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
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

Genomic context

Location:: 11q23.3

Exon count:: 16

Annotation release	Status	Assembly	Chr	Location
109.20200522	current	GRCh38.p13 (GCF_000001405.39)	11	NC_000011.10 (119206339..119308149)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	11	NC_000011.9 (119076986..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?

Depletion of cbl proto-oncogene E3 ubiquitin-protein ligase (c-Cbl) leads to increased levels of differential display and activated by p53 protein (DDA3), resulting in increased recruitment of HK2 kinesin protein (Kif2a) to the mitotic spindle, a concomitant reduction in spindle formation, and chromosome alignment defects. c-Cbl depletion induces centrosome over-duplication and centriole amplification.
Title: c-Cbl Acts as an E3 Ligase Against DDA3 for Spindle Dynamics and Centriole Duplication during Mitosis.
Our results show that c-Cbl is down-regulated in gastric cancer (GC) tissues compared with normal gastric tissue, which may play an important role in the development and progression of GC.
Title: Loss of c-Cbl expression correlates with de-differentiation status and lymphatic metastasis in gastric cancer.
multiple E2 ubiquitin-conjugating enzymes can interact with Cbl and modulate its E3 activity in vitro and in cells
Title: Cbl interacts with multiple E2s in vitro and in cells.
Low C-CBL expression is associated with Colorectal Cancer.
Title: c-Cbl Expression Correlates with Human Colorectal Cancer Survival and Its Wnt/β-Catenin Suppressor Function Is Regulated by Tyr371 Phosphorylation.
the interaction of TRAF6 with c-Cbl causes lysine 48-linked polyubiquitination for both negative feedback regulation and signaling cross-talk between RANKL and IFN-gamma.
Title: C-Cbl negatively regulates TRAF6-mediated NF-<i>κ</i>B activation by promoting K48-linked polyubiquitination of TRAF6.
CBL gene status could be a potential target and indicator for MET inhibitors and future RTK regulation investigations, especially in those that will look into whether CBL should be evaluated before RTK inhibitors are considered.
Title: Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL.
The LMP2A of Epstein-Barr Virus was found to interfer with cofilin degradation in nasopharyngeal cancer cells by accelerating the proteasomal degradation of Cbl and Syk.
Title: Degradation of cofilin is regulated by Cbl, AIP4 and Syk resulting in increased migration of LMP2A positive nasopharyngeal carcinoma cells.
The host-Mycobacterium tuberculosis (Mtb) interaction map revealed two factors involved in Mtb pathogenesis-the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL.
Title: An Mtb-Human Protein-Protein Interaction Map Identifies a Switch between Host Antiviral and Antibacterial Responses.
C-CBL is likely to play a tumor suppressive role by antagonizing a robust oncogenic signaling driven by c-Src.
Title: The E3 ligase C-CBL inhibits cancer cell migration by neddylating the proto-oncogene c-Src.
Our results suggested that c-Cbl can reverse tamoxifen resistance in HER2-overexpressing breast cancer cells
Title: C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells.

Submit: New GeneRIF Correction See all GeneRIFs (214)

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
Juvenile myelomonocytic leukemia MedGen: C0349639 OMIM: 607785 GeneReviews: Not available	Compare labs
Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia MedGen: C3150803 OMIM: 613563 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

NHGRI GWAS Catalog

Description
New gene functions in megakaryopoiesis and platelet formation. NHGRI GWA Catalog NHGRI GWA 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: 317 organisms have orthologs with human gene CBL
Orthologs

Gene Ontology Provided by GOA

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

Process	Evidence Code	Pubs
cell surface receptor signaling pathway	TAS Traceable Author Statement more info	PubMed
cellular response to DNA damage stimulus	IEA Inferred from Electronic Annotation more info
cellular response to epidermal growth factor stimulus	IEA Inferred from Electronic Annotation more info
cellular response to nerve growth factor stimulus	IEA Inferred from Electronic Annotation more info
cellular response to oxygen-glucose deprivation	IEA Inferred from Electronic Annotation more info
cellular response to platelet-derived growth factor stimulus	IEA Inferred from Electronic Annotation more info
cytokine-mediated signaling pathway	TAS Traceable Author Statement more info
entry of bacterium into host cell	TAS Traceable Author Statement more info
epidermal growth factor receptor signaling pathway	TAS Traceable Author Statement more info	PubMed
fibroblast growth factor receptor signaling pathway	TAS Traceable Author Statement more info
interleukin-6-mediated signaling pathway	TAS Traceable Author Statement more info
male gonad development	IEA Inferred from Electronic Annotation more info
mast cell degranulation	IEA Inferred from Electronic Annotation more info
membrane organization	TAS Traceable Author Statement more info
negative regulation of apoptotic process	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of epidermal growth factor receptor signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of epidermal growth factor receptor signaling pathway	TAS Traceable Author Statement more info
negative regulation of epidermal growth factor-activated receptor activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
negative regulation of neuron death	IEA Inferred from Electronic Annotation more info
neuron death	IEA Inferred from Electronic Annotation more info
positive regulation of epidermal growth factor receptor signaling pathway	TAS Traceable Author Statement more info
positive regulation of phosphatidylinositol 3-kinase signaling	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of receptor-mediated endocytosis	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of receptor-mediated endocytosis	TAS Traceable Author Statement more info	PubMed
protein monoubiquitination	IEA Inferred from Electronic Annotation more info
protein polyubiquitination	IEA Inferred from Electronic Annotation more info
protein ubiquitination	TAS Traceable Author Statement more info	PubMed
regulation of Rap protein signal transduction	IEA Inferred from Electronic Annotation more info
regulation of platelet-derived growth factor receptor-alpha signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
response to activity	IEA Inferred from Electronic Annotation more info
response to antibiotic	IEA Inferred from Electronic Annotation more info
response to ethanol	IEA Inferred from Electronic Annotation more info
response to gamma radiation	IEA Inferred from Electronic Annotation more info
response to starvation	IEA Inferred from Electronic Annotation more info
response to testosterone	IEA Inferred from Electronic Annotation more info
signal transduction	IBA Inferred from Biological aspect of Ancestor more info	PubMed
transforming growth factor beta receptor signaling pathway	TAS Traceable Author Statement more info
ubiquitin-dependent protein catabolic process	IMP Inferred from Mutant Phenotype more info	PubMed

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

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