{"gene":"STRIP1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2008,"finding":"STRIP1 (FAM40A) is a novel component of the STRIPAK complex, a large multiprotein assembly containing PP2A catalytic and scaffolding subunits, striatins (PP2A B''' regulatory subunits), Mob3, STRIP2, CCM3, and germinal center kinase III family Ste20 kinases; STRIPAK establishes mutually exclusive interactions with either CTTNBP2 proteins or a subcomplex of SLMAP/SIKE/FGFR1OP2.","method":"Iterative affinity purification/mass spectrometry (AP-MS) interaction mapping","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal AP-MS across multiple baits, replicated across multiple labs subsequently","pmids":["18782753"],"is_preprint":false},{"year":2011,"finding":"FAM40A (STRIP1) depletion by RNAi reduces cell spreading and alters actin filament distribution in human cells, while FAM40B (STRIP2) depletion causes cell elongation and tail retraction defects, indicating that the two paralogs have distinct functions in cytoskeletal organization and cell migration.","method":"RNAi knockdown with morphological phenotype scoring (cell shape, actin staining, migration assay)","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with defined cellular phenotypes (cell spreading, actin organization, migration) in human cells, single lab","pmids":["21834987"],"is_preprint":false},{"year":2012,"finding":"In yeast, Far11 (ortholog of FAM40A/STRIP1) interacts physically with PP2A components Tpd3 and Pph21, and genetic epistasis shows that deletion of Far11 or PP2A subunits suppresses lethality caused by TORC2 deficiency (lst8Δ, tor2-21), placing Far11 as an antagonist of TORC2 signaling via PP2A.","method":"Genetic suppressor screen, co-immunoprecipitation, phosphorylation assay of TORC2 substrate Slm1","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — genetic epistasis combined with biochemical interaction and substrate phosphorylation assay, yeast ortholog study","pmids":["22298706"],"is_preprint":false},{"year":2014,"finding":"FAM40A (STRIP1) negatively regulates MST3 and MST4 kinases within the STRIPAK complex; loss of FAM40A promotes co-localization of contractile actomyosin machinery with ERM proteins via MST3/4-mediated phosphorylation of PPP1CB inhibitors (PPP1R14A-D), reducing cell speed on planar surfaces but favouring migration in confined environments. FAM40B mutations found in human tumours uncouple it from PP2A, enabling a contractile phenotype.","method":"RNAi knockdown, computational modelling, in vitro migration assays, in vivo breast cancer metastasis assays, co-immunoprecipitation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, kinase regulation, functional rescue, in vivo metastasis assay, multiple orthogonal methods in one study","pmids":["25531779"],"is_preprint":false},{"year":2016,"finding":"FARL-11, the C. elegans ortholog of STRIP1/2, localizes to the endoplasmic reticulum and is required for cell cycle-dependent ER morphological changes in embryos; in the germline, FARL-11 is required for normal ER morphology and for proper membrane localization of the GLP-1/Notch receptor, which is necessary for germline stem cell maintenance.","method":"Loss-of-function genetic analysis, immunofluorescence localization, GLP-1 receptor membrane localization assay in C. elegans","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (receptor mislocalization), loss-of-function with defined phenotype, single lab","pmids":["27510976"],"is_preprint":false},{"year":2017,"finding":"STRIP1 is essential for mesoderm migration in vivo in mouse embryos; Strip1-null mutants arrest at midgestation with failure of anterior axial mesoderm extension, and cultured mesoderm cells from null mutants show decreased spreading, abnormal focal adhesions, disorganized actin cytoskeleton, and reduced migration velocity.","method":"Mouse knockout, embryo phenotyping, mesoderm explant culture, mouse embryonic fibroblast migration assays, immunofluorescence for focal adhesions and actin","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with defined developmental phenotype, corroborated by ex vivo cell migration assays with multiple cytoskeletal readouts","pmids":["29203676"],"is_preprint":false},{"year":2018,"finding":"FAM40A (STRIP1) interacts with CCM3 and its knockdown in endothelial cells increases stress fibers and reduces in vitro angiogenic loop formation; these effects are reverted by ROCK kinase inhibition, placing STRIP1 upstream of ROCK-mediated endothelial contractility.","method":"RNAi knockdown, co-immunoprecipitation, stress fiber quantification, in vitro angiogenesis assay, ROCK inhibitor rescue","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, RNAi with phenotypic rescue by ROCK inhibitor, single lab","pmids":["30509168"],"is_preprint":false},{"year":2018,"finding":"FAM40A (STRIP1) localizes to the nucleus and perinuclear zone in mouse podocytes; its silencing or over-expression alters podocyte morphology and F-actin organization, and a point mutant (p521M>T) causes blunted podocyte morphology, disordered F-actin distribution, and reduced nephrin expression, demonstrating a role in podocyte cytoskeletal integrity.","method":"siRNA knockdown, overexpression, mutant overexpression, immunofluorescence, RT-qPCR, Western blot in mouse podocytes","journal":"Archives of medical science : AMS","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple gain- and loss-of-function models with cytoskeletal readouts, single lab, no pathway placement","pmids":["30697267"],"is_preprint":false},{"year":2019,"finding":"Within the STRIPAK-Hippo complex, STRIP1 constitutes one of two 'arms' by which STRN3 controls loading of the Hippo kinase MST2; a decreased cell density triggers dissociation of the STRIP1 arm from STRIPAK, reflecting dynamic assembly of the complex in response to upstream signals. Disrupting the STRIP1-containing arm abrogates STRIPAK's regulatory effect on Hippo signaling.","method":"Co-immunoprecipitation, crystallography (defining STRN3-SIKE1 and SIKE1-SLMAP interfaces), cell-density-dependent dissociation assay, functional Hippo pathway reporter assay","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystallographic structure, co-IP interaction mapping, and functional pathway assay in one study, single lab","pmids":["30622739"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of the human STRIPAK core (PP2AA, PP2AC, STRN3, STRIP1, MOB4) at 3.2-Å resolution reveals that STRIPAK is a non-canonical PP2A complex: it contains four copies of STRN3 forming an elongated homotetrameric coiled-coil scaffold. STRIP1 incorporates an inositol hexakisphosphate (IP6) as a structural cofactor. Mutations at subunit interfaces disrupt complex integrity and cause aberrant Hippo pathway activation.","method":"Cryo-EM structure determination, interface mutagenesis, Hippo pathway activation assay","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM structure with mutagenesis validation and functional pathway readout, single rigorous study","pmids":["33633399"],"is_preprint":false},{"year":2020,"finding":"Loss of STRIP1 in MDA-MB-231 breast cancer cells induces cell cycle arrest and decreased proliferation through induction of CDK inhibitors p21 and p27; this induction occurs in a subpopulation with low DNA damage response (p21high/γH2AXlow), and is rescued by co-depletion of MST3 and MST4 kinases, placing STRIP1 upstream of MST3/4 in regulation of p21/p27.","method":"RNAi knockdown, flow cytometry, single-cell immunofluorescence for p21/γH2AX, MST3/4 co-depletion rescue","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via co-depletion rescue, multiple readouts, single lab","pmids":["32258031"],"is_preprint":false},{"year":2022,"finding":"In zebrafish, Strip1 interacts with Striatin 3 (Strn3) and both are required for retinal ganglion cell (RGC) survival; loss of Strip1 or Strn3 activates the pro-apoptotic transcription factor Jun in RGCs, and Jun knockdown rescues RGC survival in strip1 mutants, placing Strip1 upstream of Jun-mediated apoptosis. Strip1 is additionally required for RGC dendritic patterning.","method":"Zebrafish genetic mutant analysis, co-immunoprecipitation (Strip1-Strn3 interaction), Jun activation assay, morpholino-mediated Jun knockdown rescue","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (Jun knockdown rescues strip1 mutant), co-IP for interaction, multiple orthogonal in vivo methods","pmids":["35314028"],"is_preprint":false},{"year":2023,"finding":"In C. elegans, FARL-11 (STRIP1/2 ortholog) and CASH-1 (striatin) form a complex in vivo and both localize to the sarcoplasmic reticulum (SR); missense mutations or single-amino-acid deletions in farl-11 or cash-1 cause sarcomere disorganization, disruption of SR organization around M-lines, and altered levels of the SR Ca²⁺ release channel UNC-68.","method":"Co-immunoprecipitation, immunofluorescence localization, genetic missense/deletion mutant analysis, immunoblot for UNC-68 levels in C. elegans","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo complex formation by co-IP, direct localization to SR, genetic loss-of-function with multiple structural phenotypes in one study","pmids":["37314837"],"is_preprint":false},{"year":2024,"finding":"Strip1 localizes to the nucleolus in neonatal rat ventricular cardiomyocytes (NRVCMs) and acts as a negative regulator of cardiomyocyte hypertrophy; Strip1 knockdown increases cell size and activates the hypertrophic gene program, whereas its expression is reduced in human dilated and ischemic cardiomyopathies. Mechanistically, Strip1 associates with cardiac STRIPAK and modulates MST1/MST2 and MST4 kinase activities, influencing Hippo- and Calcineurin/NFAT-related pro-hypertrophic signaling. Morpholino-driven Strip1 reduction in zebrafish causes impaired cardiac function.","method":"siRNA knockdown in NRVCMs, immunofluorescence for nucleolar localization, co-immunoprecipitation for STRIPAK association, kinase activity assay (MST1/2/4), zebrafish morpholino knockdown cardiac function assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, kinase assay, in vivo zebrafish model, localization experiment, single lab with multiple orthogonal methods","pmids":["41892331"],"is_preprint":false}],"current_model":"STRIP1 (FAM40A) is a core structural component of the STRIPAK (striatin-interacting phosphatase and kinase) complex, a non-canonical PP2A holoenzyme whose cryo-EM structure reveals STRIP1 binds an IP6 cofactor and bridges STRN3 to PP2A; within this complex STRIP1 negatively regulates MST3/4 kinases and dynamically dissociates in response to cell-density signals to modulate Hippo pathway activity, while also controlling actomyosin cortex contractility, ER/SR organization, cell migration, and apoptosis via Jun suppression in retinal ganglion cells."},"narrative":{"mechanistic_narrative":"STRIP1 (FAM40A) is a core structural subunit of the STRIPAK complex, a non-canonical PP2A holoenzyme that links phosphatase activity to germinal center kinase III signaling to control cytoskeletal organization, cell migration, and Hippo-pathway output [PMID:18782753, PMID:25531779]. The cryo-EM structure of the human STRIPAK core establishes STRIP1 as a scaffold that incorporates an inositol hexakisphosphate (IP6) cofactor and bridges the STRN3 coiled-coil tetramer to the PP2A A/C dimer, with interface mutations disrupting complex integrity and causing aberrant Hippo activation [#11...,#9]. Functionally, STRIP1 negatively regulates the MST3 and MST4 kinases within STRIPAK; its loss derepresses MST3/4-mediated phosphorylation of PP1-inhibitory PPP1R14 proteins, increasing actomyosin contractility, altering focal adhesions and actin organization, and reshaping cell migration and spreading [PMID:25531779, PMID:29203676]. This MST3/4-restraining activity also restrains the cell cycle, as STRIP1 loss induces p21/p27 in a manner rescued by MST3/4 co-depletion [PMID:32258031]. STRIP1 constitutes one of two regulatory 'arms' through which STRN3 loads the Hippo kinases (MST1/MST2), and this arm dynamically dissociates in response to decreased cell density, coupling complex assembly to Hippo signaling [PMID:30622739]. STRIP1 is essential in vivo for mesoderm migration during mouse development [PMID:29203676], and in other systems it associates with STRN3/striatin to suppress Jun-mediated apoptosis in retinal ganglion cells [PMID:35314028] and to restrain cardiomyocyte hypertrophy via MST1/2/4 [PMID:41892331]. STRIP1 orthologs additionally localize to and organize the endoplasmic/sarcoplasmic reticulum and antagonize TORC2 signaling through PP2A [PMID:22298706, PMID:27510976, PMID:37314837].","teleology":[{"year":2008,"claim":"Established STRIP1 as a bona fide subunit of a defined multiprotein assembly rather than an orphan protein, mapping the compositional architecture of STRIPAK.","evidence":"Iterative reciprocal AP-MS interaction mapping in human cells","pmids":["18782753"],"confidence":"High","gaps":["Did not assign STRIP1 a molecular function within the complex","Stoichiometry and architecture unresolved","No structural model"]},{"year":2011,"claim":"Showed STRIP1 and its paralog STRIP2 have non-redundant roles in shaping the actin cytoskeleton and migration, distinguishing the two FAM40 proteins functionally.","evidence":"RNAi knockdown with cell-shape, actin, and migration phenotyping in human cells","pmids":["21834987"],"confidence":"Medium","gaps":["Mechanism connecting STRIP1 to actin not defined","No link to PP2A or kinase activity in this study","Single lab"]},{"year":2012,"claim":"Connected STRIP1 (via yeast Far11) physically and genetically to PP2A and positioned it as an antagonist of TORC2 signaling.","evidence":"Yeast genetic suppressor screen, co-IP, and TORC2 substrate (Slm1) phosphorylation assay","pmids":["22298706"],"confidence":"High","gaps":["TORC2 antagonism not demonstrated for human STRIP1","Direct phosphatase substrate not identified","Ortholog-based inference"]},{"year":2014,"claim":"Defined the core enzymatic logic: STRIP1 restrains MST3/4 kinases within STRIPAK, controlling actomyosin contractility and context-dependent migration through PPP1R14/PP1.","evidence":"RNAi, reciprocal co-IP, in vitro/in vivo migration and metastasis assays, computational modelling","pmids":["25531779"],"confidence":"High","gaps":["How STRIP1 negatively regulates MST3/4 mechanistically not resolved","Direct substrate of the phosphatase not pinpointed"]},{"year":2016,"claim":"Revealed an ER-associated role, showing the STRIP ortholog organizes ER morphology and is required for receptor membrane localization and stem-cell maintenance.","evidence":"Loss-of-function genetics, immunolocalization, and GLP-1/Notch localization assay in C. elegans","pmids":["27510976"],"confidence":"Medium","gaps":["Whether human STRIP1 has the same ER role unclear","Link between ER function and STRIPAK kinase regulation not established"]},{"year":2017,"claim":"Demonstrated an essential in vivo developmental requirement: STRIP1 is needed for mesoderm migration and cytoskeletal/focal-adhesion organization in the mouse embryo.","evidence":"Mouse knockout, embryo phenotyping, mesoderm explant and MEF migration assays with cytoskeletal readouts","pmids":["29203676"],"confidence":"High","gaps":["Whether the phenotype is fully STRIPAK/MST3-4-dependent in vivo not dissected","Molecular link to focal adhesion regulation undefined"]},{"year":2018,"claim":"Extended STRIP1 cytoskeletal control to endothelial and renal cells, placing it upstream of ROCK-mediated contractility and showing a CCM3 interaction.","evidence":"RNAi, co-IP, stress-fiber and angiogenesis assays with ROCK-inhibitor rescue (endothelial); gain/loss-of-function with mutant in podocytes","pmids":["30509168","30697267"],"confidence":"Medium","gaps":["Direct biochemical link between STRIP1 and ROCK not shown","Nuclear/perinuclear localization in podocytes unreconciled with cytoplasmic complex","Single labs"]},{"year":2019,"claim":"Showed STRIP1 forms one of two regulatory arms by which STRN3 loads Hippo kinase MST2, with the arm dissociating upon decreased cell density — coupling dynamic complex assembly to Hippo signaling.","evidence":"Co-IP, crystallography of STRN3-SIKE1/SIKE1-SLMAP interfaces, density-dependent dissociation and Hippo reporter assays","pmids":["30622739"],"confidence":"High","gaps":["Signal that triggers density-dependent dissociation unknown","Structure of the STRIP1 arm itself not solved here"]},{"year":2020,"claim":"Placed STRIP1 upstream of MST3/4 in cell-cycle control, showing its loss induces p21/p27 and arrest via MST3/4.","evidence":"RNAi, flow cytometry, single-cell p21/γH2AX immunofluorescence, MST3/4 co-depletion rescue in breast cancer cells","pmids":["32258031"],"confidence":"Medium","gaps":["How MST3/4 drive p21/p27 induction unresolved","Subpopulation specificity (low DDR) mechanism unclear"]},{"year":2021,"claim":"Provided the atomic-resolution architecture, establishing STRIPAK as a non-canonical PP2A complex with a STRN3 homotetramer scaffold and STRIP1 bound to an IP6 structural cofactor whose interface integrity gates Hippo output.","evidence":"3.2-Å cryo-EM of human STRIPAK core (PP2AA/C, STRN3, STRIP1, MOB4) with interface mutagenesis and Hippo activation readout","pmids":["33633399"],"confidence":"High","gaps":["Functional role of the IP6 cofactor not biochemically dissected","How density signals are transmitted to this core not shown"]},{"year":2022,"claim":"Linked STRIP1 to neuronal survival, showing it acts with STRN3 to suppress pro-apoptotic Jun in retinal ganglion cells.","evidence":"Zebrafish mutants, Strip1-Strn3 co-IP, Jun activation assay, morpholino Jun-knockdown rescue, dendritic patterning analysis","pmids":["35314028"],"confidence":"High","gaps":["Phosphatase/kinase step connecting STRIP1 to Jun not defined","Whether MST kinases mediate the apoptotic effect not tested here"]},{"year":2023,"claim":"Demonstrated that the STRIP-striatin complex localizes to and organizes the sarcoplasmic reticulum and sarcomere, regulating a Ca²⁺ release channel.","evidence":"Co-IP, SR immunolocalization, missense/deletion mutant analysis, and UNC-68 immunoblot in C. elegans","pmids":["37314837"],"confidence":"High","gaps":["Mechanism by which the complex controls SR/M-line organization unknown","Direct effect on UNC-68 vs indirect not resolved"]},{"year":2024,"claim":"Identified STRIP1 as a negative regulator of cardiomyocyte hypertrophy acting through cardiac STRIPAK and MST1/2/4 kinases, with reduced expression in human cardiomyopathies.","evidence":"siRNA in NRVCMs, nucleolar immunolocalization, STRIPAK co-IP, MST1/2/4 kinase assays, zebrafish morpholino cardiac function assay","pmids":["41892331"],"confidence":"Medium","gaps":["Nucleolar localization function not mechanistically explained","Hippo vs Calcineurin/NFAT contributions not separated","Single lab"]},{"year":null,"claim":"How a single STRIP1-containing STRIPAK complex selects among its diverse outputs — actomyosin contractility, Hippo signaling, ER/SR organization, cell-cycle arrest, and apoptosis — and how upstream signals such as cell density are transmitted to STRIP1 remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified direct phosphatase substrate of the STRIP1-PP2A holoenzyme","Signal-to-complex transmission mechanism for density-dependent arm dissociation unknown","Function of nuclear/nucleolar STRIP1 pools undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,9,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,10,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,5,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11]}],"complexes":["STRIPAK"],"partners":["STRN3","PPP2CA","PPP2R1A","MOB4","CCM3","MST3","MST4","MST2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5VSL9","full_name":"Striatin-interacting protein 1","aliases":["Protein FAM40A"],"length_aa":837,"mass_kda":95.6,"function":"Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the cortical actin filament dynamics and cell shape. Part of the striatin-interacting phosphatase and kinase (STRIPAK) complexes. 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","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q5VSL9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STRIP1","classification":"Not Classified","n_dependent_lines":502,"n_total_lines":1208,"dependency_fraction":0.4155629139072848},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MAP4K4","stoichiometry":4.0},{"gene":"CTTN","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2},{"gene":"PPP2CB","stoichiometry":0.2},{"gene":"STK24","stoichiometry":0.2},{"gene":"STK25","stoichiometry":0.2},{"gene":"STK26","stoichiometry":0.2},{"gene":"STRN3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/STRIP1","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":"614766","title":"STRIATIN, CALMODULIN-BINDING PROTEIN 3; STRN3","url":"https://www.omim.org/entry/614766"},{"mim_id":"610742","title":"MOV10 RISC COMPLEX RNA HELICASE; MOV10","url":"https://www.omim.org/entry/610742"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STRIP1"},"hgnc":{"alias_symbol":["FLJ14743","KIAA1761","FAR11A"],"prev_symbol":["FAM40A"]},"alphafold":{"accession":"Q5VSL9","domains":[{"cath_id":"-","chopping":"77-309_503-741","consensus_level":"medium","plddt":93.5171,"start":77,"end":741},{"cath_id":"-","chopping":"429-472","consensus_level":"medium","plddt":89.2457,"start":429,"end":472},{"cath_id":"-","chopping":"797-833","consensus_level":"medium","plddt":78.9232,"start":797,"end":833}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VSL9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VSL9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VSL9-F1-predicted_aligned_error_v6.png","plddt_mean":80.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STRIP1","jax_strain_url":"https://www.jax.org/strain/search?query=STRIP1"},"sequence":{"accession":"Q5VSL9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VSL9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VSL9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VSL9"}},"corpus_meta":[{"pmid":"18782753","id":"PMC_18782753","title":"A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein.","date":"2008","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18782753","citation_count":303,"is_preprint":false},{"pmid":"24333164","id":"PMC_24333164","title":"STRIPAK complexes: structure, biological function, and involvement in human diseases.","date":"2013","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24333164","citation_count":185,"is_preprint":false},{"pmid":"21834987","id":"PMC_21834987","title":"Identification and characterization of a set of conserved and new regulators of cytoskeletal organization, cell morphology and migration.","date":"2011","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/21834987","citation_count":166,"is_preprint":false},{"pmid":"25531779","id":"PMC_25531779","title":"STRIPAK components determine mode of cancer cell migration and metastasis.","date":"2014","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25531779","citation_count":148,"is_preprint":false},{"pmid":"30622739","id":"PMC_30622739","title":"Architecture, substructures, and dynamic assembly of STRIPAK complexes in Hippo signaling.","date":"2019","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/30622739","citation_count":59,"is_preprint":false},{"pmid":"33633399","id":"PMC_33633399","title":"Cryo-EM structure of the Hippo signaling integrator human STRIPAK.","date":"2021","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33633399","citation_count":48,"is_preprint":false},{"pmid":"26439752","id":"PMC_26439752","title":"The composition and function of the striatin-interacting phosphatases and kinases (STRIPAK) complex in fungi.","date":"2015","source":"Fungal genetics and biology : FG & B","url":"https://pubmed.ncbi.nlm.nih.gov/26439752","citation_count":48,"is_preprint":false},{"pmid":"22298706","id":"PMC_22298706","title":"TORC2 signaling is antagonized by protein phosphatase 2A and the Far complex in Saccharomyces cerevisiae.","date":"2012","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22298706","citation_count":41,"is_preprint":false},{"pmid":"30883543","id":"PMC_30883543","title":"Assembly of a heptameric STRIPAK complex is required for coordination of light-dependent multicellular fungal development with secondary metabolism in Aspergillus nidulans.","date":"2019","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30883543","citation_count":36,"is_preprint":false},{"pmid":"29203676","id":"PMC_29203676","title":"STRIP1, a core component of STRIPAK complexes, is essential for normal mesoderm migration in 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/40924252","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14379,"output_tokens":3784,"usd":0.049948,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11532,"output_tokens":4469,"usd":0.084693,"stage2_stop_reason":"end_turn"},"total_usd":0.134641,"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\": 2008,\n      \"finding\": \"STRIP1 (FAM40A) is a novel component of the STRIPAK complex, a large multiprotein assembly containing PP2A catalytic and scaffolding subunits, striatins (PP2A B''' regulatory subunits), Mob3, STRIP2, CCM3, and germinal center kinase III family Ste20 kinases; STRIPAK establishes mutually exclusive interactions with either CTTNBP2 proteins or a subcomplex of SLMAP/SIKE/FGFR1OP2.\",\n      \"method\": \"Iterative affinity purification/mass spectrometry (AP-MS) interaction mapping\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal AP-MS across multiple baits, replicated across multiple labs subsequently\",\n      \"pmids\": [\"18782753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FAM40A (STRIP1) depletion by RNAi reduces cell spreading and alters actin filament distribution in human cells, while FAM40B (STRIP2) depletion causes cell elongation and tail retraction defects, indicating that the two paralogs have distinct functions in cytoskeletal organization and cell migration.\",\n      \"method\": \"RNAi knockdown with morphological phenotype scoring (cell shape, actin staining, migration assay)\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with defined cellular phenotypes (cell spreading, actin organization, migration) in human cells, single lab\",\n      \"pmids\": [\"21834987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In yeast, Far11 (ortholog of FAM40A/STRIP1) interacts physically with PP2A components Tpd3 and Pph21, and genetic epistasis shows that deletion of Far11 or PP2A subunits suppresses lethality caused by TORC2 deficiency (lst8Δ, tor2-21), placing Far11 as an antagonist of TORC2 signaling via PP2A.\",\n      \"method\": \"Genetic suppressor screen, co-immunoprecipitation, phosphorylation assay of TORC2 substrate Slm1\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — genetic epistasis combined with biochemical interaction and substrate phosphorylation assay, yeast ortholog study\",\n      \"pmids\": [\"22298706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FAM40A (STRIP1) negatively regulates MST3 and MST4 kinases within the STRIPAK complex; loss of FAM40A promotes co-localization of contractile actomyosin machinery with ERM proteins via MST3/4-mediated phosphorylation of PPP1CB inhibitors (PPP1R14A-D), reducing cell speed on planar surfaces but favouring migration in confined environments. FAM40B mutations found in human tumours uncouple it from PP2A, enabling a contractile phenotype.\",\n      \"method\": \"RNAi knockdown, computational modelling, in vitro migration assays, in vivo breast cancer metastasis assays, co-immunoprecipitation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, kinase regulation, functional rescue, in vivo metastasis assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25531779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FARL-11, the C. elegans ortholog of STRIP1/2, localizes to the endoplasmic reticulum and is required for cell cycle-dependent ER morphological changes in embryos; in the germline, FARL-11 is required for normal ER morphology and for proper membrane localization of the GLP-1/Notch receptor, which is necessary for germline stem cell maintenance.\",\n      \"method\": \"Loss-of-function genetic analysis, immunofluorescence localization, GLP-1 receptor membrane localization assay in C. elegans\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (receptor mislocalization), loss-of-function with defined phenotype, single lab\",\n      \"pmids\": [\"27510976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STRIP1 is essential for mesoderm migration in vivo in mouse embryos; Strip1-null mutants arrest at midgestation with failure of anterior axial mesoderm extension, and cultured mesoderm cells from null mutants show decreased spreading, abnormal focal adhesions, disorganized actin cytoskeleton, and reduced migration velocity.\",\n      \"method\": \"Mouse knockout, embryo phenotyping, mesoderm explant culture, mouse embryonic fibroblast migration assays, immunofluorescence for focal adhesions and actin\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with defined developmental phenotype, corroborated by ex vivo cell migration assays with multiple cytoskeletal readouts\",\n      \"pmids\": [\"29203676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAM40A (STRIP1) interacts with CCM3 and its knockdown in endothelial cells increases stress fibers and reduces in vitro angiogenic loop formation; these effects are reverted by ROCK kinase inhibition, placing STRIP1 upstream of ROCK-mediated endothelial contractility.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, stress fiber quantification, in vitro angiogenesis assay, ROCK inhibitor rescue\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, RNAi with phenotypic rescue by ROCK inhibitor, single lab\",\n      \"pmids\": [\"30509168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAM40A (STRIP1) localizes to the nucleus and perinuclear zone in mouse podocytes; its silencing or over-expression alters podocyte morphology and F-actin organization, and a point mutant (p521M>T) causes blunted podocyte morphology, disordered F-actin distribution, and reduced nephrin expression, demonstrating a role in podocyte cytoskeletal integrity.\",\n      \"method\": \"siRNA knockdown, overexpression, mutant overexpression, immunofluorescence, RT-qPCR, Western blot in mouse podocytes\",\n      \"journal\": \"Archives of medical science : AMS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple gain- and loss-of-function models with cytoskeletal readouts, single lab, no pathway placement\",\n      \"pmids\": [\"30697267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Within the STRIPAK-Hippo complex, STRIP1 constitutes one of two 'arms' by which STRN3 controls loading of the Hippo kinase MST2; a decreased cell density triggers dissociation of the STRIP1 arm from STRIPAK, reflecting dynamic assembly of the complex in response to upstream signals. Disrupting the STRIP1-containing arm abrogates STRIPAK's regulatory effect on Hippo signaling.\",\n      \"method\": \"Co-immunoprecipitation, crystallography (defining STRN3-SIKE1 and SIKE1-SLMAP interfaces), cell-density-dependent dissociation assay, functional Hippo pathway reporter assay\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystallographic structure, co-IP interaction mapping, and functional pathway assay in one study, single lab\",\n      \"pmids\": [\"30622739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of the human STRIPAK core (PP2AA, PP2AC, STRN3, STRIP1, MOB4) at 3.2-Å resolution reveals that STRIPAK is a non-canonical PP2A complex: it contains four copies of STRN3 forming an elongated homotetrameric coiled-coil scaffold. STRIP1 incorporates an inositol hexakisphosphate (IP6) as a structural cofactor. Mutations at subunit interfaces disrupt complex integrity and cause aberrant Hippo pathway activation.\",\n      \"method\": \"Cryo-EM structure determination, interface mutagenesis, Hippo pathway activation assay\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM structure with mutagenesis validation and functional pathway readout, single rigorous study\",\n      \"pmids\": [\"33633399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of STRIP1 in MDA-MB-231 breast cancer cells induces cell cycle arrest and decreased proliferation through induction of CDK inhibitors p21 and p27; this induction occurs in a subpopulation with low DNA damage response (p21high/γH2AXlow), and is rescued by co-depletion of MST3 and MST4 kinases, placing STRIP1 upstream of MST3/4 in regulation of p21/p27.\",\n      \"method\": \"RNAi knockdown, flow cytometry, single-cell immunofluorescence for p21/γH2AX, MST3/4 co-depletion rescue\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via co-depletion rescue, multiple readouts, single lab\",\n      \"pmids\": [\"32258031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In zebrafish, Strip1 interacts with Striatin 3 (Strn3) and both are required for retinal ganglion cell (RGC) survival; loss of Strip1 or Strn3 activates the pro-apoptotic transcription factor Jun in RGCs, and Jun knockdown rescues RGC survival in strip1 mutants, placing Strip1 upstream of Jun-mediated apoptosis. Strip1 is additionally required for RGC dendritic patterning.\",\n      \"method\": \"Zebrafish genetic mutant analysis, co-immunoprecipitation (Strip1-Strn3 interaction), Jun activation assay, morpholino-mediated Jun knockdown rescue\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (Jun knockdown rescues strip1 mutant), co-IP for interaction, multiple orthogonal in vivo methods\",\n      \"pmids\": [\"35314028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, FARL-11 (STRIP1/2 ortholog) and CASH-1 (striatin) form a complex in vivo and both localize to the sarcoplasmic reticulum (SR); missense mutations or single-amino-acid deletions in farl-11 or cash-1 cause sarcomere disorganization, disruption of SR organization around M-lines, and altered levels of the SR Ca²⁺ release channel UNC-68.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, genetic missense/deletion mutant analysis, immunoblot for UNC-68 levels in C. elegans\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo complex formation by co-IP, direct localization to SR, genetic loss-of-function with multiple structural phenotypes in one study\",\n      \"pmids\": [\"37314837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Strip1 localizes to the nucleolus in neonatal rat ventricular cardiomyocytes (NRVCMs) and acts as a negative regulator of cardiomyocyte hypertrophy; Strip1 knockdown increases cell size and activates the hypertrophic gene program, whereas its expression is reduced in human dilated and ischemic cardiomyopathies. Mechanistically, Strip1 associates with cardiac STRIPAK and modulates MST1/MST2 and MST4 kinase activities, influencing Hippo- and Calcineurin/NFAT-related pro-hypertrophic signaling. Morpholino-driven Strip1 reduction in zebrafish causes impaired cardiac function.\",\n      \"method\": \"siRNA knockdown in NRVCMs, immunofluorescence for nucleolar localization, co-immunoprecipitation for STRIPAK association, kinase activity assay (MST1/2/4), zebrafish morpholino knockdown cardiac function assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, kinase assay, in vivo zebrafish model, localization experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41892331\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STRIP1 (FAM40A) is a core structural component of the STRIPAK (striatin-interacting phosphatase and kinase) complex, a non-canonical PP2A holoenzyme whose cryo-EM structure reveals STRIP1 binds an IP6 cofactor and bridges STRN3 to PP2A; within this complex STRIP1 negatively regulates MST3/4 kinases and dynamically dissociates in response to cell-density signals to modulate Hippo pathway activity, while also controlling actomyosin cortex contractility, ER/SR organization, cell migration, and apoptosis via Jun suppression in retinal ganglion cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STRIP1 (FAM40A) is a core structural subunit of the STRIPAK complex, a non-canonical PP2A holoenzyme that links phosphatase activity to germinal center kinase III signaling to control cytoskeletal organization, cell migration, and Hippo-pathway output [#0, #3]. The cryo-EM structure of the human STRIPAK core establishes STRIP1 as a scaffold that incorporates an inositol hexakisphosphate (IP6) cofactor and bridges the STRN3 coiled-coil tetramer to the PP2A A/C dimer, with interface mutations disrupting complex integrity and causing aberrant Hippo activation [#11... ,#9]. Functionally, STRIP1 negatively regulates the MST3 and MST4 kinases within STRIPAK; its loss derepresses MST3/4-mediated phosphorylation of PP1-inhibitory PPP1R14 proteins, increasing actomyosin contractility, altering focal adhesions and actin organization, and reshaping cell migration and spreading [#3, #5]. This MST3/4-restraining activity also restrains the cell cycle, as STRIP1 loss induces p21/p27 in a manner rescued by MST3/4 co-depletion [#10]. STRIP1 constitutes one of two regulatory 'arms' through which STRN3 loads the Hippo kinases (MST1/MST2), and this arm dynamically dissociates in response to decreased cell density, coupling complex assembly to Hippo signaling [#8]. STRIP1 is essential in vivo for mesoderm migration during mouse development [#5], and in other systems it associates with STRN3/striatin to suppress Jun-mediated apoptosis in retinal ganglion cells [#11] and to restrain cardiomyocyte hypertrophy via MST1/2/4 [#13]. STRIP1 orthologs additionally localize to and organize the endoplasmic/sarcoplasmic reticulum and antagonize TORC2 signaling through PP2A [#2, #4, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established STRIP1 as a bona fide subunit of a defined multiprotein assembly rather than an orphan protein, mapping the compositional architecture of STRIPAK.\",\n      \"evidence\": \"Iterative reciprocal AP-MS interaction mapping in human cells\",\n      \"pmids\": [\"18782753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not assign STRIP1 a molecular function within the complex\", \"Stoichiometry and architecture unresolved\", \"No structural model\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed STRIP1 and its paralog STRIP2 have non-redundant roles in shaping the actin cytoskeleton and migration, distinguishing the two FAM40 proteins functionally.\",\n      \"evidence\": \"RNAi knockdown with cell-shape, actin, and migration phenotyping in human cells\",\n      \"pmids\": [\"21834987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting STRIP1 to actin not defined\", \"No link to PP2A or kinase activity in this study\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected STRIP1 (via yeast Far11) physically and genetically to PP2A and positioned it as an antagonist of TORC2 signaling.\",\n      \"evidence\": \"Yeast genetic suppressor screen, co-IP, and TORC2 substrate (Slm1) phosphorylation assay\",\n      \"pmids\": [\"22298706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TORC2 antagonism not demonstrated for human STRIP1\", \"Direct phosphatase substrate not identified\", \"Ortholog-based inference\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the core enzymatic logic: STRIP1 restrains MST3/4 kinases within STRIPAK, controlling actomyosin contractility and context-dependent migration through PPP1R14/PP1.\",\n      \"evidence\": \"RNAi, reciprocal co-IP, in vitro/in vivo migration and metastasis assays, computational modelling\",\n      \"pmids\": [\"25531779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How STRIP1 negatively regulates MST3/4 mechanistically not resolved\", \"Direct substrate of the phosphatase not pinpointed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an ER-associated role, showing the STRIP ortholog organizes ER morphology and is required for receptor membrane localization and stem-cell maintenance.\",\n      \"evidence\": \"Loss-of-function genetics, immunolocalization, and GLP-1/Notch localization assay in C. elegans\",\n      \"pmids\": [\"27510976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether human STRIP1 has the same ER role unclear\", \"Link between ER function and STRIPAK kinase regulation not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated an essential in vivo developmental requirement: STRIP1 is needed for mesoderm migration and cytoskeletal/focal-adhesion organization in the mouse embryo.\",\n      \"evidence\": \"Mouse knockout, embryo phenotyping, mesoderm explant and MEF migration assays with cytoskeletal readouts\",\n      \"pmids\": [\"29203676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the phenotype is fully STRIPAK/MST3-4-dependent in vivo not dissected\", \"Molecular link to focal adhesion regulation undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended STRIP1 cytoskeletal control to endothelial and renal cells, placing it upstream of ROCK-mediated contractility and showing a CCM3 interaction.\",\n      \"evidence\": \"RNAi, co-IP, stress-fiber and angiogenesis assays with ROCK-inhibitor rescue (endothelial); gain/loss-of-function with mutant in podocytes\",\n      \"pmids\": [\"30509168\", \"30697267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between STRIP1 and ROCK not shown\", \"Nuclear/perinuclear localization in podocytes unreconciled with cytoplasmic complex\", \"Single labs\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed STRIP1 forms one of two regulatory arms by which STRN3 loads Hippo kinase MST2, with the arm dissociating upon decreased cell density — coupling dynamic complex assembly to Hippo signaling.\",\n      \"evidence\": \"Co-IP, crystallography of STRN3-SIKE1/SIKE1-SLMAP interfaces, density-dependent dissociation and Hippo reporter assays\",\n      \"pmids\": [\"30622739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that triggers density-dependent dissociation unknown\", \"Structure of the STRIP1 arm itself not solved here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed STRIP1 upstream of MST3/4 in cell-cycle control, showing its loss induces p21/p27 and arrest via MST3/4.\",\n      \"evidence\": \"RNAi, flow cytometry, single-cell p21/γH2AX immunofluorescence, MST3/4 co-depletion rescue in breast cancer cells\",\n      \"pmids\": [\"32258031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How MST3/4 drive p21/p27 induction unresolved\", \"Subpopulation specificity (low DDR) mechanism unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the atomic-resolution architecture, establishing STRIPAK as a non-canonical PP2A complex with a STRN3 homotetramer scaffold and STRIP1 bound to an IP6 structural cofactor whose interface integrity gates Hippo output.\",\n      \"evidence\": \"3.2-Å cryo-EM of human STRIPAK core (PP2AA/C, STRN3, STRIP1, MOB4) with interface mutagenesis and Hippo activation readout\",\n      \"pmids\": [\"33633399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of the IP6 cofactor not biochemically dissected\", \"How density signals are transmitted to this core not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked STRIP1 to neuronal survival, showing it acts with STRN3 to suppress pro-apoptotic Jun in retinal ganglion cells.\",\n      \"evidence\": \"Zebrafish mutants, Strip1-Strn3 co-IP, Jun activation assay, morpholino Jun-knockdown rescue, dendritic patterning analysis\",\n      \"pmids\": [\"35314028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase/kinase step connecting STRIP1 to Jun not defined\", \"Whether MST kinases mediate the apoptotic effect not tested here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that the STRIP-striatin complex localizes to and organizes the sarcoplasmic reticulum and sarcomere, regulating a Ca²⁺ release channel.\",\n      \"evidence\": \"Co-IP, SR immunolocalization, missense/deletion mutant analysis, and UNC-68 immunoblot in C. elegans\",\n      \"pmids\": [\"37314837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the complex controls SR/M-line organization unknown\", \"Direct effect on UNC-68 vs indirect not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified STRIP1 as a negative regulator of cardiomyocyte hypertrophy acting through cardiac STRIPAK and MST1/2/4 kinases, with reduced expression in human cardiomyopathies.\",\n      \"evidence\": \"siRNA in NRVCMs, nucleolar immunolocalization, STRIPAK co-IP, MST1/2/4 kinase assays, zebrafish morpholino cardiac function assay\",\n      \"pmids\": [\"41892331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nucleolar localization function not mechanistically explained\", \"Hippo vs Calcineurin/NFAT contributions not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single STRIP1-containing STRIPAK complex selects among its diverse outputs — actomyosin contractility, Hippo signaling, ER/SR organization, cell-cycle arrest, and apoptosis — and how upstream signals such as cell density are transmitted to STRIP1 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified direct phosphatase substrate of the STRIP1-PP2A holoenzyme\", \"Signal-to-complex transmission mechanism for density-dependent arm dissociation unknown\", \"Function of nuclear/nucleolar STRIP1 pools undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 9, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 10, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\"STRIPAK\"],\n    \"partners\": [\"STRN3\", \"PPP2CA\", \"PPP2R1A\", \"MOB4\", \"CCM3\", \"MST3\", \"MST4\", \"MST2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}