CBL Gene

HGNC Family	Zinc fingers
Name	Cbl proto-oncogene, E3 ubiquitin protein ligase
Description	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]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The CBL family of proteins—including c‐CBL and CBL‐b—act as multifunctional regulators of receptor signaling by functioning both as E3 ubiquitin ligases and adaptor molecules. Their canonical role is to bind activated receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR), hepatocyte growth factor (HGF) receptor (Met), and c‐Kit, thereby promoting receptor ubiquitination, internalization, and degradation to effectively terminate signal transduction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In addition, CBL proteins recruit accessory proteins such as CIN85, endophilins, and even modulators like Sprouty2, which can alter the receptor’s fate by either facilitating endocytosis or inhibiting degradative ubiquitination."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Beyond their control of receptor turnover, the CBL family regulates key cellular processes in distinct biological systems. For instance, in hematopoietic cells, loss or mutation of CBL (or the related CBL‐b) disrupts the negative regulation of cytokine and growth factor signaling, leading to enhanced and prolonged activation of downstream pathways that contribute to myeloid neoplasms and other cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Similarly, in the immune system, genetic inactivation of CBL‐b has been shown to license natural killer cell activity and enhance T‐cell receptor down‐modulation through regulatory mechanisms that involve PD‐L1/PD‐1–mediated up‐regulation of CBL‐b."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " CBL also contributes to non‐immune functions; for example, in osteoclasts, CBL‐mediated ubiquitination regulates the degradation of pro‐apoptotic molecules such as Bim, thereby influencing bone resorption"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and in hematopoietic stem cells, c‐CBL restrains c‐Kit signaling, helping to define hierarchically distinct stem cell populations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Moreover, de novo mutations in CBL have been implicated in developmental and neurological disorders, including severe early‐onset epilepsy, underscoring its importance in cell signaling across diverse tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Collectively, these studies underscore that precise control of receptor internalization and downstream signaling by CBL proteins is essential for maintaining cellular homeostasis, and that perturbations in CBL function—whether by mutation or deregulated signaling—can contribute to oncogenic transformation and other disease states.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Philippe Soubeyran, Katarzyna Kowanetz, Iwona Szymkiewicz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/416183a"}], "href": "https://doi.org/10.1038/416183a"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11894095"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11894095"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Annalisa Petrelli, Giorgio F Gilestro, Stefania Lanzardo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/416187a"}], "href": "https://doi.org/10.1038/416187a"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11894096"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11894096"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Karianne E Longva, Froydis D Blystad, Espen Stang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitination and proteasomal activity is required for transport of the EGF receptor to inner membranes of multivesicular bodies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200106056"}], "href": "https://doi.org/10.1083/jcb.200106056"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11864992"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11864992"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kirstine Roepstorff, Michael Vibo Grandal, Lasse Henriksen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential effects of EGFR ligands on endocytic sorting of the receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Traffic (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1600-0854.2009.00943.x"}], "href": "https://doi.org/10.1111/j.1600-0854.2009.00943.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19531065"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19531065"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Gal Gur, Chanan Rubin, Menachem Katz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.emboj.7600342"}], "href": "https://doi.org/10.1038/sj.emboj.7600342"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15282549"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15282549"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Silvia Goldoni, Ashley Humphries, Alexander Nyström, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Decorin is a novel antagonistic ligand of the Met receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200901129"}], "href": "https://doi.org/10.1083/jcb.200901129"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19433454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19433454"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Masashi Sanada, Takahiro Suzuki, Lee-Yung Shih, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature08240"}], "href": "https://doi.org/10.1038/nature08240"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19620960"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19620960"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Hideki Makishima, Heather Cazzolli, Hadrian Szpurka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2009.23.7503"}], "href": "https://doi.org/10.1200/JCO.2009.23.7503"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19901108"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19901108"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Magdalena Paolino, Axel Choidas, Stephanie Wallner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature12998"}], "href": "https://doi.org/10.1038/nature12998"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24553136"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24553136"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Katarzyna Karwacz, Christopher Bricogne, Douglas MacDonald, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Mol Med (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/emmm.201100165"}], "href": "https://doi.org/10.1002/emmm.201100165"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21739608"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21739608"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Toru Akiyama, Phillippe Bouillet, Tsuyoshi Miyazaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/emboj/cdg635"}], "href": "https://doi.org/10.1093/emboj/cdg635"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14657036"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14657036"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Joseph Y Shin, Wenhuo Hu, Mayumi Naramura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High c-Kit expression identifies hematopoietic stem cells with impaired self-renewal and megakaryocytic bias."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20131128"}], "href": "https://doi.org/10.1084/jem.20131128"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24446491"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24446491"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Hilary C Martin, Grace E Kim, Alistair T Pagnamenta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu030"}], "href": "https://doi.org/10.1093/hmg/ddu030"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24463883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24463883"}]}]}]}
Synonyms	CBL2, RNF55, FRA11B, C-CBL, NSLL
Proteins	CBL_HUMAN
NCBI Gene ID	867
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

CBL has 12,090 functional associations with biological entities spanning 9 categories (molecular profile, organism, functional term, phrase or reference, disease, phenotype or trait, chemical, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 148 datasets.

Click the + buttons to view associations for CBL from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

CBL Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by CBL gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CBL gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of CBL gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of CBL gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of CBL gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of CBL gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CBL gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	Biocarta Pathways	pathways involving CBL protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of CBL gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CBL gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CBL gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of CBL gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of CBL gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with CBL gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with CBL protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CBL gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of CBL gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of CBL gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations	phenotypes associated with CBL gene from the curated ClinVar Gene-Phenotype Associations dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with CBL gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing CBL protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of CBL gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing CBL protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing CBL protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing CBL protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with CBL protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with CBL protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	CORUM Protein Complexes	protein complexs containing CBL protein from the CORUM Protein Complexes dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of CBL gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with CBL gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with CBL gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with CBL gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with CBL gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by CBL gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DEPOD Substrates of Phosphatases	phosphatases that dephosphorylate CBL protein from the curated DEPOD Substrates of Phosphatases dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores	diseases involving CBL gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving CBL gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with CBL gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with CBL gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with CBL gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.