Affinage

CBL

E3 ubiquitin-protein ligase CBL · UniProt P22681

Length
906 aa
Mass
99.6 kDa
Annotated
2026-06-09
100 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

c-Cbl (CBL) is a RING-type, E2-dependent E3 ubiquitin ligase and signaling adaptor that enforces negative feedback on activated tyrosine-kinase signaling by recognizing phosphotyrosine substrates and targeting them for ubiquitination and lysosomal or proteasomal degradation (PMID:10514377). It binds tyrosine-phosphorylated substrates through its SH2/TKB domain and recruits and allosterically activates an E2 conjugating enzyme (e.g., UbcH7) through its RING domain, with rigid coupling between the substrate- and E2-binding surfaces positioning ubiquitin for transfer (PMID:10514377, PMID:10966114). Catalytic output is gated by autoinhibition: in the resting state the RING E2-binding surface folds back intramolecularly, and phosphorylation of Tyr371 in the linker-helix region relieves this autoinhibition, repositions the RING and bound E2 toward the substrate, and is required for receptor tyrosine kinase ubiquitination (PMID:22266821). Through these activities c-Cbl drives ligand-induced downregulation of receptor tyrosine kinases including ErbB-1/EGFR, Neu/ErbB-2, KIT, Flt-1, EphA, and Ron, controlling their endosomal sorting toward degradation rather than recycling (PMID:9851973, PMID:10940298, PMID:15315962, PMID:12802274); CIN85/CD2AP adaptors and the SH3-mediated ternary complexes they form are required for this receptor downregulation (PMID:16228008, PMID:15001553). In hematopoietic and immune cells c-Cbl sets activation thresholds by negatively regulating Syk/ZAP-70-family signaling, promoting clearance of engaged TCR and ubiquitination of LAT and Vav, and downmodulating innate signaling components including IRF3, RelB, TRAF6, and PD-1 (PMID:9671496, PMID:12415267, PMID:17938199, PMID:12881521, PMID:27503123, PMID:33962939, PMID:31123462, PMID:31882749). Beyond catalysis, c-Cbl serves as a scaffold that recruits PI3K/p85, Grb2, and Crk, a non-catalytic function genetically separable from its E3 activity that activates Akt and shapes actin cytoskeletal organization downstream of Src-family kinases (PMID:16211006, PMID:7791764, PMID:10633073, PMID:12652654). c-Cbl also acts downstream of c-Src in osteoclast-mediated bone resorption (PMID:8849724) and possesses NEDD8 E3 (neddylation) activity toward TβRII and c-Src, which alters their trafficking and stability (PMID:23290524, PMID:29899407). CBL mutations in myeloid neoplasms selectively abolish E3 ligase activity while enhancing LYN-driven phosphorylation, p85 recruitment, and PI3K/AKT signaling, defining an oncogenic gain-of-adaptor mechanism (PMID:33512474).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    Established c-Cbl as a functional effector downstream of c-Src in a defined physiological process, before its enzymatic identity was known.

    Evidence Antisense knockdown, co-IP, immunofluorescence, and in vitro bone resorption with src-null osteoclasts

    PMID:8849724

    Open questions at the time
    • Molecular mechanism of c-Cbl action in resorption not defined
    • Substrate(s) of c-Cbl in osteoclasts not identified
  2. 1998 High

    Showed that c-Cbl physically mediates receptor ubiquitination and degradative endosomal sorting, reframing it from a passive adaptor to an active downregulator of RTKs.

    Evidence Endosomal colocalization, ubiquitination IP, and oncogenic v-Cbl rescue in ErbB-1 trafficking

    PMID:9851973

    Open questions at the time
    • Enzymatic mechanism of ubiquitin transfer not yet established
    • Did not define E2 partner or RING requirement
  3. 1998 High

    Genetically defined c-Cbl as a negative regulator of T-cell Syk/ZAP-70 kinase signaling, establishing its immune threshold-setting role.

    Evidence c-Cbl knockout mice with ZAP-70 phosphorylation readouts and lymphoid phenotyping

    PMID:9671496

    Open questions at the time
    • Whether the effect required E3 activity vs adaptor function unresolved at this stage
  4. 1999 High

    Defined the core biochemical identity of c-Cbl as a RING-type, E2-dependent E3 ligase that reads phosphotyrosine substrates and allosterically activates a conjugating enzyme.

    Evidence In vitro ubiquitination reconstitution with PDGFR substrate plus SH2 and RING mutagenesis

    PMID:10514377

    Open questions at the time
    • Structural basis of E2 recruitment not yet visualized
    • Regulation of activity in cells not addressed
  5. 2000 High

    Provided the structural logic for RING E3 catalysis, showing rigid substrate-to-E2 coupling that scaffolds ubiquitin transfer.

    Evidence X-ray crystal structure of the c-Cbl–UbcH7–kinase peptide ternary complex

    PMID:10966114

    Open questions at the time
    • Did not capture the autoinhibited or activated conformations
    • Phosphoregulation not represented in structure
  6. 2000 Medium

    Demonstrated c-Cbl is a tumor suppressor of an oncogenic RTK and that its catalytic downregulation activity has anti-tumor consequences in vivo.

    Evidence c-Cbl/v-Cbl overexpression, ubiquitination and surface-receptor assays, and a neuroblastoma tumor model

    PMID:10940298

    Open questions at the time
    • Endogenous-level regulation not tested
    • Mechanism of v-Cbl antagonism only inferred
  7. 2003 High

    Revealed an upstream OFF-switch in which Cdc42/beta-PIX sequesters c-Cbl away from EGFR, linking GTPase signaling to control of receptor downregulation and transformation.

    Evidence Reciprocal co-IP, dominant-active Cdc42, ubiquitination/ERK assays, and transformation phenotype

    PMID:14505571

    Open questions at the time
    • Stoichiometry and dynamics of the ternary complex in vivo not defined
  8. 2005 High

    Genetically separated c-Cbl's E3 ligase function from a distinct PI3K/Akt-recruiting adaptor function, establishing dual-mode action.

    Evidence RING-finger mutant knock-in mice with thymic phenotype and c-Cbl/p85 co-IP

    PMID:16211006

    Open questions at the time
    • Direct vs indirect p85 recruitment not fully resolved
    • Generality of adaptor role across cell types not tested here
  9. 2012 High

    Resolved how c-Cbl activity is switched on, showing Tyr371 phosphorylation relieves an autoinhibited RING conformation required for RTK ubiquitination.

    Evidence Crystal structures of unphosphorylated, substrate-bound, and pTyr371 activated complexes with biochemical validation

    PMID:22266821

    Open questions at the time
    • Kinetics of conformational switching in cells not measured
    • Which kinases phosphorylate Tyr371 in each context not unified
  10. 2013 High

    Expanded c-Cbl's enzymatic repertoire to NEDD8 conjugation, showing it can stabilize rather than degrade a substrate by altering its trafficking.

    Evidence In vitro neddylation, site mutagenesis (K556R/K567R), KO cells, and endosomal/reporter assays for TβRII

    PMID:23290524

    Open questions at the time
    • How c-Cbl chooses ubiquitin vs NEDD8 outputs not defined
    • E2/NEDD8 machinery details not fully resolved
  11. 2021 High

    Defined the oncogenic mechanism of CBL myeloid mutations as loss of E3 activity coupled to gain of LYN-driven adaptor signaling through PI3K/AKT.

    Evidence Phosphoproteomics, interactome MS, CBL allelic series, LYN KO/dasatinib, and CMML xenografts

    PMID:33512474

    Open questions at the time
    • Full set of dysregulated substrates in patients not enumerated
    • Therapeutic durability of LYN inhibition not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How c-Cbl integrates its competing E3-ubiquitin, NEDD8-ligase, and non-catalytic adaptor outputs to produce context-specific substrate fates remains unresolved.
  • No unified model selecting degradation vs stabilization vs signaling
  • Determinants of mono- vs K48- vs K63-linked ubiquitination unclear
  • Tissue-specific substrate repertoire incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005768 endosome 3 GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3
Partners
CD2APCIN85CRKEGFRGRB2LYNPIK3R1SRC

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 c-Cbl functions as a RING-type, E2-dependent ubiquitin-protein ligase (E3): it recognizes tyrosine-phosphorylated substrates (e.g., activated PDGF receptor) through its SH2 domain and recruits and allosterically activates an E2 ubiquitin-conjugating enzyme through its RING domain to catalyze ubiquitin transfer. In vitro ubiquitination assay, domain mutagenesis (SH2 and RING finger), biochemical reconstitution Science High 10514377
2000 Crystal structure of c-Cbl bound to E2 (UbcH7) and a kinase substrate peptide revealed that the RING domain recruits E2 through a conserved surface, and there is rigid coupling between the substrate-binding and E2-binding domains with a conserved channel from substrate to E2 active site, suggesting RING E3s scaffold substrate and E2 for ubiquitin transfer. X-ray crystallography (crystal structure of c-Cbl–UbcH7–kinase peptide ternary complex) Cell High 10966114
1998 c-Cbl is transiently recruited into ErbB-1-containing endosomes in a receptor kinase activity-dependent manner, mediates covalent ubiquitination of ErbB-1, and directs internalized ErbB-1 to lysosomal and proteasomal degradation rather than recycling; oncogenic v-Cbl inhibits this by shunting receptors to the recycling pathway. Immunofluorescence microscopy (endosomal colocalization), immunoprecipitation (ubiquitin attachment), dominant-negative/oncogenic Cbl expression, degradation assays Genes & development High 9851973
2012 c-Cbl adopts an autoinhibited RING conformation in which the RING's E2-binding surface associates intramolecularly with CBL to reduce E2 affinity; phosphorylation of Tyr371 in the linker helix region (LHR) induces conformational changes that eliminate autoinhibition, flip the RING domain and E2 into proximity of the substrate-binding site, and enhance E2 binding—this activation is required for RTK ubiquitination. X-ray crystallography (structures of unphosphorylated CBL, CBL–substrate peptide, phospho-Tyr371-CBL–E2–substrate), biochemical activity assays, mutagenesis Nature structural & molecular biology High 22266821
1996 c-Cbl is tyrosine-phosphorylated downstream of c-Src in osteoclasts and the two proteins colocalize on vesicular structures; antisense knockdown of either c-src or c-cbl inhibits in vitro bone resorption by osteoclast-like cells, placing c-Cbl downstream of c-Src in a pathway required for osteoclast-mediated bone resorption. Antisense oligonucleotide knockdown, immunoprecipitation, immunofluorescence colocalization, in vitro bone resorption assay with src-null OCLs Nature High 8849724
2001 Src-catalyzed phosphorylation of c-Cbl (likely on Tyr-371) is required for c-Cbl-dependent ubiquitination of both c-Src itself and c-Cbl (auto-ubiquitination); this requires the RING finger of c-Cbl. Active Src destabilizes the c-Cbl–UbcH7 complex in vitro. c-Cbl reduces v-Src protein levels and suppresses v-Src-induced STAT3 activation. In vitro ubiquitination assay, co-immunoprecipitation, kinase activity assays, overexpression/mutagenesis in cells The Journal of biological chemistry High 11448952
2003 Activated Cdc42 binds to p85Cool-1/beta-PIX, which directly associates with c-Cbl, thereby inhibiting c-Cbl binding to the EGF receptor and preventing Cbl-catalyzed receptor ubiquitination; constitutively active Cdc42(F28L) persistently blocks EGF receptor–Cbl interaction, leading to aberrant receptor accumulation, sustained ERK activation, and cellular transformation. Co-immunoprecipitation, dominant-active Cdc42 expression, ubiquitination assays, ERK activation assays, cell transformation assay Cell High 14505571
1995 In TCR-activated Jurkat T cells, c-Cbl constitutively associates with the Grb2 adaptor via Grb2's N-terminal SH3 domain; after TCR–CD3 plus CD4 co-stimulation, Cbl also binds Grb2's SH2 domain. TCR activation recruits PI 3-kinase activity to Cbl immunocomplexes. Cbl–Grb2 and Sos–Grb2 exist as distinct complexes. Co-immunoprecipitation with domain-specific Grb2 fusion proteins, PI 3-kinase activity assay in immunoprecipitates Molecular and cellular biology Medium 7791764
1998 In c-Cbl-deficient mice, ZAP-70 kinase phosphorylation in thymocytes is uncoupled from the requirement for CD4-mediated Lck activation following CD3ε cross-linking, demonstrating that c-Cbl negatively regulates signaling by the Syk/ZAP-70 family of protein kinases in T cells; c-Cbl-null mice also display lymphoid hyperplasia and altered T-cell receptor expression. Targeted gene disruption (c-Cbl knockout mice), flow cytometry, immunoprecipitation/Western blot for ZAP-70 phosphorylation Molecular and cellular biology High 9671496
2002 c-Cbl and Cbl-b double-knockout T cells fail to down-modulate surface TCR after ligand engagement, resulting in sustained TCR signaling and T-cell hyperresponsiveness; trafficking of internalized TCR to lysosomes was reduced, while ligand-independent internalization was normal. This demonstrates Cbl proteins negatively regulate T-cell activation by promoting clearance of engaged TCR from the cell surface. c-Cbl/Cbl-b double-knockout mouse T cells, flow cytometry (TCR surface levels), T-cell activation assays, trafficking assays Nature immunology High 12415267
2013 c-Cbl acts as a NEDD8 E3 ligase (neddylation E3) for the TGF-β type II receptor (TβRII): it conjugates NEDD8 to TβRII at Lys556 and Lys567. Neddylation promotes TβRII endocytosis to EEA1-positive early endosomes and prevents its endocytosis to caveolin-positive (degradative) compartments, thereby inhibiting TβRII ubiquitination and degradation and stabilizing/enhancing TGF-β signaling. Co-immunoprecipitation, in vitro neddylation assay, site-directed mutagenesis (K556R/K567R), c-Cbl knockout hematopoietic cells, endosomal colocalization assays, TGF-β pathway reporter assays Molecular cell High 23290524
2019 DNA damage leads to ATM-mediated phosphorylation and stabilization of c-Cbl, which in turn promotes TβRII neddylation and prevents its ubiquitination-dependent degradation, thus stabilizing TβRII and enhancing TGF-β signaling; ATM, c-Cbl, and TβRII form a ternary complex upon DNA damage. Co-immunoprecipitation (ATM-c-Cbl-TβRII complex), Western blotting (TβRII stability), mouse intestinal regeneration model after X-ray irradiation Cell reports Medium 31315051
2002 c-Cbl binds tyrosine-phosphorylated transmembrane Notch1 (by co-immunoprecipitation) and mediates ubiquitin-dependent targeting of the transmembrane form of Notch1 to lysosomal compartments for degradation in skeletal myoblasts. Co-immunoprecipitation, lysosomal inhibitor (chloroquine) treatment, proteasome inhibitor comparison, ubiquitin accumulation assay The Journal of biological chemistry Medium 11777909
2005 c-Cbl mediates mono-ubiquitination of activated PAR2 (a GPCR) in an Src-dependent manner, directing it from early endosomes to lysosomes for degradation; dominant-negative c-Cbl (RING-deleted) blocks PAR2 ubiquitination and lysosomal degradation, causing receptor retention in early endosomes and allowing recycling and continued signaling. Immunoprecipitation, immunofluorescence, dominant-negative c-Cbl expression, lysosomal degradation assays, receptor signaling recovery assays The Journal of biological chemistry Medium 15708858
2008 IL-6 stimulation induces c-Cbl-mediated K63-linked polyubiquitination of the cytokine receptor gp130; c-Cbl is recruited to gp130 via phosphorylated SHP2. Ubiquitinated gp130 is recognized by Hrs and targeted for lysosomal degradation. Deficiency of c-Cbl suppresses gp130 degradation and prolongs IL-6 signaling. Immunoprecipitation (c-Cbl–SHP2–gp130 complex), ubiquitin linkage analysis, c-Cbl siRNA knockdown, lysosomal degradation assays Molecular and cellular biology Medium 18519587
2002 APS acts as an adaptor linking the insulin receptor to c-Cbl: insulin-stimulated phosphorylation of APS Tyr618 enables APS to associate with c-Cbl, facilitating c-Cbl phosphorylation by the insulin receptor at Tyr371, Tyr700, and Tyr774, which drives c-Cbl–Crk association and is required for GLUT4 translocation. Overexpression of wild-type and Y618F APS mutant in 3T3-L1 adipocytes, co-immunoprecipitation, GLUT4 translocation assay Molecular and cellular biology Medium 11997497
2004 Upon SCF stimulation, activated KIT receptor binds and phosphorylates Cbl proteins (c-Cbl and Cbl-b), which in turn ubiquitinate KIT and themselves, mediating their mutual degradation; TKB and RING finger domains of Cbl are essential for this negative feedback loop. Co-immunoprecipitation, ubiquitination assays, domain deletion/mutagenesis, degradation assays in mast cells Blood Medium 15315962
2004 VEGF stimulation induces formation of a ternary Flt-1–c-Cbl–CD2AP complex; c-Cbl binds to pTyr1333 of Flt-1; wild-type CD2AP promotes ubiquitination and internalization/degradation of Flt-1, whereas dominant-negative CD2AP or mutant c-Cbl prevents this. Co-immunoprecipitation (ternary complex), site-directed mutagenesis (Y1333F Flt-1), dominant-negative CD2AP and c-Cbl, internalization/ubiquitination assays FASEB journal Medium 15001553
2004 c-Cbl-mediated ubiquitination is required for EGFR exit from early endosomes but not for its initial internalization; Src-inhibitor PP1 blocks Cbl-mediated ubiquitination and retains EGFR in early endosomes. Src inhibitor (PP1) treatment, mutant EGFR (Y1045F) expression, EGFR trafficking and ubiquitination assays in CHO and A549 cells The Journal of biological chemistry Medium 15210722
2005 c-Cbl mediates ubiquitination and proteasomal degradation of STAT5 in response to GH stimulation, thereby negatively regulating GH-stimulated STAT5-mediated transcription; proteasome inhibitor MG132 reverses this effect. Overexpression of c-Cbl in NIH3T3 cells, ubiquitination assays, STAT5 reporter assay, proteasome inhibitor treatment Endocrinology Medium 12193575
2003 c-Cbl mediates Vav ubiquitination via Cbl RING finger activity; this requires Cbl–Vav association through phosphorylated Tyr-700 on Cbl. Cbl-dependent ubiquitination leads to loss of phosphorylated Vav protein, and c-Cbl but not its ubiquitin ligase mutant inhibits Vav-dependent signaling in Jurkat cells. Ubiquitination assays in Cbl+/+ and Cbl−/− T cells, co-immunoprecipitation, mutagenesis (RING finger and pTyr-700), Jurkat transfection with functional reporter assays The Journal of biological chemistry Medium 12881521
2005 Loss of c-Cbl RING finger function in knock-in mice causes high-intensity TCR signaling and complete thymic deletion; the RING finger mutant c-Cbl protein itself recruits the p85 subunit of PI 3-kinase, activating Akt, whereas c-Cbl-null thymocytes do not show Akt activation—demonstrating a scaffolding/adaptor role for c-Cbl distinct from its E3 ligase function. Knock-in mouse expressing RING finger mutant c-Cbl, flow cytometry (CD5, CD69 markers), Western blotting (Erk, Akt, Ca2+ mobilization), co-immunoprecipitation (c-Cbl/p85) The EMBO journal High 16211006
2007 c-Cbl ubiquitylates the LAT adapter downstream of TCR activation in a RING-finger-dependent manner, promoting internalization of LAT-containing signaling clusters into intracellular compartments; c-Cbl RING mutants and c-Cbl-null T cells show increased cellular LAT levels and increased basal and TCR-induced phospho-LAT. Fluorescence microscopy (YFP-tagged LAT), c-Cbl RING mutant expression, T cells from c-Cbl-null mice, ubiquitination assays, Western blotting Molecular and cellular biology Medium 17938199
2000 c-Cbl colocalizes with Crk at submembranous actin lamellae in NIH 3T3 fibroblasts via SH3-binding sequences; truncation of c-Cbl's SH3-binding domain inhibits lamellipodia and membrane ruffle formation; this inhibitory effect is reversed by constitutively active Rac or by overexpression of wild-type c-Cbl, implicating c-Cbl in regulation of actin cytoskeletal organization via Crk and Rac. Immunofluorescence microscopy (colocalization with Crk and actin), truncation/mutagenesis constructs, cell morphology assays, constitutively active Rac rescue experiment Journal of cell science Medium 10633073
2000 c-Cbl is a suppressor of oncogenic Neu/ErbB-2: ectopic c-Cbl causes ubiquitination and rapid removal of Neu from the cell surface and severely reduces signaling; this requires the carboxy-terminal domain of Neu and is antagonized by v-Cbl. In an in vivo neuroblastoma model, c-Cbl-encoding retrovirus caused enhanced Neu down-regulation and tumor retardation. Overexpression of c-Cbl and v-Cbl, ubiquitination assays, surface receptor quantification, retroviral infection of neuroblastoma tumor model The Journal of biological chemistry Medium 10940298
2009 In Mycobacterium tuberculosis-infected macrophages, TNF activates a pathway (ASK1→p38→c-Abl) that phosphorylates FLIP(S), enabling FLIP(S) interaction with c-Cbl E3 ligase; c-Cbl then promotes proteasomal degradation of FLIP(S), which activates caspase-8 and apoptosis. Kinase inhibitors, co-immunoprecipitation (FLIP(S)–c-Cbl), c-Cbl-null macrophages, proteasome inhibitors, caspase-8 activation assays Nature immunology High 19597496
2010 c-Cbl facilitates CFTR endocytosis by an adaptor (ubiquitin ligase-independent) mechanism via its C-terminal region, and ubiquitinates CFTR in early endosomes to direct its lysosomal degradation; siRNA knockdown of c-Cbl increased plasma membrane CFTR and Cl- currents, while the adaptor-deficient (Cbl-480) but not the RING mutant (70Z-Cbl) blocked CFTR endocytosis. siRNA knockdown, dominant-negative/truncation constructs (70Z-Cbl, Cbl-480), co-immunoprecipitation, CFTR surface expression quantification, Cl- current measurement (electrophysiology) The Journal of biological chemistry Medium 20525683
2016 c-Cbl negatively regulates the antiviral innate immune response by interacting with IRF3 (via TKB domain of c-Cbl and IRF association domain of IRF3) and promoting K48-linked polyubiquitination and proteasomal degradation of IRF3, thereby suppressing IFN-β production. Co-immunoprecipitation (domain mapping), siRNA knockdown and overexpression, in vivo ubiquitination assay (K48-linkage), IFN-β reporter assay Cellular signalling Medium 27503123
2019 c-Cbl ubiquitinates PD-1 in immune cells (CD8+ T cells and macrophages) via its RING finger domain, targeting PD-1 for proteasomal degradation; the C-terminus of c-Cbl interacts with the cytoplasmic tail of PD-1. Loss of c-Cbl (c-Cbl+/- mice) results in increased PD-1 levels and impaired macrophage tumor phagocytosis. Syngeneic CRC xenografts in c-Cbl+/- mice, co-immunoprecipitation (c-Cbl–PD-1 interaction), ubiquitination assays, RING mutant constructs, anti-PD-1 neutralizing antibody rescue of phagocytosis Scientific reports Medium 31882749
2018 c-Cbl acts as an E3 ligase for neddylation of c-Src; after neddylation, c-Src undergoes polyubiquitination and proteasomal degradation, suppressing the PI3K-AKT signaling pathway responsible for cancer cell migration. Neddylation assay, co-immunoprecipitation, neddylation blockade, c-Cbl overexpression/knockdown, cell migration assay, lung cancer tissue analysis Oncogene Medium 29899407
2002 c-Cbl co-immunoprecipitates with Src and associates with Golgi membranes in multiple unstimulated cell types; approximately 10% of c-Cbl is membrane-associated, enriched in Golgi fractions; activated (but not wild-type) Src increases the amount of Src co-immunoprecipitating with c-Cbl at the Golgi, suggesting a Golgi-localized activated Src–c-Cbl complex. Confocal immunofluorescence (Golgi marker colocalization), subcellular fractionation (isopycnic density centrifugation and free-flow electrophoresis), co-immunoprecipitation, brefeldin A treatment European journal of cell biology Medium 11893076
2003 c-Cbl macrophages (c-cbl-/-) exhibit impaired chemokinetic and chemotactic migration and altered actin cytoskeletal structures similar to hck-/-fgr-/- macrophages, placing c-Cbl tyrosine phosphorylation downstream of Src family kinases (Hck/Fgr) in a pathway controlling macrophage motility. c-cbl-/- macrophages (genetic KO), migration/chemotaxis assays, comparison with hck-/-fgr-/- macrophages, Cbl phosphorylation Western blotting Journal of cellular physiology Medium 12652654
2019 c-Cbl functions downstream of Dectin-2/Dectin-3 in dendritic cells to mediate ubiquitination and proteasomal degradation of the noncanonical NF-κB subunit RelB; c-Cbl deficiency in DCs promotes α-mannan-induced RelB activation, which suppresses IL-10 transcription and aggravates colitis. c-Cbl interacts with c-Abl tyrosine kinase in this pathway. DC-specific c-Cbl knockout mice, DSS colitis model, co-immunoprecipitation (c-Cbl–RelB and c-Cbl–c-Abl), ubiquitination assay, NF-κB reporter, IL-10 ELISA Science advances Medium 33962939
2021 CBL mutations found in myeloid neoplasms selectively abolish E3 ubiquitin ligase activity while enhancing interaction with LYN kinase; mutant CBL shows increased LYN-driven phosphorylation, PIK3R1 (p85) recruitment, and PI3K/AKT activation. All CBL adaptor domains (TKB, proline-rich region, C-terminal phosphotyrosines) are required for oncogenic function. LYN inhibition (dasatinib) reduces mutant CBL signaling in vitro and in vivo in CMML. Phosphoproteomics (global mass spectrometry), CBL interactome MS, functional assays with CBL allelic series, domain deletion/mutagenesis, LYN knockout/dasatinib inhibition, in vivo CMML xenograft Blood High 33512474
2011 c-Cbl promotes mono-ubiquitination of integrin α3β1 and αVβ3 (but polyubiquitination of αVβ5) to direct selective translocation of KSHV and these receptors into lipid rafts for productive macropinocytic entry; c-Cbl knockdown diverts KSHV to clathrin-mediated lysosomal non-infectious pathway. siRNA knockdown of c-Cbl, lipid raft fractionation, ubiquitination assays (mono- vs. polyubiquitin), KSHV infection assays, methyl-β-cyclodextrin (lipid raft disruption) Journal of virology Medium 21937638
2011 c-Cbl ubiquitin ligase is activated by cathepsin G-induced EGFR transactivation in cardiac myocytes; c-Cbl then interacts with focal adhesion proteins and mediates their proteasomal (not lysosomal or calpain-dependent) ubiquitination and degradation, leading to myofibrillar degeneration and apoptosis. c-Cbl knockout-derived myocytes, EGFR kinase inhibitor, co-immunoprecipitation (c-Cbl–FA proteins), proteasome/lysosome/calpain inhibitors, ubiquitination assays The Journal of biological chemistry Medium 22203672
2005 Crystal structures of CIN85 and beta-PIX SH3 domains in complex with a proline-arginine (PxxxPR) peptide from Cbl-b reveal a heterotrimeric complex in which two SH3 domains are held by a single pseudo-symmetrical peptide; this trimerization occurs in solution and in vivo, and ternary CIN85–Cbl complexes are required for Cbl-mediated EGFR downregulation. X-ray crystallography (SH3–peptide complex structures), solution studies, co-immunoprecipitation (in vivo ternary complex), EGFR downregulation assay Nature structural & molecular biology High 16228008
2015 c-Cbl and Cbl-b negatively regulate osteoblast differentiation by ubiquitinating the transcription factor Osterix, promoting its proteasome-mediated degradation and suppressing its transcriptional activity; this inhibits BMP2-induced osteoblast differentiation in mesenchymal cells. Overexpression/knockdown in mesenchymal cells, co-immunoprecipitation, ubiquitination assays, proteasome inhibitor rescue, osteoblast differentiation markers Bone Medium 25744063
2019 c-Cbl promotes K48-linked polyubiquitination of TRAF6 via its proline-rich domain interaction with TRAF6, leading to TRAF6 degradation and inhibition of RANKL- and IL-1β-induced (but not TNFα-induced) NF-κB activation; RANKL or IFN-γ stimulation promotes c-Cbl binding to polyubiquitinated TRAF6. In vitro ubiquitination assay, co-immunoprecipitation with domain mapping, luciferase NF-κB reporter, in vivo ubiquitination assay in bone marrow macrophages/osteoclasts Cellular & molecular biology letters Medium 31123462
2002 EGF stimulation induces a direct association between c-Cbl and tyrosine-phosphorylated PLC-γ1, mediated by the SH3 domain of PLC-γ1; PDGF, which also phosphorylates PLC-γ1, fails to induce this association and also fails to phosphorylate c-Cbl, indicating c-Cbl phosphorylation is required for PLC-γ1 interaction. Co-immunoprecipitation in vivo, GST pull-down and overlay assay (direct binding), comparison of EGF vs. PDGF stimulation, SH3 domain deletion mutant Experimental cell research Medium 12061819
2018 c-Cbl regulation of nuclear β-catenin requires phosphorylation of c-Cbl Tyr371: the Y371H mutant interacts with but fails to ubiquitinate nuclear β-catenin, acts as a dominant negative, and in a Wnt-8 zebrafish model augments Wnt/β-catenin signaling and tumor growth. Co-immunoprecipitation, ubiquitination assay, Wnt reporter assay, Wnt-8 transgenic zebrafish model, colorectal cancer cell lines The American journal of pathology Medium 30029779
2004 TULA (an SH3- and UBA-containing protein) binds c-Cbl and ubiquitin; TULA inhibits c-Cbl-mediated EGFR downregulation and, in Jurkat T cells, upregulates ZAP-70 and NF-AT activity; TULA-mediated inhibition involves TULA-induced ubiquitylation and degradation of c-Cbl itself. Affinity chromatography and mass spectrometry (c-Cbl-interacting protein identification), co-immunoprecipitation, EGFR degradation assay, TULA modulation in Jurkat cells, NF-AT reporter assay Oncogene Medium 15107835
2003 Ephrin-A1 stimulation induces EphA3 receptor tyrosine phosphorylation that leads to c-Cbl phosphorylation in a Src-family kinase-dependent manner; phosphorylated c-Cbl associates with Crk-L and Crk-II (but not Grb2); overexpression of wild-type c-Cbl (but not 70Z mutant) down-regulates EphA receptor expression. Phosphotyrosine immunoblotting, co-immunoprecipitation, Src inhibitor (PP2) treatment, c-Cbl overexpression/70Z mutant, EphA surface expression assay Journal of immunology Medium 12794130
2003 c-Cbl down-regulates the Ron receptor tyrosine kinase: MSP stimulation recruits c-Cbl to Ron's multifunctional docking site and to a juxtamembrane autophosphorylation site; c-Cbl mediates Ron polyubiquitylation followed by endocytosis and degradation; both TKB domain and RING domain are required; Ron–Grb2–c-Cbl complexes alone are insufficient for productive ubiquitylation. Co-immunoprecipitation, domain mutagenesis (TKB and RING), ubiquitylation assay, receptor degradation and endocytosis assays Oncogene Medium 12802274
2003 c-Cbl negatively regulates platelet activation through GpVI: phosphorylation of c-Cbl in GpVI-signaled platelets requires upstream Src-family kinases Fyn and Lyn; in c-Cbl-null platelets, phosphorylation of FcRγ-chain, Syk, and PLCγ2 is increased and aggregation in response to GpVI agonist is potentiated. c-Cbl knockout mouse platelets, Fyn/Lyn-null platelets for epistasis, Western blotting (phosphorylation), platelet aggregation assays Journal of thrombosis and haemostasis Medium 14629478

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science (New York, N.Y.) 863 10514377
2000 Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell 722 10966114
1998 c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes & development 711 9851973
2002 Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nature cell biology 700 11836526
2001 Cbl: many adaptations to regulate protein tyrosine kinases. Nature reviews. Molecular cell biology 526 11283727
2000 Cbl-b regulates the CD28 dependence of T-cell activation. Nature 497 10646609
2008 The CBL-CIPK network in plant calcium signaling. Trends in plant science 376 19054707
2002 c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nature immunology 320 12415267
1998 Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Molecular and cellular biology 309 9671496
2006 The Cbl family proteins: ring leaders in regulation of cell signaling. Journal of cellular physiology 249 16741904
1996 c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption. Nature 247 8849724
1995 Interactions of Cbl with Grb2 and phosphatidylinositol 3'-kinase in activated Jurkat cells. Molecular and cellular biology 224 7791764
2005 c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses. The Biochemical journal 215 16212556
2001 Src-catalyzed phosphorylation of c-Cbl leads to the interdependent ubiquitination of both proteins. The Journal of biological chemistry 183 11448952
2003 Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation. Cell 167 14505571
2012 Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl. Nature structural & molecular biology 162 22266821
2007 Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia. Blood 138 17475912
2002 APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Molecular and cellular biology 138 11997497
2013 c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor. Molecular cell 137 23290524
2002 c-Cbl binding and ubiquitin-dependent lysosomal degradation of membrane-associated Notch1. The Journal of biological chemistry 117 11777909
2005 c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2. The Journal of biological chemistry 116 15708858
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
2013 The CBL-CIPK network mediates different signaling pathways in plants. Plant cell reports 99 24097244
1999 cbl-3: a new mammalian cbl family protein. Oncogene 99 10362357
2007 c-Cbl-mediated regulation of LAT-nucleated signaling complexes. Molecular and cellular biology 94 17938199
2004 Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl). Blood 91 15315962
2004 c-Cbl-deficient mice have reduced adiposity, higher energy expenditure, and improved peripheral insulin action. The Journal of clinical investigation 90 15520865
1997 The Cbl protooncogene product: from an enigmatic oncogene to center stage of signal transduction. Critical reviews in oncogenesis 83 9570294
2012 S-acylation-dependent association of the calcium sensor CBL2 with the vacuolar membrane is essential for proper abscisic acid responses. Cell research 81 22547024
2008 TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer. British journal of cancer 81 19002168
2002 Cbl and Cbl-b in T-cell regulation. Trends in immunology 79 11864842
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
2004 TULA: an SH3- and UBA-containing protein that binds to c-Cbl and ubiquitin. Oncogene 78 15107835
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
2005 Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation. Cell research 76 15686631
2010 The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells. Cancer research 75 20086179
2015 The CBL-CIPK signaling module in plants: a mechanistic perspective. Physiologia plantarum 73 25953089
2004 c-Cbl-mediated ubiquitinylation is required for epidermal growth factor receptor exit from the early endosomes. The Journal of biological chemistry 73 15210722
2003 The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport. The Journal of biological chemistry 70 12842890
2000 c-Cbl is a suppressor of the neu oncogene. The Journal of biological chemistry 67 10940298
2019 c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth. Scientific reports 65 31882749
2000 c-Cbl localizes to actin lamellae and regulates lamellipodia formation and cell morphology. Journal of cell science 65 10633073
2019 CircRNA CBL.11 suppresses cell proliferation by sponging miR-6778-5p in colorectal cancer. BMC cancer 62 31438886
2018 E3 ubiquitin ligases Cbl-b and c-Cbl downregulate PD-L1 in EGFR wild-type non-small cell lung cancer. FEBS letters 62 29364514
2009 A TNF- and c-Cbl-dependent FLIP(S)-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis. Nature immunology 62 19597496
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 60 16211006
2023 Targeting Cbl-b in cancer immunotherapy. Journal for immunotherapy of cancer 59 36750253
2002 Negative regulation of EphA2 receptor by Cbl. Biochemical and biophysical research communications 59 12147253
2005 Cbl promotes clustering of endocytic adaptor proteins. Nature structural & molecular biology 56 16228008
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2003 Aberrant expression of HOXA9, DEK, CBL and CSF1R in acute myeloid leukemia. Leukemia & lymphoma 55 14738146
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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 54 32139477
2003 Ephrin-A1 induces c-Cbl phosphorylation and EphA receptor down-regulation in T cells. Journal of immunology (Baltimore, Md. : 1950) 54 12794130
1999 Molecular cloning and characterization of a novel cbl-family gene, cbl-c. Gene 54 10571044
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 51 20195608
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2019 DNA Damage Activates TGF-β Signaling via ATM-c-Cbl-Mediated Stabilization of the Type II Receptor TβRII. Cell reports 47 31315051
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
2001 Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiologic findings in 14 cases. Neuropediatrics 47 11315197
2016 The E3 Ubiquitin Ligase c-Cbl Inhibits Microglia-Mediated CNS Inflammation by Regulating PI3K/Akt/NF-κB Pathway. CNS neuroscience & therapeutics 46 27156691
2016 c-Cbl-mediated ubiquitination of IRF3 negatively regulates IFN-β production and cellular antiviral response. Cellular signalling 46 27503123
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
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
2024 SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation. Cancer communications (London, England) 42 38407942
2014 c-Cbl regulates MICA- but not ULBP2-induced NKG2D down-modulation in human NK cells. European journal of immunology 42 24846123
2011 TET2, ASXL1, IDH1, IDH2, and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms. Annals of hematology 41 21904853
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2021 E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation. Science advances 37 33962939
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2002 Molecular complexes that contain both c-Cbl and c-Src associate with Golgi membranes. European journal of cell biology 37 11893076
2011 c-Cbl ubiquitin ligase regulates focal adhesion protein turnover and myofibril degeneration induced by neutrophil protease cathepsin G. The Journal of biological chemistry 36 22203672
2003 Expression and tyrosine phosphorylation of Cbl regulates macrophage chemokinetic and chemotactic movement. Journal of cellular physiology 36 12652654
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2019 C-Cbl negatively regulates TRAF6-mediated NF-κB activation by promoting K48-linked polyubiquitination of TRAF6. Cellular & molecular biology letters 30 31123462
2018 c-Cbl Expression Correlates with Human Colorectal Cancer Survival and Its Wnt/β-Catenin Suppressor Function Is Regulated by Tyr371 Phosphorylation. The American journal of pathology 29 30029779
2015 Cbl-b and c-Cbl negatively regulate osteoblast differentiation by enhancing ubiquitination and degradation of Osterix. Bone 28 25744063
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2006 Cbl and Akt regulate CXCL8-induced and CXCR1- and CXCR2-mediated chemotaxis. International immunology 28 16798838
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
2002 c-Cbl is a negative regulator of GH-stimulated STAT5-mediated transcription. Endocrinology 27 12193575
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2002 Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells. Oncogene 26 11857085
2005 TGF-beta, c-Cbl, and PDGFR-alpha the in mammary stroma. Developmental biology 25 15708558
2003 c-Cbl negatively regulates platelet activation by glycoprotein VI. Journal of thrombosis and haemostasis : JTH 24 14629478
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