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Symbol CBL contributors: mct/npt - updated : 21-08-2015
HGNC name Cas-Br-M (murine) ecotropic retroviral transforming sequence
HGNC id 1541
Corresponding disease
CBLS CBL syndrome
NS7 Noonan syndrome 7
Location 11q23.3      Physical location : 119.076.989 - 119.178.858
Synonym name
  • oncogene CBL2
  • Casitas B-lineage lymphoma proto-oncogene
  • proto-oncogene c-CBL
  • RING finger protein 55
  • signal transduction protein CBL
  • fragile site, folic acid type, rare, fra(11)(q23.3)
  • Synonym symbol(s) C-CBL, CBL2, RNF55, FRA11B, NSLL
    EC.number 6.3.2.-
    TYPE virus associated
    STRUCTURE 101.87 kb     16 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    text structure CGG trinucleotide repeat
    MAPPING cloned Y linked N status confirmed
    Map see BALMCR
    TRANSCRIPTS type untranslated
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 - 11242 120 906 - 2009 19620960
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunethymus   highly Homo sapiens
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticmature hematopoietic
    cell lineage
    cell lines
    at STAGE
  • a variant SH2 domain, with tyrosine kinase binding (TKB)
  • a potential nuclear localization signal (NLS)
  • a RING finger domain
  • C-terminus with an extensive proline-rich region containing a number of putative SH3-binding motifs, and is followed by multiple SH2-binding tyrosine phosphorylation sites and a ubiquitin-associated (UBA) domain overlapping with a leucine zipper (LZ) motif involved in ubiquitin binding and protein dimerization, respectively
  • C-terminal region plays a crucial role in the temporal and spatial control of HTR2A recycling
    CATEGORY tumor suppressor
    SUBCELLULAR LOCALIZATION     plasma membrane
    text phosphorylated CBL recruited to the insulin receptor by CAP (SORBS1) and translocated to cholesterol enriched microdomains (lipid rafts)
    basic FUNCTION
  • acting as a RING-type E3-dependent ubiquitin protein ligase, binding and stimulating the ubiquitination of PDGFRs, EGFR, CSF1R, also interacting with signal transduction molecules, key mediator of HCK (hematopoietic cell kinase) induced signaling in hematopoietic cells
  • involvement of a CBL/PTPN11complex in ubiquitination and lysosomal degradation of IL6ST upon IL6 stimulation
  • critical regulator of the functional responses of memory T cell subsets
  • both CBL and CBLB perform regulatory functions in osteoclasts that are unique to one or the other protein (i.e., functions that cannot be compensated by the other homolog)
  • may have a role in deregulating a key pathway in JMML (juvenile myelomonocytic leukemia)
  • negatively regulates JNK activation and cell death
  • E3 ubiquitin ligase that negatively regulates signal transduction of tyrosine kinases
  • negatively regulate intracellular signaling downstream of receptor tyrosine kinases (RTKs), but it also contributes to signal traffic through its adaptor function
  • angiogenic suppressor protein where upon activation it uniquely modulates PLCG1 activation by ubiquitination and subsequently inhibits VEGF-driven angiogenesis
  • has a crucial, RING-domain-dependent role in regulating dendritic cell maturation, probably by facilitating the regulatory function of NFKB1
  • CBL and particularly its phosphorylated residue Y731 plays an important role in platelet outside-in signaling contributing to platelet-spreading and clot retraction
  • plays a critical role TCR signaling downregulation during thymocyte development
  • regulates the osteoblastic differentiation program in mesenchymal cells by controlling CBL-mediated STAT5A degradation and activity
  • LCK, which plays a unique role in enforcing MHC restriction, is essential for thymic development in presence or absence of CBL, ensuring MHC restriction of T cells derived from either pathway
  • recycling regulator ARHGEF6 and the degradation factor CBL closely cooperate in the regulation of EGFR trafficking (pMID: 26177020)
  • CELLULAR PROCESS cell life, proliferation/growth
    protein, degradation
    protein, ubiquitin dependent proteolysis
    signaling signal transduction
    insulin signaling pathway
    a component
  • ubiquitination component of a complex with UBE1, UBE3*, UBE2G1, UBE2D1, UBE2E2, UBE2D1
    small molecule
  • recruiting the CRK/GRF2 complex to lipid rafts
  • interacting with signal transduction molecules : PD6FRS, EGFR, CSF1R
  • binding E2 by its RING domain regulation ZAP70, SYK tyrosine kinases
  • negatively regulating LCK
  • competition between CBL and ubiquitin binding to SH3KBP1 regulates CBL function and EGFR endocytosis
  • interacts with the TEK signalling complex in a stimulation-dependent manner, and that this interaction is required for TEK ubiquitylation, internalization and degradation
  • is an angiogenic suppressor protein where upon activation it uniquely modulates PLCG1 activation by ubiquitination and subsequently inhibits VEGFA-driven angiogenesis
  • VHL limits EGFR signaling by promoting CBL-independent poly-ubiquitylation of the activated receptor, which likely results in its degradation by proteasome
  • CBL activation induced by CTSG was mediated through EGFR transactivation as inhibition of EGFR kinase activity markedly attenuated CBL phosphorylation and focal adhesion protein degradation induced by CTSG
  • SH3KBP1 is required for CBL-mediated regulation of BCR signaling and for downstream events such as survival, growth, and differentiation of human B cells
  • ubiquitin ligase that physically associates with CD5
  • interacts with the transcription factor STAT5A, and STAT5A forms a complex with RUNX2, a master transcription factor controlling osteoblastogenesis
  • CBL ubiquitination of PIK3R1 is essential for EPO-induced EPOR endocytosis
  • CBLB and CBL increased the protein level and stability of SIRT2 and CBLB and CBL interact with SIRT2
  • CBL negatively regulates ARHGEF6-mediated cell migration and invasion and the lack of CBL in the C6 and A172 glioma cells is responsible for their malignant behavior
  • SMAD7 interaction with CBL to inhibit the ubiquitination of EGFR
  • 2008)
  • ARHGEF6 interacts with the E3 ubiquitin ligase CBL, an enzyme that attaches ubiquitin to EGFR, thereby labelling this tyrosine kinase receptor for lysosomal degradation
  • cell & other
    activated by tyrosine-phosphorylated by insulin
    Phosphorylated by PTK6, that phosphorylates and down-regulates E3 ubiquitin ligase CBL, promoting degradation of CBL through PTK6-mediated phosphorylation (PMId: 23352614)
    corresponding disease(s) NS7 , CBLS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral fusion      
    with MLL in acute myeloid leukemia (amino-terminal region of MLL to the proline-rich regions and the ubiquitin -associated leucine zipper domain of CBL)
    tumoral somatic mutation     gain of function
    in myeloid neoplasms
    tumoral germinal mutation      
    associated with juvenile myelomonocytic leukaemia
    Variant & Polymorphism
    Candidate gene
    Therapy target
    increasing CBL expression reduces osteosarcoma cell growth, survival, and metastasis in part through downregulation of RTKs (receptor tyrosine kinase), which supports the potential therapeutic interest of targeting CBL in malignant bone diseases involvin