Affinage

CBLC

E3 ubiquitin-protein ligase CBL-C · UniProt Q9ULV8

Length
474 aa
Mass
52.5 kDa
Annotated
2026-04-28
100 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    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

    PMID:10362357 PMID:10571044

    Open questions at the time
    • Enzymatic activity as E3 ligase not yet demonstrated biochemically
    • Tissue expression pattern not yet defined
    • Relationship to CBL/CBLB in EGFR regulation unknown
  2. 2002 High

    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

    PMID:12226085

    Open questions at the time
    • Whether AIP4 extends or changes ubiquitin chain type on EGFR not determined
    • Physiological consequence of dual-E3 cooperation in vivo not tested
  3. 2003 High

    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

    PMID:14560016

    Open questions at the time
    • Compensatory roles of CBL/CBLB in knockout not dissected
    • Epithelial-specific phenotypes under stress or oncogenic challenge not examined
  4. 2004 High

    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

    PMID:14661060

    Open questions at the time
    • Ubiquitin chain type on Src not characterized
    • Whether CBLC is a major Src regulator in vivo not established
  5. 2008 High

    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

    PMID:18753381

    Open questions at the time
    • Mechanism by which CD2AP converts CBLC from stabilizer to degrader unclear
    • Ubiquitin chain type difference with and without CD2AP not determined
  6. 2010 High

    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

    PMID:20525694

    Open questions at the time
    • 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
  7. 2012 High

    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

    PMID:22888118 PMID:23145173

    Open questions at the time
    • Full-length structure including RING domain not available
    • Whether Hic-5 interaction is relevant in epithelial tissues in vivo unknown
  8. 2014 High

    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

    PMID:24425877

    Open questions at the time
    • Whether CBLC/CD2AP complex operates on Ret in the nervous system in vivo not shown
    • Ubiquitin chain types on Ret not characterized
  9. 2015 Medium

    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

    PMID:25883215 PMID:26393512

    Open questions at the time
    • Golgi substrates of CBLC not identified
    • Mechanism linking CBLC to homologous recombination not defined
    • Single-lab findings for each phenotype
  10. 2018 High

    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

    PMID:29945960

    Open questions at the time
    • Whether linkage specificity is intrinsic to CBLC or dictated by the cellular E2 repertoire not determined
    • Nuclear EGFR signaling consequences not fully characterized
  11. 2019 Medium

    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

    PMID:31260484

    Open questions at the time
    • Frequency and clinical significance of CBLC RING deletions not established across cancer types
    • Single-lab characterization
  12. 2022 High

    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

    PMID:35149839 PMID:36043996

    Open questions at the time
    • How CBLC selects different chain types for stabilization versus degradation substrates not resolved
    • Whether AURKA stabilization is a general feature across epithelial cancers unknown
  13. 2024 Medium

    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

    PMID:38743987

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016874 ligase activity 4
Localization
GO:0005886 plasma membrane 2 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 5 R-HSA-1640170 Cell Cycle 1 R-HSA-9609507 Protein localization 1
Partners
ABI1AURKACD2APEGFRITCHRETSRCTGFB1I1

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. Molecular cloning, co-immunoprecipitation, EGF stimulation assays, MAP kinase activity assay, alternative splice variant characterization Oncogene High 10362357
1999 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. Molecular cloning, co-immunoprecipitation with EGFR and Fyn Gene Medium 10571044
2002 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. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, colocalization, EGFR ubiquitination assay The Journal of biological chemistry High 12226085
2004 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. Cell transformation assay, in vitro ubiquitination assay with purified proteins, Western blot (protein level), domain mutagenesis Oncogene High 14661060
2003 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. Knockout mouse generation, histological analysis, proliferation assay, EGF-stimulated ERK activation in primary keratinocytes Molecular and cellular biology High 14560016
2008 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. Co-immunoprecipitation, overexpression and siRNA knockdown in sympathetic neurons, survival assays, Ret degradation assay The Journal of neuroscience High 18753381
2010 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. In vitro ubiquitination assay, E2 binding affinity measurement, site-directed mutagenesis, Src phosphorylation assay The Journal of biological chemistry High 20525694
2012 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. Co-immunoprecipitation, domain mapping mutagenesis, in vitro ubiquitination assay, EGFR ubiquitination assay PloS one Medium 23145173
2012 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. X-ray crystallography, phosphopeptide binding assay, mutagenesis Journal of biochemistry High 22888118
2014 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. siRNA knockdown, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis of Ret lysines, domain deletion analysis The Journal of biological chemistry High 24425877
2015 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. RNAi screen, siRNA knockdown, cell viability assay, HR repair assay Oncotarget Medium 25883215
2015 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. RNAi screen (image-based), confocal and electron microscopy, SRC inhibitor treatment, ubiquitin ligase-dead mutant rescue PloS one Medium 26393512
2018 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. siRNA depletion, ectopic overexpression, ubiquitin linkage analysis (mass spectrometry), EGFR recycling/trafficking assays, co-immunoprecipitation, xenograft model Cancer research High 29945960
2019 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. Cell transformation assay, ubiquitination assay, co-immunoprecipitation, dominant-negative competition assay, genomic sequencing PloS one Medium 31260484
2022 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. Immunoprecipitation-mass spectrometry (interactome), co-immunoprecipitation, ubiquitin linkage analysis, cycloheximide chase assay, cell cycle synchronization/flow cytometry, xenograft model Oncogene High 35149839
2022 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. Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay, rescue experiment with CTTN re-expression Journal of receptor and signal transduction research Medium 36043996
2024 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. Co-immunoprecipitation, ubiquitination assay, overexpression and knockdown gain/loss-of-function, ERK pathway analysis, xenograft model Translational oncology Medium 38743987

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nature genetics 303 16311595
2011 Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management. Journal of inherited metabolic disease 176 21748409
2014 Clinical presentation and outcome in a series of 88 patients with the cblC defect. Journal of inherited metabolic disease 135 24599607
2006 Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. Molecular genetics and metabolism 112 16714133
2009 Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product. Molecular genetics and metabolism 102 19447654
1999 cbl-3: a new mammalian cbl family protein. Oncogene 99 10362357
2007 Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. Molecular genetics and metabolism 81 18164228
2007 Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder. Pediatric nephrology (Berlin, Germany) 79 17874135
2009 Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Human mutation 76 19760748
2002 Interaction between two ubiquitin-protein isopeptide ligases of different classes, CBLC and AIP4/ITCH. The Journal of biological chemistry 73 12226085
2010 Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China. Journal of inherited metabolic disease 71 20924684
2018 APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients. Nature communications 69 29302025
2007 Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance. American journal of medical genetics. Part A 54 17853453
1999 Molecular cloning and characterization of a novel cbl-family gene, cbl-c. Gene 54 10571044
2009 High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria. Molecular genetics and metabolism 52 19767224
2005 Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. American journal of kidney diseases : the official journal of the National Kidney Foundation 52 15754282
2004 Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Oncogene 52 14661060
2015 Clinical presentation, gene analysis and outcomes in young patients with early-treated combined methylmalonic acidemia and homocysteinemia (cblC type) in Shandong province, China. Brain & development 50 26563984
2018 Upregulation of E3 Ubiquitin Ligase CBLC Enhances EGFR Dysregulation and Signaling in Lung Adenocarcinoma. Cancer research 47 29945960
2010 Thermolability of mutant MMACHC protein in the vitamin B12-responsive cblC disorder. Molecular genetics and metabolism 47 20219402
2009 Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria. Molecular genetics and metabolism 45 19700356
2003 Cbl-3-deficient mice exhibit normal epithelial development. Molecular and cellular biology 38 14560016
2015 Pathogenic mutations differentially affect the catalytic activities of the human B12-processing chaperone CblC and increase futile redox cycling. The Journal of biological chemistry 34 25809485
2013 The C-terminal domain of CblD interacts with CblC and influences intracellular cobalamin partitioning. Biochimie 34 23415655
2010 The N terminus of Cbl-c regulates ubiquitin ligase activity by modulating affinity for the ubiquitin-conjugating enzyme. The Journal of biological chemistry 34 20525694
2012 A clinical and gene analysis of late-onset combined methylmalonic aciduria and homocystinuria, cblC type, in China. Journal of the neurological sciences 33 22560872
2015 The proteome of cblC defect: in vivo elucidation of altered cellular pathways in humans. Journal of inherited metabolic disease 31 25585586
2022 Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists. Orphanet journal of rare diseases 30 35109910
2018 Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria. BMC medical genetics 30 30157807
2017 Antivitamin B12 Inhibition of the Human B12 -Processing Enzyme CblC: Crystal Structure of an Inactive Ternary Complex with Glutathione as the Cosubstrate. Angewandte Chemie (International ed. in English) 30 28544088
2013 Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia. Human molecular genetics 26 23825108
2022 The Follow-Up of Chinese Patients in cblC Type Methylmalonic Acidemia Identified Through Expanded Newborn Screening. Frontiers in genetics 24 35242167
2017 Coordination chemistry controls the thiol oxidase activity of the B12-trafficking protein CblC. The Journal of biological chemistry 22 28442570
2008 CD2AP and Cbl-3/Cbl-c constitute a critical checkpoint in the regulation of ret signal transduction. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 18753381
2010 Early onset methylmalonic aciduria and homocystinuria cblC type with demyelinating neuropathy. Pediatric neurology 21 20610126
2015 Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull's Eye Maculopathy. Ophthalmic genetics 19 25687216
2020 The human B12 trafficking protein CblC processes nitrocobalamin. The Journal of biological chemistry 18 32457044
2020 Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type. Developmental biology 18 32941884
2012 Cbl-c ubiquitin ligase activity is increased via the interaction of its RING finger domain with a LIM domain of the paxillin homolog, Hic 5. PloS one 18 23145173
2007 Marfanoid features in a child with combined methylmalonic aciduria and homocystinuria (CblC type). Journal of inherited metabolic disease 18 17768669
2018 Hydrocephalus in cblC type methylmalonic acidemia. Metabolic brain disease 17 30564975
2024 Late-onset methylmalonic acidemia and homocysteinemia (cblC disease): systematic review. Orphanet journal of rare diseases 16 38245797
2017 Atypical hemolytic uremic syndrome induced by CblC subtype of methylmalonic academia: A case report and literature review. Medicine 16 29068997
2015 Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity. Oncotarget 16 25883215
2022 Stabilization of AURKA by the E3 ubiquitin ligase CBLC in lung adenocarcinoma. Oncogene 15 35149839
2010 Treatment of cobalamin C (cblC) deficiency during pregnancy. Journal of inherited metabolic disease 15 20830523
2021 PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations. Clinical epigenetics 14 34215320
2013 Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type. JIMD reports 14 23580368
2022 Late-onset cblC deficiency around puberty: a retrospective study of the clinical characteristics, diagnosis, and treatment. Orphanet journal of rare diseases 13 36056359
2020 Thiolatocobalamins repair the activity of pathogenic variants of the human cobalamin processing enzyme CblC. Biochimie 12 33190793
2019 Loss of function Cbl-c mutations in solid tumors. PloS one 12 31260484
2014 CD2-associated protein (CD2AP) enhances casitas B lineage lymphoma-3/c (Cbl-3/c)-mediated Ret isoform-specific ubiquitination and degradation via its amino-terminal Src homology 3 domains. The Journal of biological chemistry 12 24425877
2014 First Chinese case of successful pregnancy with combined methylmalonic aciduria and homocystinuria, cblC type. Brain & development 12 24974159
2011 Combined methylmalonic aciduria and homocystinuria cblC type of a Taiwanese infant with c.609G>A and C.567dupT mutations in the MMACHC gene. Pediatrics and neonatology 12 21835369
2010 Different altered pattern expression of genes related to apoptosis in isolated methylmalonic aciduria cblB type and combined with homocystinuria cblC type. Biochimica et biophysica acta 12 20696242
2022 Epimutations in both the TESK2 and MMACHC promoters in the Epi-cblC inherited disorder of intracellular metabolism of vitamin B12. Clinical epigenetics 11 35440018
2012 Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c. Journal of biochemistry 11 22888118
2022 Intracellular processing of vitamin B12 by MMACHC (CblC). Vitamins and hormones 10 35337623
2019 Noninvasive prenatal diagnosis of cobalamin C (cblC) deficiency through target region sequencing of cell-free DNA in maternal plasma. Prenatal diagnosis 10 31697851
2023 Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort. World journal of pediatrics : WJP 8 38070096
2021 Clinical features and outcomes of patients with cblC type methylmalonic acidemia carrying gene c.609G>A mutation. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 8 34704411
2020 Chlorocob(II)alamin Formation Which Enhances the Thiol Oxidase Activity of the B12-Trafficking Protein CblC. Inorganic chemistry 8 33074687
2017 Optical coherence tomography morphology and evolution in cblC disease-related maculopathy in a case series of very young patients. Acta ophthalmologica 8 28481040
2022 Noninvasive Prenatal Testing of Methylmalonic Acidemia cblC Type Using the cSMART Assay for MMACHC Gene Mutations. Frontiers in genetics 7 35069678
2021 Epimutation of MMACHC compound to a genetic mutation in cblC cases. Molecular genetics & genomic medicine 7 33982424
2023 Abnormal chondrocyte development in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant. Differentiation; research in biological diversity 6 37167860
2022 The human B12 trafficking chaperones: CblA, ATR, CblC and CblD. Methods in enzymology 6 35589192
2022 Investigation on a MMACHC mutant from cblC disease: The c.394C>T variant. Biochimica et biophysica acta. Proteins and proteomics 6 35618206
2022 Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial. Orphanet journal of rare diseases 6 36376887
2015 The Ubiquitin Ligase CBLC Maintains the Network Organization of the Golgi Apparatus. PloS one 6 26393512
2009 Abnormal mammary gland development in MMTV-CBLC transgenic mouse. In vivo (Athens, Greece) 6 19414407
2023 Would, early, versus late hydroxocobalamin dose intensification treatment, prevent cognitive decline, macular degeneration and ocular disease, in 5 patients with early-onset cblC deficiency? Molecular genetics and metabolism 5 37604084
2022 CBLC inhibits the proliferation and metastasis of breast cancer cells via ubiquitination and degradation of CTTN. Journal of receptor and signal transduction research 5 36043996
2020 Generation of a Human iPSC line (SDQLCHi021-A) from a patient with methylmalonic acidemia cblC type carrying compound heterozygous mutations in MMAHC gene. Stem cell research 5 32058304
2020 Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing. Human molecular genetics 5 32068834
2015 Genetic analysis of four cases of methylmalonic aciduria and homocystinuria, cblC type#. International journal of clinical and experimental pathology 5 26464686
2001 Characterization of the mouse Cblc/Cbl3 gene. Biochemical and biophysical research communications 5 11162497
1991 Metabolic cooperation among cell lines from patients with inborn errors of vitamin B12 metabolism: differential response of cblC and cblD. Clinical and investigative medicine. Medecine clinique et experimentale 5 1676355
2022 Acute Lymphoblastic Leukemia in Combined Methylmalonic Acidemia and Homocysteinemia (cblC Type): A Case Report and Literature Review. Frontiers in genetics 4 35495149
1992 Clinical and biochemical observations in a patient with combined Pompe disease and cblC mutation. European journal of pediatrics 4 1537354
2022 Antivitamins B12: Synthesis and application as inhibitory ligand of the B12-tailoring enzyme CblC. Methods in enzymology 3 35589193
2021 Preimplantation Genetic Testing for Rare Inherited Disease of MMA-CblC: an Unaffected Live Birth. Reproductive sciences (Thousand Oaks, Calif.) 3 34076870
2017 Neuropsychological implications of Cobalamin C (CblC) disease in Hispanic children detected through newborn screening. Applied neuropsychology. Child 3 28071971
2010 [Analysis of clinical features and gene mutations in two Chinese pedigrees with late-onset methylmalonic acidemia, cblC type]. Zhonghua er ke za zhi = Chinese journal of pediatrics 3 21055272
2024 The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients. Molecular genetics and metabolism 2 38387306
2022 [Factors affecting phenotypes in the patients with MMACHC gene c.609G>A homozygous variant cblC type methylmalonic acidemia combined with homocysteinuria]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 35773756
2019 [Construction of a mouse model of cblC type methylmalonic acidemia with W203X mutation based on the CRISPR/Cas9 technology]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 2 31416510
2025 Accelerating the diagnosis of Chinese cblC type MMA patients by multiplex PCR sequencing method. Pediatric research 1 39815091
2025 Missense mutations in MMACHC protein from cblC disease affect its conformational stability and vitamin B12-binding activity: The example of R161Q mutation. Molecular genetics and metabolism 1 40441036
2025 Long-term outcome of CblC deficiency complicated with pulmonary hypertension. Orphanet journal of rare diseases 1 40468431
2025 Variable phenotypes and outcomes associated with the MMACHC c.1A>G variant in Chinese patients with combined methylmalonic acidemia and homocystinuria cblC type. Molecular genetics and metabolism 1 40544542
2024 Adult-onset combined methylmalonic acidemia and hyperhomocysteinemia, cblC type with aortic dissection and acute kidney injury: a case report. BMC nephrology 1 38178022
2023 Case report: An asymptomatic mother with an inborn error of cobalamin metabolism (cblC) detected through high homocysteine levels during prenatal diagnosis. Frontiers in nutrition 1 37252234
2022 [Genetic variant analysis and prenatal diagnosis for Chinese pedigrees affected with cblC methylmalonic acidemia]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 36184083
2022 A teenager with combined methylmalonic aciduria and homocystinuria (CblC type) presenting with neurological symptoms and congenital heart diseases: a case report. Neurocase 1 36219783
2025 A Noncatalytic Cysteine Residue Modulates Cobalamin Reactivity in the Human B12 Processing Enzyme CblC. Biochemistry 0 39862167
2025 Analysis of hydroxocobalamin dosage in patients with CblC deficiency. Orphanet journal of rare diseases 0 40841656
2024 CBLC promotes the development of colorectal cancer by promoting ABI1 degradation to activate the ERK signaling pathway. Translational oncology 0 38743987
2024 A case series of Cypriot patients with CblC defect: Clinical, biochemical and molecular characteristics. Molecular genetics and metabolism reports 0 39584041
2023 Abnormal chondrocyte intercalation in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant. bioRxiv : the preprint server for biology 0 36711998