CBL Cbl proto-oncogene [Homo sapiens (human)] - Gene

Summary

Official Symbol: CBLprovided by HGNC
Official Full Name: Cbl proto-oncogeneprovided by HGNC
Primary source: HGNC:HGNC:1541
See related: Ensembl:ENSG00000110395 MIM:165360; AllianceGenome:HGNC:1541
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: CBL2; NSLL; C-CBL; RNF55; FRA11B
Summary: This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]
Expression: Broad expression in testis (RPKM 12.3), lymph node (RPKM 6.0) and 23 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 11q23.3

Exon count:: 16

Annotation release	Status	Assembly	Chr	Location
110	current	GRCh38.p14 (GCF_000001405.40)	11	NC_000011.10 (119206339..119308149)
110	current	T2T-CHM13v2.0 (GCF_009914755.1)	11	NC_060935.1 (119226712..119328785)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	11	NC_000011.9 (119077049..119178859)

Chromosome 11 - NC_000011.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Pro-prion, as a membrane adaptor protein for E3 ligase c-Cbl, facilitates the ubiquitination of IGF-1R, promoting melanoma metastasis.
Title: Pro-prion, as a membrane adaptor protein for E3 ligase c-Cbl, facilitates the ubiquitination of IGF-1R, promoting melanoma metastasis.
[CBL inhibits proliferation and invasion of breast cancer cells by ubiquitylation-mediated degradation of NCK2].
Title: [CBL inhibits proliferation and invasion of breast cancer cells by ubiquitylation-mediated degradation of NCK2].
Fluctuations in AKT and PTEN Activity Are Linked by the E3 Ubiquitin Ligase cCBL.
Title: Fluctuations in AKT and PTEN Activity Are Linked by the E3 Ubiquitin Ligase cCBL.
Knockout of c-Cbl slows EGFR endocytic trafficking and enhances EGFR signaling despite incompletely blocking receptor ubiquitylation.
Title: Knockout of c-Cbl slows EGFR endocytic trafficking and enhances EGFR signaling despite incompletely blocking receptor ubiquitylation.
A novel, germline, deactivating CBL variant p.L493F alters domain orientation and is associated with multiple childhood cancers.
Title: A novel, germline, deactivating CBL variant p.L493F alters domain orientation and is associated with multiple childhood cancers.
E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK-CBL-CIN85 axis.
Title: E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK-CBL-CIN85 axis.
Sleuthing biochemical evidence to elucidate unassigned electron density in a CBL-SLAP2 crystal complex.
Title: Sleuthing biochemical evidence to elucidate unassigned electron density in a CBL-SLAP2 crystal complex.
CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1.
Title: CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1.
E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy.
Title: E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy.
Morphologic and Immunophenotypic Differences in Juvenile Myelomonocytic Leukemias With CBL and Other Canonical RAS-pathway Gene Mutations: A Single Institutional Experience.
Title: Morphologic and Immunophenotypic Differences in Juvenile Myelomonocytic Leukemias With CBL and Other Canonical RAS-pathway Gene Mutations: A Single Institutional Experience.

Submit: New GeneRIF Correction See all GeneRIFs (228)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
CBL-related disorder MedGen: C3150803 OMIM: 613563 GeneReviews: Not available	Compare labs
Juvenile myelomonocytic leukemia MedGen: C0349639 OMIM: 607785 GeneReviews: Not available	Compare labs

Copy number response

Description
Copy number response Haploinsufficency No evidence available (Last evaluated 2019-04-24) ClinGen Genome Curation Page Triplosensitivity No evidence available (Last evaluated 2019-04-24) ClinGen Genome Curation Page

EBI GWAS Catalog

Description
New gene functions in megakaryopoiesis and platelet formation. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Protein interactions

Protein	Gene	Interaction	Pubs
Nef	nef	In the presence of Nef, lipid raft Cdc42 is activated and forms a ternary complex between the c-Cbl-interacting protein p85Cool-1/betaPix and c-Cbl, displacing UbcH7 from rafts	PubMed
	nef	HIV-1 Nef enhances the phosphorylation of c-Cbl in CD4+ T cells, an effect that requires the Src tyrosine kinase Lck	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

CBL (e-PCR)
- UniSTS:46104

RH103536 (e-PCR)
- UniSTS:97861

PMC86017P1 (e-PCR)
- UniSTS:273505

RH93709 (e-PCR)
- UniSTS:89958

GDB:198117 (e-PCR)
- UniSTS:156019

STS-X57110 (e-PCR)
- UniSTS:51828

G15959 (e-PCR)
- UniSTS:82572

WI-14589 (e-PCR)
- UniSTS:1963

D11S1941E (e-PCR)
- UniSTS:53441

CBL_4518 (e-PCR)
- UniSTS:462794

G59879 (e-PCR)
- UniSTS:137162

RH47875 (e-PCR)
- UniSTS:42453

WI-8978 (e-PCR)
- UniSTS:8926

D11S1941E (e-PCR)
- UniSTS:473317

Homology

Homologs of the CBL gene: The CBL gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.
Orthologs from Annotation Pipeline: 464 organisms have orthologs with human gene CBL
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables SH3 domain binding	IBA Inferred from Biological aspect of Ancestor more info	PubMed
enables SH3 domain binding	IPI Inferred from Physical Interaction more info	PubMed
enables cadherin binding	HDA more info	PubMed
enables calcium ion binding	IEA Inferred from Electronic Annotation more info
enables ephrin receptor binding	IPI Inferred from Physical Interaction more info	PubMed
enables phosphatidylinositol 3-kinase regulatory subunit binding	IEA Inferred from Electronic Annotation more info
enables phosphotyrosine residue binding	IEA Inferred from Electronic Annotation more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables receptor tyrosine kinase binding	IBA Inferred from Biological aspect of Ancestor more info	PubMed
enables ubiquitin protein ligase activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
enables ubiquitin protein ligase activity	TAS Traceable Author Statement more info
enables ubiquitin-protein transferase activity	TAS Traceable Author Statement more info	PubMed

Process	Evidence Code	Pubs
involved_in cell surface receptor signaling pathway	TAS Traceable Author Statement more info	PubMed
involved_in cellular response to DNA damage stimulus	IEA Inferred from Electronic Annotation more info
involved_in cellular response to nerve growth factor stimulus	IEA Inferred from Electronic Annotation more info
involved_in cellular response to oxygen-glucose deprivation	IEA Inferred from Electronic Annotation more info
involved_in cellular response to platelet-derived growth factor stimulus	IEA Inferred from Electronic Annotation more info
involved_in cytokine-mediated signaling pathway	TAS Traceable Author Statement more info
involved_in entry of bacterium into host cell	TAS Traceable Author Statement more info
involved_in epidermal growth factor receptor signaling pathway	TAS Traceable Author Statement more info	PubMed
involved_in male gonad development	IEA Inferred from Electronic Annotation more info
involved_in mast cell degranulation	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of apoptotic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of epidermal growth factor receptor signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of epidermal growth factor receptor signaling pathway	TAS Traceable Author Statement more info
involved_in negative regulation of epidermal growth factor-activated receptor activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
involved_in negative regulation of neuron death	IEA Inferred from Electronic Annotation more info
involved_in neuron death	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of epidermal growth factor receptor signaling pathway	TAS Traceable Author Statement more info
involved_in positive regulation of phosphatidylinositol 3-kinase signaling	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of receptor-mediated endocytosis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of receptor-mediated endocytosis	TAS Traceable Author Statement more info	PubMed
involved_in protein autoubiquitination	IEA Inferred from Electronic Annotation more info
involved_in protein monoubiquitination	IEA Inferred from Electronic Annotation more info
involved_in protein polyubiquitination	IEA Inferred from Electronic Annotation more info
involved_in protein ubiquitination	IDA Inferred from Direct Assay more info	PubMed
involved_in protein ubiquitination	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in protein ubiquitination	TAS Traceable Author Statement more info	PubMed
involved_in regulation of Rap protein signal transduction	IEA Inferred from Electronic Annotation more info
involved_in regulation of platelet-derived growth factor receptor-alpha signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
involved_in response to activity	IEA Inferred from Electronic Annotation more info
involved_in response to antibiotic	IEA Inferred from Electronic Annotation more info
involved_in response to ethanol	IEA Inferred from Electronic Annotation more info
involved_in response to gamma radiation	IEA Inferred from Electronic Annotation more info
involved_in response to starvation	IEA Inferred from Electronic Annotation more info
involved_in response to testosterone	IEA Inferred from Electronic Annotation more info
involved_in signal transduction	IBA Inferred from Biological aspect of Ancestor more info	PubMed
involved_in ubiquitin-dependent protein catabolic process	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
located_in Golgi apparatus	IDA Inferred from Direct Assay more info	PubMed
located_in cilium	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	IDA Inferred from Direct Assay more info
located_in cytosol	TAS Traceable Author Statement more info
part_of flotillin complex	ISS Inferred from Sequence or Structural Similarity more info
located_in focal adhesion	IEA Inferred from Electronic Annotation more info
located_in growth cone	IEA Inferred from Electronic Annotation more info
is_active_in membrane raft	IBA Inferred from Biological aspect of Ancestor more info	PubMed
located_in perinuclear region of cytoplasm	IEA Inferred from Electronic Annotation more info
is_active_in plasma membrane	IBA Inferred from Biological aspect of Ancestor more info	PubMed
located_in plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	TAS Traceable Author Statement more info

General protein information

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Preferred Names: E3 ubiquitin-protein ligase CBL

Names: Cas-Br-M (murine) ecotropic retroviral transforming sequence; Cbl proto-oncogene, E3 ubiquitin protein ligase; RING finger protein 55; RING-type E3 ubiquitin transferase CBL; casitas B-lineage lymphoma proto-oncogene; fragile site, folic acid type, rare, fra(11)(q23.3); oncogene CBL2; proto-oncogene c-Cbl; signal transduction protein CBL

NP_005179.2

EC 2.3.2.27

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_016808.1 RefSeqGene

Range

4997..106870

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_608

mRNA and Protein(s)

NM_005188.4 → NP_005179.2 E3 ubiquitin-protein ligase CBL

See identical proteins and their annotated locations for NP_005179.2

Status: REVIEWED

Source sequence(s)

AA806454, AP002956, BC132733, DB457271

Consensus CDS

CCDS8418.1

UniProtKB/Swiss-Prot

A3KMP8, P22681

Related

ENSP00000264033.3, ENST00000264033.6

Conserved Domains (6) summary

cd09920
Location:256 → 352

SH2_Cbl-b_TKB; Src homology 2 (SH2) domain found in the Cbl-b TKB domain

cd14393
Location:857 → 896

UBA_c-Cbl; UBA domain found in E3 ubiquitin-protein ligase Cbl and similar proteins

pfam02262
Location:54 → 175

Cbl_N; CBL proto-oncogene N-terminal domain 1

pfam02761
Location:179 → 262

Cbl_N2; CBL proto-oncogene N-terminus, EF hand-like domain

cd16709
Location:362 → 427

RING-HC_Cbl-b; RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl-b and similar proteins

cl26464
Location:480 → 810

Atrophin-1; Atrophin-1 family