{"gene":"CBLC","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1999,"finding":"CBLC (Cbl-3/Cbl-c) was identified as a novel CBL family E3 ubiquitin ligase with a phosphotyrosine-binding (TKB) domain and RING finger; the protein is phosphorylated and recruited to EGFR upon EGF stimulation and inhibits EGF-stimulated MAP kinase activation. An alternatively spliced form lacking a critical PTB region does not interact with EGFR nor inhibit MAP kinase activation.","method":"Molecular cloning, co-immunoprecipitation, EGF stimulation assays, MAP kinase activity assay, alternative splice variant characterization","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, functional kinase assay, domain deletion analysis; replicated in same year by independent cloning paper","pmids":["10362357"],"is_preprint":false},{"year":1999,"finding":"CBLC (Cbl-c) protein binds to the EGF receptor and Fyn tyrosine kinase, establishing it as an adaptor/ubiquitin ligase that regulates intracellular signaling mediated by various tyrosine kinases.","method":"Molecular cloning, co-immunoprecipitation with EGFR and Fyn","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP/pulldown, corroborated by contemporaneous independent cloning paper","pmids":["10571044"],"is_preprint":false},{"year":2002,"finding":"CBLC interacts with the HECT-domain E3 ligase AIP4/ITCH through a two-hybrid screen, confirmed by GST pulldown, co-immunoprecipitation, and colocalization. Both proteins are tyrosine-phosphorylated after EGF stimulation; CBLC increases EGFR ubiquitination and co-expression of CBLC with AIP4 induces down-regulation of EGFR signaling.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, colocalization, EGFR ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Y2H, pulldown, Co-IP, ubiquitination assay) in single study","pmids":["12226085"],"is_preprint":false},{"year":2004,"finding":"CBLC (Cbl-c) promotes ubiquitination and lysosome-dependent degradation of activated Src (phosphorylated at Tyr419); the TKB domain and RING finger of Cbl-c are required for this activity. In vitro, Cbl-c together with UbcH5 ubiquitinates Src. Non-phosphorylated Src is not ubiquitinated by Cbl-c, indicating specificity for the activated form.","method":"Cell transformation assay, in vitro ubiquitination assay with purified proteins, Western blot (protein level), domain mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of ubiquitination with mutagenesis; domain requirements mapped","pmids":["14661060"],"is_preprint":false},{"year":2003,"finding":"Cbl-3 (CBLC) is expressed specifically in epithelial cells of the gastrointestinal tract, epidermis, and other epithelial tissues. Cbl-3-deficient mice are viable and fertile with no histological abnormalities, and Cbl-3 is not required for attenuation of EGF-stimulated Erk activation in primary keratinocytes.","method":"Knockout mouse generation, histological analysis, proliferation assay, EGF-stimulated ERK activation in primary keratinocytes","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined cellular and tissue phenotype; expression pattern by Northern/immunostaining","pmids":["14560016"],"is_preprint":false},{"year":2008,"finding":"CBLC (Cbl-3) interacts with unphosphorylated Ret receptor tyrosine kinase under basal conditions and dissociates after GDNF-mediated Ret activation; CBLC overexpression stabilizes activated Ret and enhances neuronal survival, but in combination with CD2AP, CBLC promotes rapid Ret degradation, acting as a switch that controls Ret downregulation sensitivity.","method":"Co-immunoprecipitation, overexpression and siRNA knockdown in sympathetic neurons, survival assays, Ret degradation assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, gain- and loss-of-function in neurons with defined phenotypic readouts","pmids":["18753381"],"is_preprint":false},{"year":2010,"finding":"The N-terminal EF-hand and SH2 domains of CBLC inhibit its E3 ubiquitin ligase activity by increasing affinity for the E2 enzyme UbcH5b. Phosphorylation of Tyr-341 in the linker region by Src (or phosphomimetic Y341E mutation) decreases affinity for UbcH5b, leading to more rapid E2 turnover and increased E3 activity.","method":"In vitro ubiquitination assay, E2 binding affinity measurement, site-directed mutagenesis, Src phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay with mutagenesis mapping the activation mechanism","pmids":["20525694"],"is_preprint":false},{"year":2012,"finding":"CBLC interacts with the adaptor protein Hic-5 through a novel RING finger–LIM2 domain interaction; this interaction enhances CBLC ubiquitin ligase activity (once activated by Src phosphorylation) and increases EGFR ubiquitination.","method":"Co-immunoprecipitation, domain mapping mutagenesis, in vitro ubiquitination assay, EGFR ubiquitination assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mapping and functional ubiquitination assay; single lab","pmids":["23145173"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the TKB domain of CBLC (Cbl-c/Cbl-3) revealed restricted structural flexibility upon phosphopeptide binding compared to Cbl. A mutation in the TKB domain that augments flexibility enhanced binding to target phosphoproteins, demonstrating that structural flexibility regulates phosphopeptide-binding activity.","method":"X-ray crystallography, phosphopeptide binding assay, mutagenesis","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis-based functional validation","pmids":["22888118"],"is_preprint":false},{"year":2014,"finding":"CD2AP enhances CBLC (Cbl-3/c)-mediated ubiquitination and degradation of Ret51 (but not Ret9) via its N-terminal SH3 domains. CBLC requires a functional RING finger and TKB domain for Ret51 ubiquitination, and the two primary ubiquitination sites on Ret51 are Lys1060 and Lys1107. Activated Ret induces degradation of CD2AP but not CBLC.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis of Ret lysines, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, Co-IP, mutagenesis, site mapping) with defined mechanistic outcome","pmids":["24425877"],"is_preprint":false},{"year":2015,"finding":"CBLC silencing causes increased sensitivity to the PARP inhibitor olaparib in breast cancer cell lines, associated with defective homologous recombination DNA repair, identifying CBLC as a modifier of PARP inhibitor response through the ubiquitin/DNA damage response axis.","method":"RNAi screen, siRNA knockdown, cell viability assay, HR repair assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi screen validated with functional HR assay; single lab","pmids":["25883215"],"is_preprint":false},{"year":2015,"finding":"CBLC partially localizes on Golgi membranes (localization enhanced by SRC kinase activation); depletion of CBLC induces Golgi fragmentation (loss of ribbon organization) without perturbing individual stacks. This regulation requires CBLC's ubiquitin ligase activity and involves antagonism of SRC kinase.","method":"RNAi screen (image-based), confocal and electron microscopy, SRC inhibitor treatment, ubiquitin ligase-dead mutant rescue","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by microscopy linked to functional consequence (Golgi fragmentation); ligase-dead mutant tested; single lab","pmids":["26393512"],"is_preprint":false},{"year":2018,"finding":"CBLC is epigenetically upregulated in NSCLC and ubiquitinates activated EGFR via K6 and K11 polyubiquitin linkages (not the canonical K63 used by CBL), which promotes EGFR recycling back to the plasma membrane or trafficking to the nucleus rather than lysosomal degradation, thereby sustaining EGFR activation and competing with CBL for EGFR binding.","method":"siRNA depletion, ectopic overexpression, ubiquitin linkage analysis (mass spectrometry), EGFR recycling/trafficking assays, co-immunoprecipitation, xenograft model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (MS-based linkage analysis, trafficking assay, Co-IP, in vivo xenograft); mechanistic distinction from CBL established","pmids":["29945960"],"is_preprint":false},{"year":2019,"finding":"A RING finger deletion mutant of CBLC found in mammary tumors fails to ubiquitinate activated EGFR and acts in a dominant-negative manner by binding EGFR and preventing recruitment of wild-type CBL family proteins, consistent with a loss-of-function oncogenic mechanism analogous to CBL mutations in myeloid neoplasms.","method":"Cell transformation assay, ubiquitination assay, co-immunoprecipitation, dominant-negative competition assay, genomic sequencing","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and cell-based ubiquitination plus Co-IP; mechanistic dominant-negative characterization; single lab","pmids":["31260484"],"is_preprint":false},{"year":2022,"finding":"CBLC interacts with the kinase domain of Aurora kinase A (AURKA) and stabilizes AURKA by conjugating monoubiquitination and K11/K63-linked polyubiquitination (protective from degrading K48-linked polyubiquitination). CBLC depletion decreases AURKA half-life, delays mitotic entry, reduces the mitotic population, and increases apoptosis in lung adenocarcinoma cells.","method":"Immunoprecipitation-mass spectrometry (interactome), co-immunoprecipitation, ubiquitin linkage analysis, cycloheximide chase assay, cell cycle synchronization/flow cytometry, xenograft model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — IP-MS interactome validated by Co-IP, ubiquitin linkage analysis, and functional cell cycle/survival readouts; in vivo confirmation","pmids":["35149839"],"is_preprint":false},{"year":2022,"finding":"CBLC interacts with CTTN (cortactin) in the cytoplasm and promotes its degradation through the ubiquitin-proteasome pathway without affecting CTTN mRNA levels, thereby inhibiting breast cancer cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay, rescue experiment with CTTN re-expression","journal":"Journal of receptor and signal transduction research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and co-localization plus functional rescue; single lab","pmids":["36043996"],"is_preprint":false},{"year":2024,"finding":"CBLC promotes ubiquitination and proteasomal degradation of ABI1 (Abelson interactor protein-1) through its E3 ligase activity, thereby activating the ERK signaling pathway and promoting colorectal cancer cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression and knockdown gain/loss-of-function, ERK pathway analysis, xenograft model","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with ubiquitination assay and functional rescue; single lab","pmids":["38743987"],"is_preprint":false}],"current_model":"CBLC is a RING-finger E3 ubiquitin ligase expressed predominantly in epithelial cells that targets activated receptor tyrosine kinases (EGFR, Src, Ret, AURKA, CTTN, ABI1) for ubiquitination; its catalytic activity is held in check by an intramolecular N-terminal (EF-hand/SH2) inhibitory mechanism and is unleashed by Src-mediated phosphorylation of Tyr-341, which reduces affinity for the E2 enzyme UbcH5b, while its TKB domain recognizes phosphotyrosine substrates and its RING finger cooperates with interactors (AIP4/ITCH, Hic-5, CD2AP) to regulate the extent and type of ubiquitin linkages placed on substrates, with distinct K6/K11 linkages on active EGFR promoting receptor recycling rather than degradation, and K11/K63 linkages stabilizing AURKA to drive mitotic entry."},"narrative":{"teleology":[{"year":1999,"claim":"Identification of CBLC as a third mammalian CBL family member established that an additional RING-finger E3 ligase with a TKB domain operates on EGF receptor signaling in epithelial cells.","evidence":"Molecular cloning, co-immunoprecipitation with EGFR and Fyn, MAP kinase activity assay, splice variant characterization","pmids":["10362357","10571044"],"confidence":"High","gaps":["Enzymatic activity as E3 ligase not yet demonstrated biochemically","Tissue expression pattern not yet defined","Relationship to CBL/CBLB in EGFR regulation unknown"]},{"year":2002,"claim":"Discovery that CBLC cooperates with the HECT ligase AIP4/ITCH to enhance EGFR ubiquitination revealed that CBL-family RING ligases recruit secondary E3 enzymes to amplify substrate ubiquitination.","evidence":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, EGFR ubiquitination assay","pmids":["12226085"],"confidence":"High","gaps":["Whether AIP4 extends or changes ubiquitin chain type on EGFR not determined","Physiological consequence of dual-E3 cooperation in vivo not tested"]},{"year":2003,"claim":"Knockout mouse studies demonstrated that CBLC is epithelial-cell-restricted and dispensable for viability, fertility, and EGF-stimulated ERK attenuation, indicating functional redundancy with other CBL family members in vivo.","evidence":"Cbl-3 knockout mouse, histology, primary keratinocyte EGF-ERK assay","pmids":["14560016"],"confidence":"High","gaps":["Compensatory roles of CBL/CBLB in knockout not dissected","Epithelial-specific phenotypes under stress or oncogenic challenge not examined"]},{"year":2004,"claim":"Reconstitution of Src ubiquitination in vitro with CBLC and UbcH5 established that CBLC directly catalyzes ubiquitin transfer onto activated (phosphorylated) Src, requiring both TKB and RING domains.","evidence":"In vitro ubiquitination with purified proteins, domain mutagenesis, cell transformation assay","pmids":["14661060"],"confidence":"High","gaps":["Ubiquitin chain type on Src not characterized","Whether CBLC is a major Src regulator in vivo not established"]},{"year":2008,"claim":"The finding that CBLC stabilizes Ret under basal conditions but switches to promoting Ret degradation when CD2AP is present revealed a context-dependent regulatory logic controlling receptor tyrosine kinase fate.","evidence":"Co-immunoprecipitation, overexpression/siRNA in sympathetic neurons, survival and Ret degradation assays","pmids":["18753381"],"confidence":"High","gaps":["Mechanism by which CD2AP converts CBLC from stabilizer to degrader unclear","Ubiquitin chain type difference with and without CD2AP not determined"]},{"year":2010,"claim":"Biochemical dissection of the autoinhibitory mechanism showed that the N-terminal EF-hand/SH2 domains increase E2 (UbcH5b) affinity to suppress catalysis, and Src phosphorylation of Tyr-341 relieves this inhibition by reducing E2 binding, thus coupling CBLC activation to upstream kinase signaling.","evidence":"In vitro ubiquitination, E2 binding affinity measurements, site-directed mutagenesis, Src phosphorylation assay","pmids":["20525694"],"confidence":"High","gaps":["Structural basis of autoinhibition not resolved at atomic level for full-length protein","Whether other kinases besides Src phosphorylate Tyr-341 in vivo not tested"]},{"year":2012,"claim":"Crystal structure of the TKB domain and identification of Hic-5 as a RING-finger interactor that enhances ligase activity defined the structural basis of substrate recognition and a cofactor-dependent activation mode for CBLC.","evidence":"X-ray crystallography with phosphopeptide binding/mutagenesis; co-immunoprecipitation and domain mapping for Hic-5 interaction","pmids":["22888118","23145173"],"confidence":"High","gaps":["Full-length structure including RING domain not available","Whether Hic-5 interaction is relevant in epithelial tissues in vivo unknown"]},{"year":2014,"claim":"Mapping of CD2AP-enhanced Ret51 ubiquitination to specific lysines (K1060, K1107) and dependence on CD2AP SH3 domains resolved how the adaptor confers isoform-selective Ret degradation through CBLC.","evidence":"siRNA knockdown, site-directed mutagenesis of Ret lysines, domain deletion, ubiquitination assay","pmids":["24425877"],"confidence":"High","gaps":["Whether CBLC/CD2AP complex operates on Ret in the nervous system in vivo not shown","Ubiquitin chain types on Ret not characterized"]},{"year":2015,"claim":"Two independent discoveries expanded CBLC's functional scope beyond RTK signaling: its ligase activity maintains Golgi ribbon organization (antagonizing SRC), and its depletion impairs homologous recombination DNA repair, sensitizing cells to PARP inhibition.","evidence":"RNAi screens (image-based for Golgi, viability-based for PARP inhibitor sensitivity), confocal/electron microscopy, HR repair assay, ligase-dead mutant rescue","pmids":["26393512","25883215"],"confidence":"Medium","gaps":["Golgi substrates of CBLC not identified","Mechanism linking CBLC to homologous recombination not defined","Single-lab findings for each phenotype"]},{"year":2018,"claim":"Ubiquitin linkage mass spectrometry revealed that CBLC conjugates non-canonical K6/K11 chains on EGFR — distinct from CBL's K63 chains — promoting receptor recycling and nuclear trafficking rather than degradation, explaining how CBLC sustains EGFR signaling in NSCLC.","evidence":"Mass spectrometry ubiquitin linkage analysis, EGFR trafficking/recycling assays, co-immunoprecipitation, xenograft model","pmids":["29945960"],"confidence":"High","gaps":["Whether linkage specificity is intrinsic to CBLC or dictated by the cellular E2 repertoire not determined","Nuclear EGFR signaling consequences not fully characterized"]},{"year":2019,"claim":"A naturally occurring RING-finger deletion mutant of CBLC acts as a dominant-negative by occupying EGFR without ubiquitinating it, blocking wild-type CBL family access and paralleling oncogenic CBL mutations in myeloid malignancies.","evidence":"Genomic sequencing of mammary tumors, ubiquitination assay, dominant-negative competition assay, co-immunoprecipitation","pmids":["31260484"],"confidence":"Medium","gaps":["Frequency and clinical significance of CBLC RING deletions not established across cancer types","Single-lab characterization"]},{"year":2022,"claim":"Identification of AURKA and cortactin as CBLC substrates demonstrated that CBLC extends beyond RTK regulation: K11/K63 ubiquitination stabilizes AURKA to facilitate mitotic entry, while cortactin ubiquitination promotes its proteasomal degradation to suppress cell invasion.","evidence":"IP-mass spectrometry interactome, ubiquitin linkage analysis, cycloheximide chase, cell cycle/flow cytometry, xenograft for AURKA; co-IP, co-localization, ubiquitination assay, rescue for cortactin","pmids":["35149839","36043996"],"confidence":"High","gaps":["How CBLC selects different chain types for stabilization versus degradation substrates not resolved","Whether AURKA stabilization is a general feature across epithelial cancers unknown"]},{"year":2024,"claim":"CBLC-mediated ubiquitination and degradation of ABI1 was shown to activate ERK signaling and promote colorectal cancer progression, revealing that CBLC can act as a pro-oncogenic E3 by removing tumor-suppressive substrates.","evidence":"Co-immunoprecipitation, ubiquitination assay, gain/loss-of-function, ERK pathway analysis, xenograft model","pmids":["38743987"],"confidence":"Medium","gaps":["Ubiquitin chain type on ABI1 not characterized","Whether ABI1 degradation is the primary mechanism of ERK activation by CBLC not fully resolved","Single-lab finding"]},{"year":null,"claim":"The mechanism by which CBLC selects distinct ubiquitin chain topologies (K6/K11 for recycling, K11/K63 for stabilization, K48 for degradation) on different substrates remains unresolved, as does the structural basis of full-length autoinhibited versus active CBLC and its physiological roles in epithelial homeostasis beyond cancer models.","evidence":"","pmids":[],"confidence":"Low","gaps":["Full-length structure of CBLC in autoinhibited and active states not determined","E2 selectivity mechanism underlying chain-type specificity unknown","In vivo epithelial phenotypes under oncogenic or inflammatory stress in knockout mice not explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,6,7,9,12,14,15,16]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3,6,12,14]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,12,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,6,9,14,15,16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[14]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[12]}],"complexes":[],"partners":["EGFR","SRC","RET","CD2AP","ITCH","TGFB1I1","AURKA","ABI1"],"other_free_text":[]},"mechanistic_narrative":"CBLC is a RING-finger E3 ubiquitin ligase expressed predominantly in epithelial tissues that regulates receptor tyrosine kinase signaling and cell cycle progression through substrate-specific ubiquitin chain conjugation. Its TKB domain recognizes phosphotyrosine-containing substrates including activated EGFR, Src, Ret, AURKA, cortactin, and ABI1, while an intramolecular autoinhibitory mechanism involving the N-terminal EF-hand/SH2 domains is relieved by Src-mediated phosphorylation of Tyr-341, which decreases E2 (UbcH5b) affinity and accelerates catalytic turnover [PMID:20525694]. Unlike CBL, CBLC conjugates non-canonical K6/K11 ubiquitin linkages on EGFR that promote receptor recycling rather than lysosomal degradation [PMID:29945960], and places K11/K63 linkages on AURKA that stabilize the kinase and facilitate mitotic entry [PMID:35149839]. Cooperative interactions with the HECT ligase AIP4/ITCH and the adaptor CD2AP modulate substrate ubiquitination outcome, as exemplified by CD2AP-dependent switching of Ret from stabilization to degradation [PMID:18753381, PMID:24425877]."},"prefetch_data":{"uniprot":{"accession":"Q9ULV8","full_name":"E3 ubiquitin-protein ligase CBL-C","aliases":["RING finger protein 57","RING-type E3 ubiquitin transferase CBL-C","SH3-binding protein CBL-3","SH3-binding protein CBL-C","Signal transduction protein CBL-C"],"length_aa":474,"mass_kda":52.5,"function":"Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Functionally coupled with the E2 ubiquitin-protein ligases UB2D1, UB2D2 and UB2D3. Regulator of EGFR mediated signal transduction; upon EGF activation, ubiquitinates EGFR. Isoform 1, but not isoform 2, inhibits EGF stimulated MAPK1 activation. Promotes ubiquitination of SRC phosphorylated at 'Tyr-419'. In collaboration with CD2AP may act as regulatory checkpoint for Ret signaling by modulating the rate of RET degradation after ligand activation; CD2AP converts it from an inhibitor to a promoter of RET degradation; the function limits the potency of GDNF on neuronal survival","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9ULV8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CBLC","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CBLC","total_profiled":1310},"omim":[{"mim_id":"620953","title":"METHYLMALONIC ACIDURIA, cblD TYPE; MACD","url":"https://www.omim.org/entry/620953"},{"mim_id":"620952","title":"HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblD TYPE; HMAD","url":"https://www.omim.org/entry/620952"},{"mim_id":"620940","title":"METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblL TYPE; MAHCL","url":"https://www.omim.org/entry/620940"},{"mim_id":"609831","title":"METABOLISM OF COBALAMIN ASSOCIATED C; MMACHC","url":"https://www.omim.org/entry/609831"},{"mim_id":"609119","title":"THAP DOMAIN-CONTAINING PROTEIN 11; THAP11","url":"https://www.omim.org/entry/609119"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Aggresome","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":38.2},{"tissue":"intestine","ntpm":47.9},{"tissue":"skin 1","ntpm":40.7}],"url":"https://www.proteinatlas.org/search/CBLC"},"hgnc":{"alias_symbol":["CBL-3","CBL-SL","RNF57"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULV8","domains":[{"cath_id":"1.20.930.20","chopping":"11-147","consensus_level":"medium","plddt":88.5864,"start":11,"end":147},{"cath_id":"1.10.238.10","chopping":"150-235","consensus_level":"medium","plddt":94.7988,"start":150,"end":235},{"cath_id":"3.30.505.10","chopping":"236-323","consensus_level":"high","plddt":92.1307,"start":236,"end":323},{"cath_id":"3.30.40.10","chopping":"330-403","consensus_level":"high","plddt":86.4936,"start":330,"end":403}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULV8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULV8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULV8-F1-predicted_aligned_error_v6.png","plddt_mean":80.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CBLC","jax_strain_url":"https://www.jax.org/strain/search?query=CBLC"},"sequence":{"accession":"Q9ULV8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULV8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULV8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULV8"}},"corpus_meta":[{"pmid":"16311595","id":"PMC_16311595","title":"Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.","date":"2005","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16311595","citation_count":303,"is_preprint":false},{"pmid":"21748409","id":"PMC_21748409","title":"Combined methylmalonic acidemia and homocystinuria, cblC type. 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pulmonary hypertension.","date":"2025","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40468431","citation_count":1,"is_preprint":false},{"pmid":"40544542","id":"PMC_40544542","title":"Variable phenotypes and outcomes associated with the MMACHC c.1A>G variant in Chinese patients with combined methylmalonic acidemia and homocystinuria cblC type.","date":"2025","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40544542","citation_count":1,"is_preprint":false},{"pmid":"36219783","id":"PMC_36219783","title":"A teenager with combined methylmalonic aciduria and homocystinuria (CblC type) presenting with neurological symptoms and congenital heart diseases: a case report.","date":"2022","source":"Neurocase","url":"https://pubmed.ncbi.nlm.nih.gov/36219783","citation_count":1,"is_preprint":false},{"pmid":"38178022","id":"PMC_38178022","title":"Adult-onset combined methylmalonic acidemia and hyperhomocysteinemia, cblC type with aortic dissection and acute kidney injury: a case report.","date":"2024","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/38178022","citation_count":1,"is_preprint":false},{"pmid":"36184083","id":"PMC_36184083","title":"[Genetic variant analysis and prenatal diagnosis for Chinese pedigrees affected with cblC methylmalonic acidemia].","date":"2022","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36184083","citation_count":1,"is_preprint":false},{"pmid":"37252234","id":"PMC_37252234","title":"Case report: An asymptomatic mother with an inborn error of cobalamin metabolism (cblC) detected through high homocysteine levels during prenatal diagnosis.","date":"2023","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/37252234","citation_count":1,"is_preprint":false},{"pmid":"39815091","id":"PMC_39815091","title":"Accelerating the diagnosis of Chinese cblC type MMA patients by multiplex PCR sequencing method.","date":"2025","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/39815091","citation_count":1,"is_preprint":false},{"pmid":"40441036","id":"PMC_40441036","title":"Missense mutations in MMACHC protein from cblC disease affect its conformational stability and vitamin B12-binding activity: The example of R161Q mutation.","date":"2025","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40441036","citation_count":1,"is_preprint":false},{"pmid":"40841656","id":"PMC_40841656","title":"Analysis of hydroxocobalamin dosage in patients with CblC deficiency.","date":"2025","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40841656","citation_count":0,"is_preprint":false},{"pmid":"38743987","id":"PMC_38743987","title":"CBLC promotes the development of colorectal cancer by promoting ABI1 degradation to activate the ERK signaling pathway.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38743987","citation_count":0,"is_preprint":false},{"pmid":"39584041","id":"PMC_39584041","title":"A case series of Cypriot patients with CblC defect: Clinical, biochemical and molecular characteristics.","date":"2024","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/39584041","citation_count":0,"is_preprint":false},{"pmid":"36711998","id":"PMC_36711998","title":"Abnormal chondrocyte intercalation in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36711998","citation_count":0,"is_preprint":false},{"pmid":"39862167","id":"PMC_39862167","title":"A Noncatalytic Cysteine Residue Modulates Cobalamin Reactivity in the Human B12 Processing Enzyme 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An alternatively spliced form lacking a critical PTB region does not interact with EGFR nor inhibit MAP kinase activation.\",\n      \"method\": \"Molecular cloning, co-immunoprecipitation, EGF stimulation assays, MAP kinase activity assay, alternative splice variant characterization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, functional kinase assay, domain deletion analysis; replicated in same year by independent cloning paper\",\n      \"pmids\": [\"10362357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CBLC (Cbl-c) protein binds to the EGF receptor and Fyn tyrosine kinase, establishing it as an adaptor/ubiquitin ligase that regulates intracellular signaling mediated by various tyrosine kinases.\",\n      \"method\": \"Molecular cloning, co-immunoprecipitation with EGFR and Fyn\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/pulldown, corroborated by contemporaneous independent cloning paper\",\n      \"pmids\": [\"10571044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CBLC interacts with the HECT-domain E3 ligase AIP4/ITCH through a two-hybrid screen, confirmed by GST pulldown, co-immunoprecipitation, and colocalization. Both proteins are tyrosine-phosphorylated after EGF stimulation; CBLC increases EGFR ubiquitination and co-expression of CBLC with AIP4 induces down-regulation of EGFR signaling.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, colocalization, EGFR ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, pulldown, Co-IP, ubiquitination assay) in single study\",\n      \"pmids\": [\"12226085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CBLC (Cbl-c) promotes ubiquitination and lysosome-dependent degradation of activated Src (phosphorylated at Tyr419); the TKB domain and RING finger of Cbl-c are required for this activity. In vitro, Cbl-c together with UbcH5 ubiquitinates Src. Non-phosphorylated Src is not ubiquitinated by Cbl-c, indicating specificity for the activated form.\",\n      \"method\": \"Cell transformation assay, in vitro ubiquitination assay with purified proteins, Western blot (protein level), domain mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of ubiquitination with mutagenesis; domain requirements mapped\",\n      \"pmids\": [\"14661060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cbl-3 (CBLC) is expressed specifically in epithelial cells of the gastrointestinal tract, epidermis, and other epithelial tissues. Cbl-3-deficient mice are viable and fertile with no histological abnormalities, and Cbl-3 is not required for attenuation of EGF-stimulated Erk activation in primary keratinocytes.\",\n      \"method\": \"Knockout mouse generation, histological analysis, proliferation assay, EGF-stimulated ERK activation in primary keratinocytes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined cellular and tissue phenotype; expression pattern by Northern/immunostaining\",\n      \"pmids\": [\"14560016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CBLC (Cbl-3) interacts with unphosphorylated Ret receptor tyrosine kinase under basal conditions and dissociates after GDNF-mediated Ret activation; CBLC overexpression stabilizes activated Ret and enhances neuronal survival, but in combination with CD2AP, CBLC promotes rapid Ret degradation, acting as a switch that controls Ret downregulation sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and siRNA knockdown in sympathetic neurons, survival assays, Ret degradation assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, gain- and loss-of-function in neurons with defined phenotypic readouts\",\n      \"pmids\": [\"18753381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The N-terminal EF-hand and SH2 domains of CBLC inhibit its E3 ubiquitin ligase activity by increasing affinity for the E2 enzyme UbcH5b. Phosphorylation of Tyr-341 in the linker region by Src (or phosphomimetic Y341E mutation) decreases affinity for UbcH5b, leading to more rapid E2 turnover and increased E3 activity.\",\n      \"method\": \"In vitro ubiquitination assay, E2 binding affinity measurement, site-directed mutagenesis, Src phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with mutagenesis mapping the activation mechanism\",\n      \"pmids\": [\"20525694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CBLC interacts with the adaptor protein Hic-5 through a novel RING finger–LIM2 domain interaction; this interaction enhances CBLC ubiquitin ligase activity (once activated by Src phosphorylation) and increases EGFR ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping mutagenesis, in vitro ubiquitination assay, EGFR ubiquitination assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping and functional ubiquitination assay; single lab\",\n      \"pmids\": [\"23145173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the TKB domain of CBLC (Cbl-c/Cbl-3) revealed restricted structural flexibility upon phosphopeptide binding compared to Cbl. A mutation in the TKB domain that augments flexibility enhanced binding to target phosphoproteins, demonstrating that structural flexibility regulates phosphopeptide-binding activity.\",\n      \"method\": \"X-ray crystallography, phosphopeptide binding assay, mutagenesis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis-based functional validation\",\n      \"pmids\": [\"22888118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD2AP enhances CBLC (Cbl-3/c)-mediated ubiquitination and degradation of Ret51 (but not Ret9) via its N-terminal SH3 domains. CBLC requires a functional RING finger and TKB domain for Ret51 ubiquitination, and the two primary ubiquitination sites on Ret51 are Lys1060 and Lys1107. Activated Ret induces degradation of CD2AP but not CBLC.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis of Ret lysines, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, Co-IP, mutagenesis, site mapping) with defined mechanistic outcome\",\n      \"pmids\": [\"24425877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CBLC silencing causes increased sensitivity to the PARP inhibitor olaparib in breast cancer cell lines, associated with defective homologous recombination DNA repair, identifying CBLC as a modifier of PARP inhibitor response through the ubiquitin/DNA damage response axis.\",\n      \"method\": \"RNAi screen, siRNA knockdown, cell viability assay, HR repair assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi screen validated with functional HR assay; single lab\",\n      \"pmids\": [\"25883215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CBLC partially localizes on Golgi membranes (localization enhanced by SRC kinase activation); depletion of CBLC induces Golgi fragmentation (loss of ribbon organization) without perturbing individual stacks. This regulation requires CBLC's ubiquitin ligase activity and involves antagonism of SRC kinase.\",\n      \"method\": \"RNAi screen (image-based), confocal and electron microscopy, SRC inhibitor treatment, ubiquitin ligase-dead mutant rescue\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by microscopy linked to functional consequence (Golgi fragmentation); ligase-dead mutant tested; single lab\",\n      \"pmids\": [\"26393512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CBLC is epigenetically upregulated in NSCLC and ubiquitinates activated EGFR via K6 and K11 polyubiquitin linkages (not the canonical K63 used by CBL), which promotes EGFR recycling back to the plasma membrane or trafficking to the nucleus rather than lysosomal degradation, thereby sustaining EGFR activation and competing with CBL for EGFR binding.\",\n      \"method\": \"siRNA depletion, ectopic overexpression, ubiquitin linkage analysis (mass spectrometry), EGFR recycling/trafficking assays, co-immunoprecipitation, xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (MS-based linkage analysis, trafficking assay, Co-IP, in vivo xenograft); mechanistic distinction from CBL established\",\n      \"pmids\": [\"29945960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A RING finger deletion mutant of CBLC found in mammary tumors fails to ubiquitinate activated EGFR and acts in a dominant-negative manner by binding EGFR and preventing recruitment of wild-type CBL family proteins, consistent with a loss-of-function oncogenic mechanism analogous to CBL mutations in myeloid neoplasms.\",\n      \"method\": \"Cell transformation assay, ubiquitination assay, co-immunoprecipitation, dominant-negative competition assay, genomic sequencing\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and cell-based ubiquitination plus Co-IP; mechanistic dominant-negative characterization; single lab\",\n      \"pmids\": [\"31260484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CBLC interacts with the kinase domain of Aurora kinase A (AURKA) and stabilizes AURKA by conjugating monoubiquitination and K11/K63-linked polyubiquitination (protective from degrading K48-linked polyubiquitination). CBLC depletion decreases AURKA half-life, delays mitotic entry, reduces the mitotic population, and increases apoptosis in lung adenocarcinoma cells.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry (interactome), co-immunoprecipitation, ubiquitin linkage analysis, cycloheximide chase assay, cell cycle synchronization/flow cytometry, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — IP-MS interactome validated by Co-IP, ubiquitin linkage analysis, and functional cell cycle/survival readouts; in vivo confirmation\",\n      \"pmids\": [\"35149839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CBLC interacts with CTTN (cortactin) in the cytoplasm and promotes its degradation through the ubiquitin-proteasome pathway without affecting CTTN mRNA levels, thereby inhibiting breast cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay, rescue experiment with CTTN re-expression\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and co-localization plus functional rescue; single lab\",\n      \"pmids\": [\"36043996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CBLC promotes ubiquitination and proteasomal degradation of ABI1 (Abelson interactor protein-1) through its E3 ligase activity, thereby activating the ERK signaling pathway and promoting colorectal cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression and knockdown gain/loss-of-function, ERK pathway analysis, xenograft model\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with ubiquitination assay and functional rescue; single lab\",\n      \"pmids\": [\"38743987\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CBLC is a RING-finger E3 ubiquitin ligase expressed predominantly in epithelial cells that targets activated receptor tyrosine kinases (EGFR, Src, Ret, AURKA, CTTN, ABI1) for ubiquitination; its catalytic activity is held in check by an intramolecular N-terminal (EF-hand/SH2) inhibitory mechanism and is unleashed by Src-mediated phosphorylation of Tyr-341, which reduces affinity for the E2 enzyme UbcH5b, while its TKB domain recognizes phosphotyrosine substrates and its RING finger cooperates with interactors (AIP4/ITCH, Hic-5, CD2AP) to regulate the extent and type of ubiquitin linkages placed on substrates, with distinct K6/K11 linkages on active EGFR promoting receptor recycling rather than degradation, and K11/K63 linkages stabilizing AURKA to drive mitotic entry.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CBLC is a RING-finger E3 ubiquitin ligase expressed predominantly in epithelial tissues that regulates receptor tyrosine kinase signaling and cell cycle progression through substrate-specific ubiquitin chain conjugation. Its TKB domain recognizes phosphotyrosine-containing substrates including activated EGFR, Src, Ret, AURKA, cortactin, and ABI1, while an intramolecular autoinhibitory mechanism involving the N-terminal EF-hand/SH2 domains is relieved by Src-mediated phosphorylation of Tyr-341, which decreases E2 (UbcH5b) affinity and accelerates catalytic turnover [PMID:20525694]. Unlike CBL, CBLC conjugates non-canonical K6/K11 ubiquitin linkages on EGFR that promote receptor recycling rather than lysosomal degradation [PMID:29945960], and places K11/K63 linkages on AURKA that stabilize the kinase and facilitate mitotic entry [PMID:35149839]. Cooperative interactions with the HECT ligase AIP4/ITCH and the adaptor CD2AP modulate substrate ubiquitination outcome, as exemplified by CD2AP-dependent switching of Ret from stabilization to degradation [PMID:18753381, PMID:24425877].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of CBLC as a third mammalian CBL family member established that an additional RING-finger E3 ligase with a TKB domain operates on EGF receptor signaling in epithelial cells.\",\n      \"evidence\": \"Molecular cloning, co-immunoprecipitation with EGFR and Fyn, MAP kinase activity assay, splice variant characterization\",\n      \"pmids\": [\"10362357\", \"10571044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Enzymatic activity as E3 ligase not yet demonstrated biochemically\",\n        \"Tissue expression pattern not yet defined\",\n        \"Relationship to CBL/CBLB in EGFR regulation unknown\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery that CBLC cooperates with the HECT ligase AIP4/ITCH to enhance EGFR ubiquitination revealed that CBL-family RING ligases recruit secondary E3 enzymes to amplify substrate ubiquitination.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, EGFR ubiquitination assay\",\n      \"pmids\": [\"12226085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether AIP4 extends or changes ubiquitin chain type on EGFR not determined\",\n        \"Physiological consequence of dual-E3 cooperation in vivo not tested\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Knockout mouse studies demonstrated that CBLC is epithelial-cell-restricted and dispensable for viability, fertility, and EGF-stimulated ERK attenuation, indicating functional redundancy with other CBL family members in vivo.\",\n      \"evidence\": \"Cbl-3 knockout mouse, histology, primary keratinocyte EGF-ERK assay\",\n      \"pmids\": [\"14560016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Compensatory roles of CBL/CBLB in knockout not dissected\",\n        \"Epithelial-specific phenotypes under stress or oncogenic challenge not examined\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Reconstitution of Src ubiquitination in vitro with CBLC and UbcH5 established that CBLC directly catalyzes ubiquitin transfer onto activated (phosphorylated) Src, requiring both TKB and RING domains.\",\n      \"evidence\": \"In vitro ubiquitination with purified proteins, domain mutagenesis, cell transformation assay\",\n      \"pmids\": [\"14661060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Ubiquitin chain type on Src not characterized\",\n        \"Whether CBLC is a major Src regulator in vivo not established\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The finding that CBLC stabilizes Ret under basal conditions but switches to promoting Ret degradation when CD2AP is present revealed a context-dependent regulatory logic controlling receptor tyrosine kinase fate.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression/siRNA in sympathetic neurons, survival and Ret degradation assays\",\n      \"pmids\": [\"18753381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which CD2AP converts CBLC from stabilizer to degrader unclear\",\n        \"Ubiquitin chain type difference with and without CD2AP not determined\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Biochemical dissection of the autoinhibitory mechanism showed that the N-terminal EF-hand/SH2 domains increase E2 (UbcH5b) affinity to suppress catalysis, and Src phosphorylation of Tyr-341 relieves this inhibition by reducing E2 binding, thus coupling CBLC activation to upstream kinase signaling.\",\n      \"evidence\": \"In vitro ubiquitination, E2 binding affinity measurements, site-directed mutagenesis, Src phosphorylation assay\",\n      \"pmids\": [\"20525694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of autoinhibition not resolved at atomic level for full-length protein\",\n        \"Whether other kinases besides Src phosphorylate Tyr-341 in vivo not tested\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Crystal structure of the TKB domain and identification of Hic-5 as a RING-finger interactor that enhances ligase activity defined the structural basis of substrate recognition and a cofactor-dependent activation mode for CBLC.\",\n      \"evidence\": \"X-ray crystallography with phosphopeptide binding/mutagenesis; co-immunoprecipitation and domain mapping for Hic-5 interaction\",\n      \"pmids\": [\"22888118\", \"23145173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full-length structure including RING domain not available\",\n        \"Whether Hic-5 interaction is relevant in epithelial tissues in vivo unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping of CD2AP-enhanced Ret51 ubiquitination to specific lysines (K1060, K1107) and dependence on CD2AP SH3 domains resolved how the adaptor confers isoform-selective Ret degradation through CBLC.\",\n      \"evidence\": \"siRNA knockdown, site-directed mutagenesis of Ret lysines, domain deletion, ubiquitination assay\",\n      \"pmids\": [\"24425877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CBLC/CD2AP complex operates on Ret in the nervous system in vivo not shown\",\n        \"Ubiquitin chain types on Ret not characterized\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two independent discoveries expanded CBLC's functional scope beyond RTK signaling: its ligase activity maintains Golgi ribbon organization (antagonizing SRC), and its depletion impairs homologous recombination DNA repair, sensitizing cells to PARP inhibition.\",\n      \"evidence\": \"RNAi screens (image-based for Golgi, viability-based for PARP inhibitor sensitivity), confocal/electron microscopy, HR repair assay, ligase-dead mutant rescue\",\n      \"pmids\": [\"26393512\", \"25883215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Golgi substrates of CBLC not identified\",\n        \"Mechanism linking CBLC to homologous recombination not defined\",\n        \"Single-lab findings for each phenotype\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Ubiquitin linkage mass spectrometry revealed that CBLC conjugates non-canonical K6/K11 chains on EGFR — distinct from CBL's K63 chains — promoting receptor recycling and nuclear trafficking rather than degradation, explaining how CBLC sustains EGFR signaling in NSCLC.\",\n      \"evidence\": \"Mass spectrometry ubiquitin linkage analysis, EGFR trafficking/recycling assays, co-immunoprecipitation, xenograft model\",\n      \"pmids\": [\"29945960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether linkage specificity is intrinsic to CBLC or dictated by the cellular E2 repertoire not determined\",\n        \"Nuclear EGFR signaling consequences not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A naturally occurring RING-finger deletion mutant of CBLC acts as a dominant-negative by occupying EGFR without ubiquitinating it, blocking wild-type CBL family access and paralleling oncogenic CBL mutations in myeloid malignancies.\",\n      \"evidence\": \"Genomic sequencing of mammary tumors, ubiquitination assay, dominant-negative competition assay, co-immunoprecipitation\",\n      \"pmids\": [\"31260484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Frequency and clinical significance of CBLC RING deletions not established across cancer types\",\n        \"Single-lab characterization\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of AURKA and cortactin as CBLC substrates demonstrated that CBLC extends beyond RTK regulation: K11/K63 ubiquitination stabilizes AURKA to facilitate mitotic entry, while cortactin ubiquitination promotes its proteasomal degradation to suppress cell invasion.\",\n      \"evidence\": \"IP-mass spectrometry interactome, ubiquitin linkage analysis, cycloheximide chase, cell cycle/flow cytometry, xenograft for AURKA; co-IP, co-localization, ubiquitination assay, rescue for cortactin\",\n      \"pmids\": [\"35149839\", \"36043996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How CBLC selects different chain types for stabilization versus degradation substrates not resolved\",\n        \"Whether AURKA stabilization is a general feature across epithelial cancers unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CBLC-mediated ubiquitination and degradation of ABI1 was shown to activate ERK signaling and promote colorectal cancer progression, revealing that CBLC can act as a pro-oncogenic E3 by removing tumor-suppressive substrates.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, gain/loss-of-function, ERK pathway analysis, xenograft model\",\n      \"pmids\": [\"38743987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitin chain type on ABI1 not characterized\",\n        \"Whether ABI1 degradation is the primary mechanism of ERK activation by CBLC not fully resolved\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which CBLC selects distinct ubiquitin chain topologies (K6/K11 for recycling, K11/K63 for stabilization, K48 for degradation) on different substrates remains unresolved, as does the structural basis of full-length autoinhibited versus active CBLC and its physiological roles in epithelial homeostasis beyond cancer models.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Full-length structure of CBLC in autoinhibited and active states not determined\",\n        \"E2 selectivity mechanism underlying chain-type specificity unknown\",\n        \"In vivo epithelial phenotypes under oncogenic or inflammatory stress in knockout mice not explored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 6, 7, 9, 12, 14, 15, 16]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3, 6, 12, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 12, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 6, 9, 14, 15, 16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"EGFR\",\n      \"SRC\",\n      \"RET\",\n      \"CD2AP\",\n      \"ITCH\",\n      \"TGFB1I1\",\n      \"AURKA\",\n      \"ABI1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}