Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0004094
UniProt IDP22681
Primary gene name(s)CBL
Synonym gene name(s)CBL2, RNF55
Protein nameE3 ubiquitin-protein ligase CBL
Protein functionAdapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. 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. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. {ECO:0000269|PubMed:10514377, ECO:0000269|PubMed:11896602, ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:14739300, ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:18374639, ECO:0000269|PubMed:19689429, ECO:0000269|PubMed:21596750}.
Subcellular locationCytoplasm. Cell membrane. Note=Colocalizes with FGFR2 in lipid rafts at the cell membrane.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: P22681
Gene Ontology
(Biological Process)
Complete annatation
cell surface receptor signaling pathway [GO:0007166];
cellular response to DNA damage stimulus [GO:0006974];
cellular response to nerve growth factor stimulus [GO:1990090];
cellular response to oxygen-glucose deprivation [GO:0090650];
cellular response to platelet-derived growth factor stimulus [GO:0036120];
epidermal growth factor receptor signaling pathway [GO:0007173];
fibroblast growth factor receptor signaling pathway [GO:0008543];
negative regulation of apoptotic process [GO:0043066];
negative regulation of epidermal growth factor-activated receptor activity [GO:0007175];
negative regulation of epidermal growth factor receptor signaling pathway [GO:0042059];
neuron death [GO:0070997];
positive regulation of epidermal growth factor receptor signaling pathway [GO:0045742];
positive regulation of phosphatidylinositol 3-kinase signaling [GO:0014068];
positive regulation of receptor-mediated endocytosis [GO:0048260];
protein ubiquitination [GO:0016567];
protein ubiquitination involved in ubiquitin-dependent protein catabolic process [GO:0042787];
response to activity [GO:0014823];
response to ethanol [GO:0045471];
response to starvation [GO:0042594];
transforming growth factor beta receptor signaling pathway [GO:0007179]
Gene Ontology
(Molecular Function)
Complete annatation
calcium ion binding [GO:0005509];
ephrin receptor binding [GO:0046875];
ligase activity [GO:0016874];
SH3 domain binding [GO:0017124];
signal transducer activity [GO:0004871];
transcription factor activity, sequence-specific DNA binding [GO:0003700];
ubiquitin protein ligase activity [GO:0061630];
ubiquitin-protein transferase activity [GO:0004842];
zinc ion binding [GO:0008270]
Gene Ontology
(Cellular Component)
Complete annatation
cytoplasm [GO:0005737];
cytosol [GO:0005829];
nucleus [GO:0005634];
plasma membrane [GO:0005886]
Protein-protein interaction107315
Phylogenetic treeP22681
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
Brass et al., Science, 2008
Smith et al., J. Immunol, 2010
gene status
Lu et al., J. Virol., 2011
      Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: unknown
      Viral life cycle: unknown
      Mechanism related to antiviral activity: unknown
Anti-viral restriction factor Liu et al., Retrovirology, 2011
      unknown (Triplicates)

Gene Expression Profile       top

            Up-regulated;            Down-regulated

For brief introduction to each study, please go to the help page.

Gene expression during HIV latency

(1). Mohammadi et al., PLoS Pathog., 2014

Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model

DMSO: Dimethyl suloxyde (negative control) - 0.0033% final
SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM
CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies
IL7: Interleukin-7 based stimulation
DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM
AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD3-0.7860419951121030.01691366170852860.0405024959121295
AZA vs. DISU0.3720064976981420.1439402039221710.718797155225174
AZA vs. IL7-0.1364440442315830.4774600274448360.999311006273513
AZA vs. SAHA0.1882782727879120.4400193331670290.787415175806649
DISU vs. CD31.145140326859850.001956624579424140.00735882208339308
DISU vs. IL7-0.5174777059056330.04105328545133470.267107577458423
DISU vs. SAHA-0.1822533674596130.5360166311619660.843863642352658
DMSO vs. AZA0.02888896490399880.8628580091056431
DMSO vs. CD30.8035324726962220.0124498255590930.0300380625484518
DMSO vs. DISU-0.3449817063727710.1595545874674450.664922344336232
DMSO vs. IL7-0.1580405960213850.3788958186321170.832872524258073
DMSO vs. SAHA0.1526790131954240.517135912780020.822299571798658
HIV vs. Mock in Activation0.5525547605032430.3826856337192660.999983755607037
HIV vs. Mock in Latency0.04488384534522160.7851438717374060.999834320637052
IL7 vs. CD30.6566258969647330.04177544985364610.0946604563505725
SAHA vs. CD30.9494639012984480.007650106510832870.0204996931028438
SAHA vs. IL70.3210841245702220.1880292238089680.418257172313623
(2). Iglesias-Ussel et al., J. Virol., 2013

Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model
Log2 Fold Change P Value
unknown unknown

Gene expression during HIV infection and replication

(1). Imbeault et al., PloS Pathog., 2012

Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells
Experiment type Log2 Fold Change P Value Adjusted P Value
Infected vs. Mock unknown unknown unknown
Infected vs. Bystander unknown unknown unknown
(2). Lefebvre et al., J. Virol., 2011

Transcriptome analysis of T-cell line (Sup T1)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
Acute Fold Change Acute P Value Asymt Fold Change Asypt P Value AIDS Fold Change AIDS P Value
unknown unknown unknown unknown unknown unknown
(4). Chang et al., MBio., 2011

Transcriptome analysis of T-cell line (Sup T1)

Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation
Up-regulated (True) unknown
(5). Sherrill-Mix et al., BMC Retrovirol., 2015

Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based
Test Status Log2 Fold Change P Value
OK -0.525848 0.000305467
(6). Rotger et al., PLoS Pathog., 2010

Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient
(Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach)
Log2 Fold Change P Value
unknown unknown

Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV

(1). Greenwood et al., Elife, 2016

Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset
6 h 24 h 48 h 72 h RTi
1.034 0.98 1.196 1.391 1.114
(2). Navare et al., Virology, 2012

SUP-T1 cell line
FC-4hpi P-value FC-8hpi P-value FC-20hpi P-value Category
unknown unknown unknown unknown unknown unknown unknown
(3). Hyrcza et al., J. Virolo., 2007

Primary human CD4+ and CD8+ T Cells
Affymetrix Prob ID Fold Change In CD8? Category
unknown unknown unknown unknown

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

PDB Accession Method Resolution Chain Structure Preview
1B47 X-ray 2.2Å A/B/C=47-350.
1FBV X-ray 2.9Å A=47-434.
1YVH X-ray 2.0Å A=25-351.
2CBL X-ray 2.1Å A=47-351.
2JUJ NMR - A=851-906.
2K4D NMR - A=358-437.
2OO9 X-ray 2.1Å A/B/C=856-895.
2Y1M X-ray 2.6Å A/B/C/D/E/F=47-435.
2Y1N X-ray 2.0Å A/C=47-435.
3BUM X-ray 2.0Å B=25-351.
3BUN X-ray 2.0Å B=25-351.
3BUO X-ray 2.6Å B/D=25-351.
3BUW X-ray 1.4Å B/D=25-351.
3BUX X-ray 1.3Å B/D=25-351.
3OB1 X-ray 2.2Å B=25-351.
3OB2 X-ray 2.1Å B=25-351.
3PLF X-ray 1.9Å B/D=25-351.
4A49 X-ray 2.2Å A=354-435.
4A4B X-ray 2.7Å A=47-435.
4A4C X-ray 2.7Å A=47-435.
4GPL X-ray 3.0Å B=47-351.
5J3X X-ray 2.8Å A/B/C/D/E/F=47-435.

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

HIV Partner Interaction Type PubMed
Nef induces phosphorylation of 15892963
Nef induces complex with 16356860

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04012 ErbB signaling pathway - Homo sapiens (human)
hsa04120 Ubiquitin mediated proteolysis - Homo sapiens (human)
hsa04144 Endocytosis - Homo sapiens (human)
hsa04660 T cell receptor signaling pathway - Homo sapiens (human)
hsa04910 Insulin signaling pathway - Homo sapiens (human)
hsa05100 Bacterial invasion of epithelial cells - Homo sapiens (human)
hsa05200 Pathways in cancer - Homo sapiens (human)
hsa05205 Proteoglycans in cancer - Homo sapiens (human)
hsa05220 Chronic myeloid leukemia - Homo sapiens (human)