{"gene":"USP6","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1993,"finding":"The human Tre-2 (USP6) oncogene encodes a deubiquitinating enzyme, as inferred from its homology to the yeast Doa4 deubiquitinating enzyme, which cleaves ubiquitin from substrate remnants during proteasomal degradation.","method":"Sequence homology and functional characterization of yeast ortholog Doa4","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization performed on yeast ortholog Doa4 with mechanistic follow-through; USP6/Tre-2 DUB activity inferred by homology from a single study","pmids":["8247125"],"is_preprint":false},{"year":2003,"finding":"TRE17 (USP6) oncogene coprecipitates specifically with the active (GTP-bound) forms of Cdc42 and Rac1 in vivo, and its subcellular localization is regulated by these GTPases and by mitogens: under serum starvation TRE17 localizes to filamentous structures, while EGF or activated Cdc42/Rac1 redistribute it to the plasma membrane in an actin polymerization-dependent manner. A C-terminal truncation mutant of TRE17 induces cortical actin accumulation mimicking activated Cdc42.","method":"Co-immunoprecipitation, subcellular localization (fluorescence microscopy), dominant-active GTPase expression, actin depolymerization experiments, truncation mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, live-cell localization, mutagenesis, and pharmacological perturbation in a single focused study with multiple orthogonal methods","pmids":["12612085"],"is_preprint":false},{"year":2004,"finding":"The TBC domain of TRE17/USP6 mediates direct binding to Arf6 in its GDP-bound (inactive) state but not in its GTP-bound state. Rather than acting as a GAP, TRE17 promotes Arf6 activation (GTP loading) in vivo by facilitating its access to membrane-associated GEFs, leading to plasma membrane localization of Arf6. siRNA-mediated knockdown of TRE17 attenuates Arf6 activation.","method":"Co-immunoprecipitation with GDP- and GTP-fixed Arf6 mutants, domain-mapping pulldown, in vivo GTP-loading assay, siRNA knockdown, fluorescence microscopy","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (pulldown, GTP-loading assay, RNAi, localization) in a single focused study establishing an unexpected non-GAP function for the TBC domain","pmids":["15509780"],"is_preprint":false},{"year":2005,"finding":"Calmodulin (CaM) binds directly to TRE17/USP6 in a Ca2+-dependent manner in vitro and in vivo. The CaM-binding site maps to two hydrophobic motifs near the C terminus of the TBC domain. TRE17 is monoubiquitinated and promotes its own deubiquitination; CaM-binding-deficient point mutants show significantly reduced monoubiquitination, and the CaM inhibitor W7 also reduces TRE17 monoubiquitination. The calcium ionophore A23187 induces polyubiquitinated TRE17 in a CaM-binding-dependent manner.","method":"Co-immunoprecipitation (Ca2+-dependent), in vitro binding assay, point mutagenesis, pharmacological inhibition (W7, A23187), ubiquitination assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding + mutagenesis + cellular ubiquitination assays in a single focused study with multiple orthogonal methods","pmids":["16127172"],"is_preprint":false},{"year":2005,"finding":"The TBC domain of the Tre2 oncoprotein lacks Rab-GAP activity; chimeric protein experiments swapping regions N- and C-terminal to the TBC domain between Tre2 and active GAP RN-tre revealed that both the TBC domain itself and a 93-aa region C-terminal to it contribute to the oncoprotein's failure to function as a Rab-GAP.","method":"Yeast complementation of msb3Δ msb4Δ double mutant using chimeric Tre2/RN-tre proteins","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic complementation assay with domain-swap constructs in a single study; negative GAP activity confirmed by functional readout","pmids":["16099424"],"is_preprint":false},{"year":2010,"finding":"TRE17/USP6 overexpression in cells induces transcription of MMP-9 and MMP-10 through activation of NF-κB, a process requiring USP catalytic activity but not Arf6 binding. RhoA and its effector kinase ROCK are required for NF-κB activation by TRE17. Xenograft studies confirm that tumorigenic activity of TRE17 depends on the USP domain.","method":"Stable overexpression, reporter assays, dominant-negative/constitutively active GTPase constructs, ROCK inhibitor, site-directed mutagenesis of USP active site, xenograft mouse model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay, pharmacological inhibition, mutagenesis, in vivo xenograft) in a single focused study","pmids":["20418905"],"is_preprint":false},{"year":2010,"finding":"TRE17/USP6 potently inhibits maturation of MC3T3 pre-osteoblasts in a USP-dependent, Arf6-independent manner through an autocrine mechanism. Transcriptome analysis reveals dysregulation of BMP signaling: TRE17 simultaneously inhibits BMP-4 expression and upregulates the BMP antagonist Gremlin-1. Addition of exogenous BMP-4 rescues osteoblast maturation in TRE17-expressing cells.","method":"Stable overexpression, osteoblast differentiation assay, transcriptome analysis, cytokine rescue experiments, USP active-site mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mutagenesis, transcriptome, and functional rescue experiments establishing a mechanistic autocrine pathway","pmids":["20864534"],"is_preprint":false},{"year":2011,"finding":"TRE17/USP6 activates the classical NF-κB pathway through an atypical mechanism that does not involve IκB degradation. TRE17 co-precipitates with IKK, augments IKK activity in a USP-dependent manner, requires both IKKα and IKKβ catalytic subunits (and IKKγ/NEMO) for optimal activity, and stimulates phosphorylation of p65 at serine 536. Inhibition of NF-κB significantly attenuates TRE17-driven tumor formation in NIH3T3 cells.","method":"Co-immunoprecipitation, IKK kinase assay, USP active-site mutant, dominant-negative IKK subunits, p65-S536 phosphorylation western blot, xenograft tumorigenesis with NF-κB inhibitor","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, enzymatic assay, mutagenesis, in vivo tumor model with pharmacological inhibition—multiple orthogonal methods in a single focused study","pmids":["22081069"],"is_preprint":false},{"year":2014,"finding":"TRE17/USP6 deubiquitylates CIE (clathrin-independent endocytosis) cargo proteins, counteracting MARCH E3 ubiquitin ligase-dependent targeting of these cargos to lysosomes. The effect is dependent on USP6 deubiquitylating activity and is specific to CIE cargo (e.g., MHC class I); transferrin receptor (clathrin-dependent cargo) is unaffected. Expression of TRE17 alone stabilizes surface MHC class I.","method":"Co-expression with MARCH8, ubiquitination assays, flow cytometry for surface protein levels, USP active-site mutant, lysosomal degradation assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — enzymatic activity mutant, ubiquitination rescue assay, and surface protein quantification with appropriate controls in a single focused study","pmids":["25179595"],"is_preprint":false},{"year":2016,"finding":"USP6 deubiquitylates Frizzled (Fzd) receptors, increasing their cell-surface abundance and thereby enhancing Wnt/β-catenin signaling. Genome-wide siRNA screen identified USP6 as a potent Wnt activator. Inhibition of Wnt signaling with DKK1 or a Porcupine inhibitor significantly decreased the growth of USP6-driven xenograft tumors.","method":"Genome-wide siRNA screen, deubiquitylation assays, surface receptor quantification, DKK1 and PORCN inhibitor treatment, xenograft tumor assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen plus mechanistic follow-up with deubiquitylation assays, surface receptor quantification, and in vivo pharmacological inhibition","pmids":["27162353"],"is_preprint":false},{"year":2016,"finding":"USP6 directly deubiquitinates Jak1, leading to its stabilization and activation of STAT3 signaling. CRISPR-mediated deletion of Jak1 or STAT3 significantly attenuates USP6 tumorigenic potential. A Jak family inhibitor also reduces USP6-driven tumor formation.","method":"Co-immunoprecipitation, deubiquitination assay, CRISPR-mediated gene deletion, Jak inhibitor treatment, xenograft tumor model, transcriptomic analysis of primary clinical samples","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — substrate deubiquitination assay, CRISPR epistasis, pharmacological inhibition, and in vivo tumor model with validation in primary patient samples","pmids":["27440725"],"is_preprint":false},{"year":2017,"finding":"USP6 interacts with c-Jun and deubiquitinates it in an enzyme-activity-dependent manner, stabilizing c-Jun protein. USP6 overexpression upregulates AP-1-dependent downstream signaling and promotes cell invasion.","method":"DUB expression library screen, co-immunoprecipitation, ubiquitination assay with catalytically inactive USP6 mutant, AP-1 reporter assay, invasion assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — substrate identification by library screen, reciprocal Co-IP, enzymatic activity mutant, and functional cellular assays in a single focused study","pmids":["29061731"],"is_preprint":false},{"year":2019,"finding":"USP6 deubiquitinates GluN1 (NMDAR subunit), reducing NMDAR ubiquitination with concomitant elevation of NMDAR expression, stability, and cell-surface distribution. USP6 transgenic mice show enhanced NMDAR-dependent LTP/LTD and improved learning and memory; USP6 knockdown in human ESC-derived neurons impairs focal GluN1 distribution at postsynaptic densities and synaptic function.","method":"Transgenic mouse model, proteomic characterization (ubiquitination), cell surface biotinylation, LTP/LTD electrophysiology, behavior assays, siRNA knockdown in human ESC-derived neurons","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic substrate identification, in vivo transgenic model, electrophysiology, and loss-of-function in human neurons constituting multiple orthogonal methods","pmids":["31841517"],"is_preprint":false},{"year":2011,"finding":"USP6/TRE17 regulates cell migration and cytokinesis. Manipulating USP6 expression levels alters migration ability and progression through cytokinesis, via a pathway involving the small GTPase Arf6 and its GAP ACAP1.","method":"Overexpression and knockdown of USP6, migration assays, cytokinesis/proliferation assays, genetic epistasis with Arf6 and ACAP1","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotypes (migration, cytokinesis) with pathway placement via epistasis, single lab study","pmids":["22188517"],"is_preprint":false},{"year":2006,"finding":"The TBC domain GAP region of the Tre2 oncoprotein interacts with two cytoskeletal proteins—the light regulatory chain of myosin II (Myl2) and LOC91256 (ankyrin repeat protein)—as confirmed by GST pulldown, co-immunoprecipitation, and colocalization.","method":"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, colocalization microscopy","journal":"Biotechnology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, binding confirmed by pulldown and Co-IP but no functional consequence established for this interaction","pmids":["16555005"],"is_preprint":false},{"year":2010,"finding":"The oncogene TRE17/USP6 is identified as the first deubiquitinating enzyme to activate NF-κB (as stated in the paper reporting its mechanism); specifically, it activates the classical NF-κB pathway through an IκB-degradation-independent mechanism requiring IKK.","method":"Co-immunoprecipitation, IKK kinase assay, USP active-site mutant (see also PMID 22081069 for detailed mechanism)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — initial functional characterization; detailed mechanism covered separately in PMID 22081069","pmids":["20418905"],"is_preprint":false}],"current_model":"USP6 (TRE17) is a hominoid-specific deubiquitinating enzyme whose catalytic USP domain deubiquitinates multiple substrates—including Frizzled receptors (stabilizing Wnt signaling), Jak1 (activating STAT3), c-Jun (activating AP-1/invasion), and NMDA receptor subunits (promoting synaptic plasticity)—while its N-terminal TBC domain binds GDP-Arf6 and promotes its GTP loading at the plasma membrane, and its oncogenic overexpression (driven by promoter-swapping chromosomal translocations in aneurysmal bone cyst and nodular fasciitis) activates NF-κB via an IKK-dependent but IκB-degradation-independent mechanism, induces MMP expression through RhoA/ROCK, blocks osteoblast maturation by suppressing BMP-4 and upregulating Gremlin-1, and regulates surface abundance of CIE cargo proteins by counteracting MARCH-mediated ubiquitylation; calcium/calmodulin additionally regulates USP6 itself through direct Ca²⁺-dependent binding to its TBC domain, modulating its own ubiquitination state."},"narrative":{"mechanistic_narrative":"USP6 (TRE17) is a deubiquitinating enzyme whose catalytic USP domain drives both oncogenic and physiological programs by stabilizing diverse ubiquitylated substrates [PMID:8247125, PMID:27162353]. Through its DUB activity USP6 deubiquitinates and stabilizes Frizzled receptors to amplify Wnt/β-catenin signaling [PMID:27162353], Jak1 to activate STAT3 [PMID:27440725], and c-Jun to drive AP-1–dependent transcription and cell invasion [PMID:29061731], and it counteracts MARCH E3 ligase–mediated ubiquitylation of clathrin-independent endocytic cargo such as MHC class I to control their surface abundance [PMID:25179595]. The same catalytic activity underlies USP6 tumorigenicity: USP6 overexpression activates the classical NF-κB pathway via an IKK-dependent, IκB-degradation-independent route involving p65 Ser536 phosphorylation, inducing MMP-9/MMP-10 through RhoA/ROCK, and blocks osteoblast maturation by suppressing BMP-4 while inducing the antagonist Gremlin-1 [PMID:20418905, PMID:20864534, PMID:22081069]. Distinct from its DUB function, the N-terminal TBC domain binds GDP-bound Arf6 and promotes Arf6 GTP loading at the plasma membrane rather than acting as a GAP, linking USP6 to actin remodeling, cell migration, and cytokinesis under control of Cdc42/Rac1 and mitogenic signals [PMID:12612085, PMID:15509780, PMID:22188517]. In neurons, USP6 deubiquitinates the NMDAR subunit GluN1 to enhance receptor stability, surface delivery, and synaptic plasticity [PMID:31841517]. USP6 itself is regulated by Ca2+/calmodulin binding to its TBC domain, which modulates its mono- and polyubiquitination state [PMID:16127172].","teleology":[{"year":1993,"claim":"Established that the Tre-2/USP6 oncogene is a deubiquitinating enzyme, assigning a molecular activity to a previously enigmatic transforming gene.","evidence":"Sequence homology to and functional characterization of the yeast DUB Doa4","pmids":["8247125"],"confidence":"Medium","gaps":["DUB activity inferred by homology rather than direct enzymatic assay on USP6","No substrates identified at this stage"]},{"year":2003,"claim":"Linked USP6 to small-GTPase signaling and cytoskeletal dynamics by showing GTPase-dependent regulation of its localization, addressing how USP6 connects to membrane/actin pathways.","evidence":"Co-IP with active Cdc42/Rac1, mitogen-induced relocalization, actin depolymerization, and truncation mutagenesis","pmids":["12612085"],"confidence":"High","gaps":["Did not define the catalytic relationship between localization and DUB activity","Direct GTPase substrate or effector role unresolved"]},{"year":2004,"claim":"Resolved the function of the TBC domain by showing it binds GDP-Arf6 and promotes Arf6 activation rather than acting as a GAP, redefining TBC-domain function for this protein.","evidence":"GDP/GTP-fixed Arf6 pulldowns, domain mapping, in vivo GTP-loading assay, and siRNA knockdown","pmids":["15509780"],"confidence":"High","gaps":["Mechanism by which TBC facilitates GEF access not structurally defined","Did not connect Arf6 activation to specific downstream tumor phenotypes"]},{"year":2005,"claim":"Demonstrated that the TBC domain lacks canonical Rab-GAP activity, with both the TBC domain and an adjacent C-terminal region responsible, reinforcing the non-GAP nature of the oncoprotein.","evidence":"Yeast complementation of msb3Δ msb4Δ with Tre2/RN-tre chimeras","pmids":["16099424"],"confidence":"Medium","gaps":["Negative result from heterologous yeast assay","Structural basis of GAP inactivity not determined"]},{"year":2005,"claim":"Identified Ca2+/calmodulin as a direct regulator of USP6 that controls its own ubiquitination state, establishing an autoregulatory input.","evidence":"Ca2+-dependent CaM Co-IP and in vitro binding, CaM-site point mutants, W7 and A23187 treatment, and ubiquitination assays","pmids":["16127172"],"confidence":"High","gaps":["E3 ligase responsible for USP6 ubiquitination not identified","Functional consequence of CaM regulation on substrate DUB activity not tested"]},{"year":2010,"claim":"Tied USP6 tumorigenicity to NF-κB-driven MMP induction via RhoA/ROCK, showing the USP catalytic domain (not Arf6 binding) is required for transformation.","evidence":"Stable overexpression, MMP/NF-κB reporter assays, ROCK inhibitor, USP active-site mutant, and xenograft model","pmids":["20418905"],"confidence":"High","gaps":["Direct DUB substrate linking USP6 to NF-κB/RhoA not identified here","How RhoA is engaged downstream of USP6 unresolved"]},{"year":2010,"claim":"Explained how USP6 blocks bone-cyst-relevant osteoblast differentiation through an autocrine BMP-axis defect, connecting USP6 to aneurysmal bone cyst pathology.","evidence":"Osteoblast differentiation assays, transcriptome analysis, BMP-4 rescue, and USP active-site mutant","pmids":["20864534"],"confidence":"High","gaps":["DUB substrate driving BMP-4/Gremlin-1 dysregulation not identified","Autocrine factor mediating the effect not fully defined"]},{"year":2011,"claim":"Defined the atypical mechanism of NF-κB activation, showing USP6 binds and augments IKK activity and stimulates p65 Ser536 phosphorylation without IκB degradation.","evidence":"Co-IP, IKK kinase assay, dominant-negative IKK subunits, USP mutant, p65-S536 western, and xenograft with NF-κB inhibitor","pmids":["22081069"],"confidence":"High","gaps":["The ubiquitylated substrate within the IKK complex that USP6 acts on is unknown","How IKK is activated independent of IκB degradation not fully mechanistically resolved"]},{"year":2011,"claim":"Placed USP6 in control of migration and cytokinesis through an Arf6/ACAP1 axis, extending its non-catalytic membrane-trafficking role to cell division.","evidence":"Overexpression/knockdown migration and cytokinesis assays with Arf6 and ACAP1 epistasis","pmids":["22188517"],"confidence":"Medium","gaps":["Single-lab study without orthogonal mechanistic dissection","Whether DUB activity contributes to this phenotype not established"]},{"year":2014,"claim":"Revealed a trafficking function whereby USP6 deubiquitylates clathrin-independent endocytic cargo to oppose MARCH-mediated lysosomal targeting, controlling surface receptor abundance.","evidence":"MARCH8 co-expression, ubiquitination assays, surface MHC-I flow cytometry, USP active-site mutant, and lysosomal degradation assays","pmids":["25179595"],"confidence":"High","gaps":["Full repertoire of CIE cargo substrates not defined","Relevance to USP6-driven tumors not addressed"]},{"year":2016,"claim":"Identified Frizzled receptors as USP6 substrates, explaining how USP6 amplifies Wnt/β-catenin signaling to drive tumor growth.","evidence":"Genome-wide siRNA Wnt screen, deubiquitylation assays, surface receptor quantification, and DKK1/PORCN inhibitor xenograft assays","pmids":["27162353"],"confidence":"High","gaps":["Which specific Frizzled paralogs are preferred substrates not delineated","Crosstalk with other USP6 oncogenic pathways unresolved"]},{"year":2016,"claim":"Established the Jak1/STAT3 axis as a USP6 effector pathway by showing USP6 directly stabilizes Jak1, with epistasis confirming requirement for tumorigenicity.","evidence":"Co-IP, deubiquitination assay, CRISPR deletion of Jak1/STAT3, Jak inhibitor, xenograft model, and primary patient transcriptomics","pmids":["27440725"],"confidence":"High","gaps":["Site-specific ubiquitin linkage on Jak1 removed by USP6 not characterized","Relative contribution versus Wnt/NF-κB axes not quantified"]},{"year":2017,"claim":"Identified c-Jun as a USP6 substrate, linking USP6 DUB activity to AP-1 transcription and an invasive phenotype.","evidence":"DUB library screen, reciprocal Co-IP, ubiquitination assay with catalytically inactive mutant, AP-1 reporter, and invasion assay","pmids":["29061731"],"confidence":"High","gaps":["In vivo relevance of c-Jun stabilization not tested","Ubiquitin chain type on c-Jun not defined"]},{"year":2019,"claim":"Extended USP6 function to the nervous system by showing it deubiquitinates GluN1 to enhance NMDAR surface expression, synaptic plasticity, and learning.","evidence":"Transgenic mice, ubiquitination proteomics, surface biotinylation, LTP/LTD electrophysiology, behavior, and knockdown in human ESC-derived neurons","pmids":["31841517"],"confidence":"High","gaps":["Mechanism of USP6 recruitment to synapses not defined","Whether the same substrate logic applies in non-neuronal tissue unknown"]},{"year":null,"claim":"How USP6 substrate selectivity is governed across its many oncogenic and physiological targets, and how its two functional domains (catalytic USP vs Arf6-activating TBC) are coordinated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating USP and TBC domain functions","No unifying determinant of substrate recognition across Fzd, Jak1, c-Jun, GluN1, and CIE cargo","Whether Ca2+/CaM regulation tunes substrate-specific DUB activity untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,8,9,10,11,12]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,9,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,9,10,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,8,9,10,11]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,8,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[12]}],"complexes":[],"partners":["ARF6","JAK1","FZD","JUN","GRIN1","CHUK","CDC42","CALM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35125","full_name":"Ubiquitin carboxyl-terminal hydrolase 6","aliases":["Deubiquitinating enzyme 6","Proto-oncogene TRE-2","RN-tre","Ubiquitin thioesterase 6","Ubiquitin-specific-processing protease 6"],"length_aa":1406,"mass_kda":158.7,"function":"Deubiquitinase with an ATP-independent isopeptidase activity, cleaving at the C-terminus of the ubiquitin moiety. Catalyzes its own deubiquitination. In vitro, isoform 2, but not isoform 3, shows deubiquitinating activity. Promotes plasma membrane localization of ARF6 and selectively regulates ARF6-dependent endocytic protein trafficking. Is able to initiate tumorigenesis by inducing the production of matrix metalloproteinases following NF-kappa-B activation. May act as a GTPase-activating protein for RAB3A (PubMed:19077034)","subcellular_location":"Cell membrane; Cytoplasm; Endosome","url":"https://www.uniprot.org/uniprotkb/P35125/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USP6","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/USP6","total_profiled":1310},"omim":[{"mim_id":"616659","title":"TBC1 DOMAIN FAMILY, MEMBER 17; TBC1D17","url":"https://www.omim.org/entry/616659"},{"mim_id":"616637","title":"TBC1 DOMAIN FAMILY, MEMBER 16; TBC1D16","url":"https://www.omim.org/entry/616637"},{"mim_id":"615867","title":"TBC1 DOMAIN FAMILY, MEMBER 32; TBC1D32","url":"https://www.omim.org/entry/615867"},{"mim_id":"614855","title":"TBC1 DOMAIN FAMILY, MEMBER 14; TBC1D14","url":"https://www.omim.org/entry/614855"},{"mim_id":"613620","title":"TBC1 DOMAIN FAMILY, MEMBER 10B; TBC1D10B","url":"https://www.omim.org/entry/613620"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skeletal muscle","ntpm":19.0},{"tissue":"testis","ntpm":12.4}],"url":"https://www.proteinatlas.org/search/USP6"},"hgnc":{"alias_symbol":["Tre-2","TRE17","Tre2"],"prev_symbol":["HRP1","TRESMCR"]},"alphafold":{"accession":"P35125","domains":[{"cath_id":"1.10.8.270","chopping":"2-215","consensus_level":"medium","plddt":83.3882,"start":2,"end":215},{"cath_id":"-","chopping":"227-264_289-351","consensus_level":"medium","plddt":67.3622,"start":227,"end":351},{"cath_id":"3.90.70.10","chopping":"523-641_1312-1406","consensus_level":"medium","plddt":86.4849,"start":523,"end":1406},{"cath_id":"3.10.20.90","chopping":"717-798_1017-1025","consensus_level":"medium","plddt":86.5155,"start":717,"end":1025},{"cath_id":"-","chopping":"874-886_894-930_951-1011","consensus_level":"high","plddt":84.4348,"start":874,"end":1011}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35125","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35125-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35125-F1-predicted_aligned_error_v6.png","plddt_mean":65.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP6","jax_strain_url":"https://www.jax.org/strain/search?query=USP6"},"sequence":{"accession":"P35125","fasta_url":"https://rest.uniprot.org/uniprotkb/P35125.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35125/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35125"}},"corpus_meta":[{"pmid":"8247125","id":"PMC_8247125","title":"The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene.","date":"1993","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8247125","citation_count":350,"is_preprint":false},{"pmid":"15509545","id":"PMC_15509545","title":"USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts.","date":"2004","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15509545","citation_count":283,"is_preprint":false},{"pmid":"21826056","id":"PMC_21826056","title":"Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion.","date":"2011","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21826056","citation_count":258,"is_preprint":false},{"pmid":"15026324","id":"PMC_15026324","title":"USP6 (Tre2) fusion oncogenes in aneurysmal bone 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literature.","date":"2024","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36828621","citation_count":11,"is_preprint":false},{"pmid":"31736789","id":"PMC_31736789","title":"Evaluation of the Expression and Function of the TRE2-like and TRE2 Genes in Ecdysis of Harmonia axyridis.","date":"2019","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31736789","citation_count":10,"is_preprint":false},{"pmid":"28671529","id":"PMC_28671529","title":"Mycobacterium tuberculosis hypoxic response protein 1 (Hrp1) augments the pro-inflammatory response and enhances the survival of Mycobacterium smegmatis in murine macrophages.","date":"2017","source":"Journal of medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28671529","citation_count":10,"is_preprint":false},{"pmid":"37328256","id":"PMC_37328256","title":"Unravelling the USP6 gene: an update.","date":"2023","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37328256","citation_count":9,"is_preprint":false},{"pmid":"35175167","id":"PMC_35175167","title":"Intraneural Nodular Fasciitis of the Femoral Nerve with A Unique CTNNB1::USP6 Gene Fusion: Apropos of a Case and Review of Literature.","date":"2022","source":"International journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35175167","citation_count":9,"is_preprint":false},{"pmid":"16555005","id":"PMC_16555005","title":"The Tre2 oncoprotein, implicated in Ewing's sarcoma, interacts with two components of the cytoskeleton.","date":"2006","source":"Biotechnology letters","url":"https://pubmed.ncbi.nlm.nih.gov/16555005","citation_count":9,"is_preprint":false},{"pmid":"30076509","id":"PMC_30076509","title":"Aneurysmal Bone Cyst of the Maxillary Sinus with USP6 Rearrangement: Case Report of a Rare Entity and Review of the Literature.","date":"2018","source":"Head and neck pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30076509","citation_count":9,"is_preprint":false},{"pmid":"21536237","id":"PMC_21536237","title":"Unknown partner for USP6 and unusual SS18 rearrangement detected by fluorescence in situ hybridization in a solid aneurysmal bone cyst.","date":"2011","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21536237","citation_count":9,"is_preprint":false},{"pmid":"35962835","id":"PMC_35962835","title":"Multimodality imaging features of USP6-associated neoplasms.","date":"2022","source":"Skeletal radiology","url":"https://pubmed.ncbi.nlm.nih.gov/35962835","citation_count":8,"is_preprint":false},{"pmid":"32715361","id":"PMC_32715361","title":"Increased RNA production in Saccharomyces cerevisiae by simultaneously overexpressing FHL1, IFH1, and SSF2 and deleting HRP1.","date":"2020","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32715361","citation_count":8,"is_preprint":false},{"pmid":"16791615","id":"PMC_16791615","title":"Evidence for involvement of TRE-2 (USP6) oncogene, low-copy repeat and acrocentric heterochromatin in two families with chromosomal translocations.","date":"2006","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16791615","citation_count":8,"is_preprint":false},{"pmid":"38651320","id":"PMC_38651320","title":"Recurrent USP6 rearrangement in a subset of atypical myofibroblastic tumours of the soft tissues: low-grade myofibroblastic sarcoma or atypical/malignant nodular fasciitis?","date":"2024","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/38651320","citation_count":7,"is_preprint":false},{"pmid":"8406013","id":"PMC_8406013","title":"Identification of novel sequences in the repertoire of hypervariable TRE17 genes from immortalized nonmalignant and malignant human keratinocytes.","date":"1993","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8406013","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49404,"output_tokens":4479,"usd":0.107699,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12467,"output_tokens":4808,"usd":0.091268,"stage2_stop_reason":"end_turn"},"total_usd":0.198967,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The human Tre-2 (USP6) oncogene encodes a deubiquitinating enzyme, as inferred from its homology to the yeast Doa4 deubiquitinating enzyme, which cleaves ubiquitin from substrate remnants during proteasomal degradation.\",\n      \"method\": \"Sequence homology and functional characterization of yeast ortholog Doa4\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization performed on yeast ortholog Doa4 with mechanistic follow-through; USP6/Tre-2 DUB activity inferred by homology from a single study\",\n      \"pmids\": [\"8247125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TRE17 (USP6) oncogene coprecipitates specifically with the active (GTP-bound) forms of Cdc42 and Rac1 in vivo, and its subcellular localization is regulated by these GTPases and by mitogens: under serum starvation TRE17 localizes to filamentous structures, while EGF or activated Cdc42/Rac1 redistribute it to the plasma membrane in an actin polymerization-dependent manner. A C-terminal truncation mutant of TRE17 induces cortical actin accumulation mimicking activated Cdc42.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization (fluorescence microscopy), dominant-active GTPase expression, actin depolymerization experiments, truncation mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, live-cell localization, mutagenesis, and pharmacological perturbation in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"12612085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The TBC domain of TRE17/USP6 mediates direct binding to Arf6 in its GDP-bound (inactive) state but not in its GTP-bound state. Rather than acting as a GAP, TRE17 promotes Arf6 activation (GTP loading) in vivo by facilitating its access to membrane-associated GEFs, leading to plasma membrane localization of Arf6. siRNA-mediated knockdown of TRE17 attenuates Arf6 activation.\",\n      \"method\": \"Co-immunoprecipitation with GDP- and GTP-fixed Arf6 mutants, domain-mapping pulldown, in vivo GTP-loading assay, siRNA knockdown, fluorescence microscopy\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (pulldown, GTP-loading assay, RNAi, localization) in a single focused study establishing an unexpected non-GAP function for the TBC domain\",\n      \"pmids\": [\"15509780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Calmodulin (CaM) binds directly to TRE17/USP6 in a Ca2+-dependent manner in vitro and in vivo. The CaM-binding site maps to two hydrophobic motifs near the C terminus of the TBC domain. TRE17 is monoubiquitinated and promotes its own deubiquitination; CaM-binding-deficient point mutants show significantly reduced monoubiquitination, and the CaM inhibitor W7 also reduces TRE17 monoubiquitination. The calcium ionophore A23187 induces polyubiquitinated TRE17 in a CaM-binding-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation (Ca2+-dependent), in vitro binding assay, point mutagenesis, pharmacological inhibition (W7, A23187), ubiquitination assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding + mutagenesis + cellular ubiquitination assays in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"16127172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The TBC domain of the Tre2 oncoprotein lacks Rab-GAP activity; chimeric protein experiments swapping regions N- and C-terminal to the TBC domain between Tre2 and active GAP RN-tre revealed that both the TBC domain itself and a 93-aa region C-terminal to it contribute to the oncoprotein's failure to function as a Rab-GAP.\",\n      \"method\": \"Yeast complementation of msb3Δ msb4Δ double mutant using chimeric Tre2/RN-tre proteins\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation assay with domain-swap constructs in a single study; negative GAP activity confirmed by functional readout\",\n      \"pmids\": [\"16099424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRE17/USP6 overexpression in cells induces transcription of MMP-9 and MMP-10 through activation of NF-κB, a process requiring USP catalytic activity but not Arf6 binding. RhoA and its effector kinase ROCK are required for NF-κB activation by TRE17. Xenograft studies confirm that tumorigenic activity of TRE17 depends on the USP domain.\",\n      \"method\": \"Stable overexpression, reporter assays, dominant-negative/constitutively active GTPase constructs, ROCK inhibitor, site-directed mutagenesis of USP active site, xenograft mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay, pharmacological inhibition, mutagenesis, in vivo xenograft) in a single focused study\",\n      \"pmids\": [\"20418905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRE17/USP6 potently inhibits maturation of MC3T3 pre-osteoblasts in a USP-dependent, Arf6-independent manner through an autocrine mechanism. Transcriptome analysis reveals dysregulation of BMP signaling: TRE17 simultaneously inhibits BMP-4 expression and upregulates the BMP antagonist Gremlin-1. Addition of exogenous BMP-4 rescues osteoblast maturation in TRE17-expressing cells.\",\n      \"method\": \"Stable overexpression, osteoblast differentiation assay, transcriptome analysis, cytokine rescue experiments, USP active-site mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mutagenesis, transcriptome, and functional rescue experiments establishing a mechanistic autocrine pathway\",\n      \"pmids\": [\"20864534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRE17/USP6 activates the classical NF-κB pathway through an atypical mechanism that does not involve IκB degradation. TRE17 co-precipitates with IKK, augments IKK activity in a USP-dependent manner, requires both IKKα and IKKβ catalytic subunits (and IKKγ/NEMO) for optimal activity, and stimulates phosphorylation of p65 at serine 536. Inhibition of NF-κB significantly attenuates TRE17-driven tumor formation in NIH3T3 cells.\",\n      \"method\": \"Co-immunoprecipitation, IKK kinase assay, USP active-site mutant, dominant-negative IKK subunits, p65-S536 phosphorylation western blot, xenograft tumorigenesis with NF-κB inhibitor\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, enzymatic assay, mutagenesis, in vivo tumor model with pharmacological inhibition—multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"22081069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRE17/USP6 deubiquitylates CIE (clathrin-independent endocytosis) cargo proteins, counteracting MARCH E3 ubiquitin ligase-dependent targeting of these cargos to lysosomes. The effect is dependent on USP6 deubiquitylating activity and is specific to CIE cargo (e.g., MHC class I); transferrin receptor (clathrin-dependent cargo) is unaffected. Expression of TRE17 alone stabilizes surface MHC class I.\",\n      \"method\": \"Co-expression with MARCH8, ubiquitination assays, flow cytometry for surface protein levels, USP active-site mutant, lysosomal degradation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — enzymatic activity mutant, ubiquitination rescue assay, and surface protein quantification with appropriate controls in a single focused study\",\n      \"pmids\": [\"25179595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP6 deubiquitylates Frizzled (Fzd) receptors, increasing their cell-surface abundance and thereby enhancing Wnt/β-catenin signaling. Genome-wide siRNA screen identified USP6 as a potent Wnt activator. Inhibition of Wnt signaling with DKK1 or a Porcupine inhibitor significantly decreased the growth of USP6-driven xenograft tumors.\",\n      \"method\": \"Genome-wide siRNA screen, deubiquitylation assays, surface receptor quantification, DKK1 and PORCN inhibitor treatment, xenograft tumor assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen plus mechanistic follow-up with deubiquitylation assays, surface receptor quantification, and in vivo pharmacological inhibition\",\n      \"pmids\": [\"27162353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP6 directly deubiquitinates Jak1, leading to its stabilization and activation of STAT3 signaling. CRISPR-mediated deletion of Jak1 or STAT3 significantly attenuates USP6 tumorigenic potential. A Jak family inhibitor also reduces USP6-driven tumor formation.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, CRISPR-mediated gene deletion, Jak inhibitor treatment, xenograft tumor model, transcriptomic analysis of primary clinical samples\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — substrate deubiquitination assay, CRISPR epistasis, pharmacological inhibition, and in vivo tumor model with validation in primary patient samples\",\n      \"pmids\": [\"27440725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP6 interacts with c-Jun and deubiquitinates it in an enzyme-activity-dependent manner, stabilizing c-Jun protein. USP6 overexpression upregulates AP-1-dependent downstream signaling and promotes cell invasion.\",\n      \"method\": \"DUB expression library screen, co-immunoprecipitation, ubiquitination assay with catalytically inactive USP6 mutant, AP-1 reporter assay, invasion assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — substrate identification by library screen, reciprocal Co-IP, enzymatic activity mutant, and functional cellular assays in a single focused study\",\n      \"pmids\": [\"29061731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP6 deubiquitinates GluN1 (NMDAR subunit), reducing NMDAR ubiquitination with concomitant elevation of NMDAR expression, stability, and cell-surface distribution. USP6 transgenic mice show enhanced NMDAR-dependent LTP/LTD and improved learning and memory; USP6 knockdown in human ESC-derived neurons impairs focal GluN1 distribution at postsynaptic densities and synaptic function.\",\n      \"method\": \"Transgenic mouse model, proteomic characterization (ubiquitination), cell surface biotinylation, LTP/LTD electrophysiology, behavior assays, siRNA knockdown in human ESC-derived neurons\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic substrate identification, in vivo transgenic model, electrophysiology, and loss-of-function in human neurons constituting multiple orthogonal methods\",\n      \"pmids\": [\"31841517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USP6/TRE17 regulates cell migration and cytokinesis. Manipulating USP6 expression levels alters migration ability and progression through cytokinesis, via a pathway involving the small GTPase Arf6 and its GAP ACAP1.\",\n      \"method\": \"Overexpression and knockdown of USP6, migration assays, cytokinesis/proliferation assays, genetic epistasis with Arf6 and ACAP1\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotypes (migration, cytokinesis) with pathway placement via epistasis, single lab study\",\n      \"pmids\": [\"22188517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The TBC domain GAP region of the Tre2 oncoprotein interacts with two cytoskeletal proteins—the light regulatory chain of myosin II (Myl2) and LOC91256 (ankyrin repeat protein)—as confirmed by GST pulldown, co-immunoprecipitation, and colocalization.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, colocalization microscopy\",\n      \"journal\": \"Biotechnology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, binding confirmed by pulldown and Co-IP but no functional consequence established for this interaction\",\n      \"pmids\": [\"16555005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The oncogene TRE17/USP6 is identified as the first deubiquitinating enzyme to activate NF-κB (as stated in the paper reporting its mechanism); specifically, it activates the classical NF-κB pathway through an IκB-degradation-independent mechanism requiring IKK.\",\n      \"method\": \"Co-immunoprecipitation, IKK kinase assay, USP active-site mutant (see also PMID 22081069 for detailed mechanism)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — initial functional characterization; detailed mechanism covered separately in PMID 22081069\",\n      \"pmids\": [\"20418905\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP6 (TRE17) is a hominoid-specific deubiquitinating enzyme whose catalytic USP domain deubiquitinates multiple substrates—including Frizzled receptors (stabilizing Wnt signaling), Jak1 (activating STAT3), c-Jun (activating AP-1/invasion), and NMDA receptor subunits (promoting synaptic plasticity)—while its N-terminal TBC domain binds GDP-Arf6 and promotes its GTP loading at the plasma membrane, and its oncogenic overexpression (driven by promoter-swapping chromosomal translocations in aneurysmal bone cyst and nodular fasciitis) activates NF-κB via an IKK-dependent but IκB-degradation-independent mechanism, induces MMP expression through RhoA/ROCK, blocks osteoblast maturation by suppressing BMP-4 and upregulating Gremlin-1, and regulates surface abundance of CIE cargo proteins by counteracting MARCH-mediated ubiquitylation; calcium/calmodulin additionally regulates USP6 itself through direct Ca²⁺-dependent binding to its TBC domain, modulating its own ubiquitination state.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"USP6 (TRE17) is a deubiquitinating enzyme whose catalytic USP domain drives both oncogenic and physiological programs by stabilizing diverse ubiquitylated substrates [#0, #9]. Through its DUB activity USP6 deubiquitinates and stabilizes Frizzled receptors to amplify Wnt/\\u03b2-catenin signaling [#9], Jak1 to activate STAT3 [#10], and c-Jun to drive AP-1\\u2013dependent transcription and cell invasion [#11], and it counteracts MARCH E3 ligase\\u2013mediated ubiquitylation of clathrin-independent endocytic cargo such as MHC class I to control their surface abundance [#8]. The same catalytic activity underlies USP6 tumorigenicity: USP6 overexpression activates the classical NF-\\u03baB pathway via an IKK-dependent, I\\u03baB-degradation-independent route involving p65 Ser536 phosphorylation, inducing MMP-9/MMP-10 through RhoA/ROCK, and blocks osteoblast maturation by suppressing BMP-4 while inducing the antagonist Gremlin-1 [#5, #6, #7]. Distinct from its DUB function, the N-terminal TBC domain binds GDP-bound Arf6 and promotes Arf6 GTP loading at the plasma membrane rather than acting as a GAP, linking USP6 to actin remodeling, cell migration, and cytokinesis under control of Cdc42/Rac1 and mitogenic signals [#1, #2, #13]. In neurons, USP6 deubiquitinates the NMDAR subunit GluN1 to enhance receptor stability, surface delivery, and synaptic plasticity [#12]. USP6 itself is regulated by Ca2+/calmodulin binding to its TBC domain, which modulates its mono- and polyubiquitination state [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that the Tre-2/USP6 oncogene is a deubiquitinating enzyme, assigning a molecular activity to a previously enigmatic transforming gene.\",\n      \"evidence\": \"Sequence homology to and functional characterization of the yeast DUB Doa4\",\n      \"pmids\": [\"8247125\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"DUB activity inferred by homology rather than direct enzymatic assay on USP6\", \"No substrates identified at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked USP6 to small-GTPase signaling and cytoskeletal dynamics by showing GTPase-dependent regulation of its localization, addressing how USP6 connects to membrane/actin pathways.\",\n      \"evidence\": \"Co-IP with active Cdc42/Rac1, mitogen-induced relocalization, actin depolymerization, and truncation mutagenesis\",\n      \"pmids\": [\"12612085\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not define the catalytic relationship between localization and DUB activity\", \"Direct GTPase substrate or effector role unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the function of the TBC domain by showing it binds GDP-Arf6 and promotes Arf6 activation rather than acting as a GAP, redefining TBC-domain function for this protein.\",\n      \"evidence\": \"GDP/GTP-fixed Arf6 pulldowns, domain mapping, in vivo GTP-loading assay, and siRNA knockdown\",\n      \"pmids\": [\"15509780\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which TBC facilitates GEF access not structurally defined\", \"Did not connect Arf6 activation to specific downstream tumor phenotypes\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that the TBC domain lacks canonical Rab-GAP activity, with both the TBC domain and an adjacent C-terminal region responsible, reinforcing the non-GAP nature of the oncoprotein.\",\n      \"evidence\": \"Yeast complementation of msb3\\u0394 msb4\\u0394 with Tre2/RN-tre chimeras\",\n      \"pmids\": [\"16099424\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Negative result from heterologous yeast assay\", \"Structural basis of GAP inactivity not determined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified Ca2+/calmodulin as a direct regulator of USP6 that controls its own ubiquitination state, establishing an autoregulatory input.\",\n      \"evidence\": \"Ca2+-dependent CaM Co-IP and in vitro binding, CaM-site point mutants, W7 and A23187 treatment, and ubiquitination assays\",\n      \"pmids\": [\"16127172\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"E3 ligase responsible for USP6 ubiquitination not identified\", \"Functional consequence of CaM regulation on substrate DUB activity not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Tied USP6 tumorigenicity to NF-\\u03baB-driven MMP induction via RhoA/ROCK, showing the USP catalytic domain (not Arf6 binding) is required for transformation.\",\n      \"evidence\": \"Stable overexpression, MMP/NF-\\u03baB reporter assays, ROCK inhibitor, USP active-site mutant, and xenograft model\",\n      \"pmids\": [\"20418905\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct DUB substrate linking USP6 to NF-\\u03baB/RhoA not identified here\", \"How RhoA is engaged downstream of USP6 unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Explained how USP6 blocks bone-cyst-relevant osteoblast differentiation through an autocrine BMP-axis defect, connecting USP6 to aneurysmal bone cyst pathology.\",\n      \"evidence\": \"Osteoblast differentiation assays, transcriptome analysis, BMP-4 rescue, and USP active-site mutant\",\n      \"pmids\": [\"20864534\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"DUB substrate driving BMP-4/Gremlin-1 dysregulation not identified\", \"Autocrine factor mediating the effect not fully defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the atypical mechanism of NF-\\u03baB activation, showing USP6 binds and augments IKK activity and stimulates p65 Ser536 phosphorylation without I\\u03baB degradation.\",\n      \"evidence\": \"Co-IP, IKK kinase assay, dominant-negative IKK subunits, USP mutant, p65-S536 western, and xenograft with NF-\\u03baB inhibitor\",\n      \"pmids\": [\"22081069\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"The ubiquitylated substrate within the IKK complex that USP6 acts on is unknown\", \"How IKK is activated independent of I\\u03baB degradation not fully mechanistically resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed USP6 in control of migration and cytokinesis through an Arf6/ACAP1 axis, extending its non-catalytic membrane-trafficking role to cell division.\",\n      \"evidence\": \"Overexpression/knockdown migration and cytokinesis assays with Arf6 and ACAP1 epistasis\",\n      \"pmids\": [\"22188517\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single-lab study without orthogonal mechanistic dissection\", \"Whether DUB activity contributes to this phenotype not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a trafficking function whereby USP6 deubiquitylates clathrin-independent endocytic cargo to oppose MARCH-mediated lysosomal targeting, controlling surface receptor abundance.\",\n      \"evidence\": \"MARCH8 co-expression, ubiquitination assays, surface MHC-I flow cytometry, USP active-site mutant, and lysosomal degradation assays\",\n      \"pmids\": [\"25179595\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Full repertoire of CIE cargo substrates not defined\", \"Relevance to USP6-driven tumors not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified Frizzled receptors as USP6 substrates, explaining how USP6 amplifies Wnt/\\u03b2-catenin signaling to drive tumor growth.\",\n      \"evidence\": \"Genome-wide siRNA Wnt screen, deubiquitylation assays, surface receptor quantification, and DKK1/PORCN inhibitor xenograft assays\",\n      \"pmids\": [\"27162353\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Which specific Frizzled paralogs are preferred substrates not delineated\", \"Crosstalk with other USP6 oncogenic pathways unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the Jak1/STAT3 axis as a USP6 effector pathway by showing USP6 directly stabilizes Jak1, with epistasis confirming requirement for tumorigenicity.\",\n      \"evidence\": \"Co-IP, deubiquitination assay, CRISPR deletion of Jak1/STAT3, Jak inhibitor, xenograft model, and primary patient transcriptomics\",\n      \"pmids\": [\"27440725\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Site-specific ubiquitin linkage on Jak1 removed by USP6 not characterized\", \"Relative contribution versus Wnt/NF-\\u03baB axes not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified c-Jun as a USP6 substrate, linking USP6 DUB activity to AP-1 transcription and an invasive phenotype.\",\n      \"evidence\": \"DUB library screen, reciprocal Co-IP, ubiquitination assay with catalytically inactive mutant, AP-1 reporter, and invasion assay\",\n      \"pmids\": [\"29061731\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In vivo relevance of c-Jun stabilization not tested\", \"Ubiquitin chain type on c-Jun not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended USP6 function to the nervous system by showing it deubiquitinates GluN1 to enhance NMDAR surface expression, synaptic plasticity, and learning.\",\n      \"evidence\": \"Transgenic mice, ubiquitination proteomics, surface biotinylation, LTP/LTD electrophysiology, behavior, and knockdown in human ESC-derived neurons\",\n      \"pmids\": [\"31841517\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of USP6 recruitment to synapses not defined\", \"Whether the same substrate logic applies in non-neuronal tissue unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How USP6 substrate selectivity is governed across its many oncogenic and physiological targets, and how its two functional domains (catalytic USP vs Arf6-activating TBC) are coordinated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model integrating USP and TBC domain functions\", \"No unifying determinant of substrate recognition across Fzd, Jak1, c-Jun, GluN1, and CIE cargo\", \"Whether Ca2+/CaM regulation tunes substrate-specific DUB activity untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 8, 9, 10, 11, 12]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 9, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 8, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 8, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ARF6\", \"JAK1\", \"FZD\", \"JUN\", \"GRIN1\", \"CHUK\", \"CDC42\", \"CALM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}