Human Gene CBLB (ENST00000403724.5) from GENCODE V44
  Description: E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B- cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T- cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. May also be involved in EGFR ubiquitination and internalization. (from UniProt Q13191)
RefSeq Summary (NM_170662): This gene encodes an E3 ubiquitin-protein ligase which promotes proteosome-mediated protein degradation by transferring ubiquitin from an E2 ubiquitin-conjugating enzyme to a substrate. The encoded protein is involved in the regulation of immune response by limiting T-cell receptor, B-cell receptor, and high affinity immunoglobulin epsilon receptor activation. Studies in mouse suggest that this gene is involved in antifungal host defense and that its inhibition leads to increased fungal killing. Manipulation of this gene may be beneficial in implementing immunotherapies for a variety of conditions, including cancer, autoimmune diseases, allergies, and infections. [provided by RefSeq, Sep 2017].
Gencode Transcript: ENST00000403724.5
Gencode Gene: ENSG00000114423.23
Transcript (Including UTRs)
   Position: hg38 chr3:105,680,992-105,869,043 Size: 188,052 Total Exon Count: 15 Strand: -
Coding Region
   Position: hg38 chr3:105,681,707-105,867,577 Size: 185,871 Coding Exon Count: 14 

Page IndexSequence and LinksUniProtKB CommentsPrimersCTDRNA-Seq Expression
Microarray ExpressionRNA StructureProtein StructureOther SpeciesGO AnnotationsmRNA Descriptions
PathwaysOther NamesMethods
Data last updated at UCSC: 2023-08-18 00:09:47

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr3:105,680,992-105,869,043)mRNA (may differ from genome)Protein (770 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
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ReactomeUniProtKBWikipedia

-  Comments and Description Text from UniProtKB
  ID: CBLB_HUMAN
DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase CBL-B; EC=6.3.2.-; AltName: Full=Casitas B-lineage lymphoma proto-oncogene b; AltName: Full=RING finger protein 56; AltName: Full=SH3-binding protein CBL-B; AltName: Full=Signal transduction protein CBL-B;
FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B- cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T- cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. May also be involved in EGFR ubiquitination and internalization.
PATHWAY: Protein modification; protein ubiquitination.
SUBUNIT: Interacts with SH3 domain-containing proteins LCK, CRK and SORBS1. Interacts with LCP2 and ZAP70. May interact with CBL (By similarity). Interacts with SH3 domain-containing proteins VAV1, FYN, FGR, PLCG1, GRB2, CRKL, PIK3R1 and SH3KBP1/CIN85. Identified in heterotrimeric complexes with SH3KBP1/CIN85, CD2AP and ARHGEF7, where one CBLB peptide binds two copies of the other protein. Interacts with poly-ubiquitinated proteins. Dimerization is required for the binding of poly-ubiquitin, but not for the binding of mono-ubiquitin.
INTERACTION: P62993:GRB2; NbExp=4; IntAct=EBI-744027, EBI-401755;
SUBCELLULAR LOCATION: Cytoplasm. Note=Upon EGF stimulation, associates with endocytic vesicles.
TISSUE SPECIFICITY: Expressed in placenta, heart, lung, kidney, spleen, ovary and testis, as well as fetal brain and liver and hematopoietic cell lines, but not in adult brain, liver, pancreas, salivary gland, or skeletal muscle. Present in lymphocytes (at protein level).
DOMAIN: The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain.
DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.
DOMAIN: The UBA domain interacts with poly-ubiquitinated proteins.
PTM: Phosphorylated on tyrosine and serine residues upon TCR or BCR activation, and upon various types of cell stimulation.
PTM: Auto-ubiquitinated upon EGF-mediated cell activation or upon T-cell costimulation by CD28; which promotes proteasomal degradation.
MISCELLANEOUS: This protein has one functional calcium-binding site (By similarity).
SIMILARITY: Contains 1 Cbl-PTB (Cbl-type phosphotyrosine-binding) domain.
SIMILARITY: Contains 1 RING-type zinc finger.
SIMILARITY: Contains 1 UBA domain.
SEQUENCE CAUTION: Sequence=BAE45748.1; Type=Erroneous termination; Positions=904; Note=Translated as Arg; Sequence=CAH56175.1; Type=Erroneous initiation;
WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/CBLbID193.html";

-  Primer design for this transcript
 

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-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene
  • D001564 Benzo(a)pyrene
  • D013749 Tetrachlorodibenzodioxin
  • C006253 pirinixic acid
  • C517041 (4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)
  • D015655 1-Methyl-4-phenylpyridinium
  • C029497 2,3-bis(3'-hydroxybenzyl)butyrolactone
  • C016403 2,4-dinitrotoluene
  • C023514 2,6-dinitrotoluene
  • C035207 4-amino-2,6-dinitrotoluene
  • C027576 4-hydroxy-2-nonenal
          more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 12.90 RPKM in Adipose - Subcutaneous
Total median expression: 258.71 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -150.00322-0.466 Picture PostScript Text
3' UTR -152.80715-0.214 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR024162 - Adaptor_Cbl
IPR014741 - Adaptor_Cbl_EF_hand-like
IPR003153 - Adaptor_Cbl_N_hlx
IPR014742 - Adaptor_Cbl_SH2-like
IPR024159 - Cbl_PTB
IPR011992 - EF-hand-like_dom
IPR000980 - SH2
IPR000449 - UBA/transl_elong_EF1B_N
IPR015940 - UBA/transl_elong_EF1B_N_euk
IPR001841 - Znf_RING
IPR013083 - Znf_RING/FYVE/PHD
IPR017907 - Znf_RING_CS

Pfam Domains:
PF02262 - CBL proto-oncogene N-terminal domain 1
PF02761 - CBL proto-oncogene N-terminus, EF hand-like domain
PF02762 - CBL proto-oncogene N-terminus, SH2-like domain
PF00627 - UBA/TS-N domain

Protein Data Bank (PDB) 3-D Structure
MuPIT help
2AK5 - X-ray 2BZ8 - X-ray MuPIT 2DO6 - NMR MuPIT 2J6F - X-ray MuPIT 2JNH - NMR MuPIT 2LDR - NMR MuPIT 2OOA - X-ray MuPIT 2OOB - X-ray MuPIT 3PFV - X-ray MuPIT 3VGO - X-ray MuPIT


ModBase Predicted Comparative 3D Structure on Q13191
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-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
MGIRGD    
Protein SequenceProtein Sequence    
AlignmentAlignment    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0001784 phosphotyrosine binding
GO:0004842 ubiquitin-protein transferase activity
GO:0005509 calcium ion binding
GO:0005515 protein binding
GO:0008270 zinc ion binding
GO:0016740 transferase activity
GO:0017124 SH3 domain binding
GO:0030971 receptor tyrosine kinase binding
GO:0046872 metal ion binding
GO:0061630 ubiquitin protein ligase activity

Biological Process:
GO:0006508 proteolysis
GO:0006607 NLS-bearing protein import into nucleus
GO:0007165 signal transduction
GO:0007166 cell surface receptor signaling pathway
GO:0007173 epidermal growth factor receptor signaling pathway
GO:0007175 negative regulation of epidermal growth factor-activated receptor activity
GO:0016567 protein ubiquitination
GO:0023051 regulation of signaling

Cellular Component:
GO:0005654 nucleoplasm
GO:0005737 cytoplasm
GO:0005829 cytosol
GO:0005886 plasma membrane
GO:0045121 membrane raft


-  Descriptions from all associated GenBank mRNAs
  KJ896545 - Synthetic construct Homo sapiens clone ccsbBroadEn_05939 CBLB gene, encodes complete protein.
KR709530 - Synthetic construct Homo sapiens clone CCSBHm_00002954 CBLB (CBLB) mRNA, encodes complete protein.
KR709531 - Synthetic construct Homo sapiens clone CCSBHm_00002955 CBLB (CBLB) mRNA, encodes complete protein.
KR709532 - Synthetic construct Homo sapiens clone CCSBHm_00002956 CBLB (CBLB) mRNA, encodes complete protein.
KR709533 - Synthetic construct Homo sapiens clone CCSBHm_00002958 CBLB (CBLB) mRNA, encodes complete protein.
LF210628 - JP 2014500723-A/18131: Polycomb-Associated Non-Coding RNAs.
MA446205 - JP 2018138019-A/18131: Polycomb-Associated Non-Coding RNAs.
LF213805 - JP 2014500723-A/21308: Polycomb-Associated Non-Coding RNAs.
MA449382 - JP 2018138019-A/21308: Polycomb-Associated Non-Coding RNAs.
U26710 - Human cbl-b mRNA, complete cds.
AK292792 - Homo sapiens cDNA FLJ77240 complete cds, highly similar to Homo sapiens Cas-Br-M (murine) ecotropic retroviral transforming sequence b (CBLB), mRNA.
BC032851 - Homo sapiens Cas-Br-M (murine) ecotropic retroviral transforming sequence b, mRNA (cDNA clone MGC:33110 IMAGE:5269036), complete cds.
AK094184 - Homo sapiens cDNA FLJ36865 fis, clone ASTRO2016148, highly similar to E3 ubiquitin-protein ligase CBL-B (EC 6.3.2.-).
AK316276 - Homo sapiens cDNA, FLJ79175 complete cds, highly similar to E3 ubiquitin-protein ligase CBL-B (EC 6.3.2.-).
AK302533 - Homo sapiens cDNA FLJ56894 complete cds, highly similar to E3 ubiquitin-protein ligase CBL-B (EC 6.3.2.-).
EU176266 - Synthetic construct Homo sapiens clone IMAGE:100006378; FLH170562.01X; RZPDo839F10250D Cas-Br-M (murine) ecotropic retroviral transforming sequence b (CBLB) gene, encodes complete protein.
DQ349203 - Homo sapiens CBL-B mRNA, complete cds.
DQ349204 - Homo sapiens CBL-B variant mRNA, complete cds.
DQ894452 - Synthetic construct Homo sapiens clone IMAGE:100008912; FLH170555.01L; RZPDo839G0997D Cas-Br-M (murine) ecotropic retroviral transforming sequence b (CBLB) gene, encodes complete protein.
AB590326 - Synthetic construct DNA, clone: pFN21AE1387, Homo sapiens CBLB gene for Cas-Br-M (murine) ecotropic retroviral transforming sequence b, without stop codon, in Flexi system.
U26711 - Human cbl-b truncated form 1 lacking leucine zipper mRNA, complete cds.
U26712 - Human cbl-b truncated form 2 lacking leucine zipper mRNA, complete cds.
AK302892 - Homo sapiens cDNA FLJ52897 complete cds, moderately similar to E3 ubiquitin-protein ligase CBL-B (EC 6.3.2.-).
CU689562 - Synthetic construct Homo sapiens gateway clone IMAGE:100017873 5' read CBLB mRNA.
CR749655 - Homo sapiens mRNA; cDNA DKFZp779A0729 (from clone DKFZp779A0729).
BX649066 - Homo sapiens mRNA; cDNA DKFZp779F1443 (from clone DKFZp779F1443).
AB075490 - Homo sapiens neuroblastoma cDNA, clone:Nbla00127, full insert sequence.
AK123147 - Homo sapiens cDNA FLJ41152 fis, clone BRACE2038329, highly similar to E3 ubiquitin-protein ligase CBL-B (EC 6.3.2.-).
JD084788 - Sequence 65812 from Patent EP1572962.
LF339534 - JP 2014500723-A/147037: Polycomb-Associated Non-Coding RNAs.
MA575111 - JP 2018138019-A/147037: Polycomb-Associated Non-Coding RNAs.
JD269931 - Sequence 250955 from Patent EP1572962.
LF339529 - JP 2014500723-A/147032: Polycomb-Associated Non-Coding RNAs.
MA575106 - JP 2018138019-A/147032: Polycomb-Associated Non-Coding RNAs.
LF339519 - JP 2014500723-A/147022: Polycomb-Associated Non-Coding RNAs.
MA575096 - JP 2018138019-A/147022: Polycomb-Associated Non-Coding RNAs.
LF339490 - JP 2014500723-A/146993: Polycomb-Associated Non-Coding RNAs.
MA575067 - JP 2018138019-A/146993: Polycomb-Associated Non-Coding RNAs.
LF339483 - JP 2014500723-A/146986: Polycomb-Associated Non-Coding RNAs.
MA575060 - JP 2018138019-A/146986: Polycomb-Associated Non-Coding RNAs.
JD259604 - Sequence 240628 from Patent EP1572962.
JD386597 - Sequence 367621 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04012 - ErbB signaling pathway
hsa04120 - Ubiquitin mediated proteolysis
hsa04144 - Endocytosis
hsa04630 - Jak-STAT signaling pathway
hsa04660 - T cell receptor signaling pathway
hsa04910 - Insulin signaling pathway
hsa05100 - Bacterial invasion of epithelial cells
hsa05200 - Pathways in cancer
hsa05220 - Chronic myeloid leukemia

Reactome (by CSHL, EBI, and GO)

Protein Q13191 (Reactome details) participates in the following event(s):

R-HSA-983703 p-6Y-SYK phosphorylates BLNK (SLP65)
R-HSA-983157 Interaction of E3 with substrate and E2-Ub complex
R-HSA-983147 Release of E3 from polyubiquitinated substrate
R-HSA-983140 Transfer of Ub from E2 to substrate and release of E2
R-HSA-1112666 BLNK (SLP-65) Signalosome hydrolyzes phosphatidyinositol bisphosphate forming diacylglycerol and inositol-1,4,5-trisphosphate
R-HSA-983695 Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-983705 Signaling by the B Cell Receptor (BCR)
R-HSA-983169 Class I MHC mediated antigen processing & presentation
R-HSA-1280218 Adaptive Immune System
R-HSA-168256 Immune System

-  Other Names for This Gene
  Alternate Gene Symbols: A8K9S7, B7WNM4, CBLB_HUMAN, ENST00000403724.1, ENST00000403724.2, ENST00000403724.3, ENST00000403724.4, Nbla00127, Q13191, Q13192, Q13193, Q3LIC0, Q63Z43, Q8IVC5, RNF56, U26712, uc003dwe.1, uc003dwe.2, uc003dwe.3
UCSC ID: ENST00000403724.5
RefSeq Accession: NM_170662
Protein: Q13191 (aka CBLB_HUMAN)

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.