Affinage

CBLB

E3 ubiquitin-protein ligase CBL-B · UniProt Q13191

Length
982 aa
Mass
109.5 kDa
Annotated
2026-06-09
100 papers in source corpus 51 papers cited in narrative 51 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CBLB encodes a RING-type E3 ubiquitin ligase that functions as a master negative regulator of immune cell activation, setting the threshold and duration of antigen- and cytokine-receptor signaling across T cells, B cells, NK cells, mast cells, and innate myeloid cells (PMID:10646608, PMID:21248250, PMID:24553136). Its catalytic role is direct and central: selective genetic inactivation of CBLB E3 activity phenocopies total ablation, producing T-cell hyperactivation, spontaneous autoimmunity, impaired anergy, and spontaneous tumor rejection (PMID:21248250). CBLB couples co-stimulatory signal strength to response amplitude through two layered controls. First, in resting T cells it restrains TCR signaling by ubiquitinating and limiting the PI3K p85 subunit—an action that is proteolysis-independent and controls p85 recruitment to CD28/TCR-zeta—and by suppressing Vav1 activation, such that its loss uncouples proliferation and IL-2 production from CD28 co-stimulation (PMID:10646609, PMID:11087752, PMID:11526404). Second, CBLB itself is regulated by phosphorylation: autoinhibition by an intramolecular interaction masks the RING/E2 surface, and phosphorylation of Tyr363 disrupts this interaction to license E2 (UbcH5B) engagement (PMID:22158902), while SHP-1 dephosphorylates CBLB to protect it from degradation and CD28/PKC-theta co-stimulation drives its ubiquitination and proteasomal destruction (PMID:19549985, PMID:26416283). Through its ligase activity CBLB targets a broad substrate repertoire to terminate or tune signaling: Syk and CARMA1 in lymphocyte antigen receptor pathways (PMID:12771181, PMID:19815501), Stat6 to restrain Th2/Th9 differentiation (PMID:24508458), SMAD7 to set TGF-beta sensitivity and tumor immunity (PMID:23709694), ICOS to restrain Tfh responses and prevent lupus-like autoimmunity (PMID:38761804), TAM receptors (Tyro3/Axl/Mer) and their adaptor LAT1 in NK cells (PMID:24553136, PMID:31531847), the TLR4–MyD88 complex in monocytes (PMID:17618294), and Syk/dectin-1/dectin-2 in antifungal C-type lectin receptor signaling, routing activated receptors to lysosomal degradation via the ESCRT machinery (PMID:27428901, PMID:27428899, PMID:27432944). Beyond immunity, CBLB ubiquitinates and degrades receptor tyrosine kinases including EGFR, KIT, and IGF-IR to limit their signaling and trafficking (PMID:11375397, PMID:15315962, PMID:24885194), and a nonsense mutation in Cblb is the causative susceptibility allele for type 1 diabetes in the KDP rat, with wild-type transgene rescuing the phenotype (PMID:12118252).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1995 Medium

    Establishing CBLB as an adaptor-type signaling regulator answered whether it physically couples to the cytoplasmic signaling apparatus, revealing a RING-finger protein with a proline-rich domain that engages SH3-containing partners.

    Evidence Molecular cloning and SH3-domain binding assays defining the proline-rich/RING-finger architecture

    PMID:7784085

    Open questions at the time
    • No catalytic activity demonstrated
    • No physiological substrate identified
    • Functional consequence of binding unknown
  2. 1997 Medium

    Linking CBLB to Vav and growth-factor receptors addressed how it intersects RTK signaling, showing it forms trimeric complexes with activated receptors and dampens Vav-driven JNK activation.

    Evidence Yeast two-hybrid, Co-IP, and JNK activation assays in fibroblasts

    PMID:9399639

    Open questions at the time
    • Mechanism of JNK inhibition unresolved
    • Overexpression-based, not endogenous
    • No ubiquitination tested
  3. 1999 High

    Identifying the TCR-proximal kinases that phosphorylate CBLB answered how antigen-receptor engagement activates it, mapping Syk/ZAP-70 and Src-family kinase inputs and Crk-L docking sites.

    Evidence Co-IP, in vitro kinase assays, and mutagenesis in Jurkat T cells

    PMID:10022120

    Open questions at the time
    • Functional outcome of each phosphosite not resolved
    • Catalytic activity not yet demonstrated
    • Endogenous substrate unknown
  4. 2000 High

    Knockout mice answered the central physiological question of CBLB function, establishing it as a negative regulator that sets the CD28 co-stimulation threshold by selectively suppressing TCR-driven Vav1 activation.

    Evidence Gene-targeted Cbl-b knockout mice with proliferation, IL-2, signaling readouts, and CD28-/- genetic complementation

    PMID:10646608 PMID:10646609 PMID:11070165

    Open questions at the time
    • Molecular mechanism of Vav suppression not yet defined
    • Whether ubiquitination is required not yet tested
    • Substrate at the receptor unidentified at this stage
  5. 2000 High

    Demonstrating that CBLB is a RING-type E3 ligase targeting PI3K p85 answered how it executes negative regulation biochemically, and a later study showed this control is proteolysis-independent and governs p85 recruitment to CD28/TCR.

    Evidence In vitro ubiquitination assays, domain-deletion mutagenesis, Co-IP, and PI3K-inhibitor rescue in Cbl-b-/- T cells

    PMID:11087752 PMID:11526404

    Open questions at the time
    • Non-degradative mechanism of p85 regulation incompletely defined
    • Ubiquitin chain linkage on p85 not characterized
    • Relationship to Vav suppression unresolved
  6. 2001 High

    Defining CBLB-mediated EGFR ubiquitination and reciprocal self-degradation answered how it terminates RTK signaling, showing it shortens receptor activation and is itself degraded as part of a feedback loop.

    Evidence Ubiquitination assays, domain mutagenesis, and proteasomal/lysosomal inhibitor experiments in EGFR-expressing cells

    PMID:10086340 PMID:10542134 PMID:11375397

    Open questions at the time
    • In-cell ubiquitin linkage types not defined
    • Quantitative contribution of degradative vs non-degradative routes unclear
  7. 2002 High

    Identifying a causative Cblb nonsense mutation in the KDP rat answered whether CBLB controls autoimmunity in vivo, establishing it as a genetically validated type 1 diabetes susceptibility gene through transgenic rescue.

    Evidence Positional cloning and transgenic complementation in a spontaneous diabetes rat model

    PMID:12118252

    Open questions at the time
    • Cellular target population of the diabetes phenotype not pinpointed
    • Substrate relevant to autoimmunity not identified here
  8. 2002 High

    Extending CBLB function to B cells and TCR trafficking answered how broadly its negative regulation operates, showing roles in PLC-gamma2 signaling and Cbl-family-dependent clearance of engaged TCR from the cell surface.

    Evidence DT40 and c-Cbl/Cbl-b double-knockout systems, Co-IP, Ca2+ mobilization, and TCR internalization/lysosome trafficking assays

    PMID:12093870 PMID:12177062 PMID:12415267

    Open questions at the time
    • Distinct positive vs negative roles in B cells mechanistically separate
    • CIN85-dependent internalization vs ubiquitination contributions context-dependent
  9. 2003 High

    Identifying Syk as a BCR-proximal ubiquitination substrate answered how CBLB terminates antigen-receptor signaling in B cells, linking sustained Syk phosphorylation to loss of Syk ubiquitination.

    Evidence Cbl-b knockout B cells, BCR stimulation, ubiquitination assays, and imaging

    PMID:12771181

    Open questions at the time
    • Syk ubiquitin chain linkage and fate not fully defined
    • Stoichiometry of Syk regulation unclear
  10. 2004 High

    Extending CBLB to mast cell FceRI signaling, KIT degradation, and defining its polyubiquitin-binding UBA domain answered how it operates across innate effector cells and distinguished it functionally from c-Cbl.

    Evidence Lipid-raft fractionation, RING-finger mutagenesis, ubiquitination/degradation assays, and GST pull-downs comparing UBAb vs UBAc

    PMID:14604964 PMID:15273720 PMID:15315962

    Open questions at the time
    • Role of UBA polyubiquitin binding in substrate selection not fully resolved
    • In vivo relevance of Gab2/KIT targeting incompletely defined
  11. 2007 High

    An E3-ligase-dead knock-in answered the decisive question of whether catalytic activity underlies CBLB function in vivo, showing the catalytic mutation phenocopies full ablation in autoimmunity, anergy, and tumor rejection.

    Evidence Knock-in mice carrying an E3 ligase-dead mutation with in vivo T-cell, anergy, and tumor-rejection assays

    PMID:21248250

    Open questions at the time
    • Catalytically relevant in vivo substrates not enumerated here
    • Cell-type-specific contributions not dissected
  12. 2007 High

    Defining CBLB control of the TLR4–MyD88 complex and ExoT degradation answered how it regulates innate antibacterial responses, requiring E3 activity for NF-kB suppression and host defense in vivo.

    Evidence Co-IP, E3-mutant reporter assays, and Cbl-b-/- mouse infection models

    PMID:17235393 PMID:17618294

    Open questions at the time
    • Direct ubiquitination of TLR4/MyD88 components vs complex disruption not fully separated
    • Tissue-specific innate contributions incompletely mapped
  13. 2008 Medium

    Connecting CBLB to NF-kB regulation, PKC-theta/CARMA1 signaling, and integrin (LFA-1) activation broadened the picture of how it tunes downstream activation modules in lymphocytes and myeloid cells.

    Evidence Co-IP, Cbl-b-/- T cells, NF-kB reporters, and LFA-1/14-3-3 biochemistry with double-knockout epistasis

    PMID:18227156 PMID:18239087

    Open questions at the time
    • Whether PKC-theta/NF-kB regulation is ubiquitination-dependent not resolved here
    • Direct substrate in the integrin pathway not defined
  14. 2009 High

    Identifying CARMA1 as a non-degradative monoubiquitination substrate and mapping PKC-theta-driven CBLB degradation answered how co-stimulation reciprocally controls CBLB and how it disrupts signaling complexes without proteolysis.

    Evidence Ubiquitination assays with RING mutants, Co-IP, kinase-dead mutants, and PKC-theta/Cbl-b double-knockout epistasis

    PMID:19257814 PMID:19549985 PMID:19815501

    Open questions at the time
    • Generality of non-degradative monoubiquitination across substrates unclear
    • Determinants of degradative vs non-degradative outcomes not defined
  15. 2010 High

    Demonstrating a positive role in platelet GPVI signaling answered whether CBLB is uniformly inhibitory, showing it acts as a positive modulator downstream of Syk but upstream of BTK/PLC-gamma2 in some contexts.

    Evidence Cbl-b-/- platelets, aggregation/Ca2+ assays, Co-IP, and an in vivo thrombosis model

    PMID:20400514

    Open questions at the time
    • Molecular basis of the positive (vs negative) role unresolved
    • Whether ligase activity is required not defined
  16. 2012 High

    The structural basis of autoinhibition answered how CBLB activity is gated, showing the unphosphorylated N-terminus masks the RING–E2 surface and Tyr363 phosphorylation relieves this and enhances E2 (UbcH5B) binding.

    Evidence NMR, SAXS, phosphomimetic mutants, and E2-binding assays

    PMID:22158902

    Open questions at the time
    • Dynamics of activation in the full-length receptor-bound state not resolved
    • Quantitative kinetics of de-autoinhibition not defined
  17. 2014 High

    Identifying SMAD7, Stat6, IGF-IR, and the TAM receptors as substrates answered how CBLB controls TGF-beta sensitivity, Th2/Th9 differentiation, RTK-driven EMT, and NK-cell anti-metastatic activity, including therapeutic targeting of the CBLB/TAM axis.

    Evidence Ubiquitination assays with site mutagenesis, Co-IP, genetic epistasis (Cblb x Smad7, Cblb x Stat6), shRNA, E3-dead knock-in NK cells, and tumor-metastasis models

    PMID:23709694 PMID:24508458 PMID:24553136 PMID:24885194

    Open questions at the time
    • Hierarchy among substrates in a given cell context not defined
    • In vivo contribution of IGF-IR targeting limited to cancer models
  18. 2015 High

    Defining SHP-1-mediated dephosphorylation of CBLB answered how its phosphorylation-dependent activity and stability are reversed, with CD28 co-stimulation abrogating the SHP-1 interaction.

    Evidence Co-IP, phosphorylation assays, SHP-1 conditional knockout T cells, and in vitro/in vivo allergy models

    PMID:26416283

    Open questions at the time
    • Direct vs indirect SHP-1 action on specific phosphosites not fully mapped
    • Other phosphatases not excluded
  19. 2016 High

    Establishing CBLB control of C-type lectin receptor antifungal signaling answered how it tunes innate fungal recognition, showing ubiquitination of Syk/dectin-1/dectin-2 via FcR-gamma and ESCRT-dependent lysosomal sorting, with a CBLB inhibitory peptide protecting against Candida.

    Evidence Ubiquitination assays, Co-IP, Cblb-/- mice, dectin double-knockout epistasis, ESCRT knockdown, and in vivo infection models

    PMID:27428899 PMID:27428901 PMID:27432944

    Open questions at the time
    • Substrate prioritization (receptor vs Syk) not resolved
    • Linkage specificity of CLR ubiquitination not defined
  20. 2016 Medium

    Systems-level mapping of the CBLB TCR-signaling interactome answered which scaffolds assemble CBLB complexes over time, identifying CD5 as a key scaffold for Cbl/CBLB-mediated ubiquitylation.

    Evidence Affinity-purification quantitative mass spectrometry with mouse genetics over a TCR-stimulation time course

    PMID:27474268

    Open questions at the time
    • Functional consequence of CD5 scaffolding on specific substrates not defined
    • Novel partners not individually validated
  21. 2018 Medium

    A non-ubiquitin role in viral entry answered whether CBLB has functions beyond signaling termination, showing it acts with CD81/CAPN5 to support HCV entry at a post-binding step.

    Evidence CD81 interactome proteomics, CBLB/CAPN5 knockout, and HCV infection assays across genotypes

    PMID:30024968

    Open questions at the time
    • Whether E3 activity is required not tested
    • Mechanism of entry support undefined
    • Direct vs indirect role unresolved
  22. 2020 High

    Extending CBLB to neurons answered whether its ubiquitin activity operates outside the immune system, showing it ubiquitinates NMDAR GluN2B in spinal cord and that inflammation-driven Tyr363 dephosphorylation drives inflammatory pain.

    Evidence Ubiquitination assays, synaptic fractionation, electrophysiology, phosphomimetic mutants, and an inflammatory pain model

    PMID:32606037

    Open questions at the time
    • TKB-domain-based substrate recognition mechanism for GluN2B not fully defined
    • Generality to other CNS receptors unknown
  23. 2022 Medium

    Defining linkage- and site-specific STAT5 ubiquitination answered how CBLB and c-Cbl distinctly control dendritic cell survival, with CBLB mediating K27-linked ubiquitination of STAT5a K164 to promote apoptosis.

    Evidence DC-specific conditional double-knockout mice, Co-IP, and linkage/site-specific ubiquitination and apoptosis assays

    PMID:35354799

    Open questions at the time
    • Functional separation of CBLB vs c-Cbl STAT5 targeting in vivo not fully resolved
    • Linkage determinants not mechanistically explained
  24. 2023 High

    Identifying the STS1 phosphatase complex, the EGFR-Y1045 direct binding mode, and the structural basis of small-molecule inhibition answered how CBLB activity is fine-tuned, paralog-distinguished, and therapeutically lockable in an autoinhibited state.

    Evidence Co-IP with domain mutagenesis, phosphatase assays, E3-dead EGFR trafficking assays, and a co-crystal structure with an Nx-1607 analogue

    PMID:37903221 PMID:38091950 PMID:38104184

    Open questions at the time
    • In vivo significance of STS1-mediated pH sensing across tissues not defined
    • Generality of the Y1045 binding mode to other substrates unknown
  25. 2024 High

    Identifying ICOS as a CBL/CBLB substrate answered how it restrains follicular helper T cell programs, showing ICOS ubiquitination limits BCL6 stability and prevents lupus-like autoimmunity.

    Evidence T-cell-specific conditional double-knockout mice, ICOS ubiquitination assays, BCL6 stability analysis, and an in vivo SLE model with Tfh blockade

    PMID:38761804

    Open questions at the time
    • Relative CBLB vs c-Cbl contribution to ICOS targeting not separated
    • Connection to chaperone-mediated autophagy of BCL6 mechanistically incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CBLB selects among its diverse substrates, chooses ubiquitin chain linkages, and switches between degradative, trafficking-directed, and complex-disrupting (non-degradative) outcomes in a cell-type- and context-specific manner remains unresolved.
  • No unified model of substrate prioritization across immune and non-immune cells
  • Determinants of degradative vs non-degradative ubiquitination undefined
  • Quantitative rules linking co-stimulation strength to substrate fate unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 5 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0031386 protein tag activity 1
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 1
Partners
CIN85EGFRGRB2PI3K P85PKC-THETASTS1SYKVAV1

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Cbl-b protein was cloned and found to directly associate with SH3 domains of multiple signaling, cytoskeletal, and adaptor proteins through its proline-rich domain. It contains a C3HC4 zinc finger (RING finger) and a nuclear localization signal, indicating a role in signal transduction regulation. Molecular cloning, SH3 domain binding assays Oncogene Medium 7784085
1997 Cbl-b interacts with Vav (a GDP/GTP exchange factor for Rac-1) through the SH3-SH2-SH3 carboxy-terminal domain of Vav and proline-rich sequences in Cbl-b. Growth factor stimulation increases Vav-Cbl-b affinity and promotes trimeric complex formation with ligand-activated receptor tyrosine kinases. Overexpression of Cbl-b inhibits Vav-mediated c-Jun N-terminal kinase activation. Yeast two-hybrid, co-immunoprecipitation, overexpression in fibroblasts, JNK activation assay Oncogene Medium 9399639
1998 CBLB is tyrosine-phosphorylated following FLT3 ligand (FL) or IL-7 stimulation in pro-B cells. Phosphorylated SHC and PI3K p85 subunit associate with CBLB upon FL stimulation. CBLB constitutively binds GRB2 predominantly through its N-terminal SH3 domain, forming a complex distinct from GRB2-CBL and GRB2-SOS1 complexes. Co-immunoprecipitation, tyrosine phosphorylation assay The Journal of biological chemistry Medium 9614102
1999 Cbl-b is phosphorylated and recruited to the EGFR upon EGF stimulation, and both Cbl-b and c-Cbl bind GRB2. Overexpression of Cbl-b in 32D/EGFR cells markedly inhibits EGF-induced growth by promoting apoptosis, decreases amplitude and duration of AKT activation, and shortens duration of MAP kinase and JNK activation upon EGF stimulation. In vivo phosphorylation, co-immunoprecipitation, cell growth assay, signaling pathway analysis Oncogene Medium 10086340
1999 Cbl-b overexpression inhibits EGFR-induced apoptosis in MDA-MB-468 cells by increasing ubiquitination and degradation of the activated EGFR, shortening the duration of EGFR activation. The inhibitory effect is reversed by blocking proteasomal degradation. Overexpression, ubiquitination assay, proteasome inhibition, EGFR phosphorylation assay Molecular cell biology research communications Medium 10542134
1999 Upon TCR engagement, Cbl-b is rapidly tyrosine-phosphorylated by Syk/Zap-70 and Src (Fyn/Lck) family kinases, with Syk inducing the most prominent effect. A Tyr-316 Cbl-binding site in Syk was required for association with and maximal phosphorylation of Cbl-b. Cbl-b constitutively binds GRB2 and associates with Crk-L upon TCR stimulation, with Crk-L binding mapped to Y655DVP and Y709KIP of Cbl-b. Co-immunoprecipitation, kinase assays, mutagenesis, Jurkat T cell stimulation Oncogene High 10022120
2000 Loss of Cbl-b in T cells uncouples T-cell proliferation, IL-2 production, and Vav1 phosphorylation from the requirement for CD28 co-stimulation, establishing Cbl-b as a negative regulator of activation thresholds in T lymphocytes. Gene-targeted knockout mice, T cell proliferation assay, IL-2 production, phosphorylation analysis Nature High 10646608
2000 Cbl-b-null T cells do not require CD28 engagement for IL-2 production. The Cbl-b-null mutation fully restores T-cell-dependent antibody responses in CD28-/- mice. TCR-mediated Vav activation is significantly enhanced in Cbl-b-/- T cells, while Zap-70, Lck, Ras/MAPK, PLCγ1, and Ca2+ mobilization are not affected, indicating Cbl-b selectively suppresses TCR-mediated Vav activation to control CD28 dependence. Genetic knockout, T cell stimulation, signaling pathway analysis, genetic complementation with CD28-/- mice Nature High 10646609
2000 Cbl-b is a RING-type E3 ubiquitin ligase that targets the p85 regulatory subunit of PI3K for ubiquitin conjugation. The RING finger of Cbl-b is essential for p85 ubiquitination. A distal C-terminal proline-rich region in Cbl-b contains the primary binding sequences for the SH3 domain of p85. Deletion of either the proline-rich region of Cbl-b or the SH3 domain of p85 severely reduces ubiquitination. In vitro ubiquitination assay, co-immunoprecipitation, domain deletion mutagenesis The Journal of biological chemistry High 11087752
2000 Loss of Cbl-b in T cells relieves antigen receptor-triggered receptor clustering, lipid raft aggregation, and sustained tyrosine phosphorylation from the requirement for CD28 co-stimulation. Wiscott-Aldrich Syndrome protein (WASP) was essential for deregulated proliferation and membrane receptor reorganization of cbl-b mutant T cells. Introducing cbl-b mutation into vav1-/- background relieved functional defects of vav1-/- T cells. Genetic knockout, epistasis analysis (cbl-b x vav1 double knockout, WASP-deficient crosses), imaging, T cell functional assays Immunity High 11070165
2001 Cbl-b negatively regulates PI3K p85 in a proteolysis-independent manner through its E3 ubiquitin ligase activity. Cbl-b is involved in the recruitment of p85 to CD28 and TCR zeta. The enhanced activation of Cbl-b-/- T cells was suppressed by PI3K inhibition. Ubiquitination assay, co-immunoprecipitation, PI3K inhibitor rescue, Cbl-b-/- T cells Nature immunology High 11526404
2001 Cbl-b is ubiquitinated and degraded upon EGFR activation. EGF-induced Cbl-b degradation requires intact RING finger and tyrosine kinase binding domains, and requires Cbl-b binding to the activated EGFR. Degradation of both EGFR and Cbl-b is blocked by lysosomal and proteasomal inhibitors. Grb2 and Shc are also degraded in an EGF-induced Cbl-b-dependent fashion. Ubiquitination assay, domain mutagenesis, proteasomal/lysosomal inhibitors, co-immunoprecipitation The Journal of biological chemistry High 11375397
2002 A nonsense mutation in Cblb was identified by positional cloning as responsible for the Iddm/kdp1 major susceptibility locus for type 1 diabetes in the KDP rat. Transgenic complementation with wildtype Cblb significantly suppressed development of the KDP phenotype, demonstrating Cblb functions as a negative regulator of autoimmunity. Positional cloning, transgenic complementation, genetic analysis Nature genetics High 12118252
2002 c-Cbl and Cbl-b double knockout (dKO) T cells became hyperresponsive but did not show enhanced major TCR signaling pathways. DKO T cells failed to down-modulate surface TCR after ligand engagement, resulting in sustained TCR signaling; however, ligand-independent TCR internalization was normal. Trafficking of internalized TCR to the lysosome compartment was reduced. Cbl family proteins negatively regulate T cell activation by promoting clearance of engaged TCR from the cell surface. Genetic double knockout, flow cytometry, surface TCR internalization assay, lysosome trafficking assay Nature immunology High 12415267
2002 CIN85 binds to the carboxyl terminus of Cbl-b, and ligand-induced phosphorylation of Cbl-b further increases this interaction and leads to rapid, sustained recruitment of CIN85 into EGF or PDGF receptor complexes. Inhibition of CIN85-Cbl-b binding impairs Cbl-b-mediated EGFR internalization while being dispensable for Cbl-b-directed polyubiquitination of EGFR, revealing a ubiquitin ligase-independent pathway for receptor internalization. Co-immunoprecipitation, domain mapping, dominant-negative mutant, internalization assay, ubiquitination assay The Journal of biological chemistry High 12177062
2002 Cbl-b positively regulates Btk-mediated PLC-γ2 activation in B cells. Cbl-b-deficient DT40 B cells display reduced PLC-γ2 activation and Ca2+ mobilization upon BCR stimulation. Cbl-b interacts with PLC-γ2 and facilitates its association with Btk and BLNK. Both the N-terminal TKB domain and C-terminal half of Cbl-b are required for PLC-γ2 association and Ca2+ mobilization regulation. Genetic knockout (DT40), overexpression, co-immunoprecipitation, Ca2+ mobilization assay, domain mutagenesis The Journal of experimental medicine High 12093870
2002 CBL-B is found in a complex with mono-ubiquitinated Vav in BCR/ABL-transformed cells. CBL-B is not associated with significant PI3K activity (unlike CBL), revealing distinct signaling complex compositions for the two paralogs. BCR/ABL downregulates CBL-B protein expression and mRNA through its kinase activity. Co-immunoprecipitation, Western blot, kinase inhibitor experiments Oncogene Medium 11857085
2003 Cbl-b negatively regulates BCR signaling in B cells by targeting Syk for ubiquitination. In Cbl-b-deficient B cells, BCR cross-linking causes sustained phosphorylation of Igα, Syk, and PLC-γ2, prolonged Ca2+ mobilization, and increased ERK/JNK activation. Sustained Syk phosphorylation correlated with reduced Syk ubiquitination, establishing Cbl-b's negative regulatory role through Syk ubiquitination. Cbl-b knockout mice, BCR stimulation, co-immunoprecipitation, ubiquitination assay, imaging (BCR capping), Ca2+ mobilization The Journal of experimental medicine High 12771181
2003 Cbl-b translocates into lipid rafts after FcεRI engagement in mast cells. Overexpression of Cbl-b in lipid rafts inhibits FcεRI-mediated degranulation and cytokine gene transcription. A RING finger point mutation (Cys373) abrogates the suppression of degranulation but not cytokine gene transcription. Cbl-b ubiquitin ligase activity specifically downregulates Gab2 protein expression and its FcεRI-mediated phosphorylation. Lipid raft fractionation, overexpression, RING finger mutagenesis, ubiquitination assay, degranulation assay Blood High 14604964
2004 SCF stimulation induces KIT receptor binding to Cbl proteins, which act as E3 ligases to mediate ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl-b are essential for Cbl-mediated KIT ubiquitination and degradation, establishing a negative feedback loop. Co-immunoprecipitation, ubiquitination assay, domain mutagenesis, degradation assay Blood High 15315962
2004 The UBA domain of Cbl-b (UBAb) interacts with ubiquitinated proteins and polyubiquitin chains in vitro, with much greater affinity for polyubiquitin chains than monoubiquitin. In contrast, the UBA domain of c-Cbl does not interact with ubiquitinated proteins. Overexpression of UBAb, but not UBAc, inhibits ubiquitin-mediated processes including degradation of EGFR, Mdm-2, and Siah-1. GST pull-down, Co-IP, in vitro ubiquitin binding, functional degradation assay Oncogene High 15273720
2004 Cbl-b-/- CD4+CD25- effector T cells are resistant to suppression by regulatory T cells (both Cbl-b-/- and wild-type Tregs) in vitro. Cbl-b-/- T effector cells also demonstrate resistance to TGF-β-mediated inhibition, despite normal TGF-β receptor levels and normal Smad3 phosphorylation. In vitro Treg suppression assay, TGF-β inhibition assay, flow cytometry, Cbl-b-/- mice Journal of immunology Medium 15240694
2007 Cbl-b ubiquitin ligase activity is required for E3 ligase-dependent negative regulation of T cells in vivo. Selective genetic inactivation of Cbl-b E3 ligase activity phenocopies total Cbl-b ablation, causing T cell hyperactivation, spontaneous autoimmunity, and impaired T cell anergy induction in vivo, and promotes spontaneous tumor rejection. Knock-in mice with E3 ligase-dead mutation, T cell activation assays, tumor rejection model, in vivo anergy induction Journal of immunology High 21248250
2007 Cbl-b controls the association between TLR4 and the intracellular adaptor MyD88 in monocytes after LPS stimulation. Expression of wild-type Cbl-b, but not E3 ligase-inactive Cbl-b, prevents NF-κB reporter activation in LPS-challenged monocytes. Cbl-b deficiency impairs TLR4 downregulation on neutrophil surfaces. Co-immunoprecipitation, reporter gene assay with E3 mutant, flow cytometry for surface TLR4, Cbl-b-/- mice, bone marrow chimeras Nature medicine High 17618294
2007 Cbl-b interacts with P. aeruginosa ExoT and the ExoT substrate Crk in host cells. Following injection of ExoT into host cytosol, Cbl-b mediates ExoT polyubiquitination and proteasomal degradation. Cbl-b-/- mice (but not c-Cbl-/- mice) show increased bacterial dissemination specifically mediated by ExoT, establishing Cbl-b as essential for limiting ExoT-producing P. aeruginosa in vivo. Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, mouse infection model, genetic KO comparison The Journal of clinical investigation High 17235393
2008 Cbl-b negatively regulates TCR-induced NF-κB activation via both PI3K/Akt-dependent and PKC-θ-dependent pathways. Cbl-b associates with PKC-θ upon TCR stimulation and regulates PKC-θ activation via Vav-1. PKC-θ then couples IKKs to the CARMA1-Bcl10-MALT1 complex. Hyperactivation of Akt in Cbl-b-/- cells may potentiate CARMA1-Bcl10-MALT1 complex formation. Co-immunoprecipitation, Cbl-b-/- T cells, NF-κB reporter assay, signaling pathway analysis, PKC-θ-/- crosses Molecular and cellular biology Medium 18227156
2008 Cbl-b deficiency increases macrophage recruitment in peritonitis via LFA-1 activation. Cbl-b deficiency increases phosphorylation of T758 in the LFA-1 β2-chain, enhancing association of 14-3-3β protein with the β2-chain and activating LFA-1. Disruption of the 14-3-3/β2-integrin interaction abrogated the enhanced ICAM-1 adhesion of Cbl-b-/- macrophages. Bone marrow chimera, LFA-1/β2-integrin phosphorylation analysis, co-immunoprecipitation (14-3-3/β2 interaction), LFA-1-/- and Cbl-b-/-LFA-1-/- double-KO epistasis Blood High 18239087
2009 PKC-θ associates with Cbl-b upon TCR stimulation and, after CD28 co-stimulation, mediates Cbl-b ubiquitination and proteasomal degradation in a PKC-θ kinase activity-dependent manner. PKC-θ-deficient T cell impaired responses are partially restored by concomitant loss of cblb, establishing a nonredundant antagonism between PKC-θ and Cbl-b. Co-immunoprecipitation, ubiquitination assay, kinase-dead mutant, PKCθ-/- x cblb-/- double-KO genetic epistasis, T cell activation assays Science signaling High 19549985
2009 Cbl-b binds to and promotes monoubiquitination of CARMA1. Ubiquitin conjugation to CARMA1 by Cbl-b disrupts CARMA1 complex formation with Bcl10 without affecting CARMA1 protein stability. CARMA1-/- NKT cells are defective in IFN-γ production. Cbl-b E3 ligase activity (RING finger) is critical for NKT anergy induction. Co-immunoprecipitation, ubiquitination assay, RING finger mutant analysis, CARMA1-/- NKT cells, IFN-γ assay Proceedings of the National Academy of Sciences High 19815501
2009 Loss of Cbl-b in osteoclasts increases bone-resorbing activity, with increased RANKL-induced NF-κB, ERK, and p38 activation. Re-expression of Cbl-b in Cbl-b-/- osteoclast-like cells normalizes bone-resorbing activity; overexpression in WT cells inhibits bone resorption. Both functional TKB and RING finger domains are required for rescue. Genetic KO, osteoclast re-expression rescue, RING finger and TKB domain mutagenesis, bone resorption assay, RANKL signaling analysis Journal of bone and mineral research High 19257814
2010 Cbl-b is a positive modulator of GPVI-dependent platelet signaling. Cbl-b constitutively associates with PLC-γ2 and BTK in platelets. Cbl-b-/- platelets display inhibited GPVI agonist-induced aggregation, secretion, Ca2+ mobilization, and reduced PLC-γ2 and BTK activation, while Syk activation is unaffected. Cbl-b thus acts downstream of Syk but upstream of BTK and PLC-γ2. Co-immunoprecipitation, Cbl-b-/- platelets, platelet aggregation assay, Ca2+ mobilization, in vivo thrombosis model The Journal of biological chemistry High 20400514
2011 Autoinhibition of Cbl-b E3 activity is achieved through intramolecular interaction whereby the unphosphorylated N-terminal region masks the RING domain interaction surface with E2 ubiquitin-conjugating enzyme. Phosphorylation of Y363 (in the helix-linker region between TKB and RING domains) disrupts this interdomain interaction to expose the E2 binding surface and also enhances binding to E2 (UbcH5B) by reducing electrostatic repulsion through proximity of the phosphate group to the interaction surface. NMR, small-angle X-ray scattering (SAXS), phosphorylation-mimicking mutants, E2 binding assay Proceedings of the National Academy of Sciences High 22158902
2013 Cbl-b directly interacts with and ubiquitinates SMAD7, a negative regulator of TGFβ receptor signaling, targeting it for degradation. SMAD7 protein levels (but not mRNA) are elevated in cblb-/- T cells. Genetic loss of SMAD7 in cblb-/- mice restores TGFβ sensitivity in T cell cytokine responses and abrogates the tumor rejection phenotype. Co-immunoprecipitation, ubiquitination assay, SMAD7 protein/mRNA analysis, double-KO genetic epistasis (cblb-/- x SMAD7-/-), tumor rejection model Journal of molecular cell biology High 23709694
2014 Cbl-b ubiquitinates and degrades IGF-IR in gastric cancer cells, thereby inhibiting the Akt/ERK-miR-200c-ZEB2 axis and suppressing IGF-I-induced epithelial-mesenchymal transition. shRNA knockdown, ubiquitination assay, co-immunoprecipitation, signaling pathway analysis, patient tissue correlation Molecular cancer Medium 24885194
2014 The TAM receptor tyrosine kinases Tyro3, Axl, and Mer (Mertk) are direct ubiquitylation substrates for Cbl-b in NK cells. Cbl-b mediates NK cell inhibition downstream of TAM receptors. Genetic deletion or targeted inactivation of Cbl-b E3 ligase activity licenses NK cells to reject metastatic tumors. A TAM kinase inhibitor and warfarin exert anti-metastatic activity through the Cbl-b/TAM pathway. Ubiquitination assay, knockout mice (E3 ligase-dead knock-in), NK cell functional assays, tumor metastasis models, TAM kinase inhibitor Nature High 24553136
2014 Cbl-b associates with Stat6 upon IL-4 ligation and targets Stat6 for ubiquitination and degradation. This process is heightened in the presence of TCR/CD28 co-stimulation. K108 and K398 of Stat6 were identified as ubiquitination sites. Loss of Cbl-b facilitates Th2 and Th9 cell differentiation; Stat6 deficiency in Cblb-/- mice abrogates hyper-Th2 responses. Co-immunoprecipitation, ubiquitination assay, site mutagenesis (K108, K398), double-KO genetic epistasis (Cblb-/- x Stat6-/-), T cell differentiation assay Cell reports High 24508458
2014 Myostatin induces Cblb expression in a Smad3-dependent manner. Elevated Cblb results in ubiquitin-proteasome-mediated degradation of IRS1, contributing to insulin resistance. Overexpression or knockdown of Cblb has major impact on IRS1 and pAkt levels in the presence or absence of insulin. Overexpression/knockdown of Cblb, IRS1 ubiquitination assay, Western blot, Smad3-dependent reporter The Journal of biological chemistry Medium 24451368
2015 SHP-1 is recruited to Cbl-b and dephosphorylates it upon CD3 stimulation, preventing Cbl-b tyrosine phosphorylation and subsequent ubiquitination/degradation. CD28 co-stimulation abrogates SHP-1-Cbl-b interaction. T cells lacking SHP-1 display heightened tyrosine phosphorylation and ubiquitination of Cbl-b, with decreased Cbl-b protein levels. Co-immunoprecipitation, phosphorylation assay, SHP-1-/- conditional knockout T cells, overexpression rescue, in vitro Th2 differentiation, in vivo allergy model Journal of immunology High 26416283
2015 Cbl-b and c-Cbl target the osteogenic transcription factor Osterix for ubiquitin-proteasome-mediated degradation, inhibiting BMP2-induced osteoblast differentiation in mesenchymal cells. Overexpression, co-immunoprecipitation, ubiquitination assay, osteoblast differentiation assay Bone Medium 25744063
2016 CBLB associates with SYK and ubiquitinates SYK, dectin-1, and dectin-2 after fungal recognition in macrophages and dendritic cells, controlling proximal CLR signaling. CBLB deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. A cell-permeable CBLB inhibitory peptide protects mice from lethal C. albicans infections. Co-immunoprecipitation, ubiquitination assay, Cblb-/- mice, inflammasome/ROS assays, in vivo infection model Nature medicine High 27428901
2016 CBLB directs polyubiquitination of dectin-1 and dectin-2 and their downstream kinase SYK, inhibiting dectin-1- and dectin-2-mediated innate immune responses against Candida albicans. CBLB mediates ubiquitination of activated CLRs through association via adapter protein FcR-γ and tyrosine kinase SYK. Ubiquitinated CLRs are sorted to lysosomes for degradation by the ESCRT system. Ubiquitination assay, co-immunoprecipitation, Cblb-/- mice, dectin-1/2-/- double-KO epistasis, ESCRT subunit knockdown, in vivo infection model Nature medicine High 27428899
2016 Cbl-b negatively regulates CLR (Dectin-2 and Dectin-3)-mediated antifungal signaling by mediating ubiquitination of these activated CLRs through association via FcR-γ and Syk. Ubiquitinated CLRs are sorted to lysosomes via the ESCRT system. Deficiency of Cbl-b or ESCRT subunits significantly decreases CLR degradation and increases proinflammatory cytokine production. Co-immunoprecipitation, ubiquitination assay, Cblb-/- mice, ESCRT knockdown, cytokine measurement, in vivo infection The Journal of experimental medicine High 27432944
2016 CD5 transmembrane receptor constitutes a key scaffold for CBL- and CBLB-mediated ubiquitylation following TCR engagement. CBLB signaling complexes were characterized over 600 seconds of TCR stimulation, identifying both known and novel CBLB-interacting partners. Affinity purification coupled to quantitative mass spectrometry, mouse genetics, biochemical analysis Molecular systems biology Medium 27474268
2018 CBLB forms a complex with CD81, CAPN5, and other proteins in human liver cells. CBLB and CAPN5 support HCV entry at a post-binding, pre-replication step. Knockout of CBLB reduced susceptibility to all tested HCV genotypes but not to vesicular stomatitis virus or human coronavirus. Quantitative proteomics (CD81 interactome), CBLB/CAPN5 knockout, HCV infection assay PLoS pathogens Medium 30024968
2019 TAM receptors (Tyro3, Axl, Mer) attenuate NK cell responses via E3 ubiquitin ligase Cbl-b. Specifically, Tyro3, Axl, and Mer phosphorylate Cbl-b at tyrosine residues 133 and 363 (Tyro3 shown specifically). Gas6 ligation induces degradation of LAT1 (transmembrane adaptor for NK activating receptor signaling) in WT but not Cbl-b knockout NK cells, in a TAM kinase- and Cbl-b-dependent manner. Phosphorylation assay (Tyr133, Tyr363 on Cbl-b), Cbl-b-/- NK cells, Gas6 ligation, LAT1 degradation assay, NK cell functional assays European journal of immunology Medium 31531847
2020 Cbl-b ubiquitinates GluN2B subunits of NMDA receptors in spinal cord dorsal horn neurons through its N-terminal TKB domain. This ubiquitination decreases GluN2B-containing NMDAR-mediated synaptic transmission. Cbl-b abundance increases from P1 to P14, limiting synaptic GluN2B during development. Peripheral inflammation causes dephosphorylation of Cbl-b at Tyr363, impairing its binding to and ubiquitylation of GluN2B, enabling reappearance of GluN2B-containing NMDARs. A phosphomimetic Cbl-b mutant suppresses GluN2B-mediated synaptic currents and inflammatory pain. Co-immunoprecipitation, ubiquitination assay, synaptic fractionation, electrophysiology, in vivo knockdown, phosphomimetic mutant, inflammatory pain model Science signaling High 32606037
2022 Cbl-b mediates K27-linked ubiquitination of lysine 164 of STAT5a in dendritic cells, targeting STAT5 for degradation to promote cell apoptosis. c-Cbl mediates K29-linked ubiquitination of lysine 696 of STAT5a and K27-linked ubiquitination of lysine 140 and 694 of STAT5b. Loss of Cbl-b and c-Cbl in DCs results in sustained STAT5 activity, reduced Bim expression, and impaired cDC1 apoptosis. Conditional double-knockout mice (DC-specific), co-immunoprecipitation, ubiquitination assay with linkage and site specificity, apoptosis assay Cell death discovery Medium 35354799
2023 TCR stimulation induces formation of a molecular complex between Cbl-b and STS1 (a pH-sensitive unconventional phosphatase). The interaction depends on a proline motif in Cbl-b interacting with the STS1 SH3 domain. STS1 dephosphorylates Cbl-b-interacting phosphoproteins. Deficiency of STS1 or Cbl-b diminishes T cell sensitivity to acidic environments, promotes T cell activity in vivo, and inhibits tumor growth. Co-immunoprecipitation, phosphatase assay, proline motif mutagenesis, STS1-/- and Cbl-b-/- cells, tumor model Immunity High 38091950
2023 Co-crystal structure of Cbl-b with the small-molecule inhibitor C7683 (an analogue of clinical candidate Nx-1607) reveals that the compound interacts with both the TKBD and LHR domains of Cbl-b, but not the RING domain, locking Cbl-b in an inactive autoinhibited conformation by acting as an intramolecular glue. X-ray crystallography (co-crystal structure), biophysical binding assays, cellular activity assays Communications biology High 38104184
2023 Cbl-b independently regulates EGFR through preferential direct binding to phosphorylated Y1045 of EGFR (unlike c-Cbl which relies mainly on Grb2-dependent indirect interaction). Overexpression of E3-dead Cbl-b slows EGF-induced degradation of active EGFR and diminishes EGF-guided chemotaxis, demonstrating distinct modes of EGFR regulation by Cbl and Cbl-b. Inducible expression of E3-dead mutants, EGFR binding/ubiquitination assay, endocytosis assay, cell migration assay Molecular biology of the cell Medium 37903221
2024 CBL and CBLB ubiquitinate ICOS in CD4+ T cells, restraining BCL6 expression by promoting ICOS degradation. Loss of CBLs allows ICOS signaling to attenuate BCL6 degradation via chaperone-mediated autophagy (CMA), promoting hyper Tfh cell responses. T cell-specific CBLs-deficient mice develop hyper Tfh responses and SLE; blockade of Tfh development prevents SLE. Conditional T cell-specific double-KO mice, ubiquitination assay (ICOS), genetic epistasis (Tfh blockade), CMA analysis, BCL6 protein stability assay Immunity High 38761804

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 546 10646608
2000 Cbl-b regulates the CD28 dependence of T-cell activation. Nature 497 10646609
2014 The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 378 24553136
2002 c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nature immunology 320 12415267
2001 Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nature immunology 236 11526404
2005 c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses. The Biochemical journal 215 16212556
2000 Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 172 11070165
1995 Cloning and characterization of cbl-b: a SH3 binding protein with homology to the c-cbl proto-oncogene. Oncogene 165 7784085
2000 Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. The Journal of biological chemistry 160 11087752
2002 Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nature genetics 147 12118252
2007 Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia. Blood 138 17475912
2002 Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. Human molecular genetics 135 12471062
2011 CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia. Blood 128 21346257
2001 Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex. The Journal of biological chemistry 122 11375397
2018 miR-27b-3p inhibits proliferation and potentially reverses multi-chemoresistance by targeting CBLB/GRB2 in breast cancer cells. Cell death & disease 120 29416005
2007 Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells. The Journal of experimental medicine 120 17403934
2003 Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk. The Journal of experimental medicine 117 12771181
2021 Deletion of Cbl-b inhibits CD8+ T-cell exhaustion and promotes CAR T-cell function. Journal for immunotherapy of cancer 114 33462140
2004 Resistance to CD4+CD25+ regulatory T cells and TGF-beta in Cbl-b-/- mice. Journal of immunology (Baltimore, Md. : 1950) 104 15240694
1999 cbl-b inhibits epidermal growth factor receptor signaling. Oncogene 104 10086340
2002 CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases. The Journal of biological chemistry 101 12177062
2007 Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b. Immunity 99 17493844
2007 Ablation of Cbl-b provides protection against transplanted and spontaneous tumors. The Journal of clinical investigation 98 17364027
2016 Inhibition of CBLB protects from lethal Candida albicans sepsis. Nature medicine 94 27428901
2004 Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl). Blood 91 15315962
2007 E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury. Nature medicine 85 17618294
2016 Targeting CBLB as a potential therapeutic approach for disseminated candidiasis. Nature medicine 80 27428899
2011 Essential role of E3 ubiquitin ligase activity in Cbl-b-regulated T cell functions. Journal of immunology (Baltimore, Md. : 1950) 80 21248250
2008 T-cell receptor-induced NF-kappaB activation is negatively regulated by E3 ubiquitin ligase Cbl-b. Molecular and cellular biology 80 18227156
2015 Modulation of Immune Cell Functions by the E3 Ligase Cbl-b. Frontiers in oncology 79 25815272
2002 Cbl and Cbl-b in T-cell regulation. Trends in immunology 79 11864842
2011 Autoinhibition and phosphorylation-induced activation mechanisms of human cancer and autoimmune disease-related E3 protein Cbl-b. Proceedings of the National Academy of Sciences of the United States of America 78 22158902
2018 Regulation of immune responses by E3 ubiquitin ligase Cbl-b. Cellular immunology 75 30442330
1997 Cbl-b, a member of the Sli-1/c-Cbl protein family, inhibits Vav-mediated c-Jun N-terminal kinase activation. Oncogene 75 9399639
2014 Ubiquitin ligase Cbl-b represses IGF-I-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells. Molecular cancer 74 24885194
2004 Cbl-b interacts with ubiquitinated proteins; differential functions of the UBA domains of c-Cbl and Cbl-b. Oncogene 73 15273720
2003 The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport. The Journal of biological chemistry 70 12842890
2009 PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation. Science signaling 65 19549985
2009 Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1. Proceedings of the National Academy of Sciences of the United States of America 64 19815501
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
2014 E3 ubiquitin ligase Cbl-b in innate and adaptive immunity. Cell cycle (Georgetown, Tex.) 62 24875217
2023 Targeting Cbl-b in cancer immunotherapy. Journal for immunotherapy of cancer 59 36750253
2003 Negative regulation of FcepsilonRI-mediated mast cell activation by a ubiquitin-protein ligase Cbl-b. Blood 59 14604964
1999 Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation. Oncogene 58 10022120
2014 E3 ubiquitin ligase Cbl-b suppresses proallergic T cell development and allergic airway inflammation. Cell reports 57 24508458
2020 β-Elemene inhibits the metastasis of multidrug-resistant gastric cancer cells through miR-1323/Cbl-b/EGFR pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 55 32199253
2008 Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins. Blood 52 18239087
2016 E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity. The Journal of experimental medicine 50 27432944
2012 Adoptive transfer of siRNA Cblb-silenced CD8+ T lymphocytes augments tumor vaccine efficacy in a B16 melanoma model. PloS one 48 22962608
2010 Cbl-b in T-cell activation. Seminars in immunopathology 48 20458601
1999 cbl-b inhibits EGF-receptor-induced apoptosis by enhancing ubiquitination and degradation of activated receptors. Molecular cell biology research communications : MCBRC 47 10542134
1998 The CBL-related protein CBLB participates in FLT3 and interleukin-7 receptor signal transduction in pro-B cells. The Journal of biological chemistry 46 9614102
2018 Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB. PLoS pathogens 45 30024968
2007 Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group. Journal of inherited metabolic disease 45 17957493
2016 Co-recruitment analysis of the CBL and CBLB signalosomes in primary T cells identifies CD5 as a key regulator of TCR-induced ubiquitylation. Molecular systems biology 44 27474268
2002 Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells. The Journal of experimental medicine 44 12093870
2010 Cbl-b and itch: key regulators of peripheral T-cell tolerance. Cancer research 43 20395198
2007 Cbl-b regulates antigen-induced TCR down-regulation and IFN-gamma production by effector CD8 T cells without affecting functional avidity. Journal of immunology (Baltimore, Md. : 1950) 43 18025165
2010 T-cell regulation by casitas B-lineage lymphoma (Cblb) is a critical failsafe against autoimmune disease due to autoimmune regulator (Aire) deficiency. Proceedings of the National Academy of Sciences of the United States of America 42 20668237
2006 Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. Molecular genetics and metabolism 42 16410054
2009 Loss of Cbl-b increases osteoclast bone-resorbing activity and induces osteopenia. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 41 19257814
2005 CBLB variants in type 1 diabetes and their genetic interaction with CTLA4. Journal of leukocyte biology 39 15629882
2015 Protein Tyrosine Phosphatase SHP-1 Modulates T Cell Responses by Controlling Cbl-b Degradation. Journal of immunology (Baltimore, Md. : 1950) 38 26416283
2015 Ionizing radiation-inducible miR-30e promotes glioma cell invasion through EGFR stabilization by directly targeting CBL-B. The FEBS journal 35 25691332
2007 The ubiquitin ligase Cbl-b limits Pseudomonas aeruginosa exotoxin T-mediated virulence. The Journal of clinical investigation 35 17235393
2017 Cbl-b Deficiency Mediates Resistance to Programmed Death-Ligand 1/Programmed Death-1 Regulation. Frontiers in immunology 34 28184224
2014 Myostatin induces insulin resistance via Casitas B-lineage lymphoma b (Cblb)-mediated degradation of insulin receptor substrate 1 (IRS1) protein in response to high calorie diet intake. The Journal of biological chemistry 34 24451368
2013 Cbl-b mediates TGFβ sensitivity by downregulating inhibitory SMAD7 in primary T cells. Journal of molecular cell biology 33 23709694
2020 Bta-miR-223 Targeting CBLB Contributes to Resistance to Staphylococcus aureus Mastitis Through the PI3K/AKT/NF-κB Pathway. Frontiers in veterinary science 32 33195489
2007 Regulation of peripheral T cell tolerance by the E3 ubiquitin ligase Cbl-b. Seminars in immunology 32 17391982
2021 CBLB ablation with CRISPR/Cas9 enhances cytotoxicity of human placental stem cell-derived NK cells for cancer immunotherapy. Journal for immunotherapy of cancer 31 33741730
2019 TAM receptors attenuate murine NK-cell responses via E3 ubiquitin ligase Cbl-b. European journal of immunology 30 31531847
2015 Cbl-b and c-Cbl negatively regulate osteoblast differentiation by enhancing ubiquitination and degradation of Osterix. Bone 28 25744063
2006 Increased TGF-beta, Cbl-b and CTLA-4 levels and immunosuppression in association with chronic immune activation. International immunology 28 16608902
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
2023 The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition. Communications biology 26 38104184
2019 Bufalin induces protective autophagy by Cbl-b regulating mTOR and ERK signaling pathways in gastric cancer cells. Cell biology international 26 30468278
2002 Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells. Oncogene 26 11857085
2023 TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments. Immunity 25 38091950
2012 Releasing the brake: targeting Cbl-b to enhance lymphocyte effector functions. Clinical & developmental immunology 24 22550535
2011 Expression and function of Cbl-b in T cells from patients with systemic lupus erythematosus, and detection of the 2126 A/G Cblb gene polymorphism in the Mexican mestizo population. Lupus 24 21558139
2010 Cbl-b is a novel physiologic regulator of glycoprotein VI-dependent platelet activation. The Journal of biological chemistry 24 20400514
2020 Ubiquitination and functional modification of GluN2B subunit-containing NMDA receptors by Cbl-b in the spinal cord dorsal horn. Science signaling 23 32606037
2018 MicroRNA-29b-2-5p inhibits cell proliferation by directly targeting Cbl-b in pancreatic ductal adenocarcinoma. BMC cancer 23 29940895
2015 N-myristoylated ubiquitin ligase Cbl-b inhibitor prevents on glucocorticoid-induced atrophy in mouse skeletal muscle. Archives of biochemistry and biophysics 23 25689493
2010 Functional and structural analysis of five mutations identified in methylmalonic aciduria cblB type. Human mutation 23 20556797
2023 Cbl and Cbl-b independently regulate EGFR through distinct receptor interaction modes. Molecular biology of the cell 22 37903221
2015 Loss of Cbl and Cbl-b ubiquitin ligases abrogates hematopoietic stem cell quiescence and sensitizes leukemic disease to chemotherapy. Oncotarget 22 25871390
2014 A multiple sclerosis-associated variant of CBLB links genetic risk with type I IFN function. Journal of immunology (Baltimore, Md. : 1950) 22 25261476
2013 Cbl-b enhances sensitivity to 5-fluorouracil via EGFR- and mitochondria-mediated pathways in gastric cancer cells. International journal of molecular sciences 22 24351824
2011 Reinforcement of cancer immunotherapy by adoptive transfer of cblb-deficient CD8+ T cells combined with a DC vaccine. Immunology and cell biology 22 21383769
2017 Cblb-deficient T cells are less susceptible to PD-L1-mediated inhibition. Oncotarget 21 28611299
2022 Ablation of Cbl-b and c-Cbl in dendritic cells causes spontaneous liver cirrhosis via altering multiple properties of CD103+ cDC1s. Cell death discovery 19 35354799
2021 Cbl-b deficiency prevents functional but not phenotypic T cell anergy. The Journal of experimental medicine 19 33974042
2018 LncRNA DUXAP9-206 directly binds with Cbl-b to augment EGFR signaling and promotes non-small cell lung cancer progression. Journal of cellular and molecular medicine 19 30515972
2017 An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. Development (Cambridge, England) 19 28100467
2018 Cbl-b deficiency provides protection against UVB-induced skin damage by modulating inflammatory gene signature. Cell death & disease 18 30082827
2015 Single Nucleotide Polymorphisms in CBLB, a Regulator of T-Cell Response, Predict Radiation Pneumonitis and Outcomes After Definitive Radiotherapy for Non-Small-Cell Lung Cancer. Clinical lung cancer 18 26732495
2014 Ubiquitin ligase Cbl-b and obesity-induced insulin resistance. Endocrine journal 18 24614797
2024 Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation. Immunity 17 38761804

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