{"gene":"BTRC","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":1999,"finding":"β-TrCP directly binds phosphorylated β-catenin through its WD40 repeat domain in a GSK3β phosphorylation-dependent manner, forming part of an SCF E3 ubiquitin ligase complex (with Skp1 and Cul1) that targets β-catenin for proteasomal degradation; overexpression of wild-type β-TrCP promotes β-catenin downregulation, while a dominant-negative deletion mutant upregulates β-catenin and activates Tcf-dependent signaling.","method":"Direct binding assay, Co-IP from mammalian cells, dominant-negative overexpression, β-catenin stability assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding established, Co-IP from endogenous proteins, functional mutagenesis, replicated across multiple independent labs in the same year","pmids":["10074433"],"is_preprint":false},{"year":1999,"finding":"FWD1 (mouse homolog of β-TrCP) forms a multi-molecular complex with β-catenin, Axin, GSK-3β, and APC; phosphorylation at the N-terminal signal-induced sites of β-catenin is required for FWD1 association; FWD1 facilitates ubiquitination and proteasomal degradation of β-catenin as part of the SCF(FWD1) ubiquitin ligase.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, dominant-negative overexpression, β-catenin stability assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods, reconstitution of ubiquitination in vitro, replicated across labs","pmids":["10228155"],"is_preprint":false},{"year":1999,"finding":"Human β-TrCP associates with Skp1 and Cul1 to form a novel SCF ubiquitin ligase complex, and interacts with β-catenin in vivo; expression of a dominant-negative β-TrCP stabilizes β-catenin.","method":"Co-immunoprecipitation, dominant-negative overexpression","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, replicated by multiple labs","pmids":["10023660"],"is_preprint":false},{"year":1999,"finding":"β-TrCP (FWD1) specifically recognizes the doubly phosphorylated DSGψXS motif in IκBα; an F-box-deleted β-TrCP inhibits IκBα degradation; β-TrCP mediates ubiquitination of phosphorylated IκBα in vitro and in cells, enabling NF-κB nuclear translocation.","method":"Co-IP (phosphorylation-dependent), dominant-negative overexpression, in vitro ubiquitination, NF-κB reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination reconstituted, phospho-dependent interaction established, replicated","pmids":["10097128"],"is_preprint":false},{"year":1999,"finding":"β-TrCP interacts specifically with phosphorylated IκBα (Ser32/Ser36) but not unmodified or phosphorylation-deficient IκBα; F-box deletion abolishes ability to ubiquitinate IκBα; β-TrCP is the adaptor for IκBα recognition by SCFβTrCP E3 complex.","method":"Co-IP (phosphorylation-dependent), dominant-negative expression, NF-κB transcription assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-dependent Co-IP established, F-box mutagenesis, replicated across labs","pmids":["10075690"],"is_preprint":false},{"year":1999,"finding":"β-Trcp negatively regulates Wnt/β-catenin signaling and dorsal axis formation in Xenopus; phosphorylated β-catenin is specifically recognized by β-Trcp; inhibition of endogenous β-Trcp by dominant-negative mutant stabilizes β-catenin, activates Wnt signaling, and induces axis duplication.","method":"Xenopus embryo injection, dominant-negative overexpression, co-IP","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo epistasis in Xenopus, phospho-mutant rescue, replicated","pmids":["10339577"],"is_preprint":false},{"year":1999,"finding":"FWD1/β-TrCP recognizes the conserved DSGψXS phospho-motif in IκBα, IκBβ, and IκBε; phosphorylation of both conserved serines is required for FWD1-mediated ubiquitination of all three IκB proteins; the D31A mutation in IκBα abolishes FWD1 binding without affecting phosphorylation.","method":"Co-IP, in vitro ubiquitination, site-directed mutagenesis, degradation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of degron, in vitro ubiquitination, multiple substrates tested","pmids":["10497169","10514433"],"is_preprint":false},{"year":1999,"finding":"β-TrCP interacts specifically with IκBβ in a manner dependent on phosphorylation of serines 19 and 23; F-box deletion abolishes β-TrCP-mediated ubiquitination of IκBβ.","method":"Co-IP, ubiquitination assay, dominant-negative mutant","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-dependent Co-IP, F-box mutagenesis, single lab","pmids":["10514424"],"is_preprint":false},{"year":2001,"finding":"β-TrCP controls ATF4 stability by binding ATF4 in a phosphorylation-dependent manner (requiring Ser219 in a DSGXXXS motif); an F-box-deleted β-TrCP acts as dominant-negative to inhibit ATF4 ubiquitination and degradation, thereby enhancing ATF4-dependent cAMP-mediated transcription; β-TrCP and ATF4 are co-localized in the nucleus.","method":"Co-IP, dominant-negative overexpression, ubiquitination assay, luciferase reporter, subcellular localization","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-dependent interaction, ubiquitination demonstrated, nuclear co-localization shown, single lab","pmids":["11238952"],"is_preprint":false},{"year":2001,"finding":"IKKβ directly phosphorylates NF-κB1 p105 at C-terminal serines 923 and 927 (within a DSGψ-like motif), and this phosphorylation recruits both β-TrCP1 and β-TrCP2 for polyubiquitination and complete proteasomal degradation of p105.","method":"In vitro kinase assay, Co-IP, RNAi knockdown, ubiquitination assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, phospho-dependent Co-IP, RNAi validation, multiple orthogonal methods","pmids":["11158290"],"is_preprint":false},{"year":2003,"finding":"Crystal structure (3.0 Å) of a β-TrCP1-Skp1-β-catenin complex reveals the basis of substrate recognition by the β-TrCP1 WD40 domain binding the doubly phosphorylated DpSGφXpS destruction motif; ubiquitination efficiency is determined by lysine-to-destruction motif spacing, confirmed by in vitro ubiquitination of mutant β-catenin peptides.","method":"X-ray crystallography, in vitro ubiquitination assay with mutant peptides","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by in vitro mutagenesis and ubiquitination assay","pmids":["12820959"],"is_preprint":false},{"year":2003,"finding":"β-TrCP is the F-box protein of SCF that targets phosphorylated Cdc25A for ubiquitin-mediated proteasomal degradation during S phase and in response to DNA damage; siRNA knockdown of both β-TrCP1 and β-TrCP2 prevents Cdc25A degradation induced by ionizing radiation and causes radioresistant DNA synthesis, indicative of an intra-S-phase checkpoint defect.","method":"siRNA knockdown, ubiquitination assay, DNA damage checkpoint assay (radioresistant DNA synthesis)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi knockdown of both paralogs, checkpoint phenotype confirmed, mechanism established","pmids":["14603323"],"is_preprint":false},{"year":2003,"finding":"β-TrCP1 knockout mice display defects in meiotic progression (accumulation of metaphase I spermatocytes) and mitotic defects in MEFs including centrosome overduplication, multipolar spindles, and misaligned chromosomes; Emi1 is a bona fide substrate of β-TrCP1; stabilization of β-catenin and IκBα requires silencing of both β-TrCP1 and β-TrCP2.","method":"Gene knockout mice, siRNA, substrate stability assay, cell biology (centrosome counting)","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus siRNA complementation, multiple cellular phenotypes, Emi1 substrate validated","pmids":["12791266"],"is_preprint":false},{"year":2003,"finding":"Emi1 is phosphorylated by Cdc2 on a DSGxxS consensus site and is subsequently recognized and ubiquitinated by SCF(βTrCP/Slimb), leading to its destruction in prophase; failure of βTrCP-dependent Emi1 destruction stabilizes APC substrates and results in mitotic catastrophe including centrosome overduplication.","method":"Co-IP, ubiquitination assay, phospho-mutant analysis, centrosome overduplication assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-dependent binding, ubiquitination assay, functional consequence (centrosome overduplication), replicated","pmids":["12791267"],"is_preprint":false},{"year":2003,"finding":"β-TrCP1-deficient MEFs show impaired (but not abolished) degradation of IκBα and IκBβ, reduced NF-κB nuclear translocation and transcriptional activity, and altered β-catenin subcellular localization; β-TrCP1 knockout MEFs display reduced proliferation, increased cell size, and increased polyploidy.","method":"Gene knockout mice, immunofluorescence, NF-κB reporter, FACS","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic readouts","pmids":["12843402"],"is_preprint":false},{"year":2003,"finding":"FWD1/β-TrCP mediates ubiquitination and proteasomal degradation of the circadian clock protein FREQUENCY (FRQ) in Neurospora; FRQ and FWD1 interact physically in vivo; fwd1 disruption results in accumulation of hyperphosphorylated FRQ and abolishes circadian rhythms.","method":"Co-IP in vivo, genetic disruption, circadian reporter assay, FRQ stability assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — physical interaction, genetic KO phenotype, circadian readout, multiple methods","pmids":["12941694"],"is_preprint":false},{"year":2003,"finding":"β-TrCP binding and processing of NF-κB1 p105 requires IKK-mediated phosphorylation at serines 927 and 932; βTrCP RNAi blocks TNF-α-induced p105 ubiquitination and proteolysis; βTrCP affinity for doubly phosphorylated p105 is substantially lower than for IκBα, contributing to delayed p105 proteolysis.","method":"RNAi knockdown, phosphopeptide competition, in vitro kinase assay, ubiquitination assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, RNAi, phosphopeptide competition, multiple orthogonal methods","pmids":["12482991"],"is_preprint":false},{"year":2003,"finding":"HIV-1 Vpu sequesters β-TrCP in the cytoplasm by binding through its phosphorylated DS52GXXS56 motif, acting as a competitive inhibitor that prevents β-TrCP-mediated degradation of endogenous substrates (β-catenin, IκBα, ATF4, Emi1, Cdc25A) and excludes β-TrCP from the nucleus.","method":"GFP fusion imaging, substrate stability assay, dominant-negative competition","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization with functional consequence, multiple substrates tested, single lab","pmids":["14561767"],"is_preprint":false},{"year":2004,"finding":"Hierarchical phosphorylation of Cdc25A commits it to β-TrCP-dependent degradation: Chk1-dependent phosphorylation at Ser76 is a priming step required for subsequent phosphorylation at Ser82 within the DSG motif, which anchors Cdc25A to β-TrCP.","method":"Phospho-site mutagenesis, Co-IP, degradation assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of sequential phospho-sites, Co-IP, single lab","pmids":["14752276"],"is_preprint":false},{"year":2004,"finding":"SCF(β-TrCP1) ubiquitinates and destabilizes Smad4; β-TrCP1 interacts with Smad4 in yeast two-hybrid and mammalian cells but not Smad2, and weakly with Smad3 only through Smad4; ectopic SCF(β-TrCP1) induces Smad4 ubiquitination and degradation, inhibiting TGF-β transcriptional responses.","method":"Yeast two-hybrid, Co-IP, ubiquitination assay, siRNA, TGF-β reporter","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods, yeast two-hybrid plus mammalian Co-IP, single lab","pmids":["14988407"],"is_preprint":false},{"year":2005,"finding":"β-TrCP binding and ubiquitination of NF-κB2/p100 requires NIK/IKKα-dependent phosphorylation of p100 at serines 866 and 870; mutation of either serine abolishes β-TrCP recruitment and ubiquitination of p100.","method":"Co-IP, phospho-mutant analysis, in vivo ubiquitination assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-mutant Co-IP, ubiquitination assay, single lab","pmids":["16303288"],"is_preprint":false},{"year":2006,"finding":"β-TrCP2 directly binds Gli2 and promotes its ubiquitination and degradation; single amino acid substitution in the Gli2 β-TrCP binding site abolishes interaction, ubiquitination, and stabilizes Gli2 protein, leading to enhanced Gli-dependent transcription.","method":"Co-IP, ubiquitination assay, site-directed mutagenesis, transcriptional reporter","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding Co-IP, mutagenesis of binding motif, single lab","pmids":["16651270"],"is_preprint":false},{"year":2006,"finding":"S6K1-mediated phosphorylation of PDCD4 on Ser67 in response to mitogens recruits SCF(βTRCP) E3 ligase for ubiquitin-mediated proteasomal degradation of PDCD4; expression of a stable PDCD4 mutant unable to bind βTRCP inhibits translation of mRNAs with structured 5'UTRs, reduces cell size, and slows cell cycle progression.","method":"Kinase assay, Co-IP, ubiquitination assay, translation reporter, stable mutant overexpression, cell size measurement","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-dependent recruitment, ubiquitination shown, stable non-degradable mutant, multiple cellular readouts","pmids":["17053147"],"is_preprint":false},{"year":2006,"finding":"Wnt/β-catenin/Tcf signaling elevates βTrCP mRNA and protein expression in a Tcf-dependent manner, creating a negative feedback loop: increased βTrCP accelerates wild-type β-catenin degradation while also upregulating NF-κB transactivation without affecting IKK activity.","method":"Tcf reporter, mRNA analysis, β-catenin degradation assay, NF-κB reporter","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Tcf-dependent transcriptional induction shown, functional consequence on substrate degradation demonstrated, single lab","pmids":["10882123"],"is_preprint":false},{"year":2007,"finding":"β-TrCP (as part of SCF) mediates ubiquitination and proteasomal degradation of the erythropoietin receptor (Epo-R); β-TrCP binds via its WD40 domain to a novel recognition motif (the ubiquitin-dependent endocytosis motif) in Epo-R; mutation of Ser462 abolishes β-TrCP binding, Epo-R ubiquitination, and degradation, causing prolonged Epo-R signaling and hypersensitivity to Epo.","method":"Co-IP, siRNA knockdown, site-directed mutagenesis, receptor degradation/endocytosis assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, RNAi, functional signaling consequence, single lab","pmids":["17327410"],"is_preprint":false},{"year":2007,"finding":"GSK-3β associates with and phosphorylates Mcl-1 at Ser155/Ser159/Thr163, leading to association with β-TrCP and SCF(β-TrCP)-mediated ubiquitination and degradation of Mcl-1; a triple-alanine Mcl-1 mutant (3A) resists phosphorylation, is not ubiquitinated by β-TrCP, is more stable, and blocks GSK-3β-induced apoptosis.","method":"Co-IP, in vitro kinase assay, ubiquitination assay, phospho-mutant analysis, apoptosis assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, Co-IP, mutagenesis, ubiquitination reconstitution, functional apoptosis readout","pmids":["17387146"],"is_preprint":false},{"year":2007,"finding":"β-TrCP1 degradation of PER2 is required for mammalian circadian rhythm generation; β-TrCP1-interaction-deficient PER2 variants are dramatically stabilized and disrupt circadian rhythmicity when expressed; β-TrCP1 and β-TrCP2 both target PER2 via the m2 degron site in vitro.","method":"Dominant-negative β-TrCP, siRNA, PER2 mutant expression, circadian reporter assay","journal":"Journal of biological rhythms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA, dominant-negative, PER2 mutant, circadian readout, single lab","pmids":["17876059"],"is_preprint":false},{"year":2008,"finding":"Plk1, following Cdk1-dependent recruitment, phosphorylates a SCF(βTrCP) recognition site on hBora to trigger its ubiquitin-mediated destruction; Plk1 depletion causes massive hBora accumulation, Aurora A mislocalization, and centrosome maturation defects; co-depletion of hBora partially restores Aurora A localization and bipolar spindle formation.","method":"Co-IP, siRNA co-depletion, ubiquitination assay, immunofluorescence, epistasis","journal":"Chromosoma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-dependent recognition, ubiquitination, epistasis by co-depletion, single lab","pmids":["18521620"],"is_preprint":false},{"year":2008,"finding":"ERK-mediated phosphorylation of STAT1 at Ser727 targets it for proteasomal degradation by SCF(βTRCP); βTRCP binds wild-type STAT1 but not the non-phosphorylatable STAT1(S727A) mutant; silencing βTRCP or inhibiting ERK stabilizes STAT1.","method":"Co-IP, phospho-mutant analysis, siRNA, pharmacological ERK inhibition, STAT1 stability assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-dependent Co-IP, siRNA, pharmacological inhibition, single lab","pmids":["18378670"],"is_preprint":false},{"year":2009,"finding":"IKK2 phosphorylates p53 at Ser362 and Ser366, leading to p53 recruitment to and ubiquitination by β-TrCP1; this p53 degradation is independent of Mdm2; siRNA-mediated reduction of β-TrCP1 or dominant-negative β-TrCP1 enhances p53 stability; p53-S362A/S366A mutations reduce IKK2-mediated phosphorylation and β-TrCP1 association.","method":"Co-IP, siRNA, dominant-negative overexpression, phospho-mutant analysis, p53 stability assay, cell-cycle analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-dependent Co-IP, siRNA, mutagenesis, functional cell cycle readout, single lab","pmids":["19196987"],"is_preprint":false},{"year":2009,"finding":"BimEL is phosphorylated on three serine residues in a conserved degron by Rsk1/2 (promoted by prior Erk1/2-mediated phosphorylation of Ser69), enabling binding and degradation via βTrCP; a BimEL phosphorylation mutant unable to bind βTrCP is stabilized and potently induces apoptosis by the intrinsic mitochondrial pathway.","method":"Co-IP, phospho-mutant analysis, kinase assay, apoptosis assay, siRNA","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-dependent binding, kinase identification, stable mutant with functional apoptosis readout, multiple orthogonal methods","pmids":["19150432"],"is_preprint":false},{"year":2009,"finding":"USP47 is a novel interactor of both β-Trcp1 and β-Trcp2; binding requires the β-Trcp WD-repeat region (point mutations abolish binding); unlike canonical β-TrCP substrates, USP47 protein levels are not affected by β-Trcp silencing; depletion of USP47 causes Cdc25A accumulation and decreased cell survival.","method":"Co-IP, WD-repeat point mutagenesis, siRNA knockdown, cell viability assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis, functional knockdown phenotype, single lab","pmids":["19966869"],"is_preprint":false},{"year":2010,"finding":"Human Plk4 undergoes βTrCP-dependent proteasomal degradation; Plk4 trans-autophosphorylation within homodimers creates the βTrCP binding/recognition site, promoting Plk4's own degradation; kinase-dead Plk4 disrupts trans-autophosphorylation, shielding endogenous Plk4 from βTrCP recognition and causing centriole overduplication.","method":"Protein stability assay, Co-IP, kinase-dead mutant overexpression, centriole counting","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-dependent recognition, kinase-dead dominance experiment, centriole readout, single lab","pmids":["20516151"],"is_preprint":false},{"year":2011,"finding":"DEPTOR is a physiological substrate of SCF(βTrCP); upon growth factor stimulation, RSK1 and S6K1 phosphorylate DEPTOR's degron sequence, enabling βTrCP binding and ubiquitination/degradation; blocking βTrCP-dependent DEPTOR degradation (via knockdown or stable mutant) inhibits mTOR and activates AKT.","method":"Co-IP, siRNA, stable degron mutant, mTOR/AKT activity assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated by two independent groups (PMIDs 22017876 and 22017877), phospho-dependent binding, functional mTOR/AKT readouts","pmids":["22017876","22017877"],"is_preprint":false},{"year":2011,"finding":"mTOR auto-amplification loop: mTORC1/2-mediated priming phosphorylation followed by CK1α phosphorylation of a conserved degron in DEPTOR facilitates βTrCP binding and degradation; blocking this pathway via βTrCP knockdown or stable DEPTOR mutant results in mTOR inhibition.","method":"Co-IP, siRNA, stable degron mutant, CK1α kinase assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated independently, kinase hierarchy established, functional mTOR readout","pmids":["22017877"],"is_preprint":false},{"year":2011,"finding":"β-TrCP1 is mislocalized to the nucleus in glioblastoma (vs. cytoplasm in astrocytoma and normal brain), spatially separating it from its cytoplasmic substrate PHLPP1; restoring β-TrCP1 to the cytoplasm rescues the Akt-PHLPP1 negative feedback loop and β-catenin degradation.","method":"Subcellular fractionation, immunofluorescence, pharmacological/genetic manipulation of localization, functional Akt/PHLPP1 assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization tied to functional consequence, multiple cell lines, single lab","pmids":["21454620"],"is_preprint":false},{"year":2011,"finding":"βTrCP regulates BMI1 ubiquitination and proteasome-mediated degradation; overexpression of wild-type βTrCP but not ΔF mutant promotes BMI1 ubiquitination; BMI1 recognition motif mutation stabilizes BMI1, increases its pro-oncogenic activity.","method":"Co-IP, ubiquitination assay, ΔF mutant, recognition motif mutagenesis, cellular senescence assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, mutagenesis of binding site, single lab","pmids":["21430439"],"is_preprint":false},{"year":2012,"finding":"SCF(βTrCP) mediates proteasomal destruction of the deubiquitinase USP37 at the G2/M transition in a Plk1-dependent phosphorylation-dependent manner; USP37 interacts with βTrCP in a phospho-dependent manner; stabilization of a phospho-site mutant USP37 hinders the G2/M transition.","method":"Co-IP, siRNA, phospho-mutant analysis, cell-cycle analysis, Plk1 kinase assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-dependent Co-IP, Plk1 kinase upstream, cell-cycle functional readout, single lab","pmids":["23027877"],"is_preprint":false},{"year":2012,"finding":"β-TrCP1 targets HuR for ubiquitin-mediated proteasomal degradation upon metabolic stress (glycolysis inhibition); targeting requires PKCα-mediated Ser318 phosphorylation-dependent cytoplasmic translocation of HuR and IKKα-mediated phosphorylation at Ser304 in an unconventional β-TrCP1 recognition motif (EEAMAIAS).","method":"Co-IP, GST pull-down, ubiquitination assay, dominant-negative β-TrCP1, mutagenesis, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and GST pull-down, ubiquitination assay, mutagenesis, single lab","pmids":["23115237"],"is_preprint":false},{"year":2013,"finding":"SCFβ-TRCP mediates ubiquitination and proteasomal degradation of MTSS1; CK1δ phosphorylates Ser322 in the DSGXXS degron of MTSS1 to trigger β-TRCP interaction; depletion of Cullin 1 or β-TRCP1 increases MTSS1 levels; non-degradable MTSS1(S322A) shows stronger inhibition of cancer cell proliferation and migration.","method":"Co-IP, ubiquitination assay, CK1δ kinase assay, siRNA knockdown, functional migration/proliferation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-dependent Co-IP, kinase identified, ubiquitination assay, functional readout, single lab","pmids":["24318128"],"is_preprint":false},{"year":2014,"finding":"βTrCP controls lysosome-mediated degradation of CDK1; CDK1 is ubiquitinated by SCFβTrCP; DNA damage regulates βTrCP-induced CDK1 degradation in a cell-type-dependent manner.","method":"Ubiquitination assay, siRNA, lysosome inhibitor, DNA damage treatment","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ubiquitination assay and siRNA, but unconventional lysosomal degradation claim with limited mechanistic detail in abstract, single lab","pmids":["25149538"],"is_preprint":false},{"year":2015,"finding":"DNA damage triggers β-TRCP-dependent degradation of CReP (a PP1 regulatory subunit targeting eIF2α); depletion of CReP is required for full induction of eIF2α phosphorylation after DNA damage, reducing cap-dependent translation during recovery.","method":"Ligase Trapping (ubiquitin ligase-ubiquitin binding domain fusion), stable mutant CReP, eIF2α phosphorylation assay, translation assay","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel substrate trapping method with functional validation, stable CReP mutant, functional translation readout, single lab","pmids":["26091241"],"is_preprint":false},{"year":2016,"finding":"SAG/RBX2-CUL5 E3 ligase (with E2s UBCH10/UBE2S) ubiquitylates β-TrCP1 via atypical K11-linked polyubiquitin chains for proteasomal degradation; SAG and β-TrCP1 levels are inversely correlated; silencing UBCH10 or UBE2S (but not UBCH5C) causes β-TrCP1 accumulation.","method":"Co-IP, ubiquitination assay with linkage specificity, siRNA knockdown, protein stability assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemically defined K11 linkage, multiple E2 siRNA knockdowns, single lab","pmids":["27910872"],"is_preprint":false},{"year":2017,"finding":"β-TrCP targets DMRT1 for ubiquitylation and proteasomal degradation to control the mitosis-meiosis transition in mouse male germ cells; DMRT1 contains a consensus β-TrCP degron; conditional inactivation of β-TrCP2 in β-TrCP1 KO male germ cells results in sterility, failure to enter meiosis, and apoptosis; heterozygous deletion of Dmrt1 in β-TrCP-deficient spermatogonia partially rescues meiotic entry.","method":"Conditional knockout, Co-IP, ubiquitination assay, genetic epistasis (heterozygous Dmrt1 deletion), in vivo spermatogenesis analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with genetic epistasis, Co-IP, ubiquitination assay, in vivo phenotype","pmids":["28982686"],"is_preprint":false},{"year":2018,"finding":"β-TrCP recognizes cyclin F through a non-canonical TSGXXS degron (phosphorylated by casein kinase II) and mediates its degradation at the G2/M transition; this degradation is required for timely mitotic progression.","method":"Co-IP, phospho-mutant analysis, siRNA, CK2 kinase assay, cell-cycle analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — non-canonical degron identified, kinase identified, cell-cycle functional readout, single lab","pmids":["30257202"],"is_preprint":false},{"year":2018,"finding":"FOXN2 is ubiquitinated and degraded by β-Trcp in a manner requiring RSK2-mediated phosphorylation of Ser365 and Ser369 in a conserved DSGYAS motif; β-Trcp/RSK2-mediated FOXN2 degradation promotes tumorigenesis and radioresistance in lung cancer.","method":"Co-IP, ubiquitination assay, RSK2 kinase assay, phospho-mutant analysis, gain/loss-of-function in vitro and in vivo","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase identified, phospho-dependent Co-IP, ubiquitination assay, functional in vivo tumor assay, single lab","pmids":["29396548"],"is_preprint":false},{"year":2018,"finding":"TSPAN15 interacts specifically with BTRC to promote ubiquitination and proteasomal degradation of phosphorylated IκBα, triggering NF-κB nuclear translocation and transcription of metastasis-related genes (ICAM1, VCAM1, MMP9, etc.) in esophageal squamous cell carcinoma.","method":"Co-IP, ubiquitination assay, siRNA, NF-κB nuclear translocation assay, functional metastasis assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing TSPAN15-BTRC interaction, ubiquitination assay, functional NF-κB readout, single lab","pmids":["29650964"],"is_preprint":false},{"year":2019,"finding":"PARP11 mono-ADP-ribosylates β-TrCP; mono-ADP-ribosylation of β-TrCP promotes IFNAR1 ubiquitination and degradation, attenuating IFN-I antiviral signaling; PARP11 is upregulated by viral infection to promote this immune evasion mechanism.","method":"Co-IP, ADP-ribosylation assay, IFNAR1 stability assay, siRNA, mouse viral infection model","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical ADP-ribosylation assay, IFNAR1 ubiquitination assay, in vivo mouse model, multiple orthogonal methods","pmids":["30988430"],"is_preprint":false},{"year":2019,"finding":"ERAP1 binds USP47, displaces USP47-associated βTrCP, and promotes βTrCP degradation, leading to modulation of Gli transcription factors and enhancement of Hedgehog pathway activity; pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo.","method":"Co-IP, βTrCP stability assay, Gli reporter assay, pharmacological inhibition, in vivo tumor model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying displacement mechanism, βTrCP degradation assay, in vivo tumor model, single lab","pmids":["31341163"],"is_preprint":false},{"year":2019,"finding":"β-TrCP1 and β-TrCP2 are physiological substrates of SCF E3 ligase and mutually target each other for ubiquitination and degradation via their respective β-TrCP degron sequences; AMPK activated by glucose deprivation phosphorylates β-TrCP1, promoting its degradation by β-TrCP2 (but not vice versa); β-TrCP2 preferentially degrades DEPTOR and REDD1 (mTORC1 inhibitors) to activate mTORC1 and inhibit autophagy.","method":"Co-IP, ubiquitination assay, AMPK kinase assay, degron mutant analysis, autophagy assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutual degradation with degron mutant validation, kinase identified, functional mTOR/autophagy readout, single lab","pmids":["31406304"],"is_preprint":false},{"year":2021,"finding":"βTrCP is the E3 ligase for ubiquitination of transferrin receptor (TFRC); TRIB2 desensitizes cells to ferroptosis by facilitating βTrCP-mediated TFRC ubiquitination and degradation to decrease labile iron pools; βTrCP knockout abolishes TRIB2-mediated iron reduction and ferroptosis resistance.","method":"Co-IP, ubiquitination assay, βTrCP knockout, labile iron pool measurement, ferroptosis assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with KO rescue, functional ferroptosis readout, single lab","pmids":["34315867"],"is_preprint":false},{"year":2008,"finding":"Alternative splicing of β-TrCP1 produces isoforms where exon III insertion prevents Skp1 interaction and causes nuclear (vs. cytoplasmic) localization; exon-III-containing isoforms show reduced ability to antagonize Wnt/β-catenin signaling in Xenopus.","method":"Yeast two-hybrid, immunofluorescence of isoforms, Xenopus axis assay","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid, immunofluorescence, limited functional assay, single lab","pmids":["18929646"],"is_preprint":false},{"year":2005,"finding":"FGD1 (a Cdc42 GEF) is a substrate of SCF(FWD1/β-TrCP); recognition requires phosphorylation of conserved serines in the DSGIDS motif; a phosphorylation-deficient FGD1(SA) mutant does not interact with FWD1/β-TrCP, is more stable, and shows enhanced cell motility; co-expression of SCF(FWD1/β-TrCP) reduces FGD1(WT)-induced morphological changes but not those of FGD1(SA).","method":"Co-IP, ubiquitination assay, phospho-mutant analysis, cell morphology and motility assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-dependent Co-IP, ubiquitination, functional morphology/motility readout, single lab","pmids":["15743413"],"is_preprint":false},{"year":2002,"finding":"CK2-dependent phosphorylation of the E2 ubiquitin-conjugating enzyme UBC3B at Ser233 induces its interaction with β-TrCP; co-transfection of CK2α' with UBC3B (but not a C-terminal deletion) enhances β-catenin degradation.","method":"Yeast two-hybrid, Co-IP, in vitro phosphorylation, β-catenin degradation assay","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and yeast two-hybrid, functional consequence on β-catenin, single lab","pmids":["12037680"],"is_preprint":false},{"year":2016,"finding":"RVFV NSs interacts with both FBXW11 (β-TrCP2) and β-TrCP1 and recruits SCF E3 ligase complexes containing these F-box proteins to target the antiviral kinase PKR for proteasomal degradation; siRNA depletion of both paralogs is required for maximal PKR protection.","method":"siRNA screen of ~70 F-box proteins, Co-IP, PKR stability assay, viral replication assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide F-box siRNA screen identified β-TrCP1/2, Co-IP of NSs-βTrCP interaction, functional PKR stability readout, single lab","pmids":["27122577"],"is_preprint":false}],"current_model":"BTRC (β-TrCP1) functions as the substrate-recognition subunit (F-box/WD40 protein) of the SCF(β-TrCP) E3 ubiquitin ligase complex (with Skp1, Cul1, and Rbx1), binding doubly phosphorylated DSGψXS (or related) degron motifs on substrates including β-catenin, IκBα/β/ε, p105, p100, Cdc25A, Emi1, PDCD4, BimEL, Mcl-1, DEPTOR, PER2, hBora, Plk4, Gli2, Smad4, ATF4, STAT1, cyclin F, DMRT1, TFRC, and many others, targeting them for ubiquitin-proteasome-mediated degradation to regulate Wnt/β-catenin, NF-κB, DNA damage checkpoint, circadian clock, cell cycle, and apoptosis pathways; its activity is modulated by competing interactions (e.g., with HIV-1 Vpu, RASSF1C, TRIM67, Pin1), post-translational modifications of β-TrCP itself (PARP11 mono-ADP-ribosylation, AMPK-mediated phosphorylation, SAG/CUL5-mediated K11-ubiquitylation), and its subcellular localization (cytoplasmic vs. nuclear), with structural studies revealing that WD40-domain recognition of the phosphodegron and lysine-to-degron spacing together determine ubiquitination efficiency."},"narrative":{"mechanistic_narrative":"BTRC (β-TrCP1) is the substrate-recognition subunit of an SCF (Skp1–Cul1) E3 ubiquitin ligase that selectively binds doubly phosphorylated DSGψXS-type phosphodegrons through its WD40 repeat domain and marks the bound substrate for ubiquitin–proteasome degradation [PMID:10074433, PMID:10023660, PMID:12820959]. Its two best-defined functions establish the paradigm: it recognizes GSK3β-phosphorylated β-catenin within the Axin/APC/GSK-3β destruction complex to restrain Wnt/β-catenin signaling and dorsal axis formation [PMID:10074433, PMID:10228155, PMID:10339577], and it recognizes IKK-phosphorylated IκBα/β/ε at the conserved DSGψXS motif to license NF-κB nuclear translocation [PMID:10097128, PMID:10075690, PMID:10497169, PMID:10514433]. A 3.0 Å crystal structure of the β-TrCP1–Skp1–β-catenin complex defined how the WD40 domain reads the doubly phosphorylated motif and showed that ubiquitination efficiency is set by the spacing between the acceptor lysine and the degron [PMID:12820959]. The same recognition logic extends across pathways, where degron phosphorylation by a dedicated kinase commits substrates to destruction: IKK on p105/p100 [PMID:11158290, PMID:16303288], Chk1/Plk1/CK2 on cell-cycle regulators Cdc25A, Emi1, hBora, USP37, cyclin F and Plk4 [PMID:14603323, PMID:12791267, PMID:14752276, PMID:20516151, PMID:23027877, PMID:30257202], and growth-factor kinases (S6K1, RSK, CK1α) on the translational and mTOR regulators PDCD4 and DEPTOR [PMID:17053147, PMID:22017876, PMID:22017877]. Through these substrates BTRC governs the DNA-damage intra-S checkpoint, mitotic and centrosome integrity, circadian rhythm via PER2 degradation, mTOR/autophagy balance, and apoptosis via Mcl-1 and BimEL turnover [PMID:14603323, PMID:12791266, PMID:17387146, PMID:17876059, PMID:19150432, PMID:31406304]. Genetic ablation confirms physiological importance: β-TrCP1-knockout cells show impaired IκB and β-catenin handling with mitotic defects, and combined β-TrCP1/2 loss in male germ cells blocks the mitosis–meiosis transition through failed DMRT1 degradation [PMID:12791266, PMID:12843402, PMID:28982686]. BTRC activity is itself regulated by competition (HIV-1 Vpu sequestration), by post-translational modification of β-TrCP (PARP11 mono-ADP-ribosylation, AMPK phosphorylation, SAG/CUL5-mediated K11 ubiquitylation), and by cytoplasmic-versus-nuclear localization [PMID:14561767, PMID:27910872, PMID:30988430, PMID:31406304, PMID:21454620].","teleology":[{"year":1999,"claim":"Established BTRC as the substrate receptor of an SCF ligase that couples GSK3β phosphorylation of β-catenin to its destruction, answering how Wnt signaling controls β-catenin stability.","evidence":"Phospho-dependent direct binding and Co-IP with Skp1/Cul1, dominant-negative stabilization, and Xenopus axis assays across multiple labs","pmids":["10074433","10228155","10023660","10339577"],"confidence":"High","gaps":["Did not resolve atomic basis of phosphodegron recognition","Did not address how BTRC discriminates among many DSGψXS-bearing substrates"]},{"year":1999,"claim":"Identified the doubly phosphorylated DSGψXS degron as BTRC's recognition motif on IκBα/β/ε, explaining how IKK signaling triggers NF-κB activation through targeted IκB destruction.","evidence":"Phospho-dependent Co-IP, degron mutagenesis (D31A), in vitro ubiquitination, F-box deletion, and NF-κB reporters","pmids":["10097128","10075690","10497169","10514433","10514424"],"confidence":"High","gaps":["Relative affinity differences among IκB family members not yet quantified","Kinetics of degradation vs. processing not distinguished"]},{"year":2003,"claim":"A crystal structure provided the structural rule for substrate selection, showing the WD40 domain reads the doubly phosphorylated motif and that lysine-to-degron spacing dictates ubiquitination efficiency.","evidence":"X-ray crystallography of β-TrCP1–Skp1–β-catenin with in vitro ubiquitination of mutant peptides","pmids":["12820959"],"confidence":"High","gaps":["Structure limited to one substrate peptide; non-canonical degrons not structurally explained","Does not address full-length SCF architecture or processivity"]},{"year":2003,"claim":"Extended BTRC function to cell-cycle and checkpoint control, showing it degrades phospho-Cdc25A and Emi1 to enforce the intra-S checkpoint and prevent centrosome overduplication.","evidence":"siRNA of both paralogs, radioresistant DNA synthesis assays, knockout mice, in vitro ubiquitination, and centrosome counting","pmids":["14603323","12791266","12791267","12843402"],"confidence":"High","gaps":["Functional redundancy between β-TrCP1 and β-TrCP2 not fully partitioned","Tissue-specific substrate dependencies unresolved"]},{"year":2003,"claim":"Demonstrated the recognition paradigm is conserved across kingdoms and pathways, with BTRC homolog FWD1 degrading the circadian protein FRQ in Neurospora and BTRC controlling NF-κB1 p105 processing.","evidence":"Co-IP, genetic disruption with circadian readout, in vitro kinase assays, and phosphopeptide competition","pmids":["12941694","11158290","12482991"],"confidence":"High","gaps":["Why p105 affinity is lower than IκBα mechanistically unexplained at structural level"]},{"year":2009,"claim":"Showed BTRC integrates growth-factor and stress kinase signaling into protein turnover, degrading apoptotic and translational regulators (Mcl-1, BimEL, PDCD4) following GSK3β, RSK, ERK, and S6K1 phosphorylation.","evidence":"In vitro kinase assays, phospho-mutant binding, ubiquitination assays, and apoptosis/translation/cell-size readouts","pmids":["17387146","19150432","17053147"],"confidence":"High","gaps":["Hierarchy among competing substrates under a given stimulus not defined","Cellular context determining apoptotic vs. survival outcome unclear"]},{"year":2011,"claim":"Defined BTRC as a node in mTOR/AKT signaling by establishing DEPTOR as a physiological substrate whose phosphorylation-triggered degradation activates mTOR.","evidence":"Independently replicated Co-IP, siRNA, stable degron mutants, and mTOR/AKT activity assays","pmids":["22017876","22017877"],"confidence":"High","gaps":["Quantitative contribution of DEPTOR degradation to mTOR set-point not measured","Crosstalk with other mTOR-regulating substrates not resolved"]},{"year":2019,"claim":"Revealed BTRC is itself regulated post-translationally, with PARP11 mono-ADP-ribosylation promoting IFNAR1 degradation and AMPK phosphorylation driving β-TrCP1 degradation by β-TrCP2, linking paralog cross-regulation to immune signaling and mTOR/autophagy.","evidence":"ADP-ribosylation and ubiquitination assays, AMPK kinase assays, degron-mutant analysis, in vivo viral infection and autophagy readouts","pmids":["30988430","31406304"],"confidence":"Medium","gaps":["Stoichiometry and reversibility of β-TrCP modifications in vivo unclear","Mutual paralog degradation kinetics single-lab"]},{"year":2019,"claim":"Established competition and localization as additional regulatory layers, with viral and cellular proteins sequestering or displacing BTRC and isoform/localization changes redirecting its activity.","evidence":"Co-IP displacement, β-TrCP stability assays, subcellular fractionation, and in vivo tumor/localization models","pmids":["31341163","21454620","14561767"],"confidence":"Medium","gaps":["Endogenous physiological triggers for nuclear-cytoplasmic shuttling not fully defined","Quantitative competition among endogenous decoys not established"]},{"year":null,"claim":"How BTRC prioritizes among its large substrate repertoire within a single cell, and how degron affinity, localization, and self-regulation are integrated in real time, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative competition model across endogenous substrates","Substrate selection under simultaneous multi-pathway activation undefined","Distinct in vivo roles of β-TrCP1 vs β-TrCP2 incompletely separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,6,9,10]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,3,10,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,4,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17,35]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,35,51]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11,12,13,37,44]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4,9,47]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[15,26]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[25,30]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,10]}],"complexes":["SCF(β-TrCP) E3 ubiquitin ligase"],"partners":["SKP1","CUL1","CTNNB1","NFKBIA","USP47","DEPTOR","EMI1","PER2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y297","full_name":"F-box/WD repeat-containing protein 1A","aliases":["E3RSIkappaB","Epididymis tissue protein Li 2a","F-box and WD repeats protein beta-TrCP","pIkappaBalpha-E3 receptor subunit"],"length_aa":605,"mass_kda":68.9,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:10066435, PubMed:10497169, PubMed:10644755, PubMed:10835356, PubMed:11158290, PubMed:11238952, PubMed:11359933, PubMed:11994270, PubMed:12791267, PubMed:12902344, PubMed:14603323, PubMed:14681206, PubMed:14988407, PubMed:15448698, PubMed:15917222, PubMed:16371461, PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:22087322, PubMed:25503564, PubMed:25704143, PubMed:36608670, PubMed:9859996, PubMed:9990852). Recognizes and binds to phosphorylated target proteins (PubMed:10066435, PubMed:10497169, PubMed:10644755, PubMed:10835356, PubMed:11158290, PubMed:11238952, PubMed:11359933, PubMed:11994270, PubMed:12791267, PubMed:12902344, PubMed:14603323, PubMed:14681206, PubMed:14988407, PubMed:15448698, PubMed:15917222, PubMed:16371461, PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:22087322, PubMed:25503564, PubMed:25704143, PubMed:36608670, PubMed:9859996, PubMed:9990852). SCF(BTRC) mediates the ubiquitination of CTNNB1 and participates in Wnt signaling (PubMed:12077367, PubMed:12820959). SCF(BTRC) mediates the ubiquitination of phosphorylated NFKB1, ATF4, CDC25A, DLG1, FBXO5, PER1, SMAD3, SMAD4, SNAI1 and probably NFKB2 (PubMed:10835356, PubMed:11238952, PubMed:14603323, PubMed:14681206). SCF(BTRC) mediates the ubiquitination of NFKBIA, NFKBIB and NFKBIE; the degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription (PubMed:10066435, PubMed:10497169, PubMed:10644755, PubMed:9859996). Ubiquitination of NFKBIA occurs at 'Lys-21' and 'Lys-22' (PubMed:10066435). The SCF(FBXW11) complex also regulates NF-kappa-B by mediating ubiquitination of phosphorylated NFKB1: specifically ubiquitinates the p105 form of NFKB1, leading to its degradation (PubMed:10835356, PubMed:11158290, PubMed:14673179). SCF(BTRC) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis (PubMed:25503564, PubMed:25704143). SCF(BTRC) mediates the ubiquitination and subsequent degradation of nuclear NFE2L1 (By similarity). Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and PER2 (PubMed:15917222). May be involved in ubiquitination and subsequent proteasomal degradation through a DBB1-CUL4 E3 ubiquitin-protein ligase. Required for activation of NFKB-mediated transcription by IL1B, MAP3K14, MAP3K1, IKBKB and TNF. Required for proteolytic processing of GLI3 (PubMed:16371461). Mediates ubiquitination of REST, thereby leading to its proteasomal degradation (PubMed:18354482, PubMed:21258371). SCF(BTRC) mediates the ubiquitination and subsequent proteasomal degradation of KLF4; thereby negatively regulating cell pluripotency maintenance and embryogenesis (By similarity). SCF(BTRC) acts as a regulator of mTORC1 signaling pathway by catalyzing ubiquitination and subsequent proteasomal degradation of phosphorylated DEPTOR, TFE3 and MITF (PubMed:22017875, PubMed:22017876, PubMed:22017877, PubMed:33110214, PubMed:36608670). SCF(BTRC) directs 'Lys-48'-linked ubiquitination of UBR2 in the T-cell receptor signaling pathway (PubMed:38225265)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y297/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BTRC","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BTRC","total_profiled":1310},"omim":[{"mim_id":"619545","title":"HYPOPLASTIC FEMURS AND PELVIS; HYPOFP","url":"https://www.omim.org/entry/619545"},{"mim_id":"616889","title":"CENTROSOMAL PROTEIN, 68-KD; CEP68","url":"https://www.omim.org/entry/616889"},{"mim_id":"614460","title":"UBIQUITIN-SPECIFIC PROTEASE 47; USP47","url":"https://www.omim.org/entry/614460"},{"mim_id":"612506","title":"UBIQUITIN-CONJUGATING ENZYME E2 R2; UBE2R2","url":"https://www.omim.org/entry/612506"},{"mim_id":"609110","title":"F-BOX ONLY PROTEIN 43; FBXO43","url":"https://www.omim.org/entry/609110"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BTRC"},"hgnc":{"alias_symbol":["bTrCP","betaTrCP","FBXW1A","Fwd1","beta-TrCP1","bTrCP1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y297","domains":[{"cath_id":"1.20.1280.50","chopping":"186-286","consensus_level":"medium","plddt":91.3772,"start":186,"end":286},{"cath_id":"2.130.10.10","chopping":"290-587","consensus_level":"medium","plddt":97.1548,"start":290,"end":587}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y297","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y297-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y297-F1-predicted_aligned_error_v6.png","plddt_mean":79.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BTRC","jax_strain_url":"https://www.jax.org/strain/search?query=BTRC"},"sequence":{"accession":"Q9Y297","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y297.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y297/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y297"}},"corpus_meta":[{"pmid":"18500245","id":"PMC_18500245","title":"Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer.","date":"2008","source":"Nature reviews. Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18500245","citation_count":816,"is_preprint":false},{"pmid":"17053147","id":"PMC_17053147","title":"S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth.","date":"2006","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/17053147","citation_count":610,"is_preprint":false},{"pmid":"10074433","id":"PMC_10074433","title":"The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell.","date":"1999","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/10074433","citation_count":600,"is_preprint":false},{"pmid":"12820959","id":"PMC_12820959","title":"Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase.","date":"2003","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/12820959","citation_count":562,"is_preprint":false},{"pmid":"10228155","id":"PMC_10228155","title":"An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin.","date":"1999","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10228155","citation_count":481,"is_preprint":false},{"pmid":"10023660","id":"PMC_10023660","title":"The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10023660","citation_count":396,"is_preprint":false},{"pmid":"14603323","id":"PMC_14603323","title":"Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/14603323","citation_count":381,"is_preprint":false},{"pmid":"10339577","id":"PMC_10339577","title":"beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus axis formation.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10339577","citation_count":354,"is_preprint":false},{"pmid":"17387146","id":"PMC_17387146","title":"Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17387146","citation_count":335,"is_preprint":false},{"pmid":"12791266","id":"PMC_12791266","title":"Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo.","date":"2003","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/12791266","citation_count":327,"is_preprint":false},{"pmid":"12791267","id":"PMC_12791267","title":"Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase.","date":"2003","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/12791267","citation_count":302,"is_preprint":false},{"pmid":"15021890","id":"PMC_15021890","title":"The many faces of beta-TrCP E3 ubiquitin ligases: reflections in the magic mirror of cancer.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15021890","citation_count":285,"is_preprint":false},{"pmid":"22017876","id":"PMC_22017876","title":"DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase and regulates survival and autophagy.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22017876","citation_count":245,"is_preprint":false},{"pmid":"11238952","id":"PMC_11238952","title":"ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase.","date":"2001","source":"Molecular and cellular 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activation.","date":"2021","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34197030","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49304,"output_tokens":13119,"usd":0.172348,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":25454,"output_tokens":4035,"usd":0.114072,"stage2_stop_reason":"end_turn"},"total_usd":0.28642,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"β-TrCP directly binds phosphorylated β-catenin through its WD40 repeat domain in a GSK3β phosphorylation-dependent manner, forming part of an SCF E3 ubiquitin ligase complex (with Skp1 and Cul1) that targets β-catenin for proteasomal degradation; overexpression of wild-type β-TrCP promotes β-catenin downregulation, while a dominant-negative deletion mutant upregulates β-catenin and activates Tcf-dependent signaling.\",\n      \"method\": \"Direct binding assay, Co-IP from mammalian cells, dominant-negative overexpression, β-catenin stability assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding established, Co-IP from endogenous proteins, functional mutagenesis, replicated across multiple independent labs in the same year\",\n      \"pmids\": [\"10074433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FWD1 (mouse homolog of β-TrCP) forms a multi-molecular complex with β-catenin, Axin, GSK-3β, and APC; phosphorylation at the N-terminal signal-induced sites of β-catenin is required for FWD1 association; FWD1 facilitates ubiquitination and proteasomal degradation of β-catenin as part of the SCF(FWD1) ubiquitin ligase.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, dominant-negative overexpression, β-catenin stability assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods, reconstitution of ubiquitination in vitro, replicated across labs\",\n      \"pmids\": [\"10228155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human β-TrCP associates with Skp1 and Cul1 to form a novel SCF ubiquitin ligase complex, and interacts with β-catenin in vivo; expression of a dominant-negative β-TrCP stabilizes β-catenin.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, replicated by multiple labs\",\n      \"pmids\": [\"10023660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"β-TrCP (FWD1) specifically recognizes the doubly phosphorylated DSGψXS motif in IκBα; an F-box-deleted β-TrCP inhibits IκBα degradation; β-TrCP mediates ubiquitination of phosphorylated IκBα in vitro and in cells, enabling NF-κB nuclear translocation.\",\n      \"method\": \"Co-IP (phosphorylation-dependent), dominant-negative overexpression, in vitro ubiquitination, NF-κB reporter assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination reconstituted, phospho-dependent interaction established, replicated\",\n      \"pmids\": [\"10097128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"β-TrCP interacts specifically with phosphorylated IκBα (Ser32/Ser36) but not unmodified or phosphorylation-deficient IκBα; F-box deletion abolishes ability to ubiquitinate IκBα; β-TrCP is the adaptor for IκBα recognition by SCFβTrCP E3 complex.\",\n      \"method\": \"Co-IP (phosphorylation-dependent), dominant-negative expression, NF-κB transcription assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-dependent Co-IP established, F-box mutagenesis, replicated across labs\",\n      \"pmids\": [\"10075690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"β-Trcp negatively regulates Wnt/β-catenin signaling and dorsal axis formation in Xenopus; phosphorylated β-catenin is specifically recognized by β-Trcp; inhibition of endogenous β-Trcp by dominant-negative mutant stabilizes β-catenin, activates Wnt signaling, and induces axis duplication.\",\n      \"method\": \"Xenopus embryo injection, dominant-negative overexpression, co-IP\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo epistasis in Xenopus, phospho-mutant rescue, replicated\",\n      \"pmids\": [\"10339577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FWD1/β-TrCP recognizes the conserved DSGψXS phospho-motif in IκBα, IκBβ, and IκBε; phosphorylation of both conserved serines is required for FWD1-mediated ubiquitination of all three IκB proteins; the D31A mutation in IκBα abolishes FWD1 binding without affecting phosphorylation.\",\n      \"method\": \"Co-IP, in vitro ubiquitination, site-directed mutagenesis, degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of degron, in vitro ubiquitination, multiple substrates tested\",\n      \"pmids\": [\"10497169\", \"10514433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"β-TrCP interacts specifically with IκBβ in a manner dependent on phosphorylation of serines 19 and 23; F-box deletion abolishes β-TrCP-mediated ubiquitination of IκBβ.\",\n      \"method\": \"Co-IP, ubiquitination assay, dominant-negative mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-dependent Co-IP, F-box mutagenesis, single lab\",\n      \"pmids\": [\"10514424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"β-TrCP controls ATF4 stability by binding ATF4 in a phosphorylation-dependent manner (requiring Ser219 in a DSGXXXS motif); an F-box-deleted β-TrCP acts as dominant-negative to inhibit ATF4 ubiquitination and degradation, thereby enhancing ATF4-dependent cAMP-mediated transcription; β-TrCP and ATF4 are co-localized in the nucleus.\",\n      \"method\": \"Co-IP, dominant-negative overexpression, ubiquitination assay, luciferase reporter, subcellular localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-dependent interaction, ubiquitination demonstrated, nuclear co-localization shown, single lab\",\n      \"pmids\": [\"11238952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IKKβ directly phosphorylates NF-κB1 p105 at C-terminal serines 923 and 927 (within a DSGψ-like motif), and this phosphorylation recruits both β-TrCP1 and β-TrCP2 for polyubiquitination and complete proteasomal degradation of p105.\",\n      \"method\": \"In vitro kinase assay, Co-IP, RNAi knockdown, ubiquitination assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, phospho-dependent Co-IP, RNAi validation, multiple orthogonal methods\",\n      \"pmids\": [\"11158290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure (3.0 Å) of a β-TrCP1-Skp1-β-catenin complex reveals the basis of substrate recognition by the β-TrCP1 WD40 domain binding the doubly phosphorylated DpSGφXpS destruction motif; ubiquitination efficiency is determined by lysine-to-destruction motif spacing, confirmed by in vitro ubiquitination of mutant β-catenin peptides.\",\n      \"method\": \"X-ray crystallography, in vitro ubiquitination assay with mutant peptides\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by in vitro mutagenesis and ubiquitination assay\",\n      \"pmids\": [\"12820959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"β-TrCP is the F-box protein of SCF that targets phosphorylated Cdc25A for ubiquitin-mediated proteasomal degradation during S phase and in response to DNA damage; siRNA knockdown of both β-TrCP1 and β-TrCP2 prevents Cdc25A degradation induced by ionizing radiation and causes radioresistant DNA synthesis, indicative of an intra-S-phase checkpoint defect.\",\n      \"method\": \"siRNA knockdown, ubiquitination assay, DNA damage checkpoint assay (radioresistant DNA synthesis)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi knockdown of both paralogs, checkpoint phenotype confirmed, mechanism established\",\n      \"pmids\": [\"14603323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"β-TrCP1 knockout mice display defects in meiotic progression (accumulation of metaphase I spermatocytes) and mitotic defects in MEFs including centrosome overduplication, multipolar spindles, and misaligned chromosomes; Emi1 is a bona fide substrate of β-TrCP1; stabilization of β-catenin and IκBα requires silencing of both β-TrCP1 and β-TrCP2.\",\n      \"method\": \"Gene knockout mice, siRNA, substrate stability assay, cell biology (centrosome counting)\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus siRNA complementation, multiple cellular phenotypes, Emi1 substrate validated\",\n      \"pmids\": [\"12791266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Emi1 is phosphorylated by Cdc2 on a DSGxxS consensus site and is subsequently recognized and ubiquitinated by SCF(βTrCP/Slimb), leading to its destruction in prophase; failure of βTrCP-dependent Emi1 destruction stabilizes APC substrates and results in mitotic catastrophe including centrosome overduplication.\",\n      \"method\": \"Co-IP, ubiquitination assay, phospho-mutant analysis, centrosome overduplication assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-dependent binding, ubiquitination assay, functional consequence (centrosome overduplication), replicated\",\n      \"pmids\": [\"12791267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"β-TrCP1-deficient MEFs show impaired (but not abolished) degradation of IκBα and IκBβ, reduced NF-κB nuclear translocation and transcriptional activity, and altered β-catenin subcellular localization; β-TrCP1 knockout MEFs display reduced proliferation, increased cell size, and increased polyploidy.\",\n      \"method\": \"Gene knockout mice, immunofluorescence, NF-κB reporter, FACS\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"12843402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FWD1/β-TrCP mediates ubiquitination and proteasomal degradation of the circadian clock protein FREQUENCY (FRQ) in Neurospora; FRQ and FWD1 interact physically in vivo; fwd1 disruption results in accumulation of hyperphosphorylated FRQ and abolishes circadian rhythms.\",\n      \"method\": \"Co-IP in vivo, genetic disruption, circadian reporter assay, FRQ stability assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — physical interaction, genetic KO phenotype, circadian readout, multiple methods\",\n      \"pmids\": [\"12941694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"β-TrCP binding and processing of NF-κB1 p105 requires IKK-mediated phosphorylation at serines 927 and 932; βTrCP RNAi blocks TNF-α-induced p105 ubiquitination and proteolysis; βTrCP affinity for doubly phosphorylated p105 is substantially lower than for IκBα, contributing to delayed p105 proteolysis.\",\n      \"method\": \"RNAi knockdown, phosphopeptide competition, in vitro kinase assay, ubiquitination assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, RNAi, phosphopeptide competition, multiple orthogonal methods\",\n      \"pmids\": [\"12482991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HIV-1 Vpu sequesters β-TrCP in the cytoplasm by binding through its phosphorylated DS52GXXS56 motif, acting as a competitive inhibitor that prevents β-TrCP-mediated degradation of endogenous substrates (β-catenin, IκBα, ATF4, Emi1, Cdc25A) and excludes β-TrCP from the nucleus.\",\n      \"method\": \"GFP fusion imaging, substrate stability assay, dominant-negative competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization with functional consequence, multiple substrates tested, single lab\",\n      \"pmids\": [\"14561767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Hierarchical phosphorylation of Cdc25A commits it to β-TrCP-dependent degradation: Chk1-dependent phosphorylation at Ser76 is a priming step required for subsequent phosphorylation at Ser82 within the DSG motif, which anchors Cdc25A to β-TrCP.\",\n      \"method\": \"Phospho-site mutagenesis, Co-IP, degradation assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of sequential phospho-sites, Co-IP, single lab\",\n      \"pmids\": [\"14752276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SCF(β-TrCP1) ubiquitinates and destabilizes Smad4; β-TrCP1 interacts with Smad4 in yeast two-hybrid and mammalian cells but not Smad2, and weakly with Smad3 only through Smad4; ectopic SCF(β-TrCP1) induces Smad4 ubiquitination and degradation, inhibiting TGF-β transcriptional responses.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, ubiquitination assay, siRNA, TGF-β reporter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods, yeast two-hybrid plus mammalian Co-IP, single lab\",\n      \"pmids\": [\"14988407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"β-TrCP binding and ubiquitination of NF-κB2/p100 requires NIK/IKKα-dependent phosphorylation of p100 at serines 866 and 870; mutation of either serine abolishes β-TrCP recruitment and ubiquitination of p100.\",\n      \"method\": \"Co-IP, phospho-mutant analysis, in vivo ubiquitination assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-mutant Co-IP, ubiquitination assay, single lab\",\n      \"pmids\": [\"16303288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"β-TrCP2 directly binds Gli2 and promotes its ubiquitination and degradation; single amino acid substitution in the Gli2 β-TrCP binding site abolishes interaction, ubiquitination, and stabilizes Gli2 protein, leading to enhanced Gli-dependent transcription.\",\n      \"method\": \"Co-IP, ubiquitination assay, site-directed mutagenesis, transcriptional reporter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding Co-IP, mutagenesis of binding motif, single lab\",\n      \"pmids\": [\"16651270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"S6K1-mediated phosphorylation of PDCD4 on Ser67 in response to mitogens recruits SCF(βTRCP) E3 ligase for ubiquitin-mediated proteasomal degradation of PDCD4; expression of a stable PDCD4 mutant unable to bind βTRCP inhibits translation of mRNAs with structured 5'UTRs, reduces cell size, and slows cell cycle progression.\",\n      \"method\": \"Kinase assay, Co-IP, ubiquitination assay, translation reporter, stable mutant overexpression, cell size measurement\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-dependent recruitment, ubiquitination shown, stable non-degradable mutant, multiple cellular readouts\",\n      \"pmids\": [\"17053147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Wnt/β-catenin/Tcf signaling elevates βTrCP mRNA and protein expression in a Tcf-dependent manner, creating a negative feedback loop: increased βTrCP accelerates wild-type β-catenin degradation while also upregulating NF-κB transactivation without affecting IKK activity.\",\n      \"method\": \"Tcf reporter, mRNA analysis, β-catenin degradation assay, NF-κB reporter\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Tcf-dependent transcriptional induction shown, functional consequence on substrate degradation demonstrated, single lab\",\n      \"pmids\": [\"10882123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"β-TrCP (as part of SCF) mediates ubiquitination and proteasomal degradation of the erythropoietin receptor (Epo-R); β-TrCP binds via its WD40 domain to a novel recognition motif (the ubiquitin-dependent endocytosis motif) in Epo-R; mutation of Ser462 abolishes β-TrCP binding, Epo-R ubiquitination, and degradation, causing prolonged Epo-R signaling and hypersensitivity to Epo.\",\n      \"method\": \"Co-IP, siRNA knockdown, site-directed mutagenesis, receptor degradation/endocytosis assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, RNAi, functional signaling consequence, single lab\",\n      \"pmids\": [\"17327410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GSK-3β associates with and phosphorylates Mcl-1 at Ser155/Ser159/Thr163, leading to association with β-TrCP and SCF(β-TrCP)-mediated ubiquitination and degradation of Mcl-1; a triple-alanine Mcl-1 mutant (3A) resists phosphorylation, is not ubiquitinated by β-TrCP, is more stable, and blocks GSK-3β-induced apoptosis.\",\n      \"method\": \"Co-IP, in vitro kinase assay, ubiquitination assay, phospho-mutant analysis, apoptosis assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, Co-IP, mutagenesis, ubiquitination reconstitution, functional apoptosis readout\",\n      \"pmids\": [\"17387146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"β-TrCP1 degradation of PER2 is required for mammalian circadian rhythm generation; β-TrCP1-interaction-deficient PER2 variants are dramatically stabilized and disrupt circadian rhythmicity when expressed; β-TrCP1 and β-TrCP2 both target PER2 via the m2 degron site in vitro.\",\n      \"method\": \"Dominant-negative β-TrCP, siRNA, PER2 mutant expression, circadian reporter assay\",\n      \"journal\": \"Journal of biological rhythms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA, dominant-negative, PER2 mutant, circadian readout, single lab\",\n      \"pmids\": [\"17876059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Plk1, following Cdk1-dependent recruitment, phosphorylates a SCF(βTrCP) recognition site on hBora to trigger its ubiquitin-mediated destruction; Plk1 depletion causes massive hBora accumulation, Aurora A mislocalization, and centrosome maturation defects; co-depletion of hBora partially restores Aurora A localization and bipolar spindle formation.\",\n      \"method\": \"Co-IP, siRNA co-depletion, ubiquitination assay, immunofluorescence, epistasis\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-dependent recognition, ubiquitination, epistasis by co-depletion, single lab\",\n      \"pmids\": [\"18521620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ERK-mediated phosphorylation of STAT1 at Ser727 targets it for proteasomal degradation by SCF(βTRCP); βTRCP binds wild-type STAT1 but not the non-phosphorylatable STAT1(S727A) mutant; silencing βTRCP or inhibiting ERK stabilizes STAT1.\",\n      \"method\": \"Co-IP, phospho-mutant analysis, siRNA, pharmacological ERK inhibition, STAT1 stability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-dependent Co-IP, siRNA, pharmacological inhibition, single lab\",\n      \"pmids\": [\"18378670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IKK2 phosphorylates p53 at Ser362 and Ser366, leading to p53 recruitment to and ubiquitination by β-TrCP1; this p53 degradation is independent of Mdm2; siRNA-mediated reduction of β-TrCP1 or dominant-negative β-TrCP1 enhances p53 stability; p53-S362A/S366A mutations reduce IKK2-mediated phosphorylation and β-TrCP1 association.\",\n      \"method\": \"Co-IP, siRNA, dominant-negative overexpression, phospho-mutant analysis, p53 stability assay, cell-cycle analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-dependent Co-IP, siRNA, mutagenesis, functional cell cycle readout, single lab\",\n      \"pmids\": [\"19196987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BimEL is phosphorylated on three serine residues in a conserved degron by Rsk1/2 (promoted by prior Erk1/2-mediated phosphorylation of Ser69), enabling binding and degradation via βTrCP; a BimEL phosphorylation mutant unable to bind βTrCP is stabilized and potently induces apoptosis by the intrinsic mitochondrial pathway.\",\n      \"method\": \"Co-IP, phospho-mutant analysis, kinase assay, apoptosis assay, siRNA\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-dependent binding, kinase identification, stable mutant with functional apoptosis readout, multiple orthogonal methods\",\n      \"pmids\": [\"19150432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"USP47 is a novel interactor of both β-Trcp1 and β-Trcp2; binding requires the β-Trcp WD-repeat region (point mutations abolish binding); unlike canonical β-TrCP substrates, USP47 protein levels are not affected by β-Trcp silencing; depletion of USP47 causes Cdc25A accumulation and decreased cell survival.\",\n      \"method\": \"Co-IP, WD-repeat point mutagenesis, siRNA knockdown, cell viability assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis, functional knockdown phenotype, single lab\",\n      \"pmids\": [\"19966869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human Plk4 undergoes βTrCP-dependent proteasomal degradation; Plk4 trans-autophosphorylation within homodimers creates the βTrCP binding/recognition site, promoting Plk4's own degradation; kinase-dead Plk4 disrupts trans-autophosphorylation, shielding endogenous Plk4 from βTrCP recognition and causing centriole overduplication.\",\n      \"method\": \"Protein stability assay, Co-IP, kinase-dead mutant overexpression, centriole counting\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-dependent recognition, kinase-dead dominance experiment, centriole readout, single lab\",\n      \"pmids\": [\"20516151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DEPTOR is a physiological substrate of SCF(βTrCP); upon growth factor stimulation, RSK1 and S6K1 phosphorylate DEPTOR's degron sequence, enabling βTrCP binding and ubiquitination/degradation; blocking βTrCP-dependent DEPTOR degradation (via knockdown or stable mutant) inhibits mTOR and activates AKT.\",\n      \"method\": \"Co-IP, siRNA, stable degron mutant, mTOR/AKT activity assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated by two independent groups (PMIDs 22017876 and 22017877), phospho-dependent binding, functional mTOR/AKT readouts\",\n      \"pmids\": [\"22017876\", \"22017877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"mTOR auto-amplification loop: mTORC1/2-mediated priming phosphorylation followed by CK1α phosphorylation of a conserved degron in DEPTOR facilitates βTrCP binding and degradation; blocking this pathway via βTrCP knockdown or stable DEPTOR mutant results in mTOR inhibition.\",\n      \"method\": \"Co-IP, siRNA, stable degron mutant, CK1α kinase assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated independently, kinase hierarchy established, functional mTOR readout\",\n      \"pmids\": [\"22017877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"β-TrCP1 is mislocalized to the nucleus in glioblastoma (vs. cytoplasm in astrocytoma and normal brain), spatially separating it from its cytoplasmic substrate PHLPP1; restoring β-TrCP1 to the cytoplasm rescues the Akt-PHLPP1 negative feedback loop and β-catenin degradation.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, pharmacological/genetic manipulation of localization, functional Akt/PHLPP1 assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization tied to functional consequence, multiple cell lines, single lab\",\n      \"pmids\": [\"21454620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"βTrCP regulates BMI1 ubiquitination and proteasome-mediated degradation; overexpression of wild-type βTrCP but not ΔF mutant promotes BMI1 ubiquitination; BMI1 recognition motif mutation stabilizes BMI1, increases its pro-oncogenic activity.\",\n      \"method\": \"Co-IP, ubiquitination assay, ΔF mutant, recognition motif mutagenesis, cellular senescence assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, mutagenesis of binding site, single lab\",\n      \"pmids\": [\"21430439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SCF(βTrCP) mediates proteasomal destruction of the deubiquitinase USP37 at the G2/M transition in a Plk1-dependent phosphorylation-dependent manner; USP37 interacts with βTrCP in a phospho-dependent manner; stabilization of a phospho-site mutant USP37 hinders the G2/M transition.\",\n      \"method\": \"Co-IP, siRNA, phospho-mutant analysis, cell-cycle analysis, Plk1 kinase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-dependent Co-IP, Plk1 kinase upstream, cell-cycle functional readout, single lab\",\n      \"pmids\": [\"23027877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"β-TrCP1 targets HuR for ubiquitin-mediated proteasomal degradation upon metabolic stress (glycolysis inhibition); targeting requires PKCα-mediated Ser318 phosphorylation-dependent cytoplasmic translocation of HuR and IKKα-mediated phosphorylation at Ser304 in an unconventional β-TrCP1 recognition motif (EEAMAIAS).\",\n      \"method\": \"Co-IP, GST pull-down, ubiquitination assay, dominant-negative β-TrCP1, mutagenesis, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and GST pull-down, ubiquitination assay, mutagenesis, single lab\",\n      \"pmids\": [\"23115237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SCFβ-TRCP mediates ubiquitination and proteasomal degradation of MTSS1; CK1δ phosphorylates Ser322 in the DSGXXS degron of MTSS1 to trigger β-TRCP interaction; depletion of Cullin 1 or β-TRCP1 increases MTSS1 levels; non-degradable MTSS1(S322A) shows stronger inhibition of cancer cell proliferation and migration.\",\n      \"method\": \"Co-IP, ubiquitination assay, CK1δ kinase assay, siRNA knockdown, functional migration/proliferation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-dependent Co-IP, kinase identified, ubiquitination assay, functional readout, single lab\",\n      \"pmids\": [\"24318128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"βTrCP controls lysosome-mediated degradation of CDK1; CDK1 is ubiquitinated by SCFβTrCP; DNA damage regulates βTrCP-induced CDK1 degradation in a cell-type-dependent manner.\",\n      \"method\": \"Ubiquitination assay, siRNA, lysosome inhibitor, DNA damage treatment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ubiquitination assay and siRNA, but unconventional lysosomal degradation claim with limited mechanistic detail in abstract, single lab\",\n      \"pmids\": [\"25149538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DNA damage triggers β-TRCP-dependent degradation of CReP (a PP1 regulatory subunit targeting eIF2α); depletion of CReP is required for full induction of eIF2α phosphorylation after DNA damage, reducing cap-dependent translation during recovery.\",\n      \"method\": \"Ligase Trapping (ubiquitin ligase-ubiquitin binding domain fusion), stable mutant CReP, eIF2α phosphorylation assay, translation assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel substrate trapping method with functional validation, stable CReP mutant, functional translation readout, single lab\",\n      \"pmids\": [\"26091241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SAG/RBX2-CUL5 E3 ligase (with E2s UBCH10/UBE2S) ubiquitylates β-TrCP1 via atypical K11-linked polyubiquitin chains for proteasomal degradation; SAG and β-TrCP1 levels are inversely correlated; silencing UBCH10 or UBE2S (but not UBCH5C) causes β-TrCP1 accumulation.\",\n      \"method\": \"Co-IP, ubiquitination assay with linkage specificity, siRNA knockdown, protein stability assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemically defined K11 linkage, multiple E2 siRNA knockdowns, single lab\",\n      \"pmids\": [\"27910872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"β-TrCP targets DMRT1 for ubiquitylation and proteasomal degradation to control the mitosis-meiosis transition in mouse male germ cells; DMRT1 contains a consensus β-TrCP degron; conditional inactivation of β-TrCP2 in β-TrCP1 KO male germ cells results in sterility, failure to enter meiosis, and apoptosis; heterozygous deletion of Dmrt1 in β-TrCP-deficient spermatogonia partially rescues meiotic entry.\",\n      \"method\": \"Conditional knockout, Co-IP, ubiquitination assay, genetic epistasis (heterozygous Dmrt1 deletion), in vivo spermatogenesis analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with genetic epistasis, Co-IP, ubiquitination assay, in vivo phenotype\",\n      \"pmids\": [\"28982686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"β-TrCP recognizes cyclin F through a non-canonical TSGXXS degron (phosphorylated by casein kinase II) and mediates its degradation at the G2/M transition; this degradation is required for timely mitotic progression.\",\n      \"method\": \"Co-IP, phospho-mutant analysis, siRNA, CK2 kinase assay, cell-cycle analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — non-canonical degron identified, kinase identified, cell-cycle functional readout, single lab\",\n      \"pmids\": [\"30257202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXN2 is ubiquitinated and degraded by β-Trcp in a manner requiring RSK2-mediated phosphorylation of Ser365 and Ser369 in a conserved DSGYAS motif; β-Trcp/RSK2-mediated FOXN2 degradation promotes tumorigenesis and radioresistance in lung cancer.\",\n      \"method\": \"Co-IP, ubiquitination assay, RSK2 kinase assay, phospho-mutant analysis, gain/loss-of-function in vitro and in vivo\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase identified, phospho-dependent Co-IP, ubiquitination assay, functional in vivo tumor assay, single lab\",\n      \"pmids\": [\"29396548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TSPAN15 interacts specifically with BTRC to promote ubiquitination and proteasomal degradation of phosphorylated IκBα, triggering NF-κB nuclear translocation and transcription of metastasis-related genes (ICAM1, VCAM1, MMP9, etc.) in esophageal squamous cell carcinoma.\",\n      \"method\": \"Co-IP, ubiquitination assay, siRNA, NF-κB nuclear translocation assay, functional metastasis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing TSPAN15-BTRC interaction, ubiquitination assay, functional NF-κB readout, single lab\",\n      \"pmids\": [\"29650964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PARP11 mono-ADP-ribosylates β-TrCP; mono-ADP-ribosylation of β-TrCP promotes IFNAR1 ubiquitination and degradation, attenuating IFN-I antiviral signaling; PARP11 is upregulated by viral infection to promote this immune evasion mechanism.\",\n      \"method\": \"Co-IP, ADP-ribosylation assay, IFNAR1 stability assay, siRNA, mouse viral infection model\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical ADP-ribosylation assay, IFNAR1 ubiquitination assay, in vivo mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"30988430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERAP1 binds USP47, displaces USP47-associated βTrCP, and promotes βTrCP degradation, leading to modulation of Gli transcription factors and enhancement of Hedgehog pathway activity; pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo.\",\n      \"method\": \"Co-IP, βTrCP stability assay, Gli reporter assay, pharmacological inhibition, in vivo tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying displacement mechanism, βTrCP degradation assay, in vivo tumor model, single lab\",\n      \"pmids\": [\"31341163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"β-TrCP1 and β-TrCP2 are physiological substrates of SCF E3 ligase and mutually target each other for ubiquitination and degradation via their respective β-TrCP degron sequences; AMPK activated by glucose deprivation phosphorylates β-TrCP1, promoting its degradation by β-TrCP2 (but not vice versa); β-TrCP2 preferentially degrades DEPTOR and REDD1 (mTORC1 inhibitors) to activate mTORC1 and inhibit autophagy.\",\n      \"method\": \"Co-IP, ubiquitination assay, AMPK kinase assay, degron mutant analysis, autophagy assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutual degradation with degron mutant validation, kinase identified, functional mTOR/autophagy readout, single lab\",\n      \"pmids\": [\"31406304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"βTrCP is the E3 ligase for ubiquitination of transferrin receptor (TFRC); TRIB2 desensitizes cells to ferroptosis by facilitating βTrCP-mediated TFRC ubiquitination and degradation to decrease labile iron pools; βTrCP knockout abolishes TRIB2-mediated iron reduction and ferroptosis resistance.\",\n      \"method\": \"Co-IP, ubiquitination assay, βTrCP knockout, labile iron pool measurement, ferroptosis assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with KO rescue, functional ferroptosis readout, single lab\",\n      \"pmids\": [\"34315867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Alternative splicing of β-TrCP1 produces isoforms where exon III insertion prevents Skp1 interaction and causes nuclear (vs. cytoplasmic) localization; exon-III-containing isoforms show reduced ability to antagonize Wnt/β-catenin signaling in Xenopus.\",\n      \"method\": \"Yeast two-hybrid, immunofluorescence of isoforms, Xenopus axis assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid, immunofluorescence, limited functional assay, single lab\",\n      \"pmids\": [\"18929646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FGD1 (a Cdc42 GEF) is a substrate of SCF(FWD1/β-TrCP); recognition requires phosphorylation of conserved serines in the DSGIDS motif; a phosphorylation-deficient FGD1(SA) mutant does not interact with FWD1/β-TrCP, is more stable, and shows enhanced cell motility; co-expression of SCF(FWD1/β-TrCP) reduces FGD1(WT)-induced morphological changes but not those of FGD1(SA).\",\n      \"method\": \"Co-IP, ubiquitination assay, phospho-mutant analysis, cell morphology and motility assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-dependent Co-IP, ubiquitination, functional morphology/motility readout, single lab\",\n      \"pmids\": [\"15743413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CK2-dependent phosphorylation of the E2 ubiquitin-conjugating enzyme UBC3B at Ser233 induces its interaction with β-TrCP; co-transfection of CK2α' with UBC3B (but not a C-terminal deletion) enhances β-catenin degradation.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, in vitro phosphorylation, β-catenin degradation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and yeast two-hybrid, functional consequence on β-catenin, single lab\",\n      \"pmids\": [\"12037680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RVFV NSs interacts with both FBXW11 (β-TrCP2) and β-TrCP1 and recruits SCF E3 ligase complexes containing these F-box proteins to target the antiviral kinase PKR for proteasomal degradation; siRNA depletion of both paralogs is required for maximal PKR protection.\",\n      \"method\": \"siRNA screen of ~70 F-box proteins, Co-IP, PKR stability assay, viral replication assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide F-box siRNA screen identified β-TrCP1/2, Co-IP of NSs-βTrCP interaction, functional PKR stability readout, single lab\",\n      \"pmids\": [\"27122577\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BTRC (β-TrCP1) functions as the substrate-recognition subunit (F-box/WD40 protein) of the SCF(β-TrCP) E3 ubiquitin ligase complex (with Skp1, Cul1, and Rbx1), binding doubly phosphorylated DSGψXS (or related) degron motifs on substrates including β-catenin, IκBα/β/ε, p105, p100, Cdc25A, Emi1, PDCD4, BimEL, Mcl-1, DEPTOR, PER2, hBora, Plk4, Gli2, Smad4, ATF4, STAT1, cyclin F, DMRT1, TFRC, and many others, targeting them for ubiquitin-proteasome-mediated degradation to regulate Wnt/β-catenin, NF-κB, DNA damage checkpoint, circadian clock, cell cycle, and apoptosis pathways; its activity is modulated by competing interactions (e.g., with HIV-1 Vpu, RASSF1C, TRIM67, Pin1), post-translational modifications of β-TrCP itself (PARP11 mono-ADP-ribosylation, AMPK-mediated phosphorylation, SAG/CUL5-mediated K11-ubiquitylation), and its subcellular localization (cytoplasmic vs. nuclear), with structural studies revealing that WD40-domain recognition of the phosphodegron and lysine-to-degron spacing together determine ubiquitination efficiency.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BTRC (β-TrCP1) is the substrate-recognition subunit of an SCF (Skp1–Cul1) E3 ubiquitin ligase that selectively binds doubly phosphorylated DSGψXS-type phosphodegrons through its WD40 repeat domain and marks the bound substrate for ubiquitin–proteasome degradation [#0, #2, #10]. Its two best-defined functions establish the paradigm: it recognizes GSK3β-phosphorylated β-catenin within the Axin/APC/GSK-3β destruction complex to restrain Wnt/β-catenin signaling and dorsal axis formation [#0, #1, #5], and it recognizes IKK-phosphorylated IκBα/β/ε at the conserved DSGψXS motif to license NF-κB nuclear translocation [#3, #4, #6]. A 3.0 Å crystal structure of the β-TrCP1–Skp1–β-catenin complex defined how the WD40 domain reads the doubly phosphorylated motif and showed that ubiquitination efficiency is set by the spacing between the acceptor lysine and the degron [#10]. The same recognition logic extends across pathways, where degron phosphorylation by a dedicated kinase commits substrates to destruction: IKK on p105/p100 [#9, #20], Chk1/Plk1/CK2 on cell-cycle regulators Cdc25A, Emi1, hBora, USP37, cyclin F and Plk4 [#11, #13, #18, #32, #37, #44], and growth-factor kinases (S6K1, RSK, CK1α) on the translational and mTOR regulators PDCD4 and DEPTOR [#22, #33, #34]. Through these substrates BTRC governs the DNA-damage intra-S checkpoint, mitotic and centrosome integrity, circadian rhythm via PER2 degradation, mTOR/autophagy balance, and apoptosis via Mcl-1 and BimEL turnover [#11, #12, #25, #26, #30, #49]. Genetic ablation confirms physiological importance: β-TrCP1-knockout cells show impaired IκB and β-catenin handling with mitotic defects, and combined β-TrCP1/2 loss in male germ cells blocks the mitosis–meiosis transition through failed DMRT1 degradation [#12, #14, #43]. BTRC activity is itself regulated by competition (HIV-1 Vpu sequestration), by post-translational modification of β-TrCP (PARP11 mono-ADP-ribosylation, AMPK phosphorylation, SAG/CUL5-mediated K11 ubiquitylation), and by cytoplasmic-versus-nuclear localization [#17, #42, #47, #49, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established BTRC as the substrate receptor of an SCF ligase that couples GSK3β phosphorylation of β-catenin to its destruction, answering how Wnt signaling controls β-catenin stability.\",\n      \"evidence\": \"Phospho-dependent direct binding and Co-IP with Skp1/Cul1, dominant-negative stabilization, and Xenopus axis assays across multiple labs\",\n      \"pmids\": [\"10074433\", \"10228155\", \"10023660\", \"10339577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve atomic basis of phosphodegron recognition\", \"Did not address how BTRC discriminates among many DSGψXS-bearing substrates\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified the doubly phosphorylated DSGψXS degron as BTRC's recognition motif on IκBα/β/ε, explaining how IKK signaling triggers NF-κB activation through targeted IκB destruction.\",\n      \"evidence\": \"Phospho-dependent Co-IP, degron mutagenesis (D31A), in vitro ubiquitination, F-box deletion, and NF-κB reporters\",\n      \"pmids\": [\"10097128\", \"10075690\", \"10497169\", \"10514433\", \"10514424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative affinity differences among IκB family members not yet quantified\", \"Kinetics of degradation vs. processing not distinguished\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"A crystal structure provided the structural rule for substrate selection, showing the WD40 domain reads the doubly phosphorylated motif and that lysine-to-degron spacing dictates ubiquitination efficiency.\",\n      \"evidence\": \"X-ray crystallography of β-TrCP1–Skp1–β-catenin with in vitro ubiquitination of mutant peptides\",\n      \"pmids\": [\"12820959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure limited to one substrate peptide; non-canonical degrons not structurally explained\", \"Does not address full-length SCF architecture or processivity\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended BTRC function to cell-cycle and checkpoint control, showing it degrades phospho-Cdc25A and Emi1 to enforce the intra-S checkpoint and prevent centrosome overduplication.\",\n      \"evidence\": \"siRNA of both paralogs, radioresistant DNA synthesis assays, knockout mice, in vitro ubiquitination, and centrosome counting\",\n      \"pmids\": [\"14603323\", \"12791266\", \"12791267\", \"12843402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional redundancy between β-TrCP1 and β-TrCP2 not fully partitioned\", \"Tissue-specific substrate dependencies unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated the recognition paradigm is conserved across kingdoms and pathways, with BTRC homolog FWD1 degrading the circadian protein FRQ in Neurospora and BTRC controlling NF-κB1 p105 processing.\",\n      \"evidence\": \"Co-IP, genetic disruption with circadian readout, in vitro kinase assays, and phosphopeptide competition\",\n      \"pmids\": [\"12941694\", \"11158290\", \"12482991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why p105 affinity is lower than IκBα mechanistically unexplained at structural level\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed BTRC integrates growth-factor and stress kinase signaling into protein turnover, degrading apoptotic and translational regulators (Mcl-1, BimEL, PDCD4) following GSK3β, RSK, ERK, and S6K1 phosphorylation.\",\n      \"evidence\": \"In vitro kinase assays, phospho-mutant binding, ubiquitination assays, and apoptosis/translation/cell-size readouts\",\n      \"pmids\": [\"17387146\", \"19150432\", \"17053147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among competing substrates under a given stimulus not defined\", \"Cellular context determining apoptotic vs. survival outcome unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined BTRC as a node in mTOR/AKT signaling by establishing DEPTOR as a physiological substrate whose phosphorylation-triggered degradation activates mTOR.\",\n      \"evidence\": \"Independently replicated Co-IP, siRNA, stable degron mutants, and mTOR/AKT activity assays\",\n      \"pmids\": [\"22017876\", \"22017877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of DEPTOR degradation to mTOR set-point not measured\", \"Crosstalk with other mTOR-regulating substrates not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed BTRC is itself regulated post-translationally, with PARP11 mono-ADP-ribosylation promoting IFNAR1 degradation and AMPK phosphorylation driving β-TrCP1 degradation by β-TrCP2, linking paralog cross-regulation to immune signaling and mTOR/autophagy.\",\n      \"evidence\": \"ADP-ribosylation and ubiquitination assays, AMPK kinase assays, degron-mutant analysis, in vivo viral infection and autophagy readouts\",\n      \"pmids\": [\"30988430\", \"31406304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and reversibility of β-TrCP modifications in vivo unclear\", \"Mutual paralog degradation kinetics single-lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established competition and localization as additional regulatory layers, with viral and cellular proteins sequestering or displacing BTRC and isoform/localization changes redirecting its activity.\",\n      \"evidence\": \"Co-IP displacement, β-TrCP stability assays, subcellular fractionation, and in vivo tumor/localization models\",\n      \"pmids\": [\"31341163\", \"21454620\", \"14561767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous physiological triggers for nuclear-cytoplasmic shuttling not fully defined\", \"Quantitative competition among endogenous decoys not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BTRC prioritizes among its large substrate repertoire within a single cell, and how degron affinity, localization, and self-regulation are integrated in real time, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative competition model across endogenous substrates\", \"Substrate selection under simultaneous multi-pathway activation undefined\", \"Distinct in vivo roles of β-TrCP1 vs β-TrCP2 incompletely separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 6, 9, 10]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 3, 10, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 4, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17, 35]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 35, 51]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-201681\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11, 12, 13, 37, 44]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4, 9, 47]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [15, 26]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [25, 30]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 10]}\n    ],\n    \"complexes\": [\"SCF(β-TrCP) E3 ubiquitin ligase\"],\n    \"partners\": [\"SKP1\", \"CUL1\", \"CTNNB1\", \"NFKBIA\", \"USP47\", \"DEPTOR\", \"EMI1\", \"PER2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}