_narrative":"STRN4 is a scaffold protein and core component of the STRIPAK complex that targets PP2A phosphatase activity toward Hippo pathway kinases to control YAP/TAZ activity and cell behavior [PMID:36757811, PMID:25250919]. As a STRIPAK subunit, STRN4 directly associates with MAP4K-family kinases including MINK1, TNIK, and MAP4K4, and its depletion suppresses cancer cell proliferation, migration, invasion, anchorage-independent growth, and in vivo metastasis [PMID:32640226, PMID:25250919]. Mechanistically, STRN4 mediates PP2A binding to and dephosphorylation of the Hippo kinases MST1/2, stabilizing YAP/TAZ; loss of STRN4/PP2A raises MST1/2 activity, and in tumor-associated macrophages this antagonizes STING-driven type I interferon responses [PMID:36757811]. Palmitoylation of STRN4 at Cys701 by DHHC9 reduces YAP phosphorylation, promotes nuclear YAP translocation, and induces the transcriptional targets CCN1, CCN2, and ANKRD1 to drive cancer cell migration [PMID:40903842]. STRN4 expression is induced by the transcription factor Pokemon (LRF), which binds the STRN4 promoter to promote proliferation and suppress apoptosis [PMID:31205540]. Beyond cancer, STRN4 localizes to mushroom-type dendritic spines where it maintains spine morphology through PP2A in an NMDA receptor-dependent manner [PMID:28442576].","teleology":[{"year":2014,"claim":"Established STRN4 as a physical hub linking GCK-family kinases to a large protein complex with a causal role in malignancy, framing it as more than a passive scaffold.","evidence":"Co-IP of STRN4 with MINK1/TNIK/MAP4K4 plus siRNA/shRNA loss-of-function in proliferation, invasion, and xenograft metastasis assays","pmids":["25250919"],"confidence":"Medium","gaps":["Did not define which phosphatase activity STRN4 directs","Direct vs. indirect kinase association within the complex not resolved","Mechanism connecting kinase binding to the cancer phenotype unspecified"]},{"year":2017,"claim":"Showed STRN4 has a tissue-specific structural role in neurons, demonstrating PP2A-dependent function distinct from its cancer context.","evidence":"Spine morphology analysis with STRN4 knockdown, PP2A interaction assays, NMDA receptor blockade, and dendritic mRNA localization in neurons","pmids":["28442576"],"confidence":"Medium","gaps":["PP2A substrate in spines not identified","Link between NMDA-driven local translation and spine maintenance mechanistic detail unclear","Relationship to Hippo signaling in neurons untested"]},{"year":2019,"claim":"Identified an upstream transcriptional driver of STRN4, explaining how its expression is elevated in cancer.","evidence":"ChIP showing Pokemon/LRF binding to the STRN4 promoter with knockdown and proliferation/apoptosis readouts in prostate cancer cells","pmids":["31205540"],"confidence":"Medium","gaps":["Single study, single cancer type","Whether Pokemon regulation operates in other tissues unknown","Downstream STRN4 effectors in this axis not dissected"]},{"year":2020,"claim":"Defined STRN4 as a generic STRIPAK-borne binding partner of the entire MAP4K family, generalizing the 2014 finding into a pathway-level scaffold role in Hippo signaling.","evidence":"AP-MS interactome mapping of MAP4K-family kinases in endometrial cancer","pmids":["32640226"],"confidence":"Medium","gaps":["Interactome alone does not establish directionality of regulation","Functional consequence of each MAP4K interaction not separated","Phosphatase targeting mechanism not demonstrated here"]},{"year":2023,"claim":"Resolved the core enzymatic mechanism: STRN4 couples PP2A to MST1/2 dephosphorylation to stabilize YAP/TAZ, and connected this to innate immune signaling output.","evidence":"Reciprocal Co-IP, MST1/2 dephosphorylation assays, PP2A/STRN4 knockdown/knockout, and macrophage-specific PP2A-deficient mouse tumor models","pmids":["36757811"],"confidence":"High","gaps":["Stoichiometry of the STRN4-PP2A-MST complex not defined","Whether STRN4 distinguishes MST1 vs MST2 unclear","Generality of the YAP-STING antagonism beyond macrophages untested"]},{"year":2025,"claim":"Added a post-translational switch—DHHC9 palmitoylation at Cys701—that tunes STRN4 activity toward nuclear YAP and a pro-migratory transcriptional program.","evidence":"Palmitoylation site mapping, C701 mutagenesis, YAP phosphorylation and nuclear fractionation assays, DHHC9 knockdown, and in vitro/in vivo metastasis assays","pmids":["40903842"],"confidence":"High","gaps":["How palmitoylation alters STRN4-PP2A or STRN4-membrane behavior mechanistically unresolved","Reversibility/depalmitoylation regulation not characterized","Whether palmitoylation regulates the neuronal pool of STRN4 unknown"]},{"year":null,"claim":"How STRN4's distinct activities—cancer Hippo regulation, immune modulation, and neuronal spine maintenance—are coordinated and whether they share common substrate logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the STRN4-PP2A-MST/MAP4K assembly","Full PP2A substrate repertoire directed by STRN4 unknown","Crosstalk between palmitoylation, transcriptional induction, and tissue context not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5]}],"complexes":["STRIPAK"],"partners":["PP2A","MST1","MST2","MAP4K4","MINK1","TNIK","DHHC9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NRL3","full_name":"Striatin-4","aliases":["Zinedin"],"length_aa":753,"mass_kda":80.6,"function":"Calmodulin-binding scaffolding protein which is the center of the striatin-interacting phosphatase and kinase (STRIPAK) complexes (PubMed:18782753, PubMed:32640226). STRIPAK complexes have critical roles in protein (de)phosphorylation and are regulators of multiple signaling pathways including Hippo, MAPK, nuclear receptor and cytoskeleton remodeling (PubMed:32640226). Different types of STRIPAK complexes are involved in a variety of biological processes such as cell growth, differentiation, apoptosis, metabolism and immune regulation (Probable). Key regulator of the expanded Hippo signaling pathway by interacting and allowing the inhibition of MAP4K kinases by the STRIPAK complex (PubMed:32640226)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NRL3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STRN4","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MAP4K4","stoichiometry":10.0},{"gene":"STK26","stoichiometry":10.0},{"gene":"STRN3","stoichiometry":10.0},{"gene":"DYNLL1","stoichiometry":4.0},{"gene":"DYNLL2","stoichiometry":4.0},{"gene":"PPP2CA","stoichiometry":4.0},{"gene":"STK24","stoichiometry":4.0},{"gene":"STK25","stoichiometry":4.0},{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/STRN4","total_profiled":1310},"omim":[{"mim_id":"615100","title":"CTTNBP2 N TERMINUS-LIKE PROTEIN; CTTNBP2NL","url":"https://www.omim.org/entry/615100"},{"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"},{"mim_id":"609772","title":"CORTACTIN-BINDING PROTEIN 2; CTTNBP2","url":"https://www.omim.org/entry/609772"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STRN4"},"hgnc":{"alias_symbol":["ZIN","PPP2R6C"],"prev_symbol":[]},"alphafold":{"accession":"Q9NRL3","domains":[{"cath_id":"2.130.10.10","chopping":"431-753","consensus_level":"high","plddt":92.7463,"start":431,"end":753},{"cath_id":"1.20.5","chopping":"87-137","consensus_level":"medium","plddt":90.5525,"start":87,"end":137}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRL3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRL3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRL3-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STRN4","jax_strain_url":"https://www.jax.org/strain/search?query=STRN4"},"sequence":{"accession":"Q9NRL3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRL3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRL3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRL3"}},"corpus_meta":[{"pmid":"32640226","id":"PMC_32640226","title":"MAP4K Interactome Reveals STRN4 as a Key STRIPAK Complex Component in Hippo Pathway Regulation.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32640226","citation_count":51,"is_preprint":false},{"pmid":"25250919","id":"PMC_25250919","title":"Silencing of STRN4 suppresses the malignant characteristics of cancer cells.","date":"2014","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/25250919","citation_count":39,"is_preprint":false},{"pmid":"36757811","id":"PMC_36757811","title":"PP2Ac/STRN4 negatively regulates STING-type I IFN signaling in tumor-associated macrophages.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/36757811","citation_count":36,"is_preprint":false},{"pmid":"28442576","id":"PMC_28442576","title":"Determination of dendritic spine morphology by the striatin scaffold protein STRN4 through interaction with the phosphatase PP2A.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28442576","citation_count":32,"is_preprint":false},{"pmid":"34386494","id":"PMC_34386494","title":"Long Non-coding RNA MAFG-AS1 Promotes Cell Proliferation, Migration, and EMT by miR-3196/STRN4 in Drug-Resistant Cells of Liver Cancer.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34386494","citation_count":24,"is_preprint":false},{"pmid":"31289617","id":"PMC_31289617","title":"MicroRNA-873 inhibits colorectal cancer metastasis by targeting ELK1 and STRN4.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/31289617","citation_count":17,"is_preprint":false},{"pmid":"31205540","id":"PMC_31205540","title":"Pro-oncogene Pokemon Promotes Prostate Cancer Progression by Inducing STRN4 Expression.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31205540","citation_count":12,"is_preprint":false},{"pmid":"31813135","id":"PMC_31813135","title":"miR-29b inhibits non-small cell lung cancer progression by targeting STRN4.","date":"2019","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/31813135","citation_count":11,"is_preprint":false},{"pmid":"32184620","id":"PMC_32184620","title":"MicroRNA Profile Identifies miR-6165 Could Suppress Gastric Cancer Migration and Invasion by Targeting STRN4.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32184620","citation_count":6,"is_preprint":false},{"pmid":"40903842","id":"PMC_40903842","title":"Pharmacological Targeting of DHHC9-Mediated STRN4 Palmitoylation to Suppress YAP-Driven Cancer Metastasis.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40903842","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6348,"output_tokens":1561,"usd":0.021229,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8321,"output_tokens":2660,"usd":0.054053,"stage2_stop_reason":"end_turn"},"total_usd":0.075282,"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\": 2020,\n      \"finding\": \"STRN4 is a generic binding partner for MAP4K family kinases and a key component of the STRIPAK complex that regulates MAP4Ks in the Hippo pathway; identified through proteomic (AP-MS) interactome analysis of MAP4K family kinases in endometrial cancer.\",\n      \"method\": \"Proteomic/AP-MS protein-protein interaction network (MAP4K interactome screen)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass-spectrometry-based interactome with functional follow-up in cancer context, single lab\",\n      \"pmids\": [\"32640226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STRN4 mediates PP2A binding to and dephosphorylation of Hippo kinases MST1/2, resulting in stabilization of YAP/TAZ, which antagonizes STING-type I IFN signaling in macrophages; PP2A/STRN4 deficiency increased MST1/2 activity and STING-driven IFN responses in tumor-associated macrophages.\",\n      \"method\": \"Genetic knockdown/knockout of PP2A and STRN4 in macrophages, phosphorylation assays of MST1/2, co-immunoprecipitation, mouse tumor models with macrophage-specific PP2A deficiency\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, dephosphorylation assay, in vivo mouse models, multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"36757811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STRN4 is preferentially expressed in mushroom-type dendritic spines, and specifically maintains mushroom spine morphology (but not thin spines or filopodia) through its interaction with the phosphatase PP2A; local STRN4 expression in dendrites depends on NMDA receptor activation.\",\n      \"method\": \"Immunofluorescence/spine morphology analysis, STRN4 knockdown in neurons, PP2A interaction assays, NMDA receptor blockade experiments, dendritic mRNA localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (KD phenotype in spine morphology) and PP2A interaction, single lab with multiple methods\",\n      \"pmids\": [\"28442576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DHHC9 palmitoylates STRN4 at cysteine 701; this palmitoylation reduces YAP phosphorylation, promotes nuclear translocation of YAP, and activates downstream Hippo pathway transcriptional targets (CCN1, CCN2, ANKRD1), thereby driving cancer cell migration.\",\n      \"method\": \"Proteomic identification of palmitoylation site, site-directed mutagenesis (C701), YAP phosphorylation assay, nuclear fractionation/translocation assay, DHHC9 knockdown, in vitro migration and in vivo metastasis assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — palmitoylation site identified with mutagenesis, phosphorylation and localization assays, in vivo validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40903842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STRN4 directly associates with protein kinases MINK1, TNIK, and MAP4K4 as part of a large protein complex; depletion of STRN4 suppresses cancer cell proliferation, migration, invasion, anchorage-independent growth, and in vivo metastasis.\",\n      \"method\": \"Co-immunoprecipitation (STRN4 with kinases), siRNA/shRNA knockdown, proliferation/migration/invasion assays, mouse xenograft models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding partners confirmed, loss-of-function with defined cellular phenotypes in vitro and in vivo, single lab\",\n      \"pmids\": [\"25250919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The transcription factor Pokemon (LRF) binds to the STRN4 promoter and induces STRN4 expression, promoting prostate cancer cell proliferation and suppressing apoptosis via a Pokemon/STRN4 axis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) showing Pokemon binding to STRN4 promoter, Pokemon knockdown with measurement of STRN4 expression levels, proliferation and apoptosis assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP establishes direct promoter binding, downstream functional readout, single lab single study\",\n      \"pmids\": [\"31205540\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STRN4 is a scaffold protein and core STRIPAK complex component that acts as a regulatory B subunit directing PP2A phosphatase activity toward Hippo kinases MST1/2 (promoting YAP/TAZ stabilization and Hippo pathway suppression), interacts with MAP4K family kinases to regulate the Hippo pathway, is palmitoylated by DHHC9 at Cys701 to reduce YAP phosphorylation and drive nuclear YAP activity, and in neurons localizes to mushroom dendritic spines where it maintains their morphology via PP2A in an NMDA receptor-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STRN4 is a scaffold protein and core component of the STRIPAK complex that targets PP2A phosphatase activity toward Hippo pathway kinases to control YAP/TAZ activity and cell behavior [#1, #4]. As a STRIPAK subunit, STRN4 directly associates with MAP4K-family kinases including MINK1, TNIK, and MAP4K4, and its depletion suppresses cancer cell proliferation, migration, invasion, anchorage-independent growth, and in vivo metastasis [#0, #4]. Mechanistically, STRN4 mediates PP2A binding to and dephosphorylation of the Hippo kinases MST1/2, stabilizing YAP/TAZ; loss of STRN4/PP2A raises MST1/2 activity, and in tumor-associated macrophages this antagonizes STING-driven type I interferon responses [#1]. Palmitoylation of STRN4 at Cys701 by DHHC9 reduces YAP phosphorylation, promotes nuclear YAP translocation, and induces the transcriptional targets CCN1, CCN2, and ANKRD1 to drive cancer cell migration [#3]. STRN4 expression is induced by the transcription factor Pokemon (LRF), which binds the STRN4 promoter to promote proliferation and suppress apoptosis [#5]. Beyond cancer, STRN4 localizes to mushroom-type dendritic spines where it maintains spine morphology through PP2A in an NMDA receptor-dependent manner [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established STRN4 as a physical hub linking GCK-family kinases to a large protein complex with a causal role in malignancy, framing it as more than a passive scaffold.\",\n      \"evidence\": \"Co-IP of STRN4 with MINK1/TNIK/MAP4K4 plus siRNA/shRNA loss-of-function in proliferation, invasion, and xenograft metastasis assays\",\n      \"pmids\": [\"25250919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which phosphatase activity STRN4 directs\", \"Direct vs. indirect kinase association within the complex not resolved\", \"Mechanism connecting kinase binding to the cancer phenotype unspecified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed STRN4 has a tissue-specific structural role in neurons, demonstrating PP2A-dependent function distinct from its cancer context.\",\n      \"evidence\": \"Spine morphology analysis with STRN4 knockdown, PP2A interaction assays, NMDA receptor blockade, and dendritic mRNA localization in neurons\",\n      \"pmids\": [\"28442576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PP2A substrate in spines not identified\", \"Link between NMDA-driven local translation and spine maintenance mechanistic detail unclear\", \"Relationship to Hippo signaling in neurons untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified an upstream transcriptional driver of STRN4, explaining how its expression is elevated in cancer.\",\n      \"evidence\": \"ChIP showing Pokemon/LRF binding to the STRN4 promoter with knockdown and proliferation/apoptosis readouts in prostate cancer cells\",\n      \"pmids\": [\"31205540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study, single cancer type\", \"Whether Pokemon regulation operates in other tissues unknown\", \"Downstream STRN4 effectors in this axis not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined STRN4 as a generic STRIPAK-borne binding partner of the entire MAP4K family, generalizing the 2014 finding into a pathway-level scaffold role in Hippo signaling.\",\n      \"evidence\": \"AP-MS interactome mapping of MAP4K-family kinases in endometrial cancer\",\n      \"pmids\": [\"32640226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interactome alone does not establish directionality of regulation\", \"Functional consequence of each MAP4K interaction not separated\", \"Phosphatase targeting mechanism not demonstrated here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the core enzymatic mechanism: STRN4 couples PP2A to MST1/2 dephosphorylation to stabilize YAP/TAZ, and connected this to innate immune signaling output.\",\n      \"evidence\": \"Reciprocal Co-IP, MST1/2 dephosphorylation assays, PP2A/STRN4 knockdown/knockout, and macrophage-specific PP2A-deficient mouse tumor models\",\n      \"pmids\": [\"36757811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the STRN4-PP2A-MST complex not defined\", \"Whether STRN4 distinguishes MST1 vs MST2 unclear\", \"Generality of the YAP-STING antagonism beyond macrophages untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added a post-translational switch—DHHC9 palmitoylation at Cys701—that tunes STRN4 activity toward nuclear YAP and a pro-migratory transcriptional program.\",\n      \"evidence\": \"Palmitoylation site mapping, C701 mutagenesis, YAP phosphorylation and nuclear fractionation assays, DHHC9 knockdown, and in vitro/in vivo metastasis assays\",\n      \"pmids\": [\"40903842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How palmitoylation alters STRN4-PP2A or STRN4-membrane behavior mechanistically unresolved\", \"Reversibility/depalmitoylation regulation not characterized\", \"Whether palmitoylation regulates the neuronal pool of STRN4 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How STRN4's distinct activities—cancer Hippo regulation, immune modulation, and neuronal spine maintenance—are coordinated and whether they share common substrate logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the STRN4-PP2A-MST/MAP4K assembly\", \"Full PP2A substrate repertoire directed by STRN4 unknown\", \"Crosstalk between palmitoylation, transcriptional induction, and tissue context not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\"STRIPAK\"],\n    \"partners\": [\"PP2A\", \"MST1\", \"MST2\", \"MAP4K4\", \"MINK1\", \"TNIK\", \"DHHC9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}