{"gene":"FRAT1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":1997,"finding":"Frat1 was identified as a proto-oncogene that collaborates with Pim1 and Myc in T-cell lymphoma progression; retroviral overexpression of Frat1 conferred selective in vivo growth advantage to tumor cells already expressing high Myc and Pim1, establishing Frat1 as a progression gene in lymphomagenesis.","method":"Retroviral insertional mutagenesis, proviral tagging, Frat1-IRES-lacZ retroviral overexpression in tumor cell lines transplanted in vivo","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo retroviral overexpression with defined phenotypic readout, single lab but multiple tumor models","pmids":["9034327"],"is_preprint":false},{"year":1999,"finding":"Frat1 interacts with both Dvl and GSK3, and can be recruited into a quaternary Dvl-Axin-GSK3-Frat1 complex. Wnt-1 signaling promotes disintegration of this complex, leading to dissociation of GSK3 from Axin, suggesting Frat1 mediates GSK3 displacement from Axin downstream of Dvl.","method":"Co-immunoprecipitation, dominant-negative domain overexpression, LEF-1 luciferase reporter assay in mammalian cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional reporter assays, replicated across mammalian and Xenopus systems in same study","pmids":["10428961"],"is_preprint":false},{"year":1999,"finding":"A peptide from FRAT1 (FRATtide, residues 188-226) binds GSK3 and selectively blocks GSK3-catalysed phosphorylation of Axin and beta-catenin (Axin-dependent substrates) without suppressing GSK3 activity toward glycogen synthase or eIF2B (priming-dependent substrates), demonstrating substrate-selective inhibition of GSK3 by FRAT1.","method":"In vitro GSK3 kinase assay with FRATtide peptide against multiple substrates; direct binding assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted kinase assay with defined peptide and multiple substrates, substrate-selectivity rigorously demonstrated","pmids":["10481074"],"is_preprint":false},{"year":1999,"finding":"Frat1-deficient mice are normal and fertile, with no developmental phenotype; a second mouse gene Frat3 shares overlapping expression patterns with Frat1 and can also induce a secondary axis in Xenopus embryos, suggesting functional redundancy compensates for Frat1 loss.","method":"Frat1 knockout mouse (beta-galactosidase knock-in), LacZ reporter expression analysis, Xenopus axis induction assay","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with in vivo phenotype assessment and Xenopus functional assay, single lab","pmids":["10534617"],"is_preprint":false},{"year":1999,"finding":"Transgenic overexpression of Frat1 in mice causes focal glomerulosclerosis and nephrotic syndrome, and markedly accelerates M-MuLV-induced lymphomagenesis in combination with Pim1, providing direct in vivo evidence that Frat1 promotes lymphoma progression.","method":"Frat1 transgenic mouse generation, M-MuLV infection, tumor incidence analysis, Frat1/Pim1 bitransgenic crosses","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with defined phenotypic readout, single lab","pmids":["10557087"],"is_preprint":false},{"year":2001,"finding":"Adenoviral overexpression of FRAT1 in PC12 cells confers neuroprotection and inhibits GSK-3 activity toward Tau and beta-catenin but does not affect GSK-3-mediated phosphorylation of glycogen synthase, confirming substrate-selective GSK-3 inhibition by FRAT1 in a cellular context.","method":"Adenoviral FRAT1 overexpression in PC12 cells, GSK-3 substrate phosphorylation assays (Tau, beta-catenin, glycogen synthase), cell survival assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cellular overexpression with multiple substrate readouts, single lab, consistent with in vitro data","pmids":["11696357"],"is_preprint":false},{"year":2002,"finding":"When transiently overexpressed in COS-1 cells, both hFRAT1 and hFRAT2 proteins localize to the cytosol and are concentrated in the nucleus.","method":"Transient transfection in COS-1 cells, subcellular fractionation/localization","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization experiment without functional follow-up, single lab","pmids":["12095675"],"is_preprint":false},{"year":2003,"finding":"CKI epsilon phosphorylates Dvl-1 and enhances the binding of Dvl-1 to Frat-1; depletion of CKI epsilon by RNAi inhibits Wnt-3a-induced Dvl phosphorylation, reduces Dvl-1/Frat-1 complex formation, and decreases Wnt-3a-induced beta-catenin accumulation, placing CKI epsilon upstream of the Dvl-Frat-1 interaction in Wnt signaling.","method":"Co-immunoprecipitation, RNAi knockdown of CKI epsilon in HeLa S3 cells, Tcf-4 luciferase reporter assay, beta-catenin accumulation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus RNAi epistasis plus reporter assay, multiple orthogonal methods","pmids":["12556519"],"is_preprint":false},{"year":2003,"finding":"Expression of a FRAT1 peptide in swAPP(751) cells increases phosphorylation of GSK3alpha (Ser21) and GSK3beta (Ser9), inhibits kinase activity of both isoforms, and significantly decreases production of total Abeta and Abeta(1-42).","method":"Cellular expression of FRAT1 peptide in swAPP(751) cells, GSK3 kinase activity assay, ELISA for Abeta","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cellular functional assay with kinase activity readout and Abeta quantification, single lab","pmids":["14572648"],"is_preprint":false},{"year":2005,"finding":"Frat1 interacts with the cytoplasmic domain of LRP5 (identified by yeast two-hybrid, confirmed by co-IP); Wnt3a or constitutively active LRP5 recruits Frat1 to the cell membrane; LRP5, Frat1, and Axin co-immunoprecipitate, suggesting a membrane-proximal complex in which Frat1 inhibits GSK3 to promote beta-catenin nuclear translocation.","method":"Yeast two-hybrid, co-immunoprecipitation, cell membrane recruitment assay, TCF-1 luciferase reporter","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, functional reporter assay, single lab","pmids":["15699046"],"is_preprint":false},{"year":2006,"finding":"FRAT1 is phosphorylated at Ser188 in vitro and in intact cells by protein kinase A (PKA); activation of endogenous beta-adrenergic receptors with norepinephrine stimulates Ser188 phosphorylation; PKA-mediated Ser188 phosphorylation inhibits FRAT1's ability to activate beta-catenin-dependent transcription. GSK-3 can phosphorylate FRAT1 at Ser188 in vitro but does not significantly phosphorylate endogenous FRAT1 in cells.","method":"In vitro PKA kinase assay, phospho-site mapping by mass spectrometry, norepinephrine stimulation in intact cells, beta-catenin-dependent transcription reporter assay, GSK-3 in vitro kinase assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus intact cell stimulation plus functional reporter, multiple orthogonal methods in single rigorous study","pmids":["16982607"],"is_preprint":false},{"year":2008,"finding":"FRAT1 overexpression in esophageal squamous cell carcinoma cells induces nuclear accumulation of beta-catenin and promotes beta-catenin/TCF transcriptional activity; these effects are reversed by co-expression of GSK3beta or dominant-negative TCF4; continued c-Myc expression is required for maintenance of the FRAT1-driven growth state.","method":"FRAT1 overexpression/RNAi in ESCC cells, beta-catenin localization by immunofluorescence, TCF reporter assay, co-expression rescue experiments","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with mechanistic rescue experiments, single lab","pmids":["18498136"],"is_preprint":false},{"year":2014,"finding":"NDRG1 upregulates FRAT1 expression, which prevents association of GSK3beta with the Axin1-APC-CK1 destruction complex, thereby inhibiting beta-catenin phosphorylation at Ser33/37 and Thr41 and increasing non-phosphorylated beta-catenin at the plasma membrane in prostate and colon cancer cells.","method":"Western blotting for phospho-beta-catenin, co-immunoprecipitation of destruction complex components, siRNA knockdown/overexpression of NDRG1 and FRAT1","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of destruction complex, phospho-site-specific antibody readout, multiple cell lines, single lab","pmids":["24829151"],"is_preprint":false},{"year":2017,"finding":"FRAT1 is a direct target of miR-34a-3p; co-expression of miR-34a-3p with a reporter construct containing the FRAT1 3'UTR reduces luciferase activity, and disruption of the miR-34a-3p binding site in the FRAT1 3'UTR abolishes this regulation. In meningioma cells, miR-34a-3p overexpression decreases FRAT1 protein levels.","method":"Dual luciferase reporter assay with 3'UTR constructs and mutant binding sites, Western blotting after miR-34a-3p overexpression/inhibition","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase assay with mutation rescue, confirmed at protein level by Western blot, single lab","pmids":["28340489"],"is_preprint":false},{"year":2022,"finding":"FRAT1 and FRAT2 physically interact with each other; siRNA-mediated knockdown of FRAT2 in FRAT1-overexpressing gastric cancer cells reverses FRAT1-driven invasion, indicating the FRAT1-FRAT2 complex is required for maximal pro-invasive activity. miR-3648 directly targets FRAT1 and FRAT2 to inactivate Wnt/beta-catenin signaling.","method":"Co-immunoprecipitation of FRAT1-FRAT2, siRNA knockdown, invasion assays, dual-luciferase miRNA target validation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue experiment, in vitro and in vivo, single lab","pmids":["36153370"],"is_preprint":false},{"year":2022,"finding":"siRNA knockdown of FRAT1 in glioblastoma U251 cells reduces mRNA and protein levels of VEGFA and decreases secreted VEGFA concentration, suppressing tube formation in an angiogenesis assay, linking FRAT1 activity through Wnt/beta-catenin signaling to VEGFA-mediated angiogenesis.","method":"siRNA knockdown, RT-qPCR, Western blotting, ELISA for secreted VEGFA, in vitro tube formation assay","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown with functional readout but no direct mechanistic link established; single lab, no epistasis","pmids":["35059733"],"is_preprint":false}],"current_model":"FRAT1 is a substrate-selective inhibitor of GSK-3 that binds GSK-3 (via residues 188-226) and prevents its Axin-dependent phosphorylation of beta-catenin, while sparing priming-dependent GSK-3 substrates such as glycogen synthase; it is recruited into a quaternary Dvl-Axin-GSK3-Frat1 complex downstream of Wnt/LRP5 receptor activation (facilitated by CKI epsilon-mediated Dvl phosphorylation), and upon Wnt stimulation promotes GSK3 dissociation from Axin, allowing beta-catenin accumulation and TCF/LEF-dependent transcription; FRAT1 activity is itself regulated by PKA phosphorylation at Ser188, which inhibits its ability to activate beta-catenin-dependent transcription."},"narrative":{"mechanistic_narrative":"FRAT1 is a positive regulator of Wnt/beta-catenin signaling that acts as a substrate-selective inhibitor of GSK-3 [PMID:10481074, PMID:11696357]. A FRAT1 peptide (residues 188-226, \"FRATtide\") binds GSK-3 and blocks its phosphorylation of Axin-dependent substrates such as beta-catenin and Tau while sparing priming-dependent substrates like glycogen synthase and eIF2B, defining the molecular basis of its selectivity [PMID:10481074, PMID:11696357]. Within the Wnt pathway, FRAT1 binds both Dishevelled and GSK-3 and is recruited into a quaternary Dvl-Axin-GSK3-Frat1 complex; Wnt-1 stimulation disintegrates this complex and dissociates GSK-3 from Axin, allowing beta-catenin to accumulate [PMID:10428961, PMID:24829151]. Recruitment is organized at the membrane: FRAT1 binds the cytoplasmic tail of the Wnt co-receptor LRP5 and is drawn to the plasma membrane upon Wnt3a stimulation [PMID:15699046], and the Dvl-Frat1 interaction is licensed by CKI-epsilon-mediated phosphorylation of Dvl [PMID:12556519]. By preventing GSK-3 from associating with the Axin1-APC-CK1 destruction complex, FRAT1 reduces beta-catenin phosphorylation at Ser33/37/Thr41 and drives its nuclear accumulation and TCF/LEF-dependent transcription [PMID:18498136, PMID:24829151]. FRAT1 activity is constrained by PKA, which phosphorylates it at Ser188 to suppress its ability to activate beta-catenin-dependent transcription [PMID:16982607]. Functionally, FRAT1 is an oncogenic progression gene cooperating with Pim1 and Myc in lymphomagenesis [PMID:9034327, PMID:10557087] and promotes tumor cell invasion, angiogenesis, and beta-catenin/TCF activity in multiple carcinomas, with FRAT1-FRAT2 heterodimerization required for maximal pro-invasive activity [PMID:18498136, PMID:36153370].","teleology":[{"year":1997,"claim":"Established FRAT1 as an oncogenic progression gene before its biochemical function was known, motivating the search for its mechanism.","evidence":"Retroviral insertional mutagenesis and Frat1 overexpression in T-cell lymphoma models in vivo","pmids":["9034327"],"confidence":"Medium","gaps":["No molecular mechanism linking Frat1 to tumor growth identified","Pathway context unknown at this stage"]},{"year":1999,"claim":"Placed FRAT1 within the Wnt pathway by showing it bridges Dvl and GSK3 and that Wnt signaling dissolves a Dvl-Axin-GSK3-Frat1 complex, explaining how FRAT1 relieves beta-catenin from GSK3.","evidence":"Co-immunoprecipitation, dominant-negative domains, and LEF-1 reporter assays in mammalian and Xenopus systems","pmids":["10428961"],"confidence":"High","gaps":["Precise step at which GSK3 dissociates from Axin not resolved","Stoichiometry of the quaternary complex undefined"]},{"year":1999,"claim":"Defined the biochemical basis of FRAT1 action as substrate-selective GSK3 inhibition, distinguishing Axin-dependent from priming-dependent substrates.","evidence":"In vitro GSK3 kinase assays with the FRATtide peptide (residues 188-226) against beta-catenin, Axin, glycogen synthase, and eIF2B","pmids":["10481074"],"confidence":"High","gaps":["Structural mechanism of selectivity not determined","Whether full-length FRAT1 behaves identically to the peptide not addressed here"]},{"year":1999,"claim":"Tested the in vivo requirement for Frat1, revealing functional redundancy with Frat3 that masks a loss-of-function phenotype.","evidence":"Frat1 knockout mouse with LacZ knock-in and Xenopus axis-induction assays","pmids":["10534617"],"confidence":"Medium","gaps":["Redundancy not formally proven by compound knockout","Physiological Wnt context where Frat1 is non-redundant unidentified"]},{"year":1999,"claim":"Provided gain-of-function in vivo confirmation that Frat1 drives lymphoma progression and causes renal pathology.","evidence":"Frat1 transgenic mice, M-MuLV infection, and Frat1/Pim1 bitransgenic crosses","pmids":["10557087"],"confidence":"Medium","gaps":["Mechanism connecting Frat1 to glomerulosclerosis not defined","Whether oncogenic effect requires beta-catenin not tested here"]},{"year":2001,"claim":"Confirmed substrate-selective GSK3 inhibition in a cellular context and extended FRAT1 function to neuroprotection via reduced Tau phosphorylation.","evidence":"Adenoviral FRAT1 overexpression in PC12 cells with substrate phosphorylation and survival assays","pmids":["11696357"],"confidence":"Medium","gaps":["Direct neuronal relevance beyond PC12 cells not established","Mechanism of survival benefit not dissected"]},{"year":2003,"claim":"Identified CKI-epsilon as an upstream licensing kinase that phosphorylates Dvl to promote the Dvl-Frat1 interaction and downstream beta-catenin accumulation.","evidence":"Co-IP, CKI-epsilon RNAi epistasis, and Tcf-4 reporter assays in HeLa S3 cells","pmids":["12556519"],"confidence":"High","gaps":["Phospho-residues on Dvl mediating Frat1 binding not mapped","Direct versus indirect effect on complex assembly not fully separated"]},{"year":2003,"claim":"Connected FRAT1-mediated GSK3 inhibition to reduced amyloid-beta production, implicating the pathway in Alzheimer-relevant processing.","evidence":"FRAT1 peptide expression in swAPP(751) cells with GSK3 kinase activity assays and Abeta ELISA","pmids":["14572648"],"confidence":"Medium","gaps":["Mechanism linking GSK3 inhibition to Abeta reduction not detailed","In vivo relevance not tested"]},{"year":2005,"claim":"Localized FRAT1 recruitment to the Wnt receptor by demonstrating direct interaction with the LRP5 cytoplasmic domain and Wnt-induced membrane recruitment.","evidence":"Yeast two-hybrid, co-IP, membrane recruitment assays, and TCF-1 reporter","pmids":["15699046"],"confidence":"Medium","gaps":["Whether LRP5 binding is required for GSK3 inhibition not isolated","Order of LRP5, Frat1, Axin assembly undefined"]},{"year":2006,"claim":"Revealed a regulatory input controlling FRAT1 itself, showing PKA phosphorylation at Ser188 dampens its beta-catenin-activating function.","evidence":"In vitro PKA kinase assay, phospho-site mass spectrometry, norepinephrine stimulation, and beta-catenin reporter assays","pmids":["16982607"],"confidence":"High","gaps":["How Ser188 phosphorylation alters GSK3 binding not mechanistically resolved","Physiological contexts engaging this regulation not defined"]},{"year":2008,"claim":"Demonstrated that FRAT1 drives beta-catenin/TCF transcription and a c-Myc-dependent growth state in carcinoma, with GSK3beta as the antagonized node.","evidence":"FRAT1 gain/loss-of-function in ESCC cells with GSK3beta and dominant-negative TCF4 rescue","pmids":["18498136"],"confidence":"Medium","gaps":["Direct biochemical block of GSK3 in these cells not shown","Generality across tumor types not tested here"]},{"year":2014,"claim":"Refined the mechanism to show FRAT1 prevents GSK3beta association with the Axin1-APC-CK1 destruction complex, blocking beta-catenin Ser33/37/Thr41 phosphorylation.","evidence":"Phospho-specific Western blotting, destruction-complex co-IP, and NDRG1/FRAT1 knockdown/overexpression in prostate and colon cancer cells","pmids":["24829151"],"confidence":"Medium","gaps":["Mechanism by which NDRG1 upregulates FRAT1 not defined","Direct contact preventing GSK3-complex association not mapped"]},{"year":2017,"claim":"Identified post-transcriptional control of FRAT1 by miR-34a-3p, providing a route to modulate FRAT1 levels.","evidence":"Dual-luciferase 3'UTR reporter with binding-site mutation and Western blot in meningioma cells","pmids":["28340489"],"confidence":"Medium","gaps":["Functional consequence on Wnt output in this context not shown","Other regulatory miRNAs not surveyed"]},{"year":2022,"claim":"Established FRAT1-FRAT2 heterodimerization as required for maximal pro-invasive activity and identified miR-3648 as a dual regulator.","evidence":"Co-IP, FRAT2 siRNA rescue, invasion assays, and miRNA target validation in gastric cancer cells","pmids":["36153370"],"confidence":"Medium","gaps":["Structural basis of FRAT1-FRAT2 interaction unknown","Whether heterodimer alters GSK3 inhibition not tested"]},{"year":2022,"claim":"Linked FRAT1 to tumor angiogenesis via VEGFA expression in glioblastoma cells.","evidence":"siRNA knockdown with RT-qPCR, Western blot, VEGFA ELISA, and tube formation assay in U251 cells","pmids":["35059733"],"confidence":"Low","gaps":["No epistasis establishing a direct Wnt/beta-catenin-to-VEGFA mechanism","Single cell line, knockdown-only evidence"]},{"year":null,"claim":"The structural mechanism by which FRAT1 confers substrate selectivity on GSK3 and how Ser188 phosphorylation, LRP5 binding, and FRAT1-FRAT2 heterodimerization are integrated to control GSK3 release from Axin remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the FRAT1-GSK3 complex in the timeline","Integration of regulatory inputs into a single quantitative model not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,4,11]}],"complexes":["Dvl-Axin-GSK3-Frat1 complex","FRAT1-FRAT2 heterodimer"],"partners":["GSK3B","DVL1","AXIN1","LRP5","CSNK1E","FRAT2","PRKACA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92837","full_name":"Proto-oncogene FRAT1","aliases":["Frequently rearranged in advanced T-cell lymphomas 1","FRAT-1"],"length_aa":279,"mass_kda":29.1,"function":"Positively regulates the Wnt signaling pathway by stabilizing beta-catenin through the association with GSK-3. May play a role in tumor progression and collaborate with PIM1 and MYC in lymphomagenesis","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q92837/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FRAT1","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FRAT1","total_profiled":1310},"omim":[{"mim_id":"606784","title":"GLYCOGEN SYNTHASE KINASE 3-ALPHA; GSK3A","url":"https://www.omim.org/entry/606784"},{"mim_id":"605006","title":"FREQUENTLY REARRANGED IN ADVANCED T-CELL LYMPHOMAS 2; FRAT2","url":"https://www.omim.org/entry/605006"},{"mim_id":"602503","title":"FREQUENTLY REARRANGED IN ADVANCED T-CELL LYMPHOMAS; FRAT1","url":"https://www.omim.org/entry/602503"},{"mim_id":"600982","title":"MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 1; MAP3K1","url":"https://www.omim.org/entry/600982"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FRAT1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q92837","domains":[{"cath_id":"-","chopping":"200-230","consensus_level":"medium","plddt":91.9835,"start":200,"end":230}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92837","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92837-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92837-F1-predicted_aligned_error_v6.png","plddt_mean":59.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FRAT1","jax_strain_url":"https://www.jax.org/strain/search?query=FRAT1"},"sequence":{"accession":"Q92837","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92837.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92837/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92837"}},"corpus_meta":[{"pmid":"10428961","id":"PMC_10428961","title":"Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1.","date":"1999","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10428961","citation_count":342,"is_preprint":false},{"pmid":"10481074","id":"PMC_10481074","title":"A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and beta-catenin.","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10481074","citation_count":200,"is_preprint":false},{"pmid":"9034327","id":"PMC_9034327","title":"Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9034327","citation_count":123,"is_preprint":false},{"pmid":"24829151","id":"PMC_24829151","title":"The metastasis suppressor NDRG1 modulates the phosphorylation and nuclear translocation of β-catenin through mechanisms involving FRAT1 and PAK4.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24829151","citation_count":98,"is_preprint":false},{"pmid":"12556519","id":"PMC_12556519","title":"Casein kinase I epsilon enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of beta-catenin.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12556519","citation_count":96,"is_preprint":false},{"pmid":"11696357","id":"PMC_11696357","title":"GSK-3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and beta-catenin stabilisation without elevation of glycogen synthase activity.","date":"2001","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/11696357","citation_count":82,"is_preprint":false},{"pmid":"11894125","id":"PMC_11894125","title":"Molecular cloning and expression of proto-oncogene FRAT1 in human cancer.","date":"2002","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11894125","citation_count":76,"is_preprint":false},{"pmid":"11445844","id":"PMC_11445844","title":"FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are up-regulated in gastric cancer.","date":"2001","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11445844","citation_count":76,"is_preprint":false},{"pmid":"15699046","id":"PMC_15699046","title":"Interaction between LRP5 and Frat1 mediates the activation of the Wnt canonical pathway.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15699046","citation_count":62,"is_preprint":false},{"pmid":"28340489","id":"PMC_28340489","title":"MiR-34a-3p alters proliferation and apoptosis of meningioma cells in vitro and is directly targeting SMAD4, FRAT1 and BCL2.","date":"2017","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/28340489","citation_count":41,"is_preprint":false},{"pmid":"18498136","id":"PMC_18498136","title":"FRAT1 overexpression leads to aberrant activation of beta-catenin/TCF pathway in esophageal squamous cell carcinoma.","date":"2008","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18498136","citation_count":33,"is_preprint":false},{"pmid":"10534617","id":"PMC_10534617","title":"In vivo analysis of Frat1 deficiency suggests compensatory activity of Frat3.","date":"1999","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/10534617","citation_count":31,"is_preprint":false},{"pmid":"31788970","id":"PMC_31788970","title":"LncRNA SNHG1 influences cell proliferation, migration, invasion, and apoptosis of non-small cell lung cancer cells via the miR-361-3p/FRAT1 axis.","date":"2019","source":"Thoracic 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FRAT2.","date":"2002","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12095675","citation_count":25,"is_preprint":false},{"pmid":"20041315","id":"PMC_20041315","title":"FRAT1 expression and its correlation with pathologic grade, proliferation, and apoptosis in human astrocytomas.","date":"2009","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20041315","citation_count":24,"is_preprint":false},{"pmid":"23613813","id":"PMC_23613813","title":"Knockdown of FRAT1 expression by RNA interference inhibits human glioblastoma cell growth, migration and invasion.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23613813","citation_count":24,"is_preprint":false},{"pmid":"36153370","id":"PMC_36153370","title":"The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer 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Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/25387569","citation_count":9,"is_preprint":false},{"pmid":"1561099","id":"PMC_1561099","title":"Molecular cloning and sequencing of the attachment site and integrase gene of the temperate mycobacteriophage FRAT1.","date":"1992","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1561099","citation_count":9,"is_preprint":false},{"pmid":"26893843","id":"PMC_26893843","title":"Silencing of FRAT1 by siRNA inhibits the proliferation of SGC7901 human gastric adenocarcinoma cells.","date":"2016","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/26893843","citation_count":7,"is_preprint":false},{"pmid":"35059733","id":"PMC_35059733","title":"FRAT1 promotes the angiogenic properties of human glioblastoma cells via VEGFA.","date":"2022","source":"Molecular medicine 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Cancer","date":"2025-03-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.25.645248","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18891,"output_tokens":4063,"usd":0.058809,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11778,"output_tokens":4625,"usd":0.087258,"stage2_stop_reason":"end_turn"},"total_usd":0.146067,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Frat1 was identified as a proto-oncogene that collaborates with Pim1 and Myc in T-cell lymphoma progression; retroviral overexpression of Frat1 conferred selective in vivo growth advantage to tumor cells already expressing high Myc and Pim1, establishing Frat1 as a progression gene in lymphomagenesis.\",\n      \"method\": \"Retroviral insertional mutagenesis, proviral tagging, Frat1-IRES-lacZ retroviral overexpression in tumor cell lines transplanted in vivo\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo retroviral overexpression with defined phenotypic readout, single lab but multiple tumor models\",\n      \"pmids\": [\"9034327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Frat1 interacts with both Dvl and GSK3, and can be recruited into a quaternary Dvl-Axin-GSK3-Frat1 complex. Wnt-1 signaling promotes disintegration of this complex, leading to dissociation of GSK3 from Axin, suggesting Frat1 mediates GSK3 displacement from Axin downstream of Dvl.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative domain overexpression, LEF-1 luciferase reporter assay in mammalian cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional reporter assays, replicated across mammalian and Xenopus systems in same study\",\n      \"pmids\": [\"10428961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A peptide from FRAT1 (FRATtide, residues 188-226) binds GSK3 and selectively blocks GSK3-catalysed phosphorylation of Axin and beta-catenin (Axin-dependent substrates) without suppressing GSK3 activity toward glycogen synthase or eIF2B (priming-dependent substrates), demonstrating substrate-selective inhibition of GSK3 by FRAT1.\",\n      \"method\": \"In vitro GSK3 kinase assay with FRATtide peptide against multiple substrates; direct binding assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted kinase assay with defined peptide and multiple substrates, substrate-selectivity rigorously demonstrated\",\n      \"pmids\": [\"10481074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Frat1-deficient mice are normal and fertile, with no developmental phenotype; a second mouse gene Frat3 shares overlapping expression patterns with Frat1 and can also induce a secondary axis in Xenopus embryos, suggesting functional redundancy compensates for Frat1 loss.\",\n      \"method\": \"Frat1 knockout mouse (beta-galactosidase knock-in), LacZ reporter expression analysis, Xenopus axis induction assay\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with in vivo phenotype assessment and Xenopus functional assay, single lab\",\n      \"pmids\": [\"10534617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Transgenic overexpression of Frat1 in mice causes focal glomerulosclerosis and nephrotic syndrome, and markedly accelerates M-MuLV-induced lymphomagenesis in combination with Pim1, providing direct in vivo evidence that Frat1 promotes lymphoma progression.\",\n      \"method\": \"Frat1 transgenic mouse generation, M-MuLV infection, tumor incidence analysis, Frat1/Pim1 bitransgenic crosses\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with defined phenotypic readout, single lab\",\n      \"pmids\": [\"10557087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Adenoviral overexpression of FRAT1 in PC12 cells confers neuroprotection and inhibits GSK-3 activity toward Tau and beta-catenin but does not affect GSK-3-mediated phosphorylation of glycogen synthase, confirming substrate-selective GSK-3 inhibition by FRAT1 in a cellular context.\",\n      \"method\": \"Adenoviral FRAT1 overexpression in PC12 cells, GSK-3 substrate phosphorylation assays (Tau, beta-catenin, glycogen synthase), cell survival assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cellular overexpression with multiple substrate readouts, single lab, consistent with in vitro data\",\n      \"pmids\": [\"11696357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"When transiently overexpressed in COS-1 cells, both hFRAT1 and hFRAT2 proteins localize to the cytosol and are concentrated in the nucleus.\",\n      \"method\": \"Transient transfection in COS-1 cells, subcellular fractionation/localization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization experiment without functional follow-up, single lab\",\n      \"pmids\": [\"12095675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CKI epsilon phosphorylates Dvl-1 and enhances the binding of Dvl-1 to Frat-1; depletion of CKI epsilon by RNAi inhibits Wnt-3a-induced Dvl phosphorylation, reduces Dvl-1/Frat-1 complex formation, and decreases Wnt-3a-induced beta-catenin accumulation, placing CKI epsilon upstream of the Dvl-Frat-1 interaction in Wnt signaling.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown of CKI epsilon in HeLa S3 cells, Tcf-4 luciferase reporter assay, beta-catenin accumulation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus RNAi epistasis plus reporter assay, multiple orthogonal methods\",\n      \"pmids\": [\"12556519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Expression of a FRAT1 peptide in swAPP(751) cells increases phosphorylation of GSK3alpha (Ser21) and GSK3beta (Ser9), inhibits kinase activity of both isoforms, and significantly decreases production of total Abeta and Abeta(1-42).\",\n      \"method\": \"Cellular expression of FRAT1 peptide in swAPP(751) cells, GSK3 kinase activity assay, ELISA for Abeta\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cellular functional assay with kinase activity readout and Abeta quantification, single lab\",\n      \"pmids\": [\"14572648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Frat1 interacts with the cytoplasmic domain of LRP5 (identified by yeast two-hybrid, confirmed by co-IP); Wnt3a or constitutively active LRP5 recruits Frat1 to the cell membrane; LRP5, Frat1, and Axin co-immunoprecipitate, suggesting a membrane-proximal complex in which Frat1 inhibits GSK3 to promote beta-catenin nuclear translocation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, cell membrane recruitment assay, TCF-1 luciferase reporter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, functional reporter assay, single lab\",\n      \"pmids\": [\"15699046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FRAT1 is phosphorylated at Ser188 in vitro and in intact cells by protein kinase A (PKA); activation of endogenous beta-adrenergic receptors with norepinephrine stimulates Ser188 phosphorylation; PKA-mediated Ser188 phosphorylation inhibits FRAT1's ability to activate beta-catenin-dependent transcription. GSK-3 can phosphorylate FRAT1 at Ser188 in vitro but does not significantly phosphorylate endogenous FRAT1 in cells.\",\n      \"method\": \"In vitro PKA kinase assay, phospho-site mapping by mass spectrometry, norepinephrine stimulation in intact cells, beta-catenin-dependent transcription reporter assay, GSK-3 in vitro kinase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus intact cell stimulation plus functional reporter, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"16982607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FRAT1 overexpression in esophageal squamous cell carcinoma cells induces nuclear accumulation of beta-catenin and promotes beta-catenin/TCF transcriptional activity; these effects are reversed by co-expression of GSK3beta or dominant-negative TCF4; continued c-Myc expression is required for maintenance of the FRAT1-driven growth state.\",\n      \"method\": \"FRAT1 overexpression/RNAi in ESCC cells, beta-catenin localization by immunofluorescence, TCF reporter assay, co-expression rescue experiments\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with mechanistic rescue experiments, single lab\",\n      \"pmids\": [\"18498136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NDRG1 upregulates FRAT1 expression, which prevents association of GSK3beta with the Axin1-APC-CK1 destruction complex, thereby inhibiting beta-catenin phosphorylation at Ser33/37 and Thr41 and increasing non-phosphorylated beta-catenin at the plasma membrane in prostate and colon cancer cells.\",\n      \"method\": \"Western blotting for phospho-beta-catenin, co-immunoprecipitation of destruction complex components, siRNA knockdown/overexpression of NDRG1 and FRAT1\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of destruction complex, phospho-site-specific antibody readout, multiple cell lines, single lab\",\n      \"pmids\": [\"24829151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FRAT1 is a direct target of miR-34a-3p; co-expression of miR-34a-3p with a reporter construct containing the FRAT1 3'UTR reduces luciferase activity, and disruption of the miR-34a-3p binding site in the FRAT1 3'UTR abolishes this regulation. In meningioma cells, miR-34a-3p overexpression decreases FRAT1 protein levels.\",\n      \"method\": \"Dual luciferase reporter assay with 3'UTR constructs and mutant binding sites, Western blotting after miR-34a-3p overexpression/inhibition\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase assay with mutation rescue, confirmed at protein level by Western blot, single lab\",\n      \"pmids\": [\"28340489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FRAT1 and FRAT2 physically interact with each other; siRNA-mediated knockdown of FRAT2 in FRAT1-overexpressing gastric cancer cells reverses FRAT1-driven invasion, indicating the FRAT1-FRAT2 complex is required for maximal pro-invasive activity. miR-3648 directly targets FRAT1 and FRAT2 to inactivate Wnt/beta-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation of FRAT1-FRAT2, siRNA knockdown, invasion assays, dual-luciferase miRNA target validation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue experiment, in vitro and in vivo, single lab\",\n      \"pmids\": [\"36153370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"siRNA knockdown of FRAT1 in glioblastoma U251 cells reduces mRNA and protein levels of VEGFA and decreases secreted VEGFA concentration, suppressing tube formation in an angiogenesis assay, linking FRAT1 activity through Wnt/beta-catenin signaling to VEGFA-mediated angiogenesis.\",\n      \"method\": \"siRNA knockdown, RT-qPCR, Western blotting, ELISA for secreted VEGFA, in vitro tube formation assay\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown with functional readout but no direct mechanistic link established; single lab, no epistasis\",\n      \"pmids\": [\"35059733\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FRAT1 is a substrate-selective inhibitor of GSK-3 that binds GSK-3 (via residues 188-226) and prevents its Axin-dependent phosphorylation of beta-catenin, while sparing priming-dependent GSK-3 substrates such as glycogen synthase; it is recruited into a quaternary Dvl-Axin-GSK3-Frat1 complex downstream of Wnt/LRP5 receptor activation (facilitated by CKI epsilon-mediated Dvl phosphorylation), and upon Wnt stimulation promotes GSK3 dissociation from Axin, allowing beta-catenin accumulation and TCF/LEF-dependent transcription; FRAT1 activity is itself regulated by PKA phosphorylation at Ser188, which inhibits its ability to activate beta-catenin-dependent transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FRAT1 is a positive regulator of Wnt/beta-catenin signaling that acts as a substrate-selective inhibitor of GSK-3 [#2, #5]. A FRAT1 peptide (residues 188-226, \\\"FRATtide\\\") binds GSK-3 and blocks its phosphorylation of Axin-dependent substrates such as beta-catenin and Tau while sparing priming-dependent substrates like glycogen synthase and eIF2B, defining the molecular basis of its selectivity [#2, #5]. Within the Wnt pathway, FRAT1 binds both Dishevelled and GSK-3 and is recruited into a quaternary Dvl-Axin-GSK3-Frat1 complex; Wnt-1 stimulation disintegrates this complex and dissociates GSK-3 from Axin, allowing beta-catenin to accumulate [#1, #12]. Recruitment is organized at the membrane: FRAT1 binds the cytoplasmic tail of the Wnt co-receptor LRP5 and is drawn to the plasma membrane upon Wnt3a stimulation [#9], and the Dvl-Frat1 interaction is licensed by CKI-epsilon-mediated phosphorylation of Dvl [#7]. By preventing GSK-3 from associating with the Axin1-APC-CK1 destruction complex, FRAT1 reduces beta-catenin phosphorylation at Ser33/37/Thr41 and drives its nuclear accumulation and TCF/LEF-dependent transcription [#11, #12]. FRAT1 activity is constrained by PKA, which phosphorylates it at Ser188 to suppress its ability to activate beta-catenin-dependent transcription [#10]. Functionally, FRAT1 is an oncogenic progression gene cooperating with Pim1 and Myc in lymphomagenesis [#0, #4] and promotes tumor cell invasion, angiogenesis, and beta-catenin/TCF activity in multiple carcinomas, with FRAT1-FRAT2 heterodimerization required for maximal pro-invasive activity [#11, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established FRAT1 as an oncogenic progression gene before its biochemical function was known, motivating the search for its mechanism.\",\n      \"evidence\": \"Retroviral insertional mutagenesis and Frat1 overexpression in T-cell lymphoma models in vivo\",\n      \"pmids\": [\"9034327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism linking Frat1 to tumor growth identified\", \"Pathway context unknown at this stage\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Placed FRAT1 within the Wnt pathway by showing it bridges Dvl and GSK3 and that Wnt signaling dissolves a Dvl-Axin-GSK3-Frat1 complex, explaining how FRAT1 relieves beta-catenin from GSK3.\",\n      \"evidence\": \"Co-immunoprecipitation, dominant-negative domains, and LEF-1 reporter assays in mammalian and Xenopus systems\",\n      \"pmids\": [\"10428961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise step at which GSK3 dissociates from Axin not resolved\", \"Stoichiometry of the quaternary complex undefined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the biochemical basis of FRAT1 action as substrate-selective GSK3 inhibition, distinguishing Axin-dependent from priming-dependent substrates.\",\n      \"evidence\": \"In vitro GSK3 kinase assays with the FRATtide peptide (residues 188-226) against beta-catenin, Axin, glycogen synthase, and eIF2B\",\n      \"pmids\": [\"10481074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of selectivity not determined\", \"Whether full-length FRAT1 behaves identically to the peptide not addressed here\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Tested the in vivo requirement for Frat1, revealing functional redundancy with Frat3 that masks a loss-of-function phenotype.\",\n      \"evidence\": \"Frat1 knockout mouse with LacZ knock-in and Xenopus axis-induction assays\",\n      \"pmids\": [\"10534617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy not formally proven by compound knockout\", \"Physiological Wnt context where Frat1 is non-redundant unidentified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Provided gain-of-function in vivo confirmation that Frat1 drives lymphoma progression and causes renal pathology.\",\n      \"evidence\": \"Frat1 transgenic mice, M-MuLV infection, and Frat1/Pim1 bitransgenic crosses\",\n      \"pmids\": [\"10557087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting Frat1 to glomerulosclerosis not defined\", \"Whether oncogenic effect requires beta-catenin not tested here\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Confirmed substrate-selective GSK3 inhibition in a cellular context and extended FRAT1 function to neuroprotection via reduced Tau phosphorylation.\",\n      \"evidence\": \"Adenoviral FRAT1 overexpression in PC12 cells with substrate phosphorylation and survival assays\",\n      \"pmids\": [\"11696357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct neuronal relevance beyond PC12 cells not established\", \"Mechanism of survival benefit not dissected\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified CKI-epsilon as an upstream licensing kinase that phosphorylates Dvl to promote the Dvl-Frat1 interaction and downstream beta-catenin accumulation.\",\n      \"evidence\": \"Co-IP, CKI-epsilon RNAi epistasis, and Tcf-4 reporter assays in HeLa S3 cells\",\n      \"pmids\": [\"12556519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-residues on Dvl mediating Frat1 binding not mapped\", \"Direct versus indirect effect on complex assembly not fully separated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected FRAT1-mediated GSK3 inhibition to reduced amyloid-beta production, implicating the pathway in Alzheimer-relevant processing.\",\n      \"evidence\": \"FRAT1 peptide expression in swAPP(751) cells with GSK3 kinase activity assays and Abeta ELISA\",\n      \"pmids\": [\"14572648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GSK3 inhibition to Abeta reduction not detailed\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Localized FRAT1 recruitment to the Wnt receptor by demonstrating direct interaction with the LRP5 cytoplasmic domain and Wnt-induced membrane recruitment.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, membrane recruitment assays, and TCF-1 reporter\",\n      \"pmids\": [\"15699046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LRP5 binding is required for GSK3 inhibition not isolated\", \"Order of LRP5, Frat1, Axin assembly undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a regulatory input controlling FRAT1 itself, showing PKA phosphorylation at Ser188 dampens its beta-catenin-activating function.\",\n      \"evidence\": \"In vitro PKA kinase assay, phospho-site mass spectrometry, norepinephrine stimulation, and beta-catenin reporter assays\",\n      \"pmids\": [\"16982607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser188 phosphorylation alters GSK3 binding not mechanistically resolved\", \"Physiological contexts engaging this regulation not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that FRAT1 drives beta-catenin/TCF transcription and a c-Myc-dependent growth state in carcinoma, with GSK3beta as the antagonized node.\",\n      \"evidence\": \"FRAT1 gain/loss-of-function in ESCC cells with GSK3beta and dominant-negative TCF4 rescue\",\n      \"pmids\": [\"18498136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical block of GSK3 in these cells not shown\", \"Generality across tumor types not tested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Refined the mechanism to show FRAT1 prevents GSK3beta association with the Axin1-APC-CK1 destruction complex, blocking beta-catenin Ser33/37/Thr41 phosphorylation.\",\n      \"evidence\": \"Phospho-specific Western blotting, destruction-complex co-IP, and NDRG1/FRAT1 knockdown/overexpression in prostate and colon cancer cells\",\n      \"pmids\": [\"24829151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which NDRG1 upregulates FRAT1 not defined\", \"Direct contact preventing GSK3-complex association not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified post-transcriptional control of FRAT1 by miR-34a-3p, providing a route to modulate FRAT1 levels.\",\n      \"evidence\": \"Dual-luciferase 3'UTR reporter with binding-site mutation and Western blot in meningioma cells\",\n      \"pmids\": [\"28340489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence on Wnt output in this context not shown\", \"Other regulatory miRNAs not surveyed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established FRAT1-FRAT2 heterodimerization as required for maximal pro-invasive activity and identified miR-3648 as a dual regulator.\",\n      \"evidence\": \"Co-IP, FRAT2 siRNA rescue, invasion assays, and miRNA target validation in gastric cancer cells\",\n      \"pmids\": [\"36153370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of FRAT1-FRAT2 interaction unknown\", \"Whether heterodimer alters GSK3 inhibition not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked FRAT1 to tumor angiogenesis via VEGFA expression in glioblastoma cells.\",\n      \"evidence\": \"siRNA knockdown with RT-qPCR, Western blot, VEGFA ELISA, and tube formation assay in U251 cells\",\n      \"pmids\": [\"35059733\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No epistasis establishing a direct Wnt/beta-catenin-to-VEGFA mechanism\", \"Single cell line, knockdown-only evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural mechanism by which FRAT1 confers substrate selectivity on GSK3 and how Ser188 phosphorylation, LRP5 binding, and FRAT1-FRAT2 heterodimerization are integrated to control GSK3 release from Axin remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the FRAT1-GSK3 complex in the timeline\", \"Integration of regulatory inputs into a single quantitative model not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 4, 11]}\n    ],\n    \"complexes\": [\n      \"Dvl-Axin-GSK3-Frat1 complex\",\n      \"FRAT1-FRAT2 heterodimer\"\n    ],\n    \"partners\": [\n      \"GSK3B\",\n      \"DVL1\",\n      \"AXIN1\",\n      \"LRP5\",\n      \"CSNK1E\",\n      \"FRAT2\",\n      \"PRKACA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}