CBL

Chr 11q23.3

Cbl proto-oncogene

Aliases:: RNF55, c-Cbl
MANE:: ENST00000264033.6

OMIM: 165360 ↗NCBI: 867 ↗Ensembl ↗

Annotations refreshed 1 month ago.

Predicted protein structure

AlphaFold predicted structure

CBL · P22681

v62025-08-01

Predicted Aligned Error matrix for CBL — diagonal shows residue index, colour shows pairwise prediction confidence (lower is better) — Predicted Aligned Error

Mean pLDDT

62.8/ 100

Low

906 residues

Confidence breakdown

Very high(≥ 90)34%
Confident(70–90)13%
Low(50–70)3%
Very low(< 50)51%

Open interactive 3D viewer

AlphaFold (Jumper et al., 2021) · CC BY 4.0

Clinical relevance (Genomics England PanelApp)

Diagnostic Grade (Green)

Adult solid tumours cancer susceptibility
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cerebral vascular malformations
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood solid tumours
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood solid tumours cancer susceptibility
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Embryonal tumour of possible germline origin
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal hydrops
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

+12 more panels — install the extension to see the full list inline on any page.

Disease associations (Open Targets)

Noonan syndrome-like disorder with juvenile myelomonocytic leukemia
0.82
CBL-related disorder
0.80
juvenile myelomonocytic leukemia
0.73
Noonan syndrome
0.64
RASopathy
0.56
listeriosis
0.54
cancer
0.53
Abnormality of the cardiovascular system
0.52
Noonan syndrome and Noonan-related syndrome
0.47
hereditary disease
0.46

Score is the Open Targets composite evidence score (0-1). Higher = stronger gene-disease association.

Protein function (UniProt)

E3 ubiquitin-protein ligase CBL

E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors (PubMed:10514377, PubMed:11896602, PubMed:14661060, PubMed:14739300, PubMed:15190072, PubMed:17509076, PubMed:18374639, PubMed:19689429, PubMed:21596750, PubMed:28381567, PubMed:40101708). Accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome (PubMed:10514377, PubMed:14661060, PubMed:14739300, PubMed:17094949, PubMed:17509076, PubMed:17974561). Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, CSF1R, EPHA8 and KDR and mediates their ubiquitination to terminate signaling (PubMed:15190072, PubMed:18374639, PubMed:21596750). Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation (PubMed:11896602). Ubiquitinates EGFR and SPRY2 (PubMed:17094949, PubMed:17974561). Involved in LAG3-mediated inhibition of TCR signaling: following ligand-binding to LAG3, catalyzes 'Lys-63'-linked ubiquitination of LAG3, unleashing the LAG3 C-terminus from the membrane, and initiating a signaling that prevents TCR activation (PubMed:40101708). Ubiquitinates NECTIN1 following association between NECTIN1 and herpes simplex virus 1/HHV-1 envelope glycoprotein D, leading to NECTIN1 removal from cell surface (PubMed:28381567). Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis (PubMed:15190072, PubMed:18374639). Essential for osteoclastic bone resorption (PubMed:14739300). The 'Tyr-731' phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:14739300). In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA (By similarity)