{"gene":"RASSF1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2000,"finding":"RASSF1 binds Ras in a GTP-dependent manner both in vivo and directly in vitro, and activated Ras enhances while dominant-negative Ras inhibits RASSF1-induced apoptosis; RASSF1-transfected cells exhibit membrane blebbing rescued by caspase inhibitor, establishing RASSF1 as a Ras effector mediating apoptosis.","method":"Co-immunoprecipitation, in vitro GST pulldown, dominant-negative/activated Ras co-transfection, caspase inhibitor rescue assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal in vivo and direct in vitro binding demonstrated, functional rescue with caspase inhibitor, multiple orthogonal methods in single study","pmids":["10998413"],"is_preprint":false},{"year":2004,"finding":"Endogenous MST1 in KB cells is specifically associated with substoichiometric amounts of RASSF1A. Co-expression of RASSF1A (and RASSF1C) with MST1 markedly suppresses MST1(Thr183) autophosphorylation in vivo and abolishes Mg-ATP-mediated MST1 autoactivation in vitro, establishing RASSF1 as an inhibitor of MST1/2 kinase autoactivation through direct association via SARAH domains.","method":"Co-immunoprecipitation of endogenous proteins, in vitro kinase autoactivation assay with recombinant proteins, in vivo co-transfection phosphorylation assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of kinase inhibition, endogenous co-IP, in vivo phosphorylation assay, multiple orthogonal methods","pmids":["15109305"],"is_preprint":false},{"year":2004,"finding":"RASSF1 (via region 74-123 of RASSF1C / 144-193 of RASSF1A) physically interacts with the catalytic second intracellular loop (region 652-748) of plasma membrane calcium ATPase PMCA4b, and this interaction inhibits EGF-dependent ERK pathway activation; blocking the interaction with a competing GFP-fusion peptide abolishes the inhibition.","method":"Yeast two-hybrid screen, co-immunoprecipitation, GST pulldown, immunofluorescence co-localization, domain-mapping with competing peptide, ERK signaling assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, GST pulldown, domain mapping, functional competition assay, multiple orthogonal methods in single study","pmids":["15145946"],"is_preprint":false},{"year":2005,"finding":"RASSF1A (but not RASSF1C when co-expressed with C19ORF5) causes paclitaxel-like microtubule hyperstabilization and disruption of mitosis; both isoforms share identical microtubule association domains, but the unique N-terminal sequence of RASSF1C prevents it from hyperstabilizing microtubules when C19ORF5 is present, conferring isoform-specific specificity on RASSF1A in microtubule hyperstabilization.","method":"Transfection/overexpression of isoforms, microtubule stabilization assays, co-expression with C19ORF5, domain deletion analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional microtubule assays with domain mapping and co-expression, single lab","pmids":["15753381"],"is_preprint":false},{"year":2005,"finding":"RASSF1A promotes microtubule stability in vivo; Rassf1A null mouse embryonic fibroblasts show increased sensitivity to microtubule depolymerizing agents, and Rassf1A null mice exhibit increased spontaneous and irradiation-induced tumorigenesis, establishing RASSF1A as a bona fide tumor suppressor that maintains microtubule integrity.","method":"Targeted gene knockout in mouse, microtubule depolymerization sensitivity assay in primary fibroblasts, in vivo tumor incidence monitoring","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined cellular and in vivo phenotypic readouts, multiple endpoints","pmids":["16135822"],"is_preprint":false},{"year":2006,"finding":"RASSF1 polypeptides bind MST1 and MST2 through the SARAH domains of each partner; recombinant RASSF1/Nore1 polypeptides inhibit MST1/2 intradimer transphosphorylation autoactivation in vitro. Additionally, RASSF1 exhibits relatively low affinity for Ras-like GTPases directly but may associate with Ras-GTP indirectly (via Nore1), in contrast to Nore1A which binds Ras-GTP with high affinity.","method":"In vitro kinase assay with recombinant proteins, SARAH domain interaction studies, Ras GTPase binding assays","journal":"Methods in enzymology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution of SARAH-domain mediated binding and kinase inhibition, single lab review/methods paper","pmids":["16757333"],"is_preprint":false},{"year":2011,"finding":"RASSF1 interacts with Daxx during mitosis and partially co-localizes with Daxx; co-depletion or expression of the Daxx-binding domain of Rassf1 stabilizes cyclin B and increases taxol resistance, defining a Daxx-Rassf1 mitotic stress checkpoint that enables cells to exit mitosis as micronucleated cells when encountering taxol.","method":"Co-immunoprecipitation, siRNA knockdown, time-lapse microscopy, cyclin B stability assay, mouse xenograft taxol response assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, knockdown with functional readouts (cyclin B, cell death), domain competition, in vivo xenograft, single lab","pmids":["21643015"],"is_preprint":false},{"year":2013,"finding":"RASSF family members (RASSF1-6) interact with MST kinases through SARAH domain-mediated interactions consistent with structural predictions; in vitro interaction studies confirm RASSF1 SARAH domain binding to MST kinase SARAH domain. RASSF7, lacking a canonical SARAH domain, was identified as a new MST kinase interacting partner.","method":"In vitro interaction studies, computational structural modeling, in silico RA and SARAH domain comparative analysis","journal":"Advances in biological regulation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro binding assay without mutagenesis or structural validation, single lab, partially computational","pmids":["23357313"],"is_preprint":false},{"year":2015,"finding":"RASSF1A restricts SRC kinase activity and prevents motility/invasion; loss of RASSF1A by promoter methylation switches transcription to RASSF1C, which targets SRC/YES to epithelial cell-cell junctions, promotes tyrosine phosphorylation of E-cadherin, β-catenin, and YAP1, and derepresses YAP1 (via reduced YAP pS127), enabling nuclear YAP1-mediated transcription of invasion genes. RASSF1A methylation correlates with increased inhibitory pY527-SRC.","method":"Affinity proteomics, proximity ligation assay, real-time molecular visualization, shRNA knockdown, overexpression, in vitro invasion/motility assays, in vivo tumorigenesis models, phospho-western blotting","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (affinity proteomics, proximity ligation, live imaging, KD/OE with defined phenotypes, in vivo), single lab but rigorous","pmids":["26549256"],"is_preprint":false},{"year":2017,"finding":"miR-193a-3p directly binds the RASSF1 3'UTR and represses RASSF1 mRNA and protein expression; excess miR-193a-3p impairs the Rassf1-Syntaxin 16 signaling pathway required for cytokinesis completion, causing polyploidy, multipolar spindles, and elevated cell death.","method":"Luciferase reporter assay (direct 3'UTR binding), immunoblotting, qRT-PCR, time-lapse microscopy, immunofluorescence","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct luciferase reporter validation of miRNA-target binding, functional cytokinesis phenotype, single lab","pmids":["28449010"],"is_preprint":false},{"year":2019,"finding":"RASSF1 functions as an upstream activator of the Hippo pathway; ursolic acid upregulates RASSF1, which activates MST1, MST2, and LATS1, leading to YAP phosphorylation (p-YAP); RASSF1 silencing reverses UA-induced p-YAP expression, placing RASSF1 upstream of MST kinases in the Hippo cascade in gastric cancer cells.","method":"siRNA knockdown of RASSF1, microarray/gene ontology analysis, Western blotting for Hippo pathway components, xenograft in vivo model","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by RASSF1 knockdown reversing p-YAP, supported by in vivo xenograft, single lab","pmids":["31547587"],"is_preprint":false},{"year":2016,"finding":"RhBMP-2 increases RASSF1 binding to MST1, activates Hippo signaling (increases MST1, MOB1, p-YAP), and RASSF1 knockdown reverses BMP2-induced p-YAP, establishing RASSF1 as necessary for BMP2-mediated Hippo pathway activation in esophageal cancer cells.","method":"Co-immunoprecipitation (RASSF1-MST1 binding upon BMP2 treatment), siRNA knockdown of RASSF1, Western blotting for p-YAP and Hippo components, in vivo xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating increased RASSF1-MST1 interaction, epistasis by knockdown, single lab","pmids":["27230238"],"is_preprint":false},{"year":2024,"finding":"P. multocida infection upregulates Rassf1 expression, and Rassf1 enhances Hippo-Yap pathway through phosphorylation of Mst1/2 and Lats1; in vitro knockdown of Rassf1 significantly enhanced Yap activity and reduced apoptosis during infection, confirming Rassf1 as a proximal activator of the Hippo kinase cascade leading to pulmonary epithelial apoptosis.","method":"RNA-seq, siRNA knockdown, pharmacological Hippo inhibition (XMU-MP-1), mouse and rabbit infection models, Western blotting for p-Mst1/2, p-Lats1, p-Yap","journal":"Veterinary research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with defined phosphorylation phenotype, multiple animal models, single lab","pmids":["38493147"],"is_preprint":false},{"year":2023,"finding":"ATF4 transcription factor binds operational binding sites in the RASSF1 promoter (demonstrated by ChIP) and activates RASSF1 transcription (demonstrated by reporter assay); RASSF1 ablation mitigates ATF4 effector BBC3 expression and abrogates tunicamycin-induced (ER stress) apoptosis, placing RASSF1 downstream of ATF4 in ER stress-associated apoptosis.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, RASSF1 knockdown/ablation, tunicamycin-induced apoptosis assay","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay for ATF4-RASSF1 promoter interaction, functional epistasis by RASSF1 ablation, single lab","pmids":["36723232"],"is_preprint":false},{"year":2025,"finding":"RFX2 transcription factor binds the RASSF1 promoter and activates RASSF1 transcription; RASSF1 knockdown reverses RFX2-mediated inhibition of immune escape and YAP phosphorylation, placing RASSF1 downstream of RFX2 in the Hippo pathway in lung adenocarcinoma.","method":"Dual-luciferase assay, ChIP-PCR (RFX2 enrichment at RASSF1 promoter), siRNA knockdown of RASSF1, co-culture with CD8+ T cells, in vivo tumor model","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase and ChIP confirm transcription factor binding; epistasis by RASSF1 knockdown, single lab","pmids":["40069841"],"is_preprint":false},{"year":2020,"finding":"SKP1 suppresses RASSF1 at both mRNA and protein levels; RASSF1 overexpression abolishes SKP1-driven YAP activation and cancer stem cell stemness, placing RASSF1 as a downstream mediator of SKP1's effect on Hippo-YAP signaling in colorectal cancer cells.","method":"Lentiviral overexpression and knockdown, Western blotting, luciferase reporter, ChIP-PCR, nuclear run-on assay, Co-IP, sphere formation, xenograft","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by RASSF1 overexpression rescuing SKP1 effects, multiple readouts, single lab","pmids":["33292299"],"is_preprint":false}],"current_model":"RASSF1A functions as a scaffold tumor suppressor that directly binds activated Ras-GTP to mediate apoptosis, inhibits MST1/2 kinase autoactivation through SARAH domain interactions while also activating the Hippo kinase cascade (MST1/2→LATS1→p-YAP) in response to upstream signals, stabilizes microtubules (with isoform-specificity conferred by C19ORF5 interaction), restricts SRC kinase activity at epithelial junctions, forms a mitotic stress checkpoint with Daxx to regulate cyclin B stability and taxol response, and is transcriptionally regulated by ATF4 (ER stress) and RFX2; its paralog isoform RASSF1C oppositely promotes SRC/YES activity and YAP-mediated invasion, illustrating that the RASSF1 locus produces functionally antagonistic isoforms whose balance is controlled by epigenetic promoter switching."},"narrative":{"mechanistic_narrative":"RASSF1 is a scaffold tumor suppressor that couples Ras signaling to apoptosis and to the Hippo kinase cascade, and whose loss—frequently by promoter methylation—drives tumorigenesis [PMID:10998413, PMID:16135822]. The RASSF1A isoform binds activated Ras-GTP and mediates Ras-dependent, caspase-dependent apoptosis [PMID:10998413], and Rassf1A-null mice show increased spontaneous and irradiation-induced tumors, establishing the gene as a bona fide tumor suppressor [PMID:16135822]. RASSF1 engages MST1/2 kinases through reciprocal SARAH-domain interactions, and depending on context it both restrains MST autoactivation in vitro [PMID:15109305, PMID:16757333] and serves as a proximal activator of the Hippo cascade (MST1/2→LATS1→phospho-YAP) in response to upstream cues including BMP2, ursolic acid, and bacterial infection [PMID:31547587, PMID:27230238, PMID:38493147]. Beyond the Hippo axis, RASSF1A stabilizes microtubules—conferring isoform-specific behavior through C19ORF5 interaction—and Rassf1A-null cells are hypersensitive to microtubule-depolymerizing agents [PMID:15753381, PMID:16135822]; RASSF1 also forms a Daxx-dependent mitotic stress checkpoint controlling cyclin B stability and taxol response [PMID:21643015], and supports cytokinesis via a Syntaxin 16 pathway [PMID:28449010]. RASSF1A restricts SRC kinase activity at epithelial junctions, and epigenetic switching to the RASSF1C isoform redirects SRC/YES to promote E-cadherin/β-catenin/YAP1 tyrosine phosphorylation and nuclear YAP1-driven invasion [PMID:26549256]. The locus is transcriptionally activated by ATF4 during ER stress to promote apoptosis [PMID:36723232] and by RFX2 [PMID:40069841], and is suppressed by SKP1 and by miR-193a-3p targeting its 3'UTR [PMID:33292299, PMID:28449010].","teleology":[{"year":2000,"claim":"Established that RASSF1 is a direct Ras effector linking Ras-GTP to apoptosis, defining its core tumor-suppressive function.","evidence":"Co-IP, in vitro GST pulldown, dominant-negative/activated Ras co-transfection, and caspase-inhibitor rescue in transfected cells","pmids":["10998413"],"confidence":"High","gaps":["Did not resolve the downstream apoptotic effectors","Ras-binding affinity quantitation absent"]},{"year":2004,"claim":"Showed RASSF1 binds MST1/2 via SARAH domains and inhibits their autoactivation, and physically couples to PMCA4b to dampen EGF-ERK signaling, defining its scaffold role over kinase activity.","evidence":"Endogenous Co-IP, in vitro kinase autoactivation assays, yeast two-hybrid and domain-mapping with competing peptide","pmids":["15109305","15145946"],"confidence":"High","gaps":["Reconciliation of MST inhibition with later Hippo-activating role not addressed","Cellular conditions governing activation versus inhibition unclear"]},{"year":2005,"claim":"Defined RASSF1A as a microtubule-stabilizing tumor suppressor and demonstrated isoform-specific behavior conferred by the N-terminus and C19ORF5.","evidence":"Isoform overexpression with C19ORF5 co-expression, domain deletion, microtubule assays, and Rassf1A knockout mouse with tumor incidence and depolymerizer sensitivity readouts","pmids":["15753381","16135822"],"confidence":"High","gaps":["Mechanism linking microtubule stabilization to tumor suppression in vivo not fully resolved","C19ORF5 binding interface not structurally defined"]},{"year":2006,"claim":"Refined the binding model: RASSF1 SARAH domains mediate MST1/2 inhibition while RASSF1 itself has low intrinsic Ras-GTP affinity, possibly engaging Ras indirectly via Nore1.","evidence":"In vitro kinase assays with recombinant SARAH polypeptides and GTPase binding assays","pmids":["16757333"],"confidence":"Medium","gaps":["Indirect Ras association via Nore1 not validated in cells","Methods/review-format limits independent confirmation"]},{"year":2011,"claim":"Identified a Daxx-RASSF1 mitotic stress checkpoint controlling cyclin B stability and taxol sensitivity, extending RASSF1 function into mitotic surveillance.","evidence":"Co-IP, siRNA, time-lapse microscopy, cyclin B stability assay, and xenograft taxol response","pmids":["21643015"],"confidence":"Medium","gaps":["Molecular mechanism by which Daxx-RASSF1 controls cyclin B undefined","Single-lab finding"]},{"year":2013,"claim":"Generalized SARAH-mediated MST binding across the RASSF family and identified non-canonical MST partners.","evidence":"In vitro interaction studies with computational structural modeling","pmids":["23357313"],"confidence":"Low","gaps":["In vitro binding without mutagenesis or structural validation","Partially computational"]},{"year":2015,"claim":"Demonstrated that RASSF1A restricts SRC at epithelial junctions and that epigenetic switching to RASSF1C redirects SRC/YES to drive YAP1-mediated invasion, explaining functional antagonism between isoforms.","evidence":"Affinity proteomics, proximity ligation, live imaging, shRNA/overexpression, invasion assays, in vivo tumorigenesis and phospho-westerns","pmids":["26549256"],"confidence":"High","gaps":["Triggers governing promoter switching not defined","Direct SRC-RASSF1 contact mechanism not structurally resolved"]},{"year":2016,"claim":"Recast RASSF1 as a proximal Hippo activator: BMP2 increases RASSF1-MST1 binding and RASSF1 is required for BMP2-induced YAP phosphorylation.","evidence":"Co-IP upon BMP2 treatment, siRNA, phospho-westerns, xenograft","pmids":["27230238"],"confidence":"Medium","gaps":["Mechanism reconciling activation with earlier MST inhibition unresolved","Single lineage tested"]},{"year":2017,"claim":"Placed RASSF1 under post-transcriptional control by miR-193a-3p and linked it to cytokinesis via Syntaxin 16.","evidence":"Luciferase 3'UTR reporter, immunoblot, qRT-PCR, time-lapse microscopy","pmids":["28449010"],"confidence":"Medium","gaps":["RASSF1-Syntaxin 16 biochemical interaction not detailed","Single-lab finding"]},{"year":2019,"claim":"Confirmed epistatically that RASSF1 acts upstream of MST1/2-LATS1 in YAP phosphorylation in response to ursolic acid.","evidence":"siRNA knockdown reversing p-YAP, microarray/GO analysis, westerns, xenograft","pmids":["31547587"],"confidence":"Medium","gaps":["Direct contribution versus indirect signaling not separated","Single cancer type"]},{"year":2023,"claim":"Defined transcriptional control of RASSF1 by ATF4 during ER stress, integrating RASSF1 into stress-induced apoptosis.","evidence":"ChIP, luciferase reporter, RASSF1 ablation, tunicamycin-induced apoptosis","pmids":["36723232"],"confidence":"Medium","gaps":["Whether ER-stress apoptosis operates through Hippo or Ras arms unclear","Single-lab finding"]},{"year":2024,"claim":"Showed RASSF1 is induced during bacterial infection and drives Hippo-mediated pulmonary epithelial apoptosis, extending its role to host-pathogen responses.","evidence":"RNA-seq, siRNA, pharmacological Hippo inhibition, mouse and rabbit infection models, phospho-westerns","pmids":["38493147"],"confidence":"Medium","gaps":["Upstream sensor coupling infection to RASSF1 induction unknown","Direct versus indirect kinase activation not separated"]},{"year":2025,"claim":"Identified RFX2 as a transcriptional activator of RASSF1 governing Hippo-dependent immune escape in lung adenocarcinoma, and SKP1 (2020) as a suppressor of RASSF1 controlling YAP and stemness.","evidence":"Dual-luciferase, ChIP-PCR, siRNA/overexpression epistasis, CD8+ T-cell co-culture, xenografts","pmids":["40069841","33292299"],"confidence":"Medium","gaps":["Mechanism of SKP1-mediated RASSF1 suppression at mRNA and protein levels not unified","Immune-escape link mechanistically indirect"]},{"year":null,"claim":"The conditions that toggle RASSF1 between inhibiting MST autoactivation and activating the MST1/2-LATS1-YAP cascade, and the molecular trigger for RASSF1A-to-RASSF1C promoter switching, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciles RASSF1 as both MST inhibitor and Hippo activator","Structural basis of isoform-specific partner selection undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,8]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,10,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,13,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,9]}],"complexes":[],"partners":["MST1","MST2","LATS1","DAXX","PMCA4B","SRC","YAP1","RAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NS23","full_name":"Ras association domain-containing protein 1","aliases":[],"length_aa":344,"mass_kda":39.2,"function":"Potential tumor suppressor. Required for death receptor-dependent apoptosis. Mediates activation of STK3/MST2 and STK4/MST1 during Fas-induced apoptosis by preventing their dephosphorylation. When associated with MOAP1, promotes BAX conformational change and translocation to mitochondrial membranes in response to TNF and TNFSF10 stimulation. Isoform A interacts with CDC20, an activator of the anaphase-promoting complex, APC, resulting in the inhibition of APC activity and mitotic progression. Inhibits proliferation by negatively regulating cell cycle progression at the level of G1/S-phase transition by regulating accumulation of cyclin D1 protein. Isoform C has been shown not to perform these roles, no function has been identified for this isoform. Isoform A disrupts interactions among MDM2, DAXX and USP7, thus contributing to the efficient activation of TP53 by promoting MDM2 self-ubiquitination in cell-cycle checkpoint control in response to DNA damage","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NS23/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RASSF1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"STK4","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RASSF1","total_profiled":1310},"omim":[{"mim_id":"612620","title":"RAS ASSOCIATION DOMAIN FAMILY, MEMBER 6; RASSF6","url":"https://www.omim.org/entry/612620"},{"mim_id":"610559","title":"RAS ASSOCIATION DOMAIN FAMILY, MEMBER 4; RASSF4","url":"https://www.omim.org/entry/610559"},{"mim_id":"609492","title":"RAS ASSOCIATION DOMAIN FAMILY PROTEIN 2; RASSF2","url":"https://www.omim.org/entry/609492"},{"mim_id":"607020","title":"RAS ASSOCIATION DOMAIN FAMILY PROTEIN 5; RASSF5","url":"https://www.omim.org/entry/607020"},{"mim_id":"607019","title":"RAS ASSOCIATION DOMAIN FAMILY PROTEIN 3; RASSF3","url":"https://www.omim.org/entry/607019"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RASSF1"},"hgnc":{"alias_symbol":["NORE2A","REH3P21","RDA32","123F2"],"prev_symbol":[]},"alphafold":{"accession":"Q9NS23","domains":[{"cath_id":"3.10.20.90","chopping":"49-121_134-182_205-290","consensus_level":"medium","plddt":79.6163,"start":49,"end":290},{"cath_id":"1.20.5","chopping":"301-341","consensus_level":"high","plddt":85.4337,"start":301,"end":341}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NS23","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NS23-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NS23-F1-predicted_aligned_error_v6.png","plddt_mean":71.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RASSF1","jax_strain_url":"https://www.jax.org/strain/search?query=RASSF1"},"sequence":{"accession":"Q9NS23","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NS23.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NS23/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NS23"}},"corpus_meta":[{"pmid":"15109305","id":"PMC_15109305","title":"Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15109305","citation_count":303,"is_preprint":false},{"pmid":"10998413","id":"PMC_10998413","title":"Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10998413","citation_count":247,"is_preprint":false},{"pmid":"16135822","id":"PMC_16135822","title":"The RASSF1A isoform of RASSF1 promotes microtubule stability and suppresses tumorigenesis.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16135822","citation_count":92,"is_preprint":false},{"pmid":"15145946","id":"PMC_15145946","title":"Novel functional interaction between the plasma membrane Ca2+ pump 4b and the proapoptotic tumor suppressor Ras-associated factor 1 (RASSF1).","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15145946","citation_count":89,"is_preprint":false},{"pmid":"11965544","id":"PMC_11965544","title":"RASSF3 and NORE1: identification and cloning of two human homologues of the putative tumor suppressor gene RASSF1.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11965544","citation_count":88,"is_preprint":false},{"pmid":"19795445","id":"PMC_19795445","title":"PTEN, RASSF1 and DAPK site-specific hypermethylation and outcome in surgically treated stage I and II nonsmall cell lung cancer patients.","date":"2010","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19795445","citation_count":79,"is_preprint":false},{"pmid":"32104074","id":"PMC_32104074","title":"CircHIPK3 Promotes Gemcitabine (GEM) Resistance in Pancreatic Cancer Cells by Sponging miR-330-5p and Targets RASSF1.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32104074","citation_count":76,"is_preprint":false},{"pmid":"16757333","id":"PMC_16757333","title":"Nore1 and RASSF1 regulation of cell proliferation and of the MST1/2 kinases.","date":"2006","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/16757333","citation_count":67,"is_preprint":false},{"pmid":"27384977","id":"PMC_27384977","title":"miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression.","date":"2016","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/27384977","citation_count":64,"is_preprint":false},{"pmid":"26549256","id":"PMC_26549256","title":"Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion.","date":"2015","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/26549256","citation_count":63,"is_preprint":false},{"pmid":"12762840","id":"PMC_12762840","title":"Novel complex integrating mitochondria and the microtubular cytoskeleton with chromosome remodeling and tumor suppressor RASSF1 deduced by in silico homology analysis, interaction cloning in yeast, and colocalization in cultured cells.","date":"2002","source":"In vitro cellular & developmental biology. 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Co-expression of RASSF1A (and RASSF1C) with MST1 markedly suppresses MST1(Thr183) autophosphorylation in vivo and abolishes Mg-ATP-mediated MST1 autoactivation in vitro, establishing RASSF1 as an inhibitor of MST1/2 kinase autoactivation through direct association via SARAH domains.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, in vitro kinase autoactivation assay with recombinant proteins, in vivo co-transfection phosphorylation assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of kinase inhibition, endogenous co-IP, in vivo phosphorylation assay, multiple orthogonal methods\",\n      \"pmids\": [\"15109305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RASSF1 (via region 74-123 of RASSF1C / 144-193 of RASSF1A) physically interacts with the catalytic second intracellular loop (region 652-748) of plasma membrane calcium ATPase PMCA4b, and this interaction inhibits EGF-dependent ERK pathway activation; blocking the interaction with a competing GFP-fusion peptide abolishes the inhibition.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, GST pulldown, immunofluorescence co-localization, domain-mapping with competing peptide, ERK signaling assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, GST pulldown, domain mapping, functional competition assay, multiple orthogonal methods in single study\",\n      \"pmids\": [\"15145946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RASSF1A (but not RASSF1C when co-expressed with C19ORF5) causes paclitaxel-like microtubule hyperstabilization and disruption of mitosis; both isoforms share identical microtubule association domains, but the unique N-terminal sequence of RASSF1C prevents it from hyperstabilizing microtubules when C19ORF5 is present, conferring isoform-specific specificity on RASSF1A in microtubule hyperstabilization.\",\n      \"method\": \"Transfection/overexpression of isoforms, microtubule stabilization assays, co-expression with C19ORF5, domain deletion analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional microtubule assays with domain mapping and co-expression, single lab\",\n      \"pmids\": [\"15753381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RASSF1A promotes microtubule stability in vivo; Rassf1A null mouse embryonic fibroblasts show increased sensitivity to microtubule depolymerizing agents, and Rassf1A null mice exhibit increased spontaneous and irradiation-induced tumorigenesis, establishing RASSF1A as a bona fide tumor suppressor that maintains microtubule integrity.\",\n      \"method\": \"Targeted gene knockout in mouse, microtubule depolymerization sensitivity assay in primary fibroblasts, in vivo tumor incidence monitoring\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined cellular and in vivo phenotypic readouts, multiple endpoints\",\n      \"pmids\": [\"16135822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RASSF1 polypeptides bind MST1 and MST2 through the SARAH domains of each partner; recombinant RASSF1/Nore1 polypeptides inhibit MST1/2 intradimer transphosphorylation autoactivation in vitro. Additionally, RASSF1 exhibits relatively low affinity for Ras-like GTPases directly but may associate with Ras-GTP indirectly (via Nore1), in contrast to Nore1A which binds Ras-GTP with high affinity.\",\n      \"method\": \"In vitro kinase assay with recombinant proteins, SARAH domain interaction studies, Ras GTPase binding assays\",\n      \"journal\": \"Methods in enzymology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution of SARAH-domain mediated binding and kinase inhibition, single lab review/methods paper\",\n      \"pmids\": [\"16757333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RASSF1 interacts with Daxx during mitosis and partially co-localizes with Daxx; co-depletion or expression of the Daxx-binding domain of Rassf1 stabilizes cyclin B and increases taxol resistance, defining a Daxx-Rassf1 mitotic stress checkpoint that enables cells to exit mitosis as micronucleated cells when encountering taxol.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, time-lapse microscopy, cyclin B stability assay, mouse xenograft taxol response assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, knockdown with functional readouts (cyclin B, cell death), domain competition, in vivo xenograft, single lab\",\n      \"pmids\": [\"21643015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RASSF family members (RASSF1-6) interact with MST kinases through SARAH domain-mediated interactions consistent with structural predictions; in vitro interaction studies confirm RASSF1 SARAH domain binding to MST kinase SARAH domain. RASSF7, lacking a canonical SARAH domain, was identified as a new MST kinase interacting partner.\",\n      \"method\": \"In vitro interaction studies, computational structural modeling, in silico RA and SARAH domain comparative analysis\",\n      \"journal\": \"Advances in biological regulation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro binding assay without mutagenesis or structural validation, single lab, partially computational\",\n      \"pmids\": [\"23357313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RASSF1A restricts SRC kinase activity and prevents motility/invasion; loss of RASSF1A by promoter methylation switches transcription to RASSF1C, which targets SRC/YES to epithelial cell-cell junctions, promotes tyrosine phosphorylation of E-cadherin, β-catenin, and YAP1, and derepresses YAP1 (via reduced YAP pS127), enabling nuclear YAP1-mediated transcription of invasion genes. RASSF1A methylation correlates with increased inhibitory pY527-SRC.\",\n      \"method\": \"Affinity proteomics, proximity ligation assay, real-time molecular visualization, shRNA knockdown, overexpression, in vitro invasion/motility assays, in vivo tumorigenesis models, phospho-western blotting\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (affinity proteomics, proximity ligation, live imaging, KD/OE with defined phenotypes, in vivo), single lab but rigorous\",\n      \"pmids\": [\"26549256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-193a-3p directly binds the RASSF1 3'UTR and represses RASSF1 mRNA and protein expression; excess miR-193a-3p impairs the Rassf1-Syntaxin 16 signaling pathway required for cytokinesis completion, causing polyploidy, multipolar spindles, and elevated cell death.\",\n      \"method\": \"Luciferase reporter assay (direct 3'UTR binding), immunoblotting, qRT-PCR, time-lapse microscopy, immunofluorescence\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct luciferase reporter validation of miRNA-target binding, functional cytokinesis phenotype, single lab\",\n      \"pmids\": [\"28449010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RASSF1 functions as an upstream activator of the Hippo pathway; ursolic acid upregulates RASSF1, which activates MST1, MST2, and LATS1, leading to YAP phosphorylation (p-YAP); RASSF1 silencing reverses UA-induced p-YAP expression, placing RASSF1 upstream of MST kinases in the Hippo cascade in gastric cancer cells.\",\n      \"method\": \"siRNA knockdown of RASSF1, microarray/gene ontology analysis, Western blotting for Hippo pathway components, xenograft in vivo model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by RASSF1 knockdown reversing p-YAP, supported by in vivo xenograft, single lab\",\n      \"pmids\": [\"31547587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RhBMP-2 increases RASSF1 binding to MST1, activates Hippo signaling (increases MST1, MOB1, p-YAP), and RASSF1 knockdown reverses BMP2-induced p-YAP, establishing RASSF1 as necessary for BMP2-mediated Hippo pathway activation in esophageal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (RASSF1-MST1 binding upon BMP2 treatment), siRNA knockdown of RASSF1, Western blotting for p-YAP and Hippo components, in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating increased RASSF1-MST1 interaction, epistasis by knockdown, single lab\",\n      \"pmids\": [\"27230238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"P. multocida infection upregulates Rassf1 expression, and Rassf1 enhances Hippo-Yap pathway through phosphorylation of Mst1/2 and Lats1; in vitro knockdown of Rassf1 significantly enhanced Yap activity and reduced apoptosis during infection, confirming Rassf1 as a proximal activator of the Hippo kinase cascade leading to pulmonary epithelial apoptosis.\",\n      \"method\": \"RNA-seq, siRNA knockdown, pharmacological Hippo inhibition (XMU-MP-1), mouse and rabbit infection models, Western blotting for p-Mst1/2, p-Lats1, p-Yap\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with defined phosphorylation phenotype, multiple animal models, single lab\",\n      \"pmids\": [\"38493147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATF4 transcription factor binds operational binding sites in the RASSF1 promoter (demonstrated by ChIP) and activates RASSF1 transcription (demonstrated by reporter assay); RASSF1 ablation mitigates ATF4 effector BBC3 expression and abrogates tunicamycin-induced (ER stress) apoptosis, placing RASSF1 downstream of ATF4 in ER stress-associated apoptosis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, RASSF1 knockdown/ablation, tunicamycin-induced apoptosis assay\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay for ATF4-RASSF1 promoter interaction, functional epistasis by RASSF1 ablation, single lab\",\n      \"pmids\": [\"36723232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RFX2 transcription factor binds the RASSF1 promoter and activates RASSF1 transcription; RASSF1 knockdown reverses RFX2-mediated inhibition of immune escape and YAP phosphorylation, placing RASSF1 downstream of RFX2 in the Hippo pathway in lung adenocarcinoma.\",\n      \"method\": \"Dual-luciferase assay, ChIP-PCR (RFX2 enrichment at RASSF1 promoter), siRNA knockdown of RASSF1, co-culture with CD8+ T cells, in vivo tumor model\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase and ChIP confirm transcription factor binding; epistasis by RASSF1 knockdown, single lab\",\n      \"pmids\": [\"40069841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SKP1 suppresses RASSF1 at both mRNA and protein levels; RASSF1 overexpression abolishes SKP1-driven YAP activation and cancer stem cell stemness, placing RASSF1 as a downstream mediator of SKP1's effect on Hippo-YAP signaling in colorectal cancer cells.\",\n      \"method\": \"Lentiviral overexpression and knockdown, Western blotting, luciferase reporter, ChIP-PCR, nuclear run-on assay, Co-IP, sphere formation, xenograft\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by RASSF1 overexpression rescuing SKP1 effects, multiple readouts, single lab\",\n      \"pmids\": [\"33292299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RASSF1A functions as a scaffold tumor suppressor that directly binds activated Ras-GTP to mediate apoptosis, inhibits MST1/2 kinase autoactivation through SARAH domain interactions while also activating the Hippo kinase cascade (MST1/2→LATS1→p-YAP) in response to upstream signals, stabilizes microtubules (with isoform-specificity conferred by C19ORF5 interaction), restricts SRC kinase activity at epithelial junctions, forms a mitotic stress checkpoint with Daxx to regulate cyclin B stability and taxol response, and is transcriptionally regulated by ATF4 (ER stress) and RFX2; its paralog isoform RASSF1C oppositely promotes SRC/YES activity and YAP-mediated invasion, illustrating that the RASSF1 locus produces functionally antagonistic isoforms whose balance is controlled by epigenetic promoter switching.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RASSF1 is a scaffold tumor suppressor that couples Ras signaling to apoptosis and to the Hippo kinase cascade, and whose loss—frequently by promoter methylation—drives tumorigenesis [#0, #4]. The RASSF1A isoform binds activated Ras-GTP and mediates Ras-dependent, caspase-dependent apoptosis [#0], and Rassf1A-null mice show increased spontaneous and irradiation-induced tumors, establishing the gene as a bona fide tumor suppressor [#4]. RASSF1 engages MST1/2 kinases through reciprocal SARAH-domain interactions, and depending on context it both restrains MST autoactivation in vitro [#1, #5] and serves as a proximal activator of the Hippo cascade (MST1/2→LATS1→phospho-YAP) in response to upstream cues including BMP2, ursolic acid, and bacterial infection [#10, #11, #12]. Beyond the Hippo axis, RASSF1A stabilizes microtubules—conferring isoform-specific behavior through C19ORF5 interaction—and Rassf1A-null cells are hypersensitive to microtubule-depolymerizing agents [#3, #4]; RASSF1 also forms a Daxx-dependent mitotic stress checkpoint controlling cyclin B stability and taxol response [#6], and supports cytokinesis via a Syntaxin 16 pathway [#9]. RASSF1A restricts SRC kinase activity at epithelial junctions, and epigenetic switching to the RASSF1C isoform redirects SRC/YES to promote E-cadherin/β-catenin/YAP1 tyrosine phosphorylation and nuclear YAP1-driven invasion [#8]. The locus is transcriptionally activated by ATF4 during ER stress to promote apoptosis [#13] and by RFX2 [#14], and is suppressed by SKP1 and by miR-193a-3p targeting its 3'UTR [#15, #9].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that RASSF1 is a direct Ras effector linking Ras-GTP to apoptosis, defining its core tumor-suppressive function.\",\n      \"evidence\": \"Co-IP, in vitro GST pulldown, dominant-negative/activated Ras co-transfection, and caspase-inhibitor rescue in transfected cells\",\n      \"pmids\": [\"10998413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the downstream apoptotic effectors\", \"Ras-binding affinity quantitation absent\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed RASSF1 binds MST1/2 via SARAH domains and inhibits their autoactivation, and physically couples to PMCA4b to dampen EGF-ERK signaling, defining its scaffold role over kinase activity.\",\n      \"evidence\": \"Endogenous Co-IP, in vitro kinase autoactivation assays, yeast two-hybrid and domain-mapping with competing peptide\",\n      \"pmids\": [\"15109305\", \"15145946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of MST inhibition with later Hippo-activating role not addressed\", \"Cellular conditions governing activation versus inhibition unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined RASSF1A as a microtubule-stabilizing tumor suppressor and demonstrated isoform-specific behavior conferred by the N-terminus and C19ORF5.\",\n      \"evidence\": \"Isoform overexpression with C19ORF5 co-expression, domain deletion, microtubule assays, and Rassf1A knockout mouse with tumor incidence and depolymerizer sensitivity readouts\",\n      \"pmids\": [\"15753381\", \"16135822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking microtubule stabilization to tumor suppression in vivo not fully resolved\", \"C19ORF5 binding interface not structurally defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Refined the binding model: RASSF1 SARAH domains mediate MST1/2 inhibition while RASSF1 itself has low intrinsic Ras-GTP affinity, possibly engaging Ras indirectly via Nore1.\",\n      \"evidence\": \"In vitro kinase assays with recombinant SARAH polypeptides and GTPase binding assays\",\n      \"pmids\": [\"16757333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Indirect Ras association via Nore1 not validated in cells\", \"Methods/review-format limits independent confirmation\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified a Daxx-RASSF1 mitotic stress checkpoint controlling cyclin B stability and taxol sensitivity, extending RASSF1 function into mitotic surveillance.\",\n      \"evidence\": \"Co-IP, siRNA, time-lapse microscopy, cyclin B stability assay, and xenograft taxol response\",\n      \"pmids\": [\"21643015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which Daxx-RASSF1 controls cyclin B undefined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Generalized SARAH-mediated MST binding across the RASSF family and identified non-canonical MST partners.\",\n      \"evidence\": \"In vitro interaction studies with computational structural modeling\",\n      \"pmids\": [\"23357313\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"In vitro binding without mutagenesis or structural validation\", \"Partially computational\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that RASSF1A restricts SRC at epithelial junctions and that epigenetic switching to RASSF1C redirects SRC/YES to drive YAP1-mediated invasion, explaining functional antagonism between isoforms.\",\n      \"evidence\": \"Affinity proteomics, proximity ligation, live imaging, shRNA/overexpression, invasion assays, in vivo tumorigenesis and phospho-westerns\",\n      \"pmids\": [\"26549256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Triggers governing promoter switching not defined\", \"Direct SRC-RASSF1 contact mechanism not structurally resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Recast RASSF1 as a proximal Hippo activator: BMP2 increases RASSF1-MST1 binding and RASSF1 is required for BMP2-induced YAP phosphorylation.\",\n      \"evidence\": \"Co-IP upon BMP2 treatment, siRNA, phospho-westerns, xenograft\",\n      \"pmids\": [\"27230238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism reconciling activation with earlier MST inhibition unresolved\", \"Single lineage tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed RASSF1 under post-transcriptional control by miR-193a-3p and linked it to cytokinesis via Syntaxin 16.\",\n      \"evidence\": \"Luciferase 3'UTR reporter, immunoblot, qRT-PCR, time-lapse microscopy\",\n      \"pmids\": [\"28449010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RASSF1-Syntaxin 16 biochemical interaction not detailed\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed epistatically that RASSF1 acts upstream of MST1/2-LATS1 in YAP phosphorylation in response to ursolic acid.\",\n      \"evidence\": \"siRNA knockdown reversing p-YAP, microarray/GO analysis, westerns, xenograft\",\n      \"pmids\": [\"31547587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct contribution versus indirect signaling not separated\", \"Single cancer type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined transcriptional control of RASSF1 by ATF4 during ER stress, integrating RASSF1 into stress-induced apoptosis.\",\n      \"evidence\": \"ChIP, luciferase reporter, RASSF1 ablation, tunicamycin-induced apoptosis\",\n      \"pmids\": [\"36723232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ER-stress apoptosis operates through Hippo or Ras arms unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed RASSF1 is induced during bacterial infection and drives Hippo-mediated pulmonary epithelial apoptosis, extending its role to host-pathogen responses.\",\n      \"evidence\": \"RNA-seq, siRNA, pharmacological Hippo inhibition, mouse and rabbit infection models, phospho-westerns\",\n      \"pmids\": [\"38493147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream sensor coupling infection to RASSF1 induction unknown\", \"Direct versus indirect kinase activation not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified RFX2 as a transcriptional activator of RASSF1 governing Hippo-dependent immune escape in lung adenocarcinoma, and SKP1 (2020) as a suppressor of RASSF1 controlling YAP and stemness.\",\n      \"evidence\": \"Dual-luciferase, ChIP-PCR, siRNA/overexpression epistasis, CD8+ T-cell co-culture, xenografts\",\n      \"pmids\": [\"40069841\", \"33292299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of SKP1-mediated RASSF1 suppression at mRNA and protein levels not unified\", \"Immune-escape link mechanistically indirect\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The conditions that toggle RASSF1 between inhibiting MST autoactivation and activating the MST1/2-LATS1-YAP cascade, and the molecular trigger for RASSF1A-to-RASSF1C promoter switching, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciles RASSF1 as both MST inhibitor and Hippo activator\", \"Structural basis of isoform-specific partner selection undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 10, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 13, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MST1\", \"MST2\", \"LATS1\", \"DAXX\", \"PMCA4b\", \"SRC\", \"YAP1\", \"RAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}