Affinage

CBL

E3 ubiquitin-protein ligase CBL · UniProt P22681

Length
906 aa
Mass
99.6 kDa
Annotated
2026-04-28
100 papers in source corpus 48 papers cited in narrative 48 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CBL (c-Cbl) is a RING-type E3 ubiquitin ligase and multivalent adaptor protein that functions as a central negative regulator of receptor and non-receptor tyrosine kinase signaling by ubiquitinating activated kinases and directing them for endosomal sorting and lysosomal or proteasomal degradation. Its TKB domain docks onto phosphotyrosine residues on activated substrates (EGFR, FLT3, Syk, Lck, Src, Met, EphA2, VEGFR-1/2, BCR-ABL, and others), while its RING domain recruits the E2 conjugating enzyme UbcH5B; phosphorylation of Tyr371 in the linker helix relieves an autoinhibited conformation that occludes the RING E2-binding surface, thereby activating ligase function (PMID:10966114, PMID:22266821, PMID:18996392). Independently of ligase activity, tyrosine-phosphorylated c-Cbl (at Tyr700/731/774, modified by Src-family kinases and Syk) scaffolds signaling complexes containing Grb2, PI3K p85, Vav, and PLCγ1 to modulate PI3K/AKT, RAS/MAPK, and cytoskeletal pathways (PMID:7791764, PMID:9525940, PMID:21967979). Oncogenic CBL mutations found in myeloid neoplasms abolish E3 ligase activity while preserving and enhancing adaptor-mediated PI3K/AKT signaling through increased LYN activation, driving myeloproliferative disease that progresses to leukemia via augmented FLT3 signaling (PMID:19620960, PMID:20951944, PMID:33512474).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Establishing c-Cbl as a signaling adaptor resolved how it participates in TCR-proximal signaling: c-Cbl constitutively associates with Grb2 and, upon TCR stimulation, recruits PI3K p85 to activate PI3-kinase, placing c-Cbl at the interface of receptor activation and lipid signaling.

    Evidence Co-immunoprecipitation, GST pulldown with SH2/SH3 domains, and PI3-kinase activity assays in Jurkat T cells

    PMID:7791764

    Open questions at the time
    • Mechanism by which c-Cbl phosphorylation recruits p85 was not structurally defined
    • Kinases responsible for c-Cbl phosphorylation in T cells not yet identified
  2. 1997 Medium

    Demonstrating that c-Cbl negatively regulates the non-receptor tyrosine kinase Syk in mast cells established c-Cbl as a negative regulator of immune receptor signaling, prior to knowledge of its E3 ligase mechanism.

    Evidence Overexpression of c-Cbl in RBL-2H3 mast cells inhibited Syk activity and suppressed FcεRI-mediated serotonin release

    PMID:9103201

    Open questions at the time
    • Overexpression approach leaves physiological stoichiometry uncertain
    • Mechanism of negative regulation (degradation vs. activity suppression) not yet determined
  3. 1998 Medium

    Mapping c-Cbl phosphorylation sites (Tyr700/731/774) and identifying Fyn, Yes, and Syk as the responsible kinases defined the molecular basis of c-Cbl's adaptor function and its signal-dependent SH2-domain interactions with downstream effectors.

    Evidence Phosphopeptide mapping and co-expression/co-immunoprecipitation in COS cells and T cells

    PMID:8900205 PMID:9525940

    Open questions at the time
    • Functional consequence of individual phosphosites not yet tested by site-directed mutagenesis in primary cells
  4. 1999 High

    Establishing the RING finger domain as essential for EGFR ubiquitination and receptor down-regulation proved c-Cbl is a bona fide E3 ubiquitin ligase, not merely an adaptor.

    Evidence RING cysteine mutagenesis abolished ubiquitination; in vitro reconstitution confirmed direct ubiquitin ligation activity

    PMID:10428778

    Open questions at the time
    • Identity of the cognate E2 enzyme not determined
    • Whether RING activity is regulated remained unknown
  5. 2000 High

    The crystal structure of c-Cbl bound to UbcH7 and a kinase peptide revealed how the RING domain recruits E2 and how rigid coupling between the TKB and RING domains positions substrate and E2 for ubiquitin transfer, establishing the structural paradigm for RING E3 ligases.

    Evidence X-ray crystallography with functional validation

    PMID:10966114

    Open questions at the time
    • UbcH7 was later shown to be catalytically inefficient with c-Cbl, raising questions about the physiological E2
    • Mechanism of RING domain regulation not addressed
  6. 2002 High

    Extension of c-Cbl's substrate repertoire to Lck, EphA2, Notch1, and the insulin receptor pathway (via APS adaptor) demonstrated that c-Cbl is a broadly acting E3 ligase for diverse receptor and non-receptor tyrosine kinases, and also controls GLUT4 translocation downstream of insulin signaling.

    Evidence Cbl−/− T cell analysis for Lck; co-IP and mutagenesis for EphA2; lysosomal inhibitor comparison for Notch1; GLUT4 translocation assays in 3T3-L1 adipocytes for APS-Cbl-insulin receptor axis

    PMID:11777909 PMID:11904433 PMID:11997497 PMID:12496371

    Open questions at the time
    • TKB recognition motifs on these diverse substrates not structurally characterized
    • Relative contribution of c-Cbl vs. Cbl-b for each substrate unclear
  7. 2003 Medium

    Discovery that Sprouty2 (hSpry2) sequesters c-Cbl away from EGFR through high-affinity RING-domain and TKB-domain interactions, and that c-Cbl reciprocally ubiquitinates Spry2 for proteasomal degradation, revealed a competitive regulatory circuit modulating RTK signal duration.

    Evidence Pulldown and co-IP identifying Spry2-RING and pY55-TKB interactions; EGFR internalization and ERK activation assays with Spry2 mutants

    PMID:11053437 PMID:12593796 PMID:12815057

    Open questions at the time
    • In vivo significance of the Spry2-Cbl axis not tested genetically
    • Whether Spry2 sequestration affects all c-Cbl substrates equally is unknown
  8. 2004 Medium

    Dissecting EGFR trafficking showed that c-Cbl-mediated ubiquitination is dispensable for initial receptor internalization but essential for exit from early endosomes, and that ubiquitin-modified EGFR recruits Eps15 via its UIM to direct endosomal sorting.

    Evidence Tyr1045Phe EGFR mutant, Src inhibitor PP1, dominant-negative Eps15-UIM, and receptor trafficking/fractionation assays

    PMID:15210722 PMID:15465819

    Open questions at the time
    • ESCRT-dependent sorting mechanism downstream of Eps15 not characterized for c-Cbl substrates
    • Whether this two-step model applies to non-EGFR substrates untested
  9. 2007 Medium

    Identification of c-Cbl as the E3 ligase for FLT3 ubiquitination/internalization, and demonstration that disease-associated c-Cbl mutants block FLT3 downregulation and confer cytokine-independent growth, linked c-Cbl loss-of-function to myeloid malignancy pathogenesis.

    Evidence Co-IP, ubiquitination, internalization, and cytokine-independent growth assays with dominant-negative and R420Q mutant c-Cbl

    PMID:17446348

    Open questions at the time
    • Whether mutant c-Cbl also fails to regulate other RTKs in hematopoietic progenitors not determined
    • Mechanism of gain-of-function beyond loss of ligase activity not yet defined
  10. 2008 High

    Structural and biochemical work resolved two critical regulatory features: the UBA domain mediates c-Cbl homodimerization required for Met ubiquitination, and the TKB domain recognizes diverse substrates (including Met in a reverse orientation) through an obligatory intrapeptidyl H-bond, explaining substrate versatility.

    Evidence X-ray crystallography and NMR of UBA domain dimerization; crystal structures of TKB-peptide complexes with ITC quantification

    PMID:17635922 PMID:18273061

    Open questions at the time
    • Whether UBA-mediated dimerization is required for all substrates or only Met is unknown
    • No structure of full-length dimeric c-Cbl available
  11. 2008 High

    Reconstitution experiments established UbcH5B as the functionally competent E2 for c-Cbl, overturning the assumption from the original crystal structure that UbcH7 was the cognate E2; UbcH7 binds the RING but its Ub thioester is too stable for transfer.

    Evidence In vitro ubiquitination reconstitution comparing UbcH5B and UbcH7, with NMR and structural analysis of thioester stability

    PMID:18996392

    Open questions at the time
    • Whether additional E2s besides UbcH5B contribute in vivo unknown
    • Chain-type specificity of UbcH5B-c-Cbl pair not fully characterized
  12. 2012 High

    Crystallography of autoinhibited, substrate-bound, and pTyr371-activated c-Cbl states revealed the complete activation mechanism: the unphosphorylated RING occludes its own E2-binding surface; Tyr371 phosphorylation flips the RING into an active conformation, providing the structural basis for the ligase switch.

    Evidence Multiple crystal structures (unphosphorylated, substrate-bound, pTyr371-bound with E2 and substrate) plus biochemical binding assays

    PMID:22266821

    Open questions at the time
    • Identity of the kinase(s) that phosphorylate Tyr371 in specific cellular contexts not fully resolved
    • Dynamics of the conformational switch in real time not captured
  13. 2009 High

    Demonstrating that CBL mutations in myeloid neoplasms are gain-of-function — not merely loss-of-function — resolved the paradox of how heterozygous loss of a tumor suppressor drives disease: mutant c-Cbl acts as a dominant negative over wild-type c-Cbl and Cbl-b while retaining and enhancing adaptor functions.

    Evidence E3 ligase assays, retroviral transduction into Cbl−/− HSPCs showing augmented cytokine sensitivity beyond loss-of-function, genetic rescue experiments

    PMID:19620960

    Open questions at the time
    • Which specific adaptor interactions are enhanced by the mutations not mapped
    • Whether all linker/RING mutations behave identically not established
  14. 2010 High

    Genetic epistasis in knock-in mice proved that c-Cbl's RING ligase activity restrains myeloid transformation specifically through FLT3 ubiquitination: RING-inactivating mutation caused myeloproliferative disease progressing to leukemia, which was fully prevented by crossing with FLT3-ligand knockout mice.

    Evidence RING-inactivating knock-in mouse crossed with Flt3lg−/− mice; signaling and leukemia progression analysis

    PMID:20951944

    Open questions at the time
    • Whether FLT3 is the sole critical substrate in vivo or one of several is not resolved
    • Human CBL-mutant leukemia may involve additional RTK substrates
  15. 2021 High

    Phosphoproteomic dissection of CBL-mutant CMML revealed that oncogenic CBL mutations drive increased LYN kinase activation and LYN-dependent phosphorylation of mutant c-Cbl, which recruits PIK3R1/p85 to activate PI3K/AKT signaling — identifying LYN as a druggable node (dasatinib-sensitive) in CBL-mutant myeloid neoplasms.

    Evidence Mass spectrometry phosphoproteomics, genetic LYN ablation, dasatinib treatment in vitro and in vivo CMML models

    PMID:33512474

    Open questions at the time
    • Whether dasatinib efficacy in CBL-mutant CMML patients holds in clinical trials unknown
    • How mutant c-Cbl specifically increases LYN activation is mechanistically unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how the kinase(s) that phosphorylate Tyr371 are recruited and regulated in different signaling contexts; how c-Cbl selects between monoubiquitination (endosomal sorting) and polyubiquitination (proteasomal degradation) of different substrates; whether UBA-mediated dimerization is universally required; and the structural basis for how oncogenic mutations enhance adaptor function while ablating ligase activity.
  • No structure of full-length c-Cbl in active dimeric form
  • Ubiquitin chain-type selectivity mechanism for different substrates unknown
  • Kinase specificity for Tyr371 activation in non-EGFR contexts unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0060090 molecular adaptor activity 6
Localization
GO:0005768 endosome 3 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 6 R-HSA-392499 Metabolism of proteins 6 R-HSA-1643685 Disease 4 R-HSA-5653656 Vesicle-mediated transport 3
Partners
EGFRFLT3FYNGRB2LYNPIK3R1SYKVAV1

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Crystal structure of c-Cbl bound to UbcH7 (E2) and a kinase peptide shows the RING domain recruits the E2 enzyme; a rigid coupling between the peptide-binding and E2-binding domains positions substrate and E2 optimally for ubiquitin transfer, establishing c-Cbl as a scaffold-type RING E3 ligase. X-ray crystallography with functional validation Cell High 10966114
1999 The RING finger zinc domain of c-Cbl is essential for EGFR ubiquitination and receptor down-regulation; mutagenesis of a single cysteine impairs ubiquitination and desensitization while retaining receptor binding; in vitro reconstitution confirms a direct role in ubiquitin ligation. Site-directed mutagenesis, in vitro ubiquitination reconstitution, cell-based ubiquitination and down-regulation assays The Journal of biological chemistry High 10428778
2012 c-Cbl adopts an autoinhibited RING conformation where the RING's E2-binding surface associates with c-Cbl itself to reduce E2 affinity; phosphorylation of Tyr371 in the linker helix region induces conformational changes that eliminate autoinhibition, flip the RING domain into proximity of the substrate-binding site, and transform the RING into an enhanced E2-binding module, activating RTK ubiquitination. X-ray crystallography of multiple CBL complexes (unphosphorylated, substrate-bound, pTyr371-CBL-E2-substrate), biochemical binding assays Nature structural & molecular biology High 22266821
1995 c-Cbl constitutively associates with Grb2 via Grb2's N-terminal SH3 domain in Jurkat T cells; upon TCR activation, tyrosine-phosphorylated c-Cbl is recruited to the Grb2 SH2 domain and associates with the p85 subunit of PI3-kinase, increasing PI3-kinase activity. Co-immunoprecipitation, GST pulldown with SH2/SH3 domains, PI3-kinase activity assay Molecular and cellular biology High 7791764
1997 c-Cbl negatively regulates the Syk tyrosine kinase in mast cells stimulated through FcεRI; overexpression of c-Cbl inhibits Syk activity and suppresses serotonin release, demonstrating direct negative regulation of a non-receptor tyrosine kinase. Overexpression studies, functional degranulation/serotonin release assay Science Medium 9103201
1998 The phosphotyrosine-binding (PTB/TKB) domain of c-Cbl binds to phosphorylated Tyr323 in the linker region of Syk; a PTB domain point mutation (G306E) abolishes this interaction and blocks c-Cbl-mediated reduction in Syk protein levels and activity. In vitro binding assays, co-immunoprecipitation in COS-7 cells, site-directed mutagenesis The Journal of biological chemistry High 9857068
2001 c-Src phosphorylates c-Cbl (likely on Tyr371), which promotes c-Cbl ubiquitination and subsequent reduction of Src protein levels; the RING finger of c-Cbl is required for Src ubiquitination; active Src destabilizes the c-Cbl–UbcH7 complex in vitro. In vitro ubiquitination assay, co-immunoprecipitation, kinase activity assays, mutagenesis The Journal of biological chemistry High 11448952
2003 c-Src overexpression promotes ubiquitylation and proteasomal destruction of c-Cbl, thereby restraining c-Cbl-dependent EGFR ubiquitylation and impairing receptor sorting to endocytosis; this explains oncogenic Src-EGFR cooperation. Co-immunoprecipitation, ubiquitination assays, receptor internalization assays in cell lines Proceedings of the National Academy of Sciences Medium 12604776
2002 c-Cbl acts as an E3 ubiquitin ligase for Lck; TCR and CD4 co-ligation enhances Cbl-Lck association and leads to Lck ubiquitination and degradation; Cbl RING finger domain is required for Lck negative regulation; Lck SH3 domain is critical for Cbl-Lck association. Co-immunoprecipitation, ubiquitination assays, c-Cbl−/− T cell line analysis, reporter assays, mutagenesis Proceedings of the National Academy of Sciences High 11904433
2002 APS serves as an adaptor linking the insulin receptor to c-Cbl; insulin-stimulated phosphorylation of APS Tyr618 is required for APS-c-Cbl association and subsequent c-Cbl tyrosine phosphorylation (at Tyr371, Tyr700, Tyr774) by the insulin receptor; this APS-facilitated Cbl phosphorylation is required for GLUT4 translocation. Co-immunoprecipitation, site-directed mutagenesis, GLUT4 translocation assay in 3T3-L1 adipocytes Molecular and cellular biology Medium 11997497
1998 Tyr700, Tyr731, and Tyr774 are the major tyrosine phosphorylation sites of c-Cbl in T cells; Fyn, Yes, and Syk are the principal kinases phosphorylating these sites; Fyn and Yes show strong binding to c-Cbl via both phosphotyrosine-dependent and -independent mechanisms. Phosphopeptide mapping, co-expression in COS cells, co-immunoprecipitation The Journal of biological chemistry Medium 9525940
2002 c-Cbl binds to activated EphA2 receptor via its TKB domain and promotes EphA2 ubiquitination and degradation; this requires both EphA2 kinase activity and an intact c-Cbl TKB domain and RING finger. Co-immunoprecipitation, degradation assays, dominant-negative and point-mutant analysis Molecular cancer research Medium 12496371
2003 c-Cbl ubiquitinates hSpry2 in an EGF-dependent manner following EGF-induced tyrosine phosphorylation of hSpry2, targeting it for 26S proteasomal degradation; this limits hSpry2's inhibitory effect on ERK activation and restores FGF sensitivity. Ubiquitination assays, proteasome inhibitor treatment, ERK activation assays Current biology Medium 12593796
2000 hSpry2 directly binds to the RING finger domain of c-Cbl via a short N-terminal sequence; this interaction abrogates c-Cbl-induced EGFR internalization; a mutant hSpry2 unable to bind c-Cbl loses this inhibitory effect. Pulldown assays, co-immunoprecipitation, EGFR internalization assay, mutagenesis The Journal of biological chemistry Medium 11053437
2003 Tyrosine phosphorylation of hSpry2 at Tyr55 enhances its interaction with the SH2-like (TKB) domain of c-Cbl; this high-affinity interaction is required for EGFR retention on the cell surface and for ERK inhibition in the FGFR pathway. Co-immunoprecipitation, mutagenesis (Y55F and residues 52-59), receptor localization assays, ERK activation assays The Journal of biological chemistry Medium 12815057
1996 c-Cbl undergoes rapid tyrosine phosphorylation and ubiquitination upon CSF-1 stimulation, translocates to the membrane, associates with tyrosine-phosphorylated Shc, and then is de-ubiquitinated and returns to cytosol by 10 min. Subcellular fractionation, co-immunoprecipitation, metabolic labeling/ubiquitination detection The Journal of biological chemistry Medium 8550554
2009 Homozygous CBL mutations found in myeloid neoplasms abolish E3 ubiquitin ligase activity but act as dominant negatives over wild-type c-Cbl and CBL-B, leading to prolonged tyrosine kinase activation; transducing mutant c-Cbl into c-Cbl−/− HSPCs further augments cytokine sensitivity beyond simple loss-of-function, demonstrating a gain-of-function mechanism. E3 ligase activity assays, retroviral transduction into HSPCs, cytokine sensitivity assays, genetic rescue experiments Nature High 19620960
2008 c-Cbl negatively regulates HSC development and function through E3 ubiquitin ligase activity; c-Cbl−/− HSCs show hyperresponsiveness to thrombopoietin and elevated STAT5 phosphorylation leading to increased c-Myc expression. c-Cbl knockout mouse analysis, HSC functional assays, phospho-signaling analysis (Western blot) Genes & development Medium 18413713
2010 RING finger-inactivating mutation in c-Cbl leads to myeloproliferative disease progressing to leukemia via augmented FLT3 signaling; mating with FLT3 ligand knockout mice prevents leukemia, placing c-Cbl's E3 ligase activity upstream of FLT3 in restraining myeloid transformation. Knock-in mouse model, genetic epistasis (crosses with FLT3LG-KO mice), signaling analysis Cancer cell High 20951944
2007 c-Cbl interacts with FLT3 and promotes its ubiquitination and internalization upon FLT3-ligand stimulation; dominant-negative c-Cbl (70Z) and an AML-associated c-Cbl point mutant (R420Q) both inhibit FLT3 ubiquitination/internalization and induce cytokine-independent growth. Co-immunoprecipitation, ubiquitination assays, internalization assays, cytokine-independent growth assays Blood Medium 17446348
2008 The UBA domain of c-Cbl mediates homodimerization via a symmetric hydrophobic interface (helices 2 and 3); disruption of dimerization by mutagenesis impairs c-Cbl phosphorylation following Met/HGF receptor activation and c-Cbl-dependent Met ubiquitination. X-ray crystallography of UBA domain, NMR chemical shift mapping, site-directed mutagenesis, ubiquitination assays The Journal of biological chemistry High 17635922
2008 The c-Cbl TKB domain recognizes diverse substrates via an obligatory intrapeptidyl H-bond between phosphotyrosine and a conserved asparagine/arginine; c-Met binds c-Cbl TKB in the reverse direction compared to other substrates; Sprouty2 has the highest affinity for c-Cbl TKB among tested substrates. X-ray crystallography of TKB-peptide complexes, mutagenesis, isothermal titration calorimetry The EMBO journal High 18273061
2004 c-Cbl forms a ternary complex with FLT-1/VEGFR-1 and CD2AP upon VEGF stimulation; c-Cbl promotes FLT-1 ubiquitination and internalization; mutation of FLT-1 Tyr1333 impairs c-Cbl binding and receptor internalization. Co-immunoprecipitation, ubiquitination assays, internalization assays, mutagenesis FASEB journal Medium 15001553
2007 c-Cbl E3 ligase activity negatively regulates PLCγ1 by forming a ternary complex with VEGFR-2 and PLCγ1; c-Cbl ubiquitinates PLCγ1 and suppresses its tyrosine phosphorylation by a proteolysis-independent mechanism; siRNA silencing of c-Cbl enhances angiogenesis. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis of VEGFR-2, siRNA knockdown, in vitro binding assays Proceedings of the National Academy of Sciences High 17372230
2008 c-Cbl-dependent monoubiquitination of gp130 (K63-linked polyubiquitination) is mediated by c-Cbl recruitment to gp130 via SHP2 in a phosphorylation-dependent manner following IL-6 stimulation, leading to lysosomal degradation of gp130 and cessation of IL-6 signaling. Co-immunoprecipitation, ubiquitination assays, lysosomal inhibitor treatment, endosomal trafficking assays, siRNA knockdown Molecular and cellular biology Medium 18519587
2003 Cbl ubiquitin ligase mediates ubiquitination and degradation of Vav; Cbl-Vav interaction requires phosphorylated Tyr700 on c-Cbl; an intact RING finger domain is required; Cbl, but not its RING mutant, inhibits Vav-dependent signaling. Cbl+/+ and Cbl−/− T cell line comparison, 293T transfection, ubiquitination assays, mutagenesis, signaling reporter assays The Journal of biological chemistry Medium 12881521
2002 c-Cbl binds Notch1 transmembrane form and promotes its lysosomal degradation via ubiquitin-dependent targeting; this is distinct from proteasomal degradation of the intracellular Notch1 fragment. Co-immunoprecipitation, lysosomal vs. proteasomal inhibitor comparison, ubiquitination accumulation assay The Journal of biological chemistry Medium 11777909
2002 c-Cbl associates with EphA2 receptor and negatively regulates it in a kinase-activity-dependent manner; the TKB domain of c-Cbl is required for binding active EphA2; a dominant-negative 70Z-Cbl abolishes this negative regulation. Co-immunoprecipitation, degradation assays, dominant-negative and point-mutant analysis Biochemical and biophysical research communications Low 12147253
2004 c-Cbl-mediated ubiquitination is required for EGFR exit from early endosomes (not for initial internalization); using Src inhibition, c-Cbl-dependent ubiquitination was pinpointed as essential for EGFR trafficking beyond early endosomes to degradation. Tyr1045Phe EGFR mutant expression, Src inhibitor PP1, cell fractionation, trafficking assays in CHO and A549 cells The Journal of biological chemistry Medium 15210722
2002 EGFR activated by H2O2 (oxidative stress) lacks phosphorylation at Tyr1045 (the c-Cbl docking site), fails to recruit c-Cbl, and consequently is not ubiquitinated or subjected to endocytosis, resulting in prolonged signaling. Phospho-specific immunoblotting, co-immunoprecipitation, ubiquitination assays, internalization assays The Journal of biological chemistry Medium 12063263
2004 c-Cbl ubiquitin ligase activity directs EGFR into an Eps15-containing endocytic pathway; c-Cbl-mediated ubiquitin functions as a docking signal recruiting Eps15 (via its ubiquitin-interacting motif) to the plasma membrane and endosomes; two distinct modes of c-Cbl-EGFR interaction exist, only one of which involves receptor ubiquitination. Mutagenesis, co-localization, dominant-negative Eps15-UIM overexpression, receptor internalization assays The Journal of biological chemistry Medium 15465819
1997 c-Cbl interacts with Vav via Vav's SH2 domain binding to tyrosine-phosphorylated c-Cbl at the conserved motif Y699MTP; this interaction is induced by TCR activation in thymocytes and peripheral T cells. Co-immunoprecipitation from primary mouse thymocytes and T cells, in vitro SH2 binding assay, mutagenesis identifying pY699 binding site Journal of immunology Medium 9200440
2005 Loss of c-Cbl RING finger function in knock-in mice causes complete thymic deletion due to high-intensity TCR signaling; the mutant c-Cbl protein itself recruits p85 regulatory subunit of PI3-kinase, activating Akt in thymocytes, which is the critical distinguishing feature from c-Cbl-null thymocytes. Knock-in mouse model (RING finger loss-of-function), comparison with c-Cbl−/− mice, signaling analysis, co-immunoprecipitation of p85 The EMBO journal High 16211006
2010 c-Cbl directly binds PD-1 via its C-terminus and promotes PD-1 ubiquitination and proteasomal degradation in immune cells; this requires c-Cbl RING finger function. Co-immunoprecipitation, ubiquitination assays, RING finger mutant analysis, c-Cbl+/− mouse model Scientific reports Medium 31882749
2016 c-Cbl interacts with IRF3 via its TKB domain (binding IRF3's IRF association domain) and promotes K48-linked polyubiquitination and proteasomal degradation of IRF3, negatively regulating IFN-β signaling and antiviral response. Co-immunoprecipitation, ubiquitination assays (K48 linkage), siRNA knockdown and overexpression, IFN-β reporter assays Cellular signalling Medium 27503123
2010 c-Cbl ubiquitinates BCR-ABL; arsenic sulfide (As4S4) binds the RING finger domain of c-Cbl to inhibit c-Cbl self-ubiquitination/degradation while preserving c-Cbl's ability to ubiquitinate BCR-ABL, leading to BCR-ABL degradation in CML. Co-immunoprecipitation, ubiquitination assays, in vivo CML mouse model, direct arsenic binding to RING finger domain Proceedings of the National Academy of Sciences Medium 21118980
2010 c-Cbl tyrosine phosphorylation is required for KSHV-induced membrane blebbing and macropinocytosis; c-Cbl interacts with non-muscle myosin heavy chain IIA (myosin IIA) at sites of bleb formation; c-Cbl promotes ubiquitination of actin and myosin during infection. c-Cbl shRNA knockdown, co-immunoprecipitation, mass spectrometry, co-localization by immunofluorescence PLoS pathogens Medium 21203488
2021 c-Cbl functions downstream of Dectin-2/Dectin-3 in dendritic cells to mediate ubiquitination and degradation of RelB (non-canonical NF-κB subunit); loss of c-Cbl in DCs leads to α-mannan-induced RelB activation, suppression of IL-10, and exacerbated colitis; c-Cbl interacts with c-Abl kinase. DC-specific c-Cbl KO mice, DSS colitis model, co-immunoprecipitation, ubiquitination assays, genetic epistasis Science advances Medium 33962939
2008 UbcH5B, but not UbcH7, efficiently transfers ubiquitin to c-Cbl substrates in a reconstituted system; both E2s bind the RING domain of c-Cbl, but the UbcH7-Ub thioester is too stable to transfer ubiquitin under assay conditions, demonstrating that E2-E3 binding is necessary but not sufficient for ubiquitin transfer. In vitro ubiquitination reconstitution, NMR, structural comparison Journal of molecular biology High 18996392
2022 Fyn phosphorylates c-Cbl at Tyr731, which facilitates c-Cbl binding to Sirt1 and promotes K48-linked polyubiquitination of Sirt1 at Lys377 and Lys513 by c-Cbl, leading to Sirt1 degradation and impaired antioxidant Foxo3a activity in diabetic nephropathy. Co-immunoprecipitation, site-directed mutagenesis, ubiquitination assays (K48 linkage), in vivo adenoviral knockdown/overexpression in diabetic mice Metabolism Medium 36538986
2021 CBL mutations in myeloid neoplasms increase LYN kinase activation and LYN-CBL interaction, driving enhanced CBL phosphorylation, PIK3R1 (p85) recruitment to CBL, and downstream PI3K/AKT signaling; LYN inhibition with dasatinib reduces this signaling and shows antiproliferative efficacy in CBL-mutant CMML. Mass spectrometry phosphoproteomics, co-immunoprecipitation, genetic LYN ablation, dasatinib treatment in vitro and in vivo Blood High 33512474
1996 c-Cbl directly associates with Fyn via both SH2 (phosphotyrosine-dependent) and phosphotyrosine-independent mechanisms in T cells; TCR/CD3 ligation increases the fraction of c-Cbl associated with Fyn; Fyn preferentially interacts with c-Cbl among Src-family kinases in T cells. Co-immunoprecipitation, phosphopeptide mapping, direct binding demonstration The Journal of biological chemistry Medium 8900205
2011 c-Cbl ubiquitin ligase activity selectively promotes monoubiquitination of integrins α3β1 and αVβ3 (directing them to macropinocytosis for productive KSHV infection) versus polyubiquitination of αVβ5 (directing it to clathrin-lysosomal non-infectious entry); c-Cbl knockdown blocks receptor translocation into lipid rafts and productive KSHV infection. c-Cbl shRNA knockdown, ubiquitination assays, lipid raft fractionation, co-localization Journal of virology Medium 21937638
2011 c-Cbl negatively regulates PLCγ1 in vivo; c-Cbl null mice show enhanced tumor angiogenesis and retinal neovascularization; loss of c-Cbl results in robust PLCγ1 activation and increased intracellular calcium; c-Cbl ubiquitination inhibits PLCγ1 tyrosine phosphorylation without degrading PLCγ1. c-Cbl knockout mouse model, endothelial cell proliferation/tube formation assays, PLCγ1 ubiquitination and phosphorylation assays, calcium imaging Oncogene Medium 21242968
2010 c-Cbl E3 ligase activity targets focal adhesion kinase (FAK) and EGFR for ubiquitination and downregulation in cardiac myocytes; c-Cbl deletion reduces myocyte apoptosis and improves cardiac function after ischemia/reperfusion. c-Cbl KO mouse model, ischemia/reperfusion injury, ubiquitination assays, Western blot for FAK and EGFR levels Circulation Medium 24583314
2010 c-Cbl acts as an adaptor protein facilitating CFTR endocytosis by a ubiquitin-independent mechanism (via its C-terminal adaptor region), and separately ubiquitinates CFTR in early endosomes to direct lysosomal degradation; these are two mechanistically distinct c-Cbl functions. siRNA knockdown, dominant-negative c-Cbl constructs (70Z-Cbl for E3 activity; Cbl-480 for adaptor), co-immunoprecipitation, CFTR surface expression and Cl− current assays The Journal of biological chemistry Medium 20525683
2002 c-Cbl associates with tyrosine-phosphorylated PLCγ1 in an EGF-dependent (but not PDGF-dependent) manner via the SH3 domain of PLCγ1; direct c-Cbl–PLCγ1 binding was demonstrated by GST pulldown. Co-immunoprecipitation, GST pulldown with PLC-γ1 SH3 domain, mutant PLCγ1 lacking SH3 Experimental cell research Medium 12061819
2011 Tyrosine phosphorylation of c-Cbl at Y700, Y731, and Y774 downstream of Src family kinases and Syk occurs during platelet integrin outside-in signaling; c-Cbl KO and Y731F knock-in platelets show significantly reduced spreading on fibrinogen and impaired clot retraction. c-Cbl KO and c-Cbl(YF/YF) knock-in mice, platelet spreading assays, clot retraction assays, site-specific phospho-antibodies, SFK and Syk inhibitors Blood Medium 21967979

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell 719 10966114
2001 Cbl: many adaptations to regulate protein tyrosine kinases. Nature reviews. Molecular cell biology 524 11283727
2000 Cbl-b regulates the CD28 dependence of T-cell activation. Nature 496 10646609
2009 Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 354 19620960
2005 The Cbl interactome and its functions. Nature reviews. Molecular cell biology 341 16227975
1999 The RING finger of c-Cbl mediates desensitization of the epidermal growth factor receptor. The Journal of biological chemistry 254 10428778
2006 The Cbl family proteins: ring leaders in regulation of cell signaling. Journal of cellular physiology 246 16741904
2009 Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 225 19571318
1995 Interactions of Cbl with Grb2 and phosphatidylinositol 3'-kinase in activated Jurkat cells. Molecular and cellular biology 224 7791764
1997 The product of the proto-oncogene c-cbl: a negative regulator of the Syk tyrosine kinase. Science (New York, N.Y.) 216 9103201
2001 Src-catalyzed phosphorylation of c-Cbl leads to the interdependent ubiquitination of both proteins. The Journal of biological chemistry 183 11448952
2007 Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 178 17446348
1995 Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2. Nature 169 7603564
2012 Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl. Nature structural & molecular biology 159 22266821
1998 Cbl-mediated negative regulation of the Syk tyrosine kinase. A critical role for Cbl phosphotyrosine-binding domain binding to Syk phosphotyrosine 323. The Journal of biological chemistry 152 9857068
1996 c-Cbl is transiently tyrosine-phosphorylated, ubiquitinated, and membrane-targeted following CSF-1 stimulation of macrophages. The Journal of biological chemistry 152 8550554
1998 Fyn, Yes, and Syk phosphorylation sites in c-Cbl map to the same tyrosine residues that become phosphorylated in activated T cells. The Journal of biological chemistry 142 9525940
2002 APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Molecular and cellular biology 138 11997497
2002 c-Cbl-dependent EphA2 protein degradation is induced by ligand binding. Molecular cancer research : MCR 133 12496371
1996 Coupling of the c-Cbl protooncogene product to ErbB-1/EGF-receptor but not to other ErbB proteins. Oncogene 131 8649804
2012 Tonoplast calcium sensors CBL2 and CBL3 control plant growth and ion homeostasis through regulating V-ATPase activity in Arabidopsis. Cell research 129 23184060
2002 Negative regulation of Lck by Cbl ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 123 11904433
2003 hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl. Current biology : CB 117 12593796
2002 c-Cbl binding and ubiquitin-dependent lysosomal degradation of membrane-associated Notch1. The Journal of biological chemistry 117 11777909
2003 Src promotes destruction of c-Cbl: implications for oncogenic synergy between Src and growth factor receptors. Proceedings of the National Academy of Sciences of the United States of America 114 12604776
2000 Evidence for direct interaction between Sprouty and Cbl. The Journal of biological chemistry 110 11053437
2003 Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function. The Journal of biological chemistry 109 12815057
2010 Cbl and human myeloid neoplasms: the Cbl oncogene comes of age. Cancer research 107 20501843
2001 Beyond the RING: CBL proteins as multivalent adapters. Oncogene 106 11607840
1999 cbl-3: a new mammalian cbl family protein. Oncogene 99 10362357
1995 Coupling of the proto-oncogene product c-Cbl to the epidermal growth factor receptor. The Journal of biological chemistry 98 7592693
1995 Specific association of the beta isoform of the p85 subunit of phosphatidylinositol-3 kinase with the proto-oncogene c-cbl. The Journal of biological chemistry 95 7629144
2008 The E3 ubiquitin ligase c-Cbl restricts development and functions of hematopoietic stem cells. Genes & development 94 18413713
2004 c-Cbl-deficient mice have reduced adiposity, higher energy expenditure, and improved peripheral insulin action. The Journal of clinical investigation 90 15520865
2002 Epidermal growth factor receptor activation under oxidative stress fails to promote c-Cbl mediated down-regulation. The Journal of biological chemistry 90 12063263
1996 Characterization of Cbl tyrosine phosphorylation and a Cbl-Syk complex in RBL-2H3 cells. The Journal of experimental medicine 83 8920860
2010 Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling. Cancer cell 82 20951944
2012 S-acylation-dependent association of the calcium sensor CBL2 with the vacuolar membrane is essential for proper abscisic acid responses. Cell research 80 22547024
2004 The c-Cbl/CD2AP complex regulates VEGF-induced endocytosis and degradation of Flt-1 (VEGFR-1). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 78 15001553
1998 Cbl: complex formation and functional implications. Cellular signalling 78 9720760
2008 c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130. Molecular and cellular biology 77 18519587
1996 Tyrosine phosphorylation of the c-cbl proto-oncogene product mediated by cell surface antigen CD38 in HL-60 cells. The Journal of biological chemistry 75 8576149
2010 The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells. Cancer research 74 20086179
2010 As4S4 targets RING-type E3 ligase c-CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia. Proceedings of the National Academy of Sciences of the United States of America 73 21118980
2004 c-Cbl-mediated ubiquitinylation is required for epidermal growth factor receptor exit from the early endosomes. The Journal of biological chemistry 73 15210722
1997 Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells. Journal of immunology (Baltimore, Md. : 1950) 70 9200440
1996 Specific association of tyrosine-phosphorylated c-Cbl with Fyn tyrosine kinase in T cells. The Journal of biological chemistry 70 8900205
2019 c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth. Scientific reports 65 31882749
2019 CircRNA CBL.11 suppresses cell proliferation by sponging miR-6778-5p in colorectal cancer. BMC cancer 62 31438886
2010 Interaction of c-Cbl with myosin IIA regulates Bleb associated macropinocytosis of Kaposi's sarcoma-associated herpesvirus. PLoS pathogens 62 21203488
2005 Negative regulation of PTK signalling by Cbl proteins. Growth factors (Chur, Switzerland) 60 16019438
2005 Loss of c-Cbl RING finger function results in high-intensity TCR signaling and thymic deletion. The EMBO journal 59 16211006
2002 Negative regulation of EphA2 receptor by Cbl. Biochemical and biophysical research communications 59 12147253
2008 Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates. The EMBO journal 58 18273061
2023 Targeting Cbl-b in cancer immunotherapy. Journal for immunotherapy of cancer 56 36750253
2007 A critical role for the E3-ligase activity of c-Cbl in VEGFR-2-mediated PLCgamma1 activation and angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 56 17372230
2003 Aberrant expression of HOXA9, DEK, CBL and CSF1R in acute myeloid leukemia. Leukemia & lymphoma 55 14738146
1998 The c-Cbl oncoprotein. The international journal of biochemistry & cell biology 55 9675877
2020 The Calcium Sensor CBL2 and Its Interacting Kinase CIPK6 Are Involved in Plant Sugar Homeostasis via Interacting with Tonoplast Sugar Transporter TST2. Plant physiology 52 32139477
2003 Cbl-mediated ubiquitinylation and negative regulation of Vav. The Journal of biological chemistry 52 12881521
2010 Mutations of the TET2 and CBL genes: novel molecular markers in myeloid malignancies. Annals of hematology 50 20195608
2019 c-Cbl: An Important Regulator and a Target in Angiogenesis and Tumorigenesis. Cells 48 31126146
2010 Cbl-b in T-cell activation. Seminars in immunopathology 48 20458601
1996 Formation of c-Cbl.phosphatidylinositol 3-kinase complexes on lymphocyte membranes by a p56lck-independent mechanism. The Journal of biological chemistry 48 8702998
2010 c-Cbl facilitates endocytosis and lysosomal degradation of cystic fibrosis transmembrane conductance regulator in human airway epithelial cells. The Journal of biological chemistry 47 20525683
1999 Tyrosine phosphorylation of C-Cbl facilitates adhesion and spreading while suppressing anchorage-independent growth of V-Abl-transformed NIH3T3 fibroblasts. Oncogene 47 10391678
2016 c-Cbl-mediated ubiquitination of IRF3 negatively regulates IFN-β production and cellular antiviral response. Cellular signalling 46 27503123
2004 Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment. The Journal of biological chemistry 46 15465819
2001 Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiologic findings in 14 cases. Neuropediatrics 46 11315197
2014 c-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia. Circulation 44 24583314
2011 c-Cbl-mediated selective virus-receptor translocations into lipid rafts regulate productive Kaposi's sarcoma-associated herpesvirus infection in endothelial cells. Journal of virology 44 21937638
2013 EphrinA2 regulates clathrin mediated KSHV endocytosis in fibroblast cells by coordinating integrin-associated signaling and c-Cbl directed polyubiquitination. PLoS pathogens 43 23874206
1991 Relationship of the human protooncogene CBL2 on 11q23 to the t(4;11), t(11;22), and t(11;14) breakpoints. Cytogenetics and cell genetics 43 2013228
2016 The E3 Ubiquitin Ligase c-Cbl Inhibits Microglia-Mediated CNS Inflammation by Regulating PI3K/Akt/NF-κB Pathway. CNS neuroscience & therapeutics 42 27156691
2022 Fyn deficiency inhibits oxidative stress by decreasing c-Cbl-mediated ubiquitination of Sirt1 to attenuate diabetic renal fibrosis. Metabolism: clinical and experimental 40 36538986
2015 Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations. Human mutation 40 25952305
2004 c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15. Journal of cell science 40 15383614
2024 SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation. Cancer communications (London, England) 37 38407942
2019 CBL-interacting protein kinase 25 contributes to root meristem development. Journal of experimental botany 37 30239807
2014 The vacuolar calcium sensors CBL2 and CBL3 affect seed size and embryonic development in Arabidopsis thaliana. The Plant journal : for cell and molecular biology 37 24479654
2008 E2-c-Cbl recognition is necessary but not sufficient for ubiquitination activity. Journal of molecular biology 37 18996392
2021 E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation. Science advances 36 33962939
2010 c-Cbl acts as a mediator of Src-induced activation of the PI3K-Akt signal transduction pathway during TRAIL treatment. Cellular signalling 36 19861161
1995 The cbl oncogene: a novel substrate of protein tyrosine kinases. Australian and New Zealand journal of medicine 36 8770364
2007 Structural basis for UBA-mediated dimerization of c-Cbl ubiquitin ligase. The Journal of biological chemistry 35 17635922
2020 CBL-CIPK module-mediated phosphoregulation: facts and hypothesis. The Biochemical journal 33 32129820
2007 The Cbl-interacting protein TULA inhibits dynamin-dependent endocytosis. Experimental cell research 33 17382318
2002 EGF-dependent association of phospholipase C-gamma1 with c-Cbl. Experimental cell research 33 12061819
2021 CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1. Blood 32 33512474
2011 An E3 ubiquitin ligase: c-Cbl: a new therapeutic target of lung cancer. Cancer 29 21607942
2011 Interferon-α sensitizes human gastric cancer cells to TRAIL-induced apoptosis via activation of the c-CBL-dependent MAPK/ERK pathway. Cancer biology & therapy 28 21725207
2011 Tyrosine phosphorylated c-Cbl regulates platelet functional responses mediated by outside-in signaling. Blood 28 21967979
2010 Deregulated intracellular signaling by mutated c-CBL in myeloid neoplasms. Clinical cancer research : an official journal of the American Association for Cancer Research 28 20547695
2008 Suppression of c-Cbl tyrosine phosphorylation inhibits neointimal formation in balloon-injured rat arteries. Circulation 28 18663086
2017 DR5-Cbl-b/c-Cbl-TRAF2 complex inhibits TRAIL-induced apoptosis by promoting TRAF2-mediated polyubiquitination of caspase-8 in gastric cancer cells. Molecular oncology 27 28972304
2016 Plant Stress Responses Mediated by CBL-CIPK Phosphorylation Network. The Enzymes 27 27776782
2011 c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1. Oncogene 26 21242968
2006 EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins. Oncogene 26 16702950
2002 Repression of c-Cbl leads to enhanced G-CSF Jak-STAT signaling without increased cell proliferation. Oncogene 26 12149655
2005 TGF-beta, c-Cbl, and PDGFR-alpha the in mammary stroma. Developmental biology 25 15708558