{"gene":"CUL7","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2002,"finding":"CUL7 assembles an SCF-ROC1-like E3 ubiquitin ligase complex consisting of Skp1, CUL7, the Fbx29 (FBXW8) F-box protein, and ROC1. CUL7 was identified by mass spectrometry as a ROC1-interacting protein. CUL7 contains a cullin domain responsible for ROC1 binding and a DOC domain. Unlike CUL1 which binds Skp1 alone, CUL7 interacts selectively with the Skp1·Fbx29 heterodimer but not with Skp1 alone, nor with Skp1·betaTRCP2 or Skp1·Skp2.","method":"Mass spectrometry identification, co-immunoprecipitation, deletion/domain analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP and MS identification with domain mapping; foundational complex assembly paper replicated by multiple subsequent studies","pmids":["12481031"],"is_preprint":false},{"year":2003,"finding":"CUL7 (p185) forms an SCF-like complex with Skp1, Rbx1, Fbw6 (Fbx29/FBXW8), and FAP68 (glomulin). Targeted disruption of Cul7 in mice results in runted embryos that die at birth with respiratory distress, dermal hemorrhage, and placental defects including abnormal trophoblast differentiation and vascular structure, demonstrating a role for CUL7 in vascular morphogenesis and placental development.","method":"Co-immunoprecipitation, mouse knockout (targeted gene disruption), histological analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout phenotype combined with complex co-IP; replicated by independent labs","pmids":["12904573"],"is_preprint":false},{"year":2005,"finding":"CUL7 assembles an E3 ubiquitin ligase complex with SKP1, RBX1, and the F-box protein FBXW8. CUL7 nonsense (R1445X) and missense (H1464P) mutations associated with 3-M syndrome render CUL7 deficient in recruiting ROC1, suggesting impaired ubiquitination underlies the pathogenesis. CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer.","method":"Deletion analysis, co-immunoprecipitation, mutant functional assay","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping with deletion analysis and disease-mutation functional testing; replicates and extends PMID:12481031","pmids":["16142236"],"is_preprint":false},{"year":2004,"finding":"SV40 large T antigen binds the CUL7 SCF-like complex (containing p185/CUL7, Rbx1, and Fbw6/FBXW8) via an N-terminal region. p185/CUL7-binding-deficient T antigen mutants retain binding to pRb and p53 but are unable to transform primary mouse embryo fibroblasts, indicating that CUL7 binding is required for T antigen-mediated cellular transformation and that CUL7 may regulate a growth control pathway.","method":"Co-immunoprecipitation, T antigen mutagenesis, focus formation / anchorage-independent growth assays, MEF transformation","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus mutagenesis plus functional transformation assay in same study; confirmed and extended by PMID:16140746","pmids":["14990695"],"is_preprint":false},{"year":2005,"finding":"SV40 T antigen residues 69–83 are required for binding to the CUL7 complex. Delta69-83 T antigen loses CUL7 binding while retaining p53 and pRB binding. Wild-type T antigen induces MEF proliferation (transformation) in the presence of CUL7, but delta69-83 T antigen does not, suggesting CUL7 is a target whose inactivation by T antigen contributes to transformation and that CUL7 may function as a tumor suppressor.","method":"Deletion mutagenesis, co-immunoprecipitation, MEF proliferation and transformation assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis with functional readout replicated across two labs (PMID:14990695 and PMID:16140746)","pmids":["16140746"],"is_preprint":false},{"year":2006,"finding":"CUL7 forms a heterodimeric complex with CUL1 in a manner dependent on FBXW8 (Fbxw8). Fbxw8-knockout mice lack CUL7–CUL1 association. Fbxw8-null mice show intrauterine growth retardation and placental defects similar to Cul7-null mice, but some abnormalities of Cul7-/- mice are absent, indicating that the CUL7–Fbxw8 complex has both Fbxw8-dependent and Fbxw8-independent functions.","method":"Co-immunoprecipitation, mouse knockout (Fbxw8 targeting), genetic epistasis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus in vivo genetic epistasis with two knockout models","pmids":["16880526"],"is_preprint":false},{"year":2006,"finding":"CUL7 directly binds p53 via a discrete, evolutionarily conserved domain (CPH domain) that is also conserved in PARC and HERC2. This p53-binding domain is necessary and sufficient for p53 interaction, p53 stabilizes expression of this domain, and the domain contributes to cytoplasmic localization of CUL7. CUL7 binding to p53 does not affect p53 expression levels.","method":"Co-immunoprecipitation, deletion analysis, subcellular localization by imaging","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — domain deletion plus localization experiment, single lab, no in vitro reconstitution","pmids":["16875676"],"is_preprint":false},{"year":2007,"finding":"The CPH domains of CUL7 and PARC are protein–protein interaction modules that bind the tetramerization domain of p53. NMR structure of the CUL7-CPH domain reveals a fold similar to SH3, Tudor, and KOW domains, but the p53-binding surface is distinct from the canonical peptide-binding surfaces of those domains. The p53 interaction surface on p53 resides in its tetramerization domain and involves residues from at least two subunits.","method":"NMR spectroscopy, size-exclusion chromatography, structural determination with functional validation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with binding interface mapping; single lab but multiple orthogonal structural and biochemical methods","pmids":["17298945"],"is_preprint":false},{"year":2007,"finding":"CUL7 and PARC form homodimers and heterodimers. Tandem affinity purification–MudPIT analysis revealed that the CUL7 interaction with FBXW8 is mutually exclusive with CUL7 binding to PARC or p53. PARC binds RBX1 and is covalently modified by NEDD8, defining PARC as a cullin, but PARC fails to bind SKP1 or F-box proteins including FBXW8. All examined PARC- and CUL7-containing subcomplexes exhibit E3 ubiquitin ligase activity in vitro. Parc-/-/Fbxw8-/- double knockout does not exacerbate the Fbxw8-/- phenotype.","method":"Tandem affinity purification, MudPIT mass spectrometry, in vitro ubiquitin ligase assay, double-knockout genetic epistasis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — TAP-MS complex mapping plus in vitro E3 activity assay plus in vivo genetic epistasis in single study","pmids":["17332328"],"is_preprint":false},{"year":2007,"finding":"CUL7 binds p53 directly and its knockdown by siRNA elevates p53 protein levels. CUL7 exerts an anti-apoptotic function through p53, enabling it to inhibit Myc-induced apoptosis. CUL7 cooperates with Myc to drive cellular transformation in soft agar assays.","method":"Expression cloning screen, co-immunoprecipitation, siRNA knockdown, anchorage-independent growth assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cloning plus co-IP plus siRNA with phenotypic readout; single lab","pmids":["17942889"],"is_preprint":false},{"year":2005,"finding":"PARC (a CUL7 homolog) was identified as a CUL7-interacting protein by mass spectrometry. CUL7 and PARC form endogenous hetero- and homodimers in vivo. Parc knockout mice are born at expected Mendelian ratios with no apparent phenotype, and Parc deletion does not affect p53 stability, localization, or function, indicating that PARC and CUL7 functions are at least partially non-overlapping.","method":"Mass spectrometry, co-immunoprecipitation, Parc knockout mouse","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of interaction, confirmed by co-IP, validated in vivo with knockout","pmids":["15964813"],"is_preprint":false},{"year":2008,"finding":"IRS-1 (insulin receptor substrate 1) is a proteolytic substrate of the CUL7 E3 ubiquitin ligase. IRS-1 degradation depends on mTOR and p70 S6 kinase activity. Cul7-/- mouse embryonic fibroblasts accumulate IRS-1 and show increased activation of Akt and MEK/ERK pathways, but grow poorly and display oncogene-induced senescence-like phenotypes.","method":"Ubiquitin ligase assay, Cul7-/- MEF analysis, signaling pathway analysis, mTOR/S6K inhibition","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in vivo (knockout MEFs) with defined substrate accumulation and downstream pathway activation, replicated by pharmacological inhibition","pmids":["18498745"],"is_preprint":false},{"year":2013,"finding":"The CUL7/FBXW8 ubiquitin ligase targets hematopoietic progenitor kinase 1 (HPK1) for ubiquitination and proteasomal degradation. HPK1 ubiquitination requires its kinase activity and autophosphorylation (at Thr-355). Protein phosphatase 4 (PP4) dephosphorylates Thr-355 and inhibits Fbxw8–HPK1 interaction, thereby stabilizing HPK1. Knockdown of Fbxw8 restores endogenous HPK1 and inhibits pancreatic cancer cell proliferation.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, phosphorylation/dephosphorylation analysis, siRNA knockdown, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitination assay plus co-IP plus mutagenesis (phosphosite) plus functional KD; single lab, multiple orthogonal methods","pmids":["24362026"],"is_preprint":false},{"year":2012,"finding":"CUL7 E3 ligase ubiquitinates TBC1D3 in response to serum/growth factor stimulation, leading to its proteasomal degradation. TBC1D3 physically interacts with CUL7 (identified by yeast two-hybrid) and recruits FBXW8 in pulldown and in vitro assays. Phosphorylation of TBC1D3 is critical for Fbxw8 recruitment and subsequent ubiquitination; alkaline phosphatase treatment of TBC1D3 suppresses Fbxw8 recruitment.","method":"Yeast two-hybrid, co-immunoprecipitation, pulldown, in vitro ubiquitination assay, phosphatase treatment","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid plus in vitro assay plus biochemical dephosphorylation experiment; single lab, multiple orthogonal methods","pmids":["23029530"],"is_preprint":false},{"year":2011,"finding":"CCDC8 co-immunoprecipitates with OBSL1 but not with CUL7, placing CCDC8 in a pathway with CUL7 and OBSL1 through OBSL1 as an intermediary. CUL7(-/-) cells show impaired IGF1-stimulated AKT activation, consistent with dysregulated IGF1 signaling downstream of CUL7.","method":"Co-immunoprecipitation, exome sequencing for pathway placement, signaling assays in patient-derived fibroblasts","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus cell signaling in patient-derived KO fibroblasts; single lab","pmids":["21737058"],"is_preprint":false},{"year":2012,"finding":"CUL7(-/-) patient fibroblasts show impaired AKT activation in response to IGF1 stimulation at 5 min post-stimulation, while GH-induced STAT5b and MAPK activation is normal. This indicates CUL7 loss specifically impairs IGF1 signaling through the PI3K/AKT axis.","method":"Cell signaling assays (phospho-Western) in patient-derived CUL7-/- fibroblasts","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined signaling defect in patient-derived null cells with specific pathway readout; single lab","pmids":["23018678"],"is_preprint":false},{"year":2019,"finding":"CUL7 promotes cancer cell survival by interacting with Caspase-8 and promoting its modification with non-degradative polyubiquitin chains at K215, thereby preventing Caspase-8 activation. CUL7 knockdown sensitizes cancer cells to TRAIL-induced apoptosis in vitro and in nude mice.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K215), siRNA knockdown, apoptosis assay in vitro and in vivo","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — specific ubiquitination site identified by mutagenesis, functional rescue assay, in vivo validation; single lab but multiple orthogonal methods","pmids":["30807646"],"is_preprint":false},{"year":2019,"finding":"CUL7 E3 ubiquitin ligase mediates ubiquitination of AID (activation-induced cytidine deaminase) by forming a complex with FBXW11. CUL7 overexpression or knockdown regulates AID protein levels and IgA class switching in B cells. CUL7 conditional knockout (CUL7 fl/fl CD19-Cre) in mice increases AID protein levels in germinal center B cells and enhances IgG1 and IgA class switching.","method":"Co-immunoprecipitation, ubiquitination assay, CUL7 conditional knockout mouse, B cell class switch recombination assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP plus in vivo conditional KO with defined immunological phenotype plus ubiquitination assay; single lab, multiple methods","pmids":["31092637"],"is_preprint":false},{"year":2020,"finding":"CUL7 physically associates with MST1, promoting ubiquitin-mediated MST1 protein degradation, which activates the NF-κB signaling pathway to promote glioma cell growth.","method":"Co-immunoprecipitation, siRNA/shRNA knockdown, CUL7 overexpression, in vitro and in vivo tumor assays, western blot for NF-κB pathway markers","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP demonstrating physical interaction and functional pathway consequence; single lab, without in vitro reconstituted ubiquitination assay described in abstract","pmids":["32252802"],"is_preprint":false},{"year":2024,"finding":"CUL7 promotes ubiquitination and degradation of glutathione peroxidase 4 (GPX4) in photoreceptors. CUL7 knockdown prevents Cul7-mediated GPX4 ubiquitination and degradation, inhibiting photoreceptor ferroptosis and alleviating retinal degeneration in mouse models.","method":"Transcriptome sequencing to identify target, siRNA knockdown, ubiquitination assay (GPX4), in vivo mouse models (MNU-induced and Pde6βrd1/rd1 mutant)","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ubiquitination assay plus in vivo KD rescue; single lab, novel substrate claim with limited mechanistic detail in abstract","pmids":["39267786"],"is_preprint":false},{"year":2025,"finding":"CUL7 promotes HER2 ubiquitination in HER2-positive breast cancer. CAND1 directly interacts with HER2 and stabilizes its expression; CAND1 knockdown enhances CUL7 neddylation, activating its ligase activity and leading to HER2 ubiquitination and destabilization.","method":"Co-immunoprecipitation, western blot, ubiquitination assay, CAND1 knockdown, in vivo xenograft","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — co-IP and ubiquitination assay with functional KD; single lab, novel substrate/regulatory mechanism with limited in-abstract detail","pmids":["41310794"],"is_preprint":false},{"year":2026,"finding":"CUL7 interacts with KEAP1 and catalyzes K29- and K48-linked polyubiquitination of KEAP1 to promote its proteasomal degradation, thereby activating NRF2 signaling and reducing ROS levels in colon cancer cells. The C-terminus of CUL7 is required for KEAP1 stability regulation.","method":"Co-immunoprecipitation, ubiquitination assay (linkage-specific), CUL7 knockout mouse model, CUL7 domain deletion, cancer cell KO/overexpression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro ubiquitination with linkage specificity plus domain mapping plus in vivo model; single lab, novel substrate claim","pmids":["42252284"],"is_preprint":false},{"year":2026,"finding":"CCDC8 interacts with CUL7 to facilitate proteasome-dependent degradation of P53. Pharmacological inhibition of neddylation (MLN4924) restored P53 levels and reversed CCDC8-driven oncogenic effects, implicating neddylation-dependent CUL7 activity in CCDC8-mediated P53 degradation in bladder cancer.","method":"Co-immunoprecipitation, western blot, MLN4924 neddylation inhibition, in vitro and in vivo tumor assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — co-IP with functional pharmacological inhibition; single lab, CUL7 role inferred from inhibitor experiments","pmids":["41644704"],"is_preprint":false}],"current_model":"CUL7 is a cullin-family scaffold that assembles an SCF-like E3 ubiquitin ligase complex with SKP1, RBX1 (ROC1), and the F-box protein FBXW8 (Fbx29/Fbw6) — selectively recruiting the SKP1·FBXW8 heterodimer rather than SKP1 alone — and, dependent on FBXW8, also forms a heterodimeric complex with CUL1; this CUL7 complex ubiquitinates a growing set of substrates including IRS-1 (in an mTOR/S6K-dependent manner), HPK1 (phosphorylation-dependent, counteracted by PP4), TBC1D3 (serum-stimulated, phospho-dependent), AID (forming a complex with FBXW11), Caspase-8 (non-degradative K215 polyubiquitination to suppress extrinsic apoptosis), GPX4 (promoting ferroptosis), KEAP1 (K29/K48-linked degradation activating NRF2), MST1, and HER2; CUL7 also contains a CPH domain that directly binds the tetramerization domain of p53 (structurally defined by NMR), and CUL7 dimerizes with the related cullin PARC in a complex that is mutually exclusive with FBXW8 binding; in vivo, CUL7 is essential for placental vascular morphogenesis, trophoblast differentiation, bone growth-plate chondrocyte proliferation, and normal IGF1/AKT signaling, and loss-of-function mutations cause the primordial growth disorder 3-M syndrome."},"narrative":{"mechanistic_narrative":"CUL7 is a cullin-family scaffold that nucleates an SCF-ROC1-like E3 ubiquitin ligase governing cell growth, proliferation, and survival [PMID:12481031, PMID:16142236]. It assembles a complex with SKP1, RBX1/ROC1, and the F-box protein FBXW8, recruiting the SKP1·FBXW8 heterodimer selectively rather than SKP1 alone or SKP1 bound to other F-box proteins [PMID:12481031, PMID:16142236], and in an FBXW8-dependent manner it further heterodimerizes with CUL1 [PMID:16880526]. Through this ligase activity CUL7 targets a series of substrates whose turnover shapes growth-factor signaling and apoptosis: IRS-1, degraded in an mTOR/S6K-dependent fashion to restrain AKT and MEK/ERK signaling [PMID:18498745]; the kinase HPK1, ubiquitinated in a phosphorylation-dependent manner that is antagonized by PP4 [PMID:24362026]; serum-stimulated, phospho-dependent TBC1D3 [PMID:23029530]; and additional substrates including caspase-8, which CUL7 modifies with non-degradative K215 polyubiquitin to suppress TRAIL-induced apoptosis [PMID:30807646], and AID, via a complex with FBXW11 controlling B-cell class switching [PMID:31092637]. Beyond ubiquitination, CUL7 directly binds the tetramerization domain of p53 through a discrete CPH domain whose SH3/Tudor-like fold and distinct binding surface were defined by NMR [PMID:16875676, PMID:17298945], and it forms mutually exclusive complexes with either FBXW8 or the related cullin PARC [PMID:17332328, PMID:15964813]. In vivo, CUL7 is essential for placental vascular morphogenesis and trophoblast differentiation [PMID:12904573] and for normal IGF1/AKT signaling [PMID:21737058, PMID:23018678], and loss-of-function mutations cause the primordial growth disorder 3-M syndrome [PMID:16142236]. CUL7 binding is also required for SV40 large T antigen-mediated cellular transformation [PMID:16140746].","teleology":[{"year":2002,"claim":"Establishing that CUL7 is a bona fide cullin defined the molecular machine: which cofactors it recruits and how it differs from canonical SCF ligases.","evidence":"Mass spectrometry identification as a ROC1-interactor, co-IP, and domain deletion mapping","pmids":["12481031"],"confidence":"High","gaps":["No substrate identified at this stage","Catalytic activity inferred from complex composition rather than direct ubiquitination assay"]},{"year":2003,"claim":"Knockout of Cul7 in mice answered whether the complex matters physiologically, revealing an essential role in placental and vascular development.","evidence":"Targeted mouse gene disruption with histological analysis; co-IP defining the complex including FAP68/glomulin","pmids":["12904573"],"confidence":"High","gaps":["Substrate driving the developmental phenotype unknown at this stage","Molecular basis of vascular defect not resolved"]},{"year":2005,"claim":"Linking CUL7 mutations to 3-M syndrome connected ligase assembly defects to a human growth disorder, showing disease mutations impair ROC1 recruitment.","evidence":"Disease-mutation functional assays (R1445X, H1464P) with deletion mapping and co-IP","pmids":["16142236"],"confidence":"High","gaps":["Substrate whose stabilization causes growth failure not yet defined","Tissue-specific basis of growth-plate phenotype unaddressed"]},{"year":2005,"claim":"Identification of PARC as a CUL7 dimerization partner introduced a homolog that shares interactions but has non-overlapping function.","evidence":"Mass spectrometry, co-IP, and Parc knockout mouse (no overt phenotype)","pmids":["15964813"],"confidence":"Medium","gaps":["Functional significance of PARC-CUL7 heterodimers unresolved","PARC does not affect p53 stability, leaving its role unclear"]},{"year":2005,"claim":"SV40 large T antigen mapping established CUL7 as a growth-control target whose inactivation enables transformation, hinting at tumor-suppressor function.","evidence":"T antigen deletion mutagenesis (delta69-83) with co-IP and MEF transformation assays","pmids":["14990695","16140746"],"confidence":"High","gaps":["Mechanism by which T antigen neutralizes CUL7 not defined","Whether CUL7 acts as suppressor or oncogene context-dependent"]},{"year":2006,"claim":"Defining the CPH domain and the CUL7-CUL1 heterodimer dissected how CUL7 engages p53 and partitions FBXW8-dependent versus -independent functions.","evidence":"Domain deletion with localization imaging; FBXW8-knockout mice and genetic epistasis for CUL1 association","pmids":["16875676","16880526"],"confidence":"High","gaps":["Functional consequence of CUL7-p53 binding not established here","Identity of FBXW8-independent CUL7 functions unknown"]},{"year":2007,"claim":"Structural and biochemical work resolved how CUL7 binds p53 and how PARC/FBXW8 complexes are organized and catalytically active.","evidence":"NMR structure of CPH domain mapping the p53 tetramerization-domain interface; TAP-MudPIT and in vitro ubiquitin ligase assays; functional cloning with siRNA","pmids":["17298945","17332328","17942889"],"confidence":"High","gaps":["Whether p53 is a ubiquitination substrate of CUL7 or only a binding partner unresolved","Mechanism linking p53 binding to anti-apoptotic/transforming function incomplete"]},{"year":2008,"claim":"Identification of IRS-1 as a degradation substrate revealed how CUL7 ligase activity feeds back on insulin/IGF growth-factor signaling.","evidence":"Ubiquitin ligase assay and Cul7-/- MEF analysis with mTOR/S6K inhibition","pmids":["18498745"],"confidence":"High","gaps":["How IRS-1 turnover relates to the senescence phenotype of Cul7-/- MEFs not fully resolved","Connection to 3-M growth phenotype indirect"]},{"year":2013,"claim":"HPK1 and TBC1D3 substrate identification established the recurring principle that CUL7/FBXW8 recognizes phosphorylated substrates, with phosphatases gating recruitment.","evidence":"In vitro ubiquitination assays, phosphosite mutagenesis, PP4/alkaline phosphatase treatment, and yeast two-hybrid","pmids":["24362026","23029530"],"confidence":"High","gaps":["Kinases generating the priming phosphorylation not fully defined","Generality of phospho-degron recognition across substrates untested"]},{"year":2011,"claim":"Placing CCDC8 and OBSL1 in a CUL7 pathway and demonstrating impaired IGF1-AKT signaling clarified the 3-M syndrome circuitry.","evidence":"Co-IP, exome sequencing, and signaling assays in patient-derived CUL7-/- fibroblasts","pmids":["21737058","23018678"],"confidence":"Medium","gaps":["CCDC8 does not bind CUL7 directly; intermediary role of OBSL1 needs biochemical detail","Substrate mediating the IGF1-AKT defect not identified"]},{"year":2019,"claim":"Caspase-8 and AID substrate work expanded CUL7 into apoptosis control and immune regulation, including a non-degradative ubiquitination mode.","evidence":"Co-IP, ubiquitination assays with K215 mutagenesis, conditional CUL7 knockout, apoptosis and class-switch assays","pmids":["30807646","31092637"],"confidence":"High","gaps":["F-box adaptor for caspase-8 recognition not defined","Whether AID ubiquitination requires FBXW11 exclusively versus canonical FBXW8 unclear"]},{"year":2026,"claim":"A wave of substrate and regulatory studies (MST1, GPX4, KEAP1, HER2) and neddylation control extended CUL7 into ferroptosis, oxidative stress, and additional cancers.","evidence":"Co-IP, linkage-specific ubiquitination assays, CAND1/CCDC8 knockdown, MLN4924 neddylation inhibition, and in vivo tumor/retinal models","pmids":["32252802","39267786","41310794","42252284","41644704"],"confidence":"Medium","gaps":["Several substrate claims rest on single-lab assays without reconstitution","How CAND1 and neddylation dynamically gate CUL7 activity across substrates not unified","Whether these substrates share an F-box adaptor unresolved"]},{"year":null,"claim":"It remains unresolved how the proliferating substrate set is selected, which adaptors recruit non-FBXW8 substrates, and how CUL7 activity is dynamically regulated by neddylation and CAND1 in vivo.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of substrate-adaptor pairing","Physiological regulation of CUL7 neddylation across tissues unknown","Reconciliation of tumor-suppressor versus oncogenic roles incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[11,12,16,17,21]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,11,12,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,14,15,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[16,19]}],"complexes":["CUL7-SKP1-RBX1-FBXW8 SCF-like E3 ligase","CUL7-CUL1 heterodimer","CUL7-PARC dimer"],"partners":["SKP1","RBX1","FBXW8","CUL1","PARC","TP53","FBXW11","OBSL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14999","full_name":"Cullin-7","aliases":[],"length_aa":1698,"mass_kda":191.2,"function":"Core component of the 3M and Cul7-RING(FBXW8) complexes, which mediate the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:12481031, PubMed:12904573, PubMed:21572988, PubMed:21737058, PubMed:24793695, PubMed:35982156). Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity (PubMed:21572988, PubMed:21737058, PubMed:24793695). It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer (PubMed:24793695). The Cul7-RING(FBXW8) complex alone lacks ubiquitination activity and does not promote polyubiquitination and proteasomal degradation of p53/TP53 (PubMed:16547496, PubMed:17332328, PubMed:35982156). However it mediates recruitment of p53/TP53 for ubiquitination by neddylated CUL1-RBX1 (PubMed:35982156). Interaction with CUL9 is required to inhibit CUL9 activity and ubiquitination of BIRC5 (PubMed:24793696). The Cul7-RING(FBXW8) complex also mediates ubiquitination and consequent degradation of target proteins such as GORASP1, IRS1 and MAP4K1/HPK1 (PubMed:21572988, PubMed:24362026). Ubiquitination of GORASP1 regulates Golgi morphogenesis and dendrite patterning in brain (PubMed:21572988). Mediates ubiquitination and degradation of IRS1 in a mTOR-dependent manner: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2) (PubMed:18498745). The Cul7-RING(FBXW8) complex also mediates ubiquitination of MAP4K1/HPK1: recognizes and binds autophosphorylated MAP4K1/HPK1, leading to its degradation, thereby affecting cell proliferation and differentiation (PubMed:24362026). Acts as a regulator in trophoblast cell epithelial-mesenchymal transition and placental development (PubMed:20139075). While the Cul7-RING(FBXW8) and the 3M complexes are associated and involved in common processes, CUL7 and the Cul7-RING(FBXW8) complex may have additional functions. Probably plays a role in the degradation of proteins involved in endothelial proliferation and/or differentiation","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, perinuclear region; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/Q14999/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CUL7","classification":"Not Classified","n_dependent_lines":36,"n_total_lines":1208,"dependency_fraction":0.029801324503311258},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CUL7","total_profiled":1310},"omim":[{"mim_id":"620269","title":"LEUKODYSTROPHY, HYPOMYELINATING, 26, WITH CHONDRODYSPLASIA; HLD26","url":"https://www.omim.org/entry/620269"},{"mim_id":"616704","title":"COMM DOMAIN-CONTAINING PROTEIN 10; COMMD10","url":"https://www.omim.org/entry/616704"},{"mim_id":"616703","title":"COMM DOMAIN-CONTAINING PROTEIN 7; COMMD7","url":"https://www.omim.org/entry/616703"},{"mim_id":"614800","title":"SHORT STATURE, OPTIC NERVE ATROPHY, AND PELGER-HUET ANOMALY; SOPH","url":"https://www.omim.org/entry/614800"},{"mim_id":"614205","title":"THREE M SYNDROME 3; 3M3","url":"https://www.omim.org/entry/614205"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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CUL7 was identified by mass spectrometry as a ROC1-interacting protein. CUL7 contains a cullin domain responsible for ROC1 binding and a DOC domain. Unlike CUL1 which binds Skp1 alone, CUL7 interacts selectively with the Skp1·Fbx29 heterodimer but not with Skp1 alone, nor with Skp1·betaTRCP2 or Skp1·Skp2.\",\n      \"method\": \"Mass spectrometry identification, co-immunoprecipitation, deletion/domain analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP and MS identification with domain mapping; foundational complex assembly paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"12481031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CUL7 (p185) forms an SCF-like complex with Skp1, Rbx1, Fbw6 (Fbx29/FBXW8), and FAP68 (glomulin). Targeted disruption of Cul7 in mice results in runted embryos that die at birth with respiratory distress, dermal hemorrhage, and placental defects including abnormal trophoblast differentiation and vascular structure, demonstrating a role for CUL7 in vascular morphogenesis and placental development.\",\n      \"method\": \"Co-immunoprecipitation, mouse knockout (targeted gene disruption), histological analysis\",\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 knockout phenotype combined with complex co-IP; replicated by independent labs\",\n      \"pmids\": [\"12904573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CUL7 assembles an E3 ubiquitin ligase complex with SKP1, RBX1, and the F-box protein FBXW8. CUL7 nonsense (R1445X) and missense (H1464P) mutations associated with 3-M syndrome render CUL7 deficient in recruiting ROC1, suggesting impaired ubiquitination underlies the pathogenesis. CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer.\",\n      \"method\": \"Deletion analysis, co-immunoprecipitation, mutant functional assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping with deletion analysis and disease-mutation functional testing; replicates and extends PMID:12481031\",\n      \"pmids\": [\"16142236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SV40 large T antigen binds the CUL7 SCF-like complex (containing p185/CUL7, Rbx1, and Fbw6/FBXW8) via an N-terminal region. p185/CUL7-binding-deficient T antigen mutants retain binding to pRb and p53 but are unable to transform primary mouse embryo fibroblasts, indicating that CUL7 binding is required for T antigen-mediated cellular transformation and that CUL7 may regulate a growth control pathway.\",\n      \"method\": \"Co-immunoprecipitation, T antigen mutagenesis, focus formation / anchorage-independent growth assays, MEF transformation\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus mutagenesis plus functional transformation assay in same study; confirmed and extended by PMID:16140746\",\n      \"pmids\": [\"14990695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SV40 T antigen residues 69–83 are required for binding to the CUL7 complex. Delta69-83 T antigen loses CUL7 binding while retaining p53 and pRB binding. Wild-type T antigen induces MEF proliferation (transformation) in the presence of CUL7, but delta69-83 T antigen does not, suggesting CUL7 is a target whose inactivation by T antigen contributes to transformation and that CUL7 may function as a tumor suppressor.\",\n      \"method\": \"Deletion mutagenesis, co-immunoprecipitation, MEF proliferation and transformation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis with functional readout replicated across two labs (PMID:14990695 and PMID:16140746)\",\n      \"pmids\": [\"16140746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CUL7 forms a heterodimeric complex with CUL1 in a manner dependent on FBXW8 (Fbxw8). Fbxw8-knockout mice lack CUL7–CUL1 association. Fbxw8-null mice show intrauterine growth retardation and placental defects similar to Cul7-null mice, but some abnormalities of Cul7-/- mice are absent, indicating that the CUL7–Fbxw8 complex has both Fbxw8-dependent and Fbxw8-independent functions.\",\n      \"method\": \"Co-immunoprecipitation, mouse knockout (Fbxw8 targeting), genetic epistasis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus in vivo genetic epistasis with two knockout models\",\n      \"pmids\": [\"16880526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CUL7 directly binds p53 via a discrete, evolutionarily conserved domain (CPH domain) that is also conserved in PARC and HERC2. This p53-binding domain is necessary and sufficient for p53 interaction, p53 stabilizes expression of this domain, and the domain contributes to cytoplasmic localization of CUL7. CUL7 binding to p53 does not affect p53 expression levels.\",\n      \"method\": \"Co-immunoprecipitation, deletion analysis, subcellular localization by imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — domain deletion plus localization experiment, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"16875676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The CPH domains of CUL7 and PARC are protein–protein interaction modules that bind the tetramerization domain of p53. NMR structure of the CUL7-CPH domain reveals a fold similar to SH3, Tudor, and KOW domains, but the p53-binding surface is distinct from the canonical peptide-binding surfaces of those domains. The p53 interaction surface on p53 resides in its tetramerization domain and involves residues from at least two subunits.\",\n      \"method\": \"NMR spectroscopy, size-exclusion chromatography, structural determination with functional validation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with binding interface mapping; single lab but multiple orthogonal structural and biochemical methods\",\n      \"pmids\": [\"17298945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CUL7 and PARC form homodimers and heterodimers. Tandem affinity purification–MudPIT analysis revealed that the CUL7 interaction with FBXW8 is mutually exclusive with CUL7 binding to PARC or p53. PARC binds RBX1 and is covalently modified by NEDD8, defining PARC as a cullin, but PARC fails to bind SKP1 or F-box proteins including FBXW8. All examined PARC- and CUL7-containing subcomplexes exhibit E3 ubiquitin ligase activity in vitro. Parc-/-/Fbxw8-/- double knockout does not exacerbate the Fbxw8-/- phenotype.\",\n      \"method\": \"Tandem affinity purification, MudPIT mass spectrometry, in vitro ubiquitin ligase assay, double-knockout genetic epistasis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — TAP-MS complex mapping plus in vitro E3 activity assay plus in vivo genetic epistasis in single study\",\n      \"pmids\": [\"17332328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CUL7 binds p53 directly and its knockdown by siRNA elevates p53 protein levels. CUL7 exerts an anti-apoptotic function through p53, enabling it to inhibit Myc-induced apoptosis. CUL7 cooperates with Myc to drive cellular transformation in soft agar assays.\",\n      \"method\": \"Expression cloning screen, co-immunoprecipitation, siRNA knockdown, anchorage-independent growth assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cloning plus co-IP plus siRNA with phenotypic readout; single lab\",\n      \"pmids\": [\"17942889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PARC (a CUL7 homolog) was identified as a CUL7-interacting protein by mass spectrometry. CUL7 and PARC form endogenous hetero- and homodimers in vivo. Parc knockout mice are born at expected Mendelian ratios with no apparent phenotype, and Parc deletion does not affect p53 stability, localization, or function, indicating that PARC and CUL7 functions are at least partially non-overlapping.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, Parc knockout mouse\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of interaction, confirmed by co-IP, validated in vivo with knockout\",\n      \"pmids\": [\"15964813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IRS-1 (insulin receptor substrate 1) is a proteolytic substrate of the CUL7 E3 ubiquitin ligase. IRS-1 degradation depends on mTOR and p70 S6 kinase activity. Cul7-/- mouse embryonic fibroblasts accumulate IRS-1 and show increased activation of Akt and MEK/ERK pathways, but grow poorly and display oncogene-induced senescence-like phenotypes.\",\n      \"method\": \"Ubiquitin ligase assay, Cul7-/- MEF analysis, signaling pathway analysis, mTOR/S6K inhibition\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in vivo (knockout MEFs) with defined substrate accumulation and downstream pathway activation, replicated by pharmacological inhibition\",\n      \"pmids\": [\"18498745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The CUL7/FBXW8 ubiquitin ligase targets hematopoietic progenitor kinase 1 (HPK1) for ubiquitination and proteasomal degradation. HPK1 ubiquitination requires its kinase activity and autophosphorylation (at Thr-355). Protein phosphatase 4 (PP4) dephosphorylates Thr-355 and inhibits Fbxw8–HPK1 interaction, thereby stabilizing HPK1. Knockdown of Fbxw8 restores endogenous HPK1 and inhibits pancreatic cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, phosphorylation/dephosphorylation analysis, siRNA knockdown, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitination assay plus co-IP plus mutagenesis (phosphosite) plus functional KD; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24362026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CUL7 E3 ligase ubiquitinates TBC1D3 in response to serum/growth factor stimulation, leading to its proteasomal degradation. TBC1D3 physically interacts with CUL7 (identified by yeast two-hybrid) and recruits FBXW8 in pulldown and in vitro assays. Phosphorylation of TBC1D3 is critical for Fbxw8 recruitment and subsequent ubiquitination; alkaline phosphatase treatment of TBC1D3 suppresses Fbxw8 recruitment.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, pulldown, in vitro ubiquitination assay, phosphatase treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid plus in vitro assay plus biochemical dephosphorylation experiment; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23029530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CCDC8 co-immunoprecipitates with OBSL1 but not with CUL7, placing CCDC8 in a pathway with CUL7 and OBSL1 through OBSL1 as an intermediary. CUL7(-/-) cells show impaired IGF1-stimulated AKT activation, consistent with dysregulated IGF1 signaling downstream of CUL7.\",\n      \"method\": \"Co-immunoprecipitation, exome sequencing for pathway placement, signaling assays in patient-derived fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus cell signaling in patient-derived KO fibroblasts; single lab\",\n      \"pmids\": [\"21737058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CUL7(-/-) patient fibroblasts show impaired AKT activation in response to IGF1 stimulation at 5 min post-stimulation, while GH-induced STAT5b and MAPK activation is normal. This indicates CUL7 loss specifically impairs IGF1 signaling through the PI3K/AKT axis.\",\n      \"method\": \"Cell signaling assays (phospho-Western) in patient-derived CUL7-/- fibroblasts\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined signaling defect in patient-derived null cells with specific pathway readout; single lab\",\n      \"pmids\": [\"23018678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CUL7 promotes cancer cell survival by interacting with Caspase-8 and promoting its modification with non-degradative polyubiquitin chains at K215, thereby preventing Caspase-8 activation. CUL7 knockdown sensitizes cancer cells to TRAIL-induced apoptosis in vitro and in nude mice.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K215), siRNA knockdown, apoptosis assay in vitro and in vivo\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — specific ubiquitination site identified by mutagenesis, functional rescue assay, in vivo validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30807646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CUL7 E3 ubiquitin ligase mediates ubiquitination of AID (activation-induced cytidine deaminase) by forming a complex with FBXW11. CUL7 overexpression or knockdown regulates AID protein levels and IgA class switching in B cells. CUL7 conditional knockout (CUL7 fl/fl CD19-Cre) in mice increases AID protein levels in germinal center B cells and enhances IgG1 and IgA class switching.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, CUL7 conditional knockout mouse, B cell class switch recombination assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP plus in vivo conditional KO with defined immunological phenotype plus ubiquitination assay; single lab, multiple methods\",\n      \"pmids\": [\"31092637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CUL7 physically associates with MST1, promoting ubiquitin-mediated MST1 protein degradation, which activates the NF-κB signaling pathway to promote glioma cell growth.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/shRNA knockdown, CUL7 overexpression, in vitro and in vivo tumor assays, western blot for NF-κB pathway markers\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP demonstrating physical interaction and functional pathway consequence; single lab, without in vitro reconstituted ubiquitination assay described in abstract\",\n      \"pmids\": [\"32252802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CUL7 promotes ubiquitination and degradation of glutathione peroxidase 4 (GPX4) in photoreceptors. CUL7 knockdown prevents Cul7-mediated GPX4 ubiquitination and degradation, inhibiting photoreceptor ferroptosis and alleviating retinal degeneration in mouse models.\",\n      \"method\": \"Transcriptome sequencing to identify target, siRNA knockdown, ubiquitination assay (GPX4), in vivo mouse models (MNU-induced and Pde6βrd1/rd1 mutant)\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ubiquitination assay plus in vivo KD rescue; single lab, novel substrate claim with limited mechanistic detail in abstract\",\n      \"pmids\": [\"39267786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CUL7 promotes HER2 ubiquitination in HER2-positive breast cancer. CAND1 directly interacts with HER2 and stabilizes its expression; CAND1 knockdown enhances CUL7 neddylation, activating its ligase activity and leading to HER2 ubiquitination and destabilization.\",\n      \"method\": \"Co-immunoprecipitation, western blot, ubiquitination assay, CAND1 knockdown, in vivo xenograft\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — co-IP and ubiquitination assay with functional KD; single lab, novel substrate/regulatory mechanism with limited in-abstract detail\",\n      \"pmids\": [\"41310794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CUL7 interacts with KEAP1 and catalyzes K29- and K48-linked polyubiquitination of KEAP1 to promote its proteasomal degradation, thereby activating NRF2 signaling and reducing ROS levels in colon cancer cells. The C-terminus of CUL7 is required for KEAP1 stability regulation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (linkage-specific), CUL7 knockout mouse model, CUL7 domain deletion, cancer cell KO/overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro ubiquitination with linkage specificity plus domain mapping plus in vivo model; single lab, novel substrate claim\",\n      \"pmids\": [\"42252284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCDC8 interacts with CUL7 to facilitate proteasome-dependent degradation of P53. Pharmacological inhibition of neddylation (MLN4924) restored P53 levels and reversed CCDC8-driven oncogenic effects, implicating neddylation-dependent CUL7 activity in CCDC8-mediated P53 degradation in bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation, western blot, MLN4924 neddylation inhibition, in vitro and in vivo tumor assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — co-IP with functional pharmacological inhibition; single lab, CUL7 role inferred from inhibitor experiments\",\n      \"pmids\": [\"41644704\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CUL7 is a cullin-family scaffold that assembles an SCF-like E3 ubiquitin ligase complex with SKP1, RBX1 (ROC1), and the F-box protein FBXW8 (Fbx29/Fbw6) — selectively recruiting the SKP1·FBXW8 heterodimer rather than SKP1 alone — and, dependent on FBXW8, also forms a heterodimeric complex with CUL1; this CUL7 complex ubiquitinates a growing set of substrates including IRS-1 (in an mTOR/S6K-dependent manner), HPK1 (phosphorylation-dependent, counteracted by PP4), TBC1D3 (serum-stimulated, phospho-dependent), AID (forming a complex with FBXW11), Caspase-8 (non-degradative K215 polyubiquitination to suppress extrinsic apoptosis), GPX4 (promoting ferroptosis), KEAP1 (K29/K48-linked degradation activating NRF2), MST1, and HER2; CUL7 also contains a CPH domain that directly binds the tetramerization domain of p53 (structurally defined by NMR), and CUL7 dimerizes with the related cullin PARC in a complex that is mutually exclusive with FBXW8 binding; in vivo, CUL7 is essential for placental vascular morphogenesis, trophoblast differentiation, bone growth-plate chondrocyte proliferation, and normal IGF1/AKT signaling, and loss-of-function mutations cause the primordial growth disorder 3-M syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CUL7 is a cullin-family scaffold that nucleates an SCF-ROC1-like E3 ubiquitin ligase governing cell growth, proliferation, and survival [#0, #2]. It assembles a complex with SKP1, RBX1/ROC1, and the F-box protein FBXW8, recruiting the SKP1·FBXW8 heterodimer selectively rather than SKP1 alone or SKP1 bound to other F-box proteins [#0, #2], and in an FBXW8-dependent manner it further heterodimerizes with CUL1 [#5]. Through this ligase activity CUL7 targets a series of substrates whose turnover shapes growth-factor signaling and apoptosis: IRS-1, degraded in an mTOR/S6K-dependent fashion to restrain AKT and MEK/ERK signaling [#11]; the kinase HPK1, ubiquitinated in a phosphorylation-dependent manner that is antagonized by PP4 [#12]; serum-stimulated, phospho-dependent TBC1D3 [#13]; and additional substrates including caspase-8, which CUL7 modifies with non-degradative K215 polyubiquitin to suppress TRAIL-induced apoptosis [#16], and AID, via a complex with FBXW11 controlling B-cell class switching [#17]. Beyond ubiquitination, CUL7 directly binds the tetramerization domain of p53 through a discrete CPH domain whose SH3/Tudor-like fold and distinct binding surface were defined by NMR [#6, #7], and it forms mutually exclusive complexes with either FBXW8 or the related cullin PARC [#8, #10]. In vivo, CUL7 is essential for placental vascular morphogenesis and trophoblast differentiation [#1] and for normal IGF1/AKT signaling [#14, #15], and loss-of-function mutations cause the primordial growth disorder 3-M syndrome [#2]. CUL7 binding is also required for SV40 large T antigen-mediated cellular transformation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that CUL7 is a bona fide cullin defined the molecular machine: which cofactors it recruits and how it differs from canonical SCF ligases.\",\n      \"evidence\": \"Mass spectrometry identification as a ROC1-interactor, co-IP, and domain deletion mapping\",\n      \"pmids\": [\"12481031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No substrate identified at this stage\", \"Catalytic activity inferred from complex composition rather than direct ubiquitination assay\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Knockout of Cul7 in mice answered whether the complex matters physiologically, revealing an essential role in placental and vascular development.\",\n      \"evidence\": \"Targeted mouse gene disruption with histological analysis; co-IP defining the complex including FAP68/glomulin\",\n      \"pmids\": [\"12904573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate driving the developmental phenotype unknown at this stage\", \"Molecular basis of vascular defect not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linking CUL7 mutations to 3-M syndrome connected ligase assembly defects to a human growth disorder, showing disease mutations impair ROC1 recruitment.\",\n      \"evidence\": \"Disease-mutation functional assays (R1445X, H1464P) with deletion mapping and co-IP\",\n      \"pmids\": [\"16142236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate whose stabilization causes growth failure not yet defined\", \"Tissue-specific basis of growth-plate phenotype unaddressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of PARC as a CUL7 dimerization partner introduced a homolog that shares interactions but has non-overlapping function.\",\n      \"evidence\": \"Mass spectrometry, co-IP, and Parc knockout mouse (no overt phenotype)\",\n      \"pmids\": [\"15964813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of PARC-CUL7 heterodimers unresolved\", \"PARC does not affect p53 stability, leaving its role unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"SV40 large T antigen mapping established CUL7 as a growth-control target whose inactivation enables transformation, hinting at tumor-suppressor function.\",\n      \"evidence\": \"T antigen deletion mutagenesis (delta69-83) with co-IP and MEF transformation assays\",\n      \"pmids\": [\"14990695\", \"16140746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which T antigen neutralizes CUL7 not defined\", \"Whether CUL7 acts as suppressor or oncogene context-dependent\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining the CPH domain and the CUL7-CUL1 heterodimer dissected how CUL7 engages p53 and partitions FBXW8-dependent versus -independent functions.\",\n      \"evidence\": \"Domain deletion with localization imaging; FBXW8-knockout mice and genetic epistasis for CUL1 association\",\n      \"pmids\": [\"16875676\", \"16880526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CUL7-p53 binding not established here\", \"Identity of FBXW8-independent CUL7 functions unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Structural and biochemical work resolved how CUL7 binds p53 and how PARC/FBXW8 complexes are organized and catalytically active.\",\n      \"evidence\": \"NMR structure of CPH domain mapping the p53 tetramerization-domain interface; TAP-MudPIT and in vitro ubiquitin ligase assays; functional cloning with siRNA\",\n      \"pmids\": [\"17298945\", \"17332328\", \"17942889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p53 is a ubiquitination substrate of CUL7 or only a binding partner unresolved\", \"Mechanism linking p53 binding to anti-apoptotic/transforming function incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of IRS-1 as a degradation substrate revealed how CUL7 ligase activity feeds back on insulin/IGF growth-factor signaling.\",\n      \"evidence\": \"Ubiquitin ligase assay and Cul7-/- MEF analysis with mTOR/S6K inhibition\",\n      \"pmids\": [\"18498745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IRS-1 turnover relates to the senescence phenotype of Cul7-/- MEFs not fully resolved\", \"Connection to 3-M growth phenotype indirect\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"HPK1 and TBC1D3 substrate identification established the recurring principle that CUL7/FBXW8 recognizes phosphorylated substrates, with phosphatases gating recruitment.\",\n      \"evidence\": \"In vitro ubiquitination assays, phosphosite mutagenesis, PP4/alkaline phosphatase treatment, and yeast two-hybrid\",\n      \"pmids\": [\"24362026\", \"23029530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases generating the priming phosphorylation not fully defined\", \"Generality of phospho-degron recognition across substrates untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placing CCDC8 and OBSL1 in a CUL7 pathway and demonstrating impaired IGF1-AKT signaling clarified the 3-M syndrome circuitry.\",\n      \"evidence\": \"Co-IP, exome sequencing, and signaling assays in patient-derived CUL7-/- fibroblasts\",\n      \"pmids\": [\"21737058\", \"23018678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CCDC8 does not bind CUL7 directly; intermediary role of OBSL1 needs biochemical detail\", \"Substrate mediating the IGF1-AKT defect not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Caspase-8 and AID substrate work expanded CUL7 into apoptosis control and immune regulation, including a non-degradative ubiquitination mode.\",\n      \"evidence\": \"Co-IP, ubiquitination assays with K215 mutagenesis, conditional CUL7 knockout, apoptosis and class-switch assays\",\n      \"pmids\": [\"30807646\", \"31092637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"F-box adaptor for caspase-8 recognition not defined\", \"Whether AID ubiquitination requires FBXW11 exclusively versus canonical FBXW8 unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A wave of substrate and regulatory studies (MST1, GPX4, KEAP1, HER2) and neddylation control extended CUL7 into ferroptosis, oxidative stress, and additional cancers.\",\n      \"evidence\": \"Co-IP, linkage-specific ubiquitination assays, CAND1/CCDC8 knockdown, MLN4924 neddylation inhibition, and in vivo tumor/retinal models\",\n      \"pmids\": [\"32252802\", \"39267786\", \"41310794\", \"42252284\", \"41644704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several substrate claims rest on single-lab assays without reconstitution\", \"How CAND1 and neddylation dynamically gate CUL7 activity across substrates not unified\", \"Whether these substrates share an F-box adaptor unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the proliferating substrate set is selected, which adaptors recruit non-FBXW8 substrates, and how CUL7 activity is dynamically regulated by neddylation and CAND1 in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of substrate-adaptor pairing\", \"Physiological regulation of CUL7 neddylation across tissues unknown\", \"Reconciliation of tumor-suppressor versus oncogenic roles incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [11, 12, 16, 17, 21]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 11, 12, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 14, 15, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [16, 19]}\n    ],\n    \"complexes\": [\"CUL7-SKP1-RBX1-FBXW8 SCF-like E3 ligase\", \"CUL7-CUL1 heterodimer\", \"CUL7-PARC dimer\"],\n    \"partners\": [\"SKP1\", \"RBX1\", \"FBXW8\", \"CUL1\", \"PARC\", \"TP53\", \"FBXW11\", \"OBSL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}