{"gene":"CBLC","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1999,"finding":"CBLC (Cbl-c) protein was identified as a novel CBL family member encoding a 52 kDa protein with a phosphotyrosine-binding domain, RING finger, and proline-rich region. The Cbl-c protein was shown to bind the EGF receptor and Fyn tyrosine kinase.","method":"Molecular cloning, co-immunoprecipitation/binding assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — initial characterization by binding assays; single lab but multiple interactions tested","pmids":["10571044"],"is_preprint":false},{"year":2001,"finding":"Mouse Cblc/Cbl3 gene was cloned; it comprises 12 exons and encodes a 496 amino acid protein sharing 67% identity with the human ortholog and 70% identity with mouse CBL over conserved SH2 and RING finger domains. Cblc mRNA is expressed ubiquitously in embryo and adult tissues.","method":"Molecular cloning, expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, gene characterization without functional mechanistic assay","pmids":["11162497"],"is_preprint":false},{"year":2002,"finding":"CBLC interacts with the HECT-domain E3 ubiquitin ligase AIP4/ITCH (and its C. elegans counterpart WWP1) via CBLC's proline-rich region and the WW domains of AIP4. This interaction was confirmed by GST pull-down, co-immunoprecipitation, and colocalization. CBLC and AIP4 both become tyrosine-phosphorylated upon EGF stimulation. Overexpression of CBLC increased EGFR ubiquitination, and coexpression of WW domains of AIP4 exerted a dominant-negative effect on EGFR ubiquitination. Coexpression of CBLC and AIP4 together downregulated EGFR signaling.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, colocalization, ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, GST pulldown, reciprocal co-IP, colocalization, functional ubiquitination assay) in single study","pmids":["12226085"],"is_preprint":false},{"year":2004,"finding":"CBLC (Cbl-c) specifically targets activated Src (phosphorylated at Tyr419) for ubiquitination and degradation via a lysosome-dependent pathway. The TKB domain and RING finger of CBLC are required for its anti-oncogenic activity. Wild-type CBLC together with UbcH5 induced ubiquitination of Src in vitro, while a RING finger mutant did not. Non-phosphorylated Src was not ubiquitinated by CBLC. CBLC suppressed v-Src-induced transformation and caused reversion of the morphological phenotype in NIH3T3 cells, distinct from the mechanism of Cbl and Cbl-b.","method":"In vitro ubiquitination assay with UbcH5, RING finger mutagenesis, cell transformation assay, protein degradation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted ubiquitination with mutational validation plus functional cellular readout","pmids":["14661060"],"is_preprint":false},{"year":2009,"finding":"Transgenic mice expressing CBLC in the mammary gland (MMTV-CBLC) showed reduced number and length of ducts during mammary gland development, supporting CBLC's role as a negative regulator of cell proliferation in epithelial tissues.","method":"Transgenic mouse model, in vivo mammary gland morphology assessment","journal":"In vivo (Athens, Greece)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, in vivo phenotype without mechanistic pathway placement","pmids":["19414407"],"is_preprint":false},{"year":2010,"finding":"The N-terminus of Cbl-c (specifically the EF-hand and SH2 domains) inhibits its E3 ubiquitin ligase activity. Phosphorylation of a critical tyrosine residue (Tyr-341) in the linker region by Src kinase, or a phosphomimetic Y341E mutation, relieves this inhibition by decreasing affinity for the E2 enzyme UbcH5b. Reduced E2 affinity leads to more rapid turnover of bound UbcH5b and increased E3 ligase activity.","method":"In vitro ubiquitination assay, site-directed mutagenesis, E2-binding affinity measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic dissection with mutagenesis, in vitro reconstitution, and binding affinity measurements in one study","pmids":["20525694"],"is_preprint":false},{"year":2012,"finding":"CBLC interacts with Hic-5 (Hydrogen peroxide Induced Construct 5) through a novel interaction between the RING finger of CBLC and the LIM2 domain of Hic-5, mediated by specific zinc-coordinating complexes. Binding of Hic-5 to CBLC increases CBLC ubiquitin ligase activity (after Src-mediated activation) and enhances CBLC-mediated ubiquitination of EGFR. This is the first example of a LIM zinc-coordinating domain enhancing RING finger E3 ligase activity.","method":"Co-immunoprecipitation, ubiquitination assay, domain mapping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping and functional ubiquitination readout, single lab","pmids":["23145173"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the tyrosine kinase binding (TKB) domain of Cbl-c/Cbl-3 revealed that, compared to Cbl TKB, the Cbl-c TKB domain shows restricted structural flexibility upon phosphopeptide binding. A mutation in Cbl-c TKB that increased structural flexibility enhanced binding to target phosphoproteins, indicating 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 / Moderate — crystal structure with functional mutagenesis validation, single lab","pmids":["22888118"],"is_preprint":false},{"year":2015,"finding":"RNAi screening identified CBLC as a modifier of PARP inhibitor (olaparib) sensitivity. Silencing of CBLC caused increased sensitivity to olaparib in breast cancer cell lines, with defective homologous recombination (HR) DNA repair identified as the likely mechanism.","method":"RNAi screen, cell viability assay, HR repair assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — validated screen hit with HR repair mechanistic link, single lab","pmids":["25883215"],"is_preprint":false},{"year":2015,"finding":"Depletion of CBLC specifically induces Golgi fragmentation (disruption of Golgi ribbon/network organization) without significantly affecting Golgi stack structure. CBLC partially localizes to Golgi membranes, and this localization is enhanced after SRC kinase activation. Inhibition of SRC reverts the Golgi fragmentation caused by CBLC depletion, indicating interplay between CBLC and SRC at the Golgi. CBLC's regulation of Golgi network organization requires its ubiquitin ligase activity. Depletion of the close homologues CBL and CBLB did not induce visible Golgi defects.","method":"RNAi knockdown, fluorescence and electron microscopy, Golgi morphology quantification, SRC inhibitor treatment, E3 mutant rescue","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — image-based RNAi screen validated with multiple microscopy methods, E3 activity requirement confirmed by mutant, SRC interplay tested pharmacologically","pmids":["26393512"],"is_preprint":false},{"year":2018,"finding":"CBLC is epigenetically upregulated (by promoter demethylation) in non-small cell lung cancer. CBLC competes with CBL for EGFR binding and, unlike CBL-mediated K63-linked ubiquitination promoting lysosomal degradation, CBLC ubiquitinates activated EGFR (aEGFR) via K6 and K11 polyubiquitin linkages, which promotes recycling of aEGFR back to the plasma membrane or trafficking to the nucleus rather than lysosomal degradation, thereby sustaining EGFR activation and downstream ERK1/2 signaling.","method":"CBLC depletion/overexpression, ubiquitin linkage analysis (mass spectrometry), co-immunoprecipitation, EGFR trafficking assay, xenograft model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — ubiquitin linkage type determined by MS, mechanism validated by OE/KD with multiple readouts including trafficking and signaling, in vivo xenograft","pmids":["29945960"],"is_preprint":false},{"year":2019,"finding":"Loss-of-function mutations in the RING finger domain of CBLC (identified in a mouse mammary tumor and in human solid tumors) abolish CBLC-mediated ubiquitination of activated EGFR and allow the mutant protein to act in a dominant-negative fashion by binding EGFR and preventing recruitment and action of wild-type CBL family proteins. A CBLC RING-finger deletion mutant enhanced NIH 3T3 cell transformation when combined with SV40 Large T antigen.","method":"Ubiquitination assay, co-immunoprecipitation, NIH 3T3 transformation assay, genomic/cDNA sequence analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic loss-of-function with ubiquitination assay and dominant-negative demonstration, single lab","pmids":["31260484"],"is_preprint":false},{"year":2022,"finding":"CBLC interacts with AURKA (Aurora kinase A) through AURKA's kinase domain, as determined by immunoprecipitation and mass spectrometry. CBLC stabilizes AURKA by conjugating monoubiquitination and K11/K63-linked polyubiquitination, protecting it from degrading K11/K48 polyubiquitination. CBLC depletion decreased AURKA half-life and delayed its accumulation/activation during mitotic entry, reducing the mitotic population and increasing apoptosis in lung adenocarcinoma cells.","method":"Immunoprecipitation/mass spectrometry, ubiquitin linkage analysis, cycloheximide chase, cell synchronization/FACS, xenograft model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — IP-MS interactome identification confirmed by ubiquitin linkage typing, protein stability assay, and mitotic cell cycle functional readout with in vivo confirmation","pmids":["35149839"],"is_preprint":false},{"year":2022,"finding":"CBLC interacts with CTTN (cortactin) in the cytoplasm, as shown by co-immunoprecipitation and immunofluorescence co-localization. CBLC promotes degradation of CTTN through the ubiquitin-proteasome pathway, and this activity inhibits breast cancer cell proliferation, migration, and invasion. Overexpression of CTTN partially rescues the inhibitory effect of CBLC.","method":"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination/proteasome assay, cell proliferation/migration/invasion assays","journal":"Journal of receptor and signal transduction research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with colocalization and functional rescue experiment, single lab","pmids":["36043996"],"is_preprint":false},{"year":2024,"finding":"CBLC ubiquitinates ABI1 (Abelson interactor protein 1), promoting its proteasomal degradation. CBLC-mediated ABI1 degradation activates the ERK signaling pathway. ABI1 overexpression abolishes the pro-tumorigenic effects of CBLC in colorectal cancer cells. CBLC also promoted tumor growth and metastasis in xenograft models.","method":"Ubiquitination assay, co-immunoprecipitation, western blot, cell proliferation/migration/invasion assays, xenograft and lung metastasis models","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination of substrate shown, rescue experiment performed, pathway placement by ERK readout; single lab","pmids":["38743987"],"is_preprint":false},{"year":2026,"finding":"CBLC ubiquitinates METTL1 (tRNA guanine-N7-methyltransferase), stabilizing it against proteasomal degradation. Stabilized METTL1 enhances N7-methylguanosine (m7G) modification of ESRRA mRNA, increasing ESRRA stability and expression, which mediates CBLC's pro-tumorigenic effects in endometrial cancer.","method":"Ubiquitination assay, co-immunoprecipitation, m7G methylation assay, mRNA stability assay, functional rescue experiments, single-cell and bulk transcriptomics","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination substrate identification with downstream m7G modification mechanistic link and rescue; single lab","pmids":["42217705"],"is_preprint":false}],"current_model":"CBLC is a RING-finger E3 ubiquitin ligase that regulates receptor tyrosine kinase signaling by ubiquitinating activated EGFR via non-canonical K6/K11-linked polyubiquitin chains that promote EGFR recycling rather than degradation (opposing canonical CBL-mediated K63/lysosomal degradation), targets activated Src for lysosomal degradation, stabilizes Aurora kinase A and METTL1 through protective ubiquitination, degrades ABI1 and cortactin via the proteasome, and maintains Golgi ribbon network organization in an E3-activity-dependent manner; its E3 activity is autoinhibited by its N-terminal EF-hand/SH2 domain and activated by Src-mediated phosphorylation of Tyr-341, which reduces affinity for E2 enzyme UbcH5b and increases ubiquitin transfer turnover, while its TKB domain binds phosphotyrosine-containing substrates with a rigidity distinct from other CBL family members."},"narrative":{"mechanistic_narrative":"CBLC is a RING-finger E3 ubiquitin ligase of the CBL family that regulates receptor tyrosine kinase signaling and protein turnover through substrate-selective ubiquitination, generally acting as a negative regulator of cell proliferation [PMID:10571044, PMID:19414407]. Its catalytic output is governed by an N-terminal EF-hand/SH2 module that autoinhibits the enzyme; Src-mediated phosphorylation of Tyr-341, or a phosphomimetic substitution, relieves this inhibition by lowering affinity for the E2 enzyme UbcH5b and accelerating ubiquitin-transfer turnover [PMID:20525694], and its TKB domain engages phosphotyrosine substrates with a constrained structural flexibility that distinguishes it from other CBL members [PMID:22888118]. The chain architecture CBLC assembles dictates whether substrates are degraded or protected: it targets activated Src for lysosomal degradation [PMID:14661060] and routes ABI1 and cortactin to the proteasome [PMID:36043996, PMID:38743987], yet builds non-canonical K6/K11-linked chains on activated EGFR that promote recycling and sustained ERK signaling rather than lysosomal degradation, in opposition to canonical CBL [PMID:29945960], and conjugates protective monoubiquitin and K11/K63 chains that stabilize Aurora kinase A and METTL1 against degradative ubiquitination [PMID:35149839, PMID:42217705]. Its activity is further tuned by partners including the HECT ligase AIP4/ITCH and the LIM protein Hic-5, which enhances CBLC-mediated EGFR ubiquitination [PMID:12226085, PMID:23145173], and CBLC also maintains Golgi ribbon network organization in an E3-activity- and SRC-dependent manner [PMID:26393512]. RING-finger loss-of-function mutations found in human and mouse tumors abolish EGFR ubiquitination and act dominant-negatively to promote transformation [PMID:31260484].","teleology":[{"year":1999,"claim":"Establishing CBLC as a distinct CBL family member with a defined domain architecture and direct kinase-binding capacity set the structural premise for all subsequent mechanistic work.","evidence":"Molecular cloning and binding assays identifying a 52 kDa protein with phosphotyrosine-binding domain, RING finger, and proline-rich region that binds EGFR and Fyn","pmids":["10571044"],"confidence":"Medium","gaps":["No enzymatic activity demonstrated","Functional consequence of EGFR/Fyn binding undefined"]},{"year":2002,"claim":"Linking CBLC to the HECT ligase AIP4/ITCH and showing cooperative EGFR downregulation placed CBLC within receptor tyrosine kinase signaling control and identified a functional partnership.","evidence":"Yeast two-hybrid, GST pull-down, reciprocal co-IP, colocalization, and EGFR ubiquitination assays","pmids":["12226085"],"confidence":"High","gaps":["Direct CBLC ubiquitination of EGFR vs. AIP4 contribution not separated","Chain linkage type not determined"]},{"year":2004,"claim":"Demonstrating that CBLC ubiquitinates activated Src for lysosomal degradation and reverses v-Src transformation established its anti-oncogenic, RING-dependent catalytic function with phospho-substrate selectivity.","evidence":"In vitro reconstituted ubiquitination with UbcH5, RING mutant controls, degradation assay, and NIH3T3 transformation reversion","pmids":["14661060"],"confidence":"High","gaps":["Lysosomal targeting mechanism not detailed","Chain linkage type unresolved"]},{"year":2010,"claim":"Resolving the autoinhibition/activation switch explained how CBLC catalysis is gated by Src phosphorylation at Tyr-341 through modulation of E2 affinity.","evidence":"In vitro ubiquitination, Y341 mutagenesis/phosphomimetic, and UbcH5b binding affinity measurements","pmids":["20525694"],"confidence":"High","gaps":["Structural basis of the EF-hand/SH2 autoinhibited state not solved","In-cell kinetics of the switch not measured"]},{"year":2012,"claim":"The TKB domain crystal structure showed that restricted flexibility relative to CBL tunes phosphopeptide binding, providing a structural rationale for CBLC's distinct substrate engagement.","evidence":"X-ray crystallography with flexibility-altering mutagenesis and phosphopeptide binding assays","pmids":["22888118"],"confidence":"High","gaps":["No co-structure with a physiological substrate","Functional consequence of flexibility in cells untested"]},{"year":2012,"claim":"Identifying Hic-5 as a RING-binding cofactor that boosts CBLC activity revealed a novel mode of E3 regulation by a LIM zinc-coordinating domain.","evidence":"Co-IP, domain mapping, and EGFR ubiquitination assays","pmids":["23145173"],"confidence":"Medium","gaps":["Mechanism by which LIM2 enhances catalysis not defined","Physiological context of Hic-5/CBLC cooperation untested in vivo"]},{"year":2015,"claim":"Connecting CBLC to PARP inhibitor sensitivity and HR repair, and to Golgi ribbon maintenance, broadened its cellular roles beyond RTK signaling.","evidence":"RNAi screen with olaparib viability and HR assays; image-based knockdown with microscopy, E3-mutant rescue, and SRC inhibitor treatment","pmids":["25883215","26393512"],"confidence":"High","gaps":["Molecular substrate linking CBLC to HR repair unidentified","Golgi substrate of CBLC ubiquitination not identified"]},{"year":2018,"claim":"Determining that CBLC builds K6/K11 chains on activated EGFR to drive recycling rather than degradation reversed the expectation of CBL-like negative regulation and explained its pro-oncogenic role in lung cancer.","evidence":"Mass-spectrometry ubiquitin linkage analysis, co-IP, EGFR trafficking assays, knockdown/overexpression, and xenografts","pmids":["29945960"],"confidence":"High","gaps":["Reconciliation with earlier anti-oncogenic findings context-dependent and unresolved","Reader/effector decoding K6/K11 chains on EGFR not identified"]},{"year":2019,"claim":"Showing that tumor-derived RING mutants are catalytically dead and dominant-negative clarified how CBLC loss-of-function contributes to transformation by blocking other CBL proteins.","evidence":"Ubiquitination assay, co-IP, and NIH 3T3 transformation assay with SV40 Large T","pmids":["31260484"],"confidence":"Medium","gaps":["Frequency and clinical impact of these mutations not established","Competition mechanism with wild-type CBL not quantified"]},{"year":2022,"claim":"Identifying AURKA and cortactin as substrates demonstrated that CBLC can either protectively stabilize (AURKA via K11/K63) or proteasomally degrade (cortactin) substrates, controlling mitosis and cell motility respectively.","evidence":"IP-MS, ubiquitin linkage typing, cycloheximide chase, cell synchronization/FACS, xenografts; co-IP, colocalization, and migration/invasion rescue assays","pmids":["35149839","36043996"],"confidence":"High","gaps":["Determinants selecting protective vs. degradative chains on different substrates unknown","Whether AURKA and CTTN regulation co-occur in the same cells untested"]},{"year":2024,"claim":"Establishing ABI1 as a degradative substrate linked CBLC to ERK pathway activation and a pro-tumorigenic role in colorectal cancer.","evidence":"Ubiquitination assay, co-IP, ERK readout, rescue with ABI1 overexpression, and xenograft/metastasis models","pmids":["38743987"],"confidence":"Medium","gaps":["Direct vs. indirect ERK activation not dissected","Chain linkage on ABI1 not typed"]},{"year":2026,"claim":"Showing CBLC stabilizes METTL1 to enhance m7G modification of ESRRA mRNA extended its substrate repertoire into RNA-modification machinery and endometrial cancer.","evidence":"Ubiquitination assay, co-IP, m7G and mRNA stability assays, rescue experiments, and transcriptomics","pmids":["42217705"],"confidence":"Medium","gaps":["Chain linkage stabilizing METTL1 not fully typed","Generality of CBLC-METTL1 axis beyond endometrial cancer untested"]},{"year":null,"claim":"What governs CBLC's context-dependent choice between degradative and protective/recycling ubiquitin chains on different substrates, and how this dictates its opposing tumor-suppressive versus pro-oncogenic outcomes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for substrate-specific chain-type selection","Tissue determinants of anti- vs. pro-oncogenic behavior undefined","Structure of full-length CBLC-substrate-E2 complex not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,5,10,12]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3,10,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,10,12,14,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,15]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,10,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,10,12,13,14,15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11]}],"complexes":[],"partners":["EGFR","SRC","AIP4","AURKA","CTTN","ABI1","METTL1","FYN"],"other_free_text":[]}},"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":304,"is_preprint":false},{"pmid":"21748409","id":"PMC_21748409","title":"Combined methylmalonic acidemia and homocystinuria, cblC type. 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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":"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":"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":"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":"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":"39862167","id":"PMC_39862167","title":"A Noncatalytic Cysteine Residue Modulates Cobalamin Reactivity in the Human B12 Processing Enzyme CblC.","date":"2025","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39862167","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":"39225018","id":"PMC_39225018","title":"Evaluation of the clinical, biochemical, and molecular spectrum of Cobalamin C (CblC) defect in 33 patients from Pakistan.","date":"2024","source":"Scandinavian journal of clinical and laboratory investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39225018","citation_count":0,"is_preprint":false},{"pmid":"40576712","id":"PMC_40576712","title":"Modulation of conformational features and oligomerization of MMACHC by cobalamin variants: impact of the R161Q mutation in cblC disease.","date":"2025","source":"European biophysics journal : EBJ","url":"https://pubmed.ncbi.nlm.nih.gov/40576712","citation_count":0,"is_preprint":false},{"pmid":"39429080","id":"PMC_39429080","title":"[Analysis of the regional distribution differences of common variations of the MMACHC gene in cblC methylmalonic acidemia patients].","date":"2024","source":"Zhonghua er ke za zhi = Chinese journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/39429080","citation_count":0,"is_preprint":false},{"pmid":"42217705","id":"PMC_42217705","title":"CBLC-mediated ubiquitination stabilizes METTL1, enhances N7-methylguanosine modification of ESRRA, and promotes the progression of endometrial cancer.","date":"2026","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/42217705","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54288,"output_tokens":4593,"usd":0.115879,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12216,"output_tokens":4121,"usd":0.082053,"stage2_stop_reason":"end_turn"},"total_usd":0.197932,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to distinguish papers about:\n1. **CBLC** (the E3 ubiquitin ligase, CBL proto-oncogene C / CBL-SL / RNF57) - the query gene\n2. **cblC** (a disease/complementation group caused by mutations in *MMACHC*) - a completely different gene/disease\n\nThe vast majority of papers (1-8, 10-17, 19-20, etc.) are about MMACHC/cblC disease, NOT about the CBLC E3 ubiquitin ligase. I must extract only from papers describing the canonical CBLC protein (E3 ubiquitin ligase).\n\nPapers about CBLC (E3 ligase): 9, 12, 14, 18, 23, 36, 41, 42, 48, 53, 61, 66, 68, 71, 93, 100\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"CBLC (Cbl-c) protein was identified as a novel CBL family member encoding a 52 kDa protein with a phosphotyrosine-binding domain, RING finger, and proline-rich region. The Cbl-c protein was shown to bind the EGF receptor and Fyn tyrosine kinase.\",\n      \"method\": \"Molecular cloning, co-immunoprecipitation/binding assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — initial characterization by binding assays; single lab but multiple interactions tested\",\n      \"pmids\": [\"10571044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Mouse Cblc/Cbl3 gene was cloned; it comprises 12 exons and encodes a 496 amino acid protein sharing 67% identity with the human ortholog and 70% identity with mouse CBL over conserved SH2 and RING finger domains. Cblc mRNA is expressed ubiquitously in embryo and adult tissues.\",\n      \"method\": \"Molecular cloning, expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, gene characterization without functional mechanistic assay\",\n      \"pmids\": [\"11162497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CBLC interacts with the HECT-domain E3 ubiquitin ligase AIP4/ITCH (and its C. elegans counterpart WWP1) via CBLC's proline-rich region and the WW domains of AIP4. This interaction was confirmed by GST pull-down, co-immunoprecipitation, and colocalization. CBLC and AIP4 both become tyrosine-phosphorylated upon EGF stimulation. Overexpression of CBLC increased EGFR ubiquitination, and coexpression of WW domains of AIP4 exerted a dominant-negative effect on EGFR ubiquitination. Coexpression of CBLC and AIP4 together downregulated EGFR signaling.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, colocalization, ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, GST pulldown, reciprocal co-IP, colocalization, functional ubiquitination assay) in single study\",\n      \"pmids\": [\"12226085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CBLC (Cbl-c) specifically targets activated Src (phosphorylated at Tyr419) for ubiquitination and degradation via a lysosome-dependent pathway. The TKB domain and RING finger of CBLC are required for its anti-oncogenic activity. Wild-type CBLC together with UbcH5 induced ubiquitination of Src in vitro, while a RING finger mutant did not. Non-phosphorylated Src was not ubiquitinated by CBLC. CBLC suppressed v-Src-induced transformation and caused reversion of the morphological phenotype in NIH3T3 cells, distinct from the mechanism of Cbl and Cbl-b.\",\n      \"method\": \"In vitro ubiquitination assay with UbcH5, RING finger mutagenesis, cell transformation assay, protein degradation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted ubiquitination with mutational validation plus functional cellular readout\",\n      \"pmids\": [\"14661060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Transgenic mice expressing CBLC in the mammary gland (MMTV-CBLC) showed reduced number and length of ducts during mammary gland development, supporting CBLC's role as a negative regulator of cell proliferation in epithelial tissues.\",\n      \"method\": \"Transgenic mouse model, in vivo mammary gland morphology assessment\",\n      \"journal\": \"In vivo (Athens, Greece)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, in vivo phenotype without mechanistic pathway placement\",\n      \"pmids\": [\"19414407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The N-terminus of Cbl-c (specifically the EF-hand and SH2 domains) inhibits its E3 ubiquitin ligase activity. Phosphorylation of a critical tyrosine residue (Tyr-341) in the linker region by Src kinase, or a phosphomimetic Y341E mutation, relieves this inhibition by decreasing affinity for the E2 enzyme UbcH5b. Reduced E2 affinity leads to more rapid turnover of bound UbcH5b and increased E3 ligase activity.\",\n      \"method\": \"In vitro ubiquitination assay, site-directed mutagenesis, E2-binding affinity measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic dissection with mutagenesis, in vitro reconstitution, and binding affinity measurements in one study\",\n      \"pmids\": [\"20525694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CBLC interacts with Hic-5 (Hydrogen peroxide Induced Construct 5) through a novel interaction between the RING finger of CBLC and the LIM2 domain of Hic-5, mediated by specific zinc-coordinating complexes. Binding of Hic-5 to CBLC increases CBLC ubiquitin ligase activity (after Src-mediated activation) and enhances CBLC-mediated ubiquitination of EGFR. This is the first example of a LIM zinc-coordinating domain enhancing RING finger E3 ligase activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, domain mapping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping and functional ubiquitination readout, single lab\",\n      \"pmids\": [\"23145173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the tyrosine kinase binding (TKB) domain of Cbl-c/Cbl-3 revealed that, compared to Cbl TKB, the Cbl-c TKB domain shows restricted structural flexibility upon phosphopeptide binding. A mutation in Cbl-c TKB that increased structural flexibility enhanced binding to target phosphoproteins, indicating 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 / Moderate — crystal structure with functional mutagenesis validation, single lab\",\n      \"pmids\": [\"22888118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RNAi screening identified CBLC as a modifier of PARP inhibitor (olaparib) sensitivity. Silencing of CBLC caused increased sensitivity to olaparib in breast cancer cell lines, with defective homologous recombination (HR) DNA repair identified as the likely mechanism.\",\n      \"method\": \"RNAi screen, cell viability assay, HR repair assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — validated screen hit with HR repair mechanistic link, single lab\",\n      \"pmids\": [\"25883215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Depletion of CBLC specifically induces Golgi fragmentation (disruption of Golgi ribbon/network organization) without significantly affecting Golgi stack structure. CBLC partially localizes to Golgi membranes, and this localization is enhanced after SRC kinase activation. Inhibition of SRC reverts the Golgi fragmentation caused by CBLC depletion, indicating interplay between CBLC and SRC at the Golgi. CBLC's regulation of Golgi network organization requires its ubiquitin ligase activity. Depletion of the close homologues CBL and CBLB did not induce visible Golgi defects.\",\n      \"method\": \"RNAi knockdown, fluorescence and electron microscopy, Golgi morphology quantification, SRC inhibitor treatment, E3 mutant rescue\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — image-based RNAi screen validated with multiple microscopy methods, E3 activity requirement confirmed by mutant, SRC interplay tested pharmacologically\",\n      \"pmids\": [\"26393512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CBLC is epigenetically upregulated (by promoter demethylation) in non-small cell lung cancer. CBLC competes with CBL for EGFR binding and, unlike CBL-mediated K63-linked ubiquitination promoting lysosomal degradation, CBLC ubiquitinates activated EGFR (aEGFR) via K6 and K11 polyubiquitin linkages, which promotes recycling of aEGFR back to the plasma membrane or trafficking to the nucleus rather than lysosomal degradation, thereby sustaining EGFR activation and downstream ERK1/2 signaling.\",\n      \"method\": \"CBLC depletion/overexpression, ubiquitin linkage analysis (mass spectrometry), co-immunoprecipitation, EGFR trafficking assay, xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ubiquitin linkage type determined by MS, mechanism validated by OE/KD with multiple readouts including trafficking and signaling, in vivo xenograft\",\n      \"pmids\": [\"29945960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss-of-function mutations in the RING finger domain of CBLC (identified in a mouse mammary tumor and in human solid tumors) abolish CBLC-mediated ubiquitination of activated EGFR and allow the mutant protein to act in a dominant-negative fashion by binding EGFR and preventing recruitment and action of wild-type CBL family proteins. A CBLC RING-finger deletion mutant enhanced NIH 3T3 cell transformation when combined with SV40 Large T antigen.\",\n      \"method\": \"Ubiquitination assay, co-immunoprecipitation, NIH 3T3 transformation assay, genomic/cDNA sequence analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic loss-of-function with ubiquitination assay and dominant-negative demonstration, single lab\",\n      \"pmids\": [\"31260484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CBLC interacts with AURKA (Aurora kinase A) through AURKA's kinase domain, as determined by immunoprecipitation and mass spectrometry. CBLC stabilizes AURKA by conjugating monoubiquitination and K11/K63-linked polyubiquitination, protecting it from degrading K11/K48 polyubiquitination. CBLC depletion decreased AURKA half-life and delayed its accumulation/activation during mitotic entry, reducing the mitotic population and increasing apoptosis in lung adenocarcinoma cells.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, ubiquitin linkage analysis, cycloheximide chase, cell synchronization/FACS, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — IP-MS interactome identification confirmed by ubiquitin linkage typing, protein stability assay, and mitotic cell cycle functional readout with 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, as shown by co-immunoprecipitation and immunofluorescence co-localization. CBLC promotes degradation of CTTN through the ubiquitin-proteasome pathway, and this activity inhibits breast cancer cell proliferation, migration, and invasion. Overexpression of CTTN partially rescues the inhibitory effect of CBLC.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination/proteasome assay, cell proliferation/migration/invasion assays\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with colocalization and functional rescue experiment, single lab\",\n      \"pmids\": [\"36043996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CBLC ubiquitinates ABI1 (Abelson interactor protein 1), promoting its proteasomal degradation. CBLC-mediated ABI1 degradation activates the ERK signaling pathway. ABI1 overexpression abolishes the pro-tumorigenic effects of CBLC in colorectal cancer cells. CBLC also promoted tumor growth and metastasis in xenograft models.\",\n      \"method\": \"Ubiquitination assay, co-immunoprecipitation, western blot, cell proliferation/migration/invasion assays, xenograft and lung metastasis models\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination of substrate shown, rescue experiment performed, pathway placement by ERK readout; single lab\",\n      \"pmids\": [\"38743987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CBLC ubiquitinates METTL1 (tRNA guanine-N7-methyltransferase), stabilizing it against proteasomal degradation. Stabilized METTL1 enhances N7-methylguanosine (m7G) modification of ESRRA mRNA, increasing ESRRA stability and expression, which mediates CBLC's pro-tumorigenic effects in endometrial cancer.\",\n      \"method\": \"Ubiquitination assay, co-immunoprecipitation, m7G methylation assay, mRNA stability assay, functional rescue experiments, single-cell and bulk transcriptomics\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination substrate identification with downstream m7G modification mechanistic link and rescue; single lab\",\n      \"pmids\": [\"42217705\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CBLC is a RING-finger E3 ubiquitin ligase that regulates receptor tyrosine kinase signaling by ubiquitinating activated EGFR via non-canonical K6/K11-linked polyubiquitin chains that promote EGFR recycling rather than degradation (opposing canonical CBL-mediated K63/lysosomal degradation), targets activated Src for lysosomal degradation, stabilizes Aurora kinase A and METTL1 through protective ubiquitination, degrades ABI1 and cortactin via the proteasome, and maintains Golgi ribbon network organization in an E3-activity-dependent manner; its E3 activity is autoinhibited by its N-terminal EF-hand/SH2 domain and activated by Src-mediated phosphorylation of Tyr-341, which reduces affinity for E2 enzyme UbcH5b and increases ubiquitin transfer turnover, while its TKB domain binds phosphotyrosine-containing substrates with a rigidity distinct from other CBL family members.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CBLC is a RING-finger E3 ubiquitin ligase of the CBL family that regulates receptor tyrosine kinase signaling and protein turnover through substrate-selective ubiquitination, generally acting as a negative regulator of cell proliferation [#0, #4]. Its catalytic output is governed by an N-terminal EF-hand/SH2 module that autoinhibits the enzyme; Src-mediated phosphorylation of Tyr-341, or a phosphomimetic substitution, relieves this inhibition by lowering affinity for the E2 enzyme UbcH5b and accelerating ubiquitin-transfer turnover [#5], and its TKB domain engages phosphotyrosine substrates with a constrained structural flexibility that distinguishes it from other CBL members [#7]. The chain architecture CBLC assembles dictates whether substrates are degraded or protected: it targets activated Src for lysosomal degradation [#3] and routes ABI1 and cortactin to the proteasome [#13, #14], yet builds non-canonical K6/K11-linked chains on activated EGFR that promote recycling and sustained ERK signaling rather than lysosomal degradation, in opposition to canonical CBL [#10], and conjugates protective monoubiquitin and K11/K63 chains that stabilize Aurora kinase A and METTL1 against degradative ubiquitination [#12, #15]. Its activity is further tuned by partners including the HECT ligase AIP4/ITCH and the LIM protein Hic-5, which enhances CBLC-mediated EGFR ubiquitination [#2, #6], and CBLC also maintains Golgi ribbon network organization in an E3-activity- and SRC-dependent manner [#9]. RING-finger loss-of-function mutations found in human and mouse tumors abolish EGFR ubiquitination and act dominant-negatively to promote transformation [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing CBLC as a distinct CBL family member with a defined domain architecture and direct kinase-binding capacity set the structural premise for all subsequent mechanistic work.\",\n      \"evidence\": \"Molecular cloning and binding assays identifying a 52 kDa protein with phosphotyrosine-binding domain, RING finger, and proline-rich region that binds EGFR and Fyn\",\n      \"pmids\": [\"10571044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity demonstrated\", \"Functional consequence of EGFR/Fyn binding undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linking CBLC to the HECT ligase AIP4/ITCH and showing cooperative EGFR downregulation placed CBLC within receptor tyrosine kinase signaling control and identified a functional partnership.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, reciprocal co-IP, colocalization, and EGFR ubiquitination assays\",\n      \"pmids\": [\"12226085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CBLC ubiquitination of EGFR vs. AIP4 contribution not separated\", \"Chain linkage type not determined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that CBLC ubiquitinates activated Src for lysosomal degradation and reverses v-Src transformation established its anti-oncogenic, RING-dependent catalytic function with phospho-substrate selectivity.\",\n      \"evidence\": \"In vitro reconstituted ubiquitination with UbcH5, RING mutant controls, degradation assay, and NIH3T3 transformation reversion\",\n      \"pmids\": [\"14661060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lysosomal targeting mechanism not detailed\", \"Chain linkage type unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolving the autoinhibition/activation switch explained how CBLC catalysis is gated by Src phosphorylation at Tyr-341 through modulation of E2 affinity.\",\n      \"evidence\": \"In vitro ubiquitination, Y341 mutagenesis/phosphomimetic, and UbcH5b binding affinity measurements\",\n      \"pmids\": [\"20525694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the EF-hand/SH2 autoinhibited state not solved\", \"In-cell kinetics of the switch not measured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The TKB domain crystal structure showed that restricted flexibility relative to CBL tunes phosphopeptide binding, providing a structural rationale for CBLC's distinct substrate engagement.\",\n      \"evidence\": \"X-ray crystallography with flexibility-altering mutagenesis and phosphopeptide binding assays\",\n      \"pmids\": [\"22888118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure with a physiological substrate\", \"Functional consequence of flexibility in cells untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying Hic-5 as a RING-binding cofactor that boosts CBLC activity revealed a novel mode of E3 regulation by a LIM zinc-coordinating domain.\",\n      \"evidence\": \"Co-IP, domain mapping, and EGFR ubiquitination assays\",\n      \"pmids\": [\"23145173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LIM2 enhances catalysis not defined\", \"Physiological context of Hic-5/CBLC cooperation untested in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connecting CBLC to PARP inhibitor sensitivity and HR repair, and to Golgi ribbon maintenance, broadened its cellular roles beyond RTK signaling.\",\n      \"evidence\": \"RNAi screen with olaparib viability and HR assays; image-based knockdown with microscopy, E3-mutant rescue, and SRC inhibitor treatment\",\n      \"pmids\": [\"25883215\", \"26393512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate linking CBLC to HR repair unidentified\", \"Golgi substrate of CBLC ubiquitination not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Determining that CBLC builds K6/K11 chains on activated EGFR to drive recycling rather than degradation reversed the expectation of CBL-like negative regulation and explained its pro-oncogenic role in lung cancer.\",\n      \"evidence\": \"Mass-spectrometry ubiquitin linkage analysis, co-IP, EGFR trafficking assays, knockdown/overexpression, and xenografts\",\n      \"pmids\": [\"29945960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with earlier anti-oncogenic findings context-dependent and unresolved\", \"Reader/effector decoding K6/K11 chains on EGFR not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that tumor-derived RING mutants are catalytically dead and dominant-negative clarified how CBLC loss-of-function contributes to transformation by blocking other CBL proteins.\",\n      \"evidence\": \"Ubiquitination assay, co-IP, and NIH 3T3 transformation assay with SV40 Large T\",\n      \"pmids\": [\"31260484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Frequency and clinical impact of these mutations not established\", \"Competition mechanism with wild-type CBL not quantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying AURKA and cortactin as substrates demonstrated that CBLC can either protectively stabilize (AURKA via K11/K63) or proteasomally degrade (cortactin) substrates, controlling mitosis and cell motility respectively.\",\n      \"evidence\": \"IP-MS, ubiquitin linkage typing, cycloheximide chase, cell synchronization/FACS, xenografts; co-IP, colocalization, and migration/invasion rescue assays\",\n      \"pmids\": [\"35149839\", \"36043996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting protective vs. degradative chains on different substrates unknown\", \"Whether AURKA and CTTN regulation co-occur in the same cells untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing ABI1 as a degradative substrate linked CBLC to ERK pathway activation and a pro-tumorigenic role in colorectal cancer.\",\n      \"evidence\": \"Ubiquitination assay, co-IP, ERK readout, rescue with ABI1 overexpression, and xenograft/metastasis models\",\n      \"pmids\": [\"38743987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect ERK activation not dissected\", \"Chain linkage on ABI1 not typed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing CBLC stabilizes METTL1 to enhance m7G modification of ESRRA mRNA extended its substrate repertoire into RNA-modification machinery and endometrial cancer.\",\n      \"evidence\": \"Ubiquitination assay, co-IP, m7G and mRNA stability assays, rescue experiments, and transcriptomics\",\n      \"pmids\": [\"42217705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chain linkage stabilizing METTL1 not fully typed\", \"Generality of CBLC-METTL1 axis beyond endometrial cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What governs CBLC's context-dependent choice between degradative and protective/recycling ubiquitin chains on different substrates, and how this dictates its opposing tumor-suppressive versus pro-oncogenic outcomes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for substrate-specific chain-type selection\", \"Tissue determinants of anti- vs. pro-oncogenic behavior undefined\", \"Structure of full-length CBLC-substrate-E2 complex not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 5, 10, 12]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3, 10, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 10, 12, 14, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 10, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 10, 12, 13, 14, 15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EGFR\", \"SRC\", \"AIP4\", \"AURKA\", \"CTTN\", \"ABI1\", \"METTL1\", \"FYN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}