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Protein

E3 ubiquitin-protein ligase CBL

Gene

Cbl

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Adapter 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-737' 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 (PubMed:10393178, PubMed:12649282, PubMed:19265199, PubMed:20100865, PubMed:9653117). In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA (PubMed:29237719).6 Publications

Miscellaneous

This protein has one functional calcium-binding site.By similarity

Catalytic activityi

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[acceptor protein]-L-lysine.2 Publications

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei292PhosphotyrosineBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Calcium bindingi225 – 238PROSITE-ProRule annotationAdd BLAST14
Zinc fingeri379 – 418RING-typePROSITE-ProRule annotationAdd BLAST40

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionTransferase
Biological processUbl conjugation pathway
LigandCalcium, Metal-binding, Zinc

Enzyme and pathway databases

BRENDAi6.3.2.19 3474
ReactomeiR-MMU-1059683 Interleukin-6 signaling
R-MMU-1295596 Spry regulation of FGF signaling
R-MMU-1433559 Regulation of KIT signaling
R-MMU-182971 EGFR downregulation
R-MMU-2173789 TGF-beta receptor signaling activates SMADs
R-MMU-5654726 Negative regulation of FGFR1 signaling
R-MMU-5654727 Negative regulation of FGFR2 signaling
R-MMU-5654732 Negative regulation of FGFR3 signaling
R-MMU-5654733 Negative regulation of FGFR4 signaling
R-MMU-6807004 Negative regulation of MET activity
R-MMU-8849469 PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1
R-MMU-8856825 Cargo recognition for clathrin-mediated endocytosis
R-MMU-8856828 Clathrin-mediated endocytosis
R-MMU-912631 Regulation of signaling by CBL
R-MMU-983695 Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
UniPathwayi
UPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase CBL (EC:2.3.2.272 Publications)
Alternative name(s):
Casitas B-lineage lymphoma proto-oncogene
Proto-oncogene c-Cbl
RING-type E3 ubiquitin transferase CBLCurated
Signal transduction protein CBL
Gene namesi
Name:Cbl
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:88279 Cbl

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasm, Golgi apparatus, Membrane

Pathology & Biotechi

Involvement in diseasei

Can be converted to an oncogenic protein by deletions or mutations that disturb its ability to down-regulate RTKs.

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi304G → E: Abolishes interaction with ZAP70, but does not affect interaction with SLA. 1 Publication1

Keywords - Diseasei

Proto-oncogene

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000558591 – 913E3 ubiquitin-protein ligase CBLAdd BLAST913

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei369PhosphotyrosineBy similarity1
Modified residuei437PhosphoserineBy similarity1
Modified residuei450PhosphoserineBy similarity1
Modified residuei481PhosphoserineBy similarity1
Modified residuei617PhosphoserineCombined sources1
Modified residuei640PhosphoserineCombined sources1
Modified residuei666PhosphoserineCombined sources1
Modified residuei667PhosphoserineCombined sources1
Modified residuei672PhosphotyrosineCombined sources1
Modified residuei692PhosphoserineCombined sources1
Modified residuei698Phosphotyrosine; by ABL1By similarity1
Modified residuei737Phosphotyrosine; by SRCBy similarity1
Modified residuei780PhosphotyrosineBy similarity1
Modified residuei907PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylated on tyrosine residues by ALK, EGFR, FGR, INSR, SYK, FYN and ZAP70. Phosphorylated on several tyrosine residues by constitutively activated FGFR3. Phosphorylated on tyrosine residues by activated PDGFRA and PDGFRB (By similarity). Phosphorylated on tyrosine residues in response to CSF1R, FLT1 and KIT signaling. Phosphorylated on tyrosine residues by HCK.By similarity8 Publications
Ubiquitinated, leading to its degradation via the proteasome. Ubiquitination is negatively regulated by IFT20.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP22682
MaxQBiP22682
PaxDbiP22682
PeptideAtlasiP22682
PRIDEiP22682

PTM databases

iPTMnetiP22682
PhosphoSitePlusiP22682

Expressioni

Gene expression databases

BgeeiENSMUSG00000034342 Expressed in 271 organ(s), highest expression level in thymus
CleanExiMM_CBL
ExpressionAtlasiP22682 baseline and differential
GenevisibleiP22682 MM

Interactioni

Subunit structurei

Forms homodimers; IFT20 promotes the formation of stable homodimers (By similarity). Interacts (phosphorylated) with PIK3R1. Interacts with phosphorylated LAT2 (By similarity). Associates with NCK via its SH3 domain. The phosphorylated C-terminus interacts with CD2AP via its second SH3 domain. Binds to UBE2L3. Interacts with adapters SLA, SLA2 and with the phosphorylated C-terminus of SH2B2. Interacts with EGFR, SYK and ZAP70 via the highly conserved Cbl-N region. Interacts with FGR. Also interacts with BLK, SORBS1 and INPPL1/SHIP2. Interacts with CBLB. Interacts with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with ALK, AXL and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates receptor degradation through ubiquitination. Interacts with HCK and LYN. Interacts with ATX2. Interacts with SH3KBP1 and this interaction is inhibited in the presence of SHKBP1 (PubMed:21830225). Interacts with SIGLEC10 (PubMed:23374343). Interacts with IFT20 (By similarity).By similarity14 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi198527, 54 interactors
CORUMiP22682
DIPiDIP-33472N
IntActiP22682, 111 interactors
MINTiP22682
STRINGi10090.ENSMUSP00000041902

Structurei

Secondary structure

1913
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP22682
SMRiP22682
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP22682

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini45 – 349Cbl-PTBPROSITE-ProRule annotationAdd BLAST305
Domaini863 – 902UBAPROSITE-ProRule annotationAdd BLAST40

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 355Sufficient for interaction with EPHB11 PublicationAdd BLAST355
Regioni45 – 1734HAdd BLAST129
Regioni174 – 246EF-hand-likeAdd BLAST73
Regioni247 – 349SH2-likeAdd BLAST103
Regioni350 – 378LinkerAdd BLAST29
Regioni646 – 913Interaction with CD2APBy similarityAdd BLAST268

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi372 – 474Asp/Glu-rich (acidic)Add BLAST103
Compositional biasi475 – 686Pro-richAdd BLAST212
Compositional biasi687 – 839Asp/Glu-rich (acidic)Add BLAST153

Domaini

The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.By similarity
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.

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri379 – 418RING-typePROSITE-ProRule annotationAdd BLAST40

Keywords - Domaini

Repeat, Zinc-finger

Phylogenomic databases

eggNOGiKOG1785 Eukaryota
ENOG410YDNH LUCA
GeneTreeiENSGT00390000011617
HOGENOMiHOG000294176
HOVERGENiHBG005255
InParanoidiP22682
KOiK04707
OrthoDBiEOG091G0GPE
TreeFamiTF314210

Family and domain databases

CDDicd16709 RING-HC_Cbl-b, 1 hit
cd09920 SH2_Cbl-b_TKB, 1 hit
Gene3Di1.20.930.20, 1 hit
3.30.40.10, 1 hit
3.30.505.10, 1 hit
InterProiView protein in InterPro
IPR024162 Adaptor_Cbl
IPR014741 Adaptor_Cbl_EF_hand-like
IPR036537 Adaptor_Cbl_N_dom_sf
IPR003153 Adaptor_Cbl_N_hlx
IPR014742 Adaptor_Cbl_SH2-like
IPR039520 CBL-B_RING-HC
IPR024159 Cbl_PTB
IPR011992 EF-hand-dom_pair
IPR036860 SH2_dom_sf
IPR015940 UBA
IPR009060 UBA-like_sf
IPR001841 Znf_RING
IPR013083 Znf_RING/FYVE/PHD
IPR017907 Znf_RING_CS
PANTHERiPTHR23007 PTHR23007, 1 hit
PfamiView protein in Pfam
PF02262 Cbl_N, 1 hit
PF02761 Cbl_N2, 1 hit
PF02762 Cbl_N3, 1 hit
PF00627 UBA, 1 hit
SMARTiView protein in SMART
SM00184 RING, 1 hit
SM00165 UBA, 1 hit
SUPFAMiSSF46934 SSF46934, 1 hit
SSF47473 SSF47473, 1 hit
SSF47668 SSF47668, 1 hit
SSF55550 SSF55550, 1 hit
PROSITEiView protein in PROSITE
PS51506 CBL_PTB, 1 hit
PS50030 UBA, 1 hit
PS00518 ZF_RING_1, 1 hit
PS50089 ZF_RING_2, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 6 potential isoforms that are computationally mapped.Show allAlign All

P22682-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MAGNVKKSSG AGGGGSGGSG AGGLIGLMKD AFQPHHHHHH LSPHPPCTVD
60 70 80 90 100
KKMVEKCWKL MDKVVRLCQN PKLALKNSPP YILDLLPDTY QHLRTVLSRY
110 120 130 140 150
EGKMETLGEN EYFRVFMENL MKKTKQTISL FKEGKERMYE ENSQPRRNLT
160 170 180 190 200
KLSLIFSHML AELKGIFPSG LFQGDTFRIT KADAAEFWRK AFGEKTIVPW
210 220 230 240 250
KSFRQALHEV HPISSGLEAM ALKSTIDLTC NDYISVFEFD IFTRLFQPWS
260 270 280 290 300
SLLRNWNSLA VTHPGYMAFL TYDEVKARLQ KFIHKPGSYI FRLSCTRLGQ
310 320 330 340 350
WAIGYVTADG NILQTIPHNK PLFQALIDGF REGFYLFPDG RNQNPDLTGL
360 370 380 390 400
CEPTPQDHIK VTQEQYELYC EMGSTFQLCK ICAENDKDVK IEPCGHLMCT
410 420 430 440 450
SCLTSWQESE GQGCPFCRCE IKGTEPIVVD PFDPRGSGSL LRQGAEGAPS
460 470 480 490 500
PNYDDDDDER ADDSLFMMKE LAGAKVERPS SPFSMAPQAS LPPVPPRLDL
510 520 530 540 550
LQQRAPVPAS TSVLGTASKA ASGSLHKDKP LPIPPTLRDL PPPPPPDRPY
560 570 580 590 600
SVGAETRPQR RPLPCTPGDC PSRDKLPPVP SSRPGDSWLS RPIPKVPVAT
610 620 630 640 650
PNPGDPWNGR ELTNRHSLPF SLPSQMEPRA DVPRLGSTFS LDTSMTMNSS
660 670 680 690 700
PVAGPESEHP KIKPSSSANA IYSLAARPLP MPKLPPGEQG ESEEDTEYMT
710 720 730 740 750
PTSRPVGVQK PEPKRPLEAT QSSRACDCDQ QIDSCTYEAM YNIQSQALSV
760 770 780 790 800
AENSASGEGN LATAHTSTGP EESENEDDGY DVPKPPVPAV LARRTLSDIS
810 820 830 840 850
NASSSFGWLS LDGDPTNFNE GSQVPERPPK PFPRRINSER KASSYQQGGG
860 870 880 890 900
ATANPVATAP SPQLSSEIER LMSQGYSYQD IQKALVIAHN NIEMAKNILR
910
EFVSISSPAH VAT
Length:913
Mass (Da):100,564
Last modified:July 27, 2011 - v3
Checksum:i22F8A5C29F0262B8
GO

Computationally mapped potential isoform sequencesi

There are 6 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A0X1KG61A0A0X1KG61_MOUSE
E3 ubiquitin-protein ligase CBL
Cbl
869Annotation score:
A0A0U1RQ85A0A0U1RQ85_MOUSE
E3 ubiquitin-protein ligase CBL
Cbl
896Annotation score:
A0A0U1RP47A0A0U1RP47_MOUSE
E3 ubiquitin-protein ligase CBL
Cbl
895Annotation score:
A0A0U1RP17A0A0U1RP17_MOUSE
E3 ubiquitin-protein ligase CBL
Cbl
51Annotation score:
A0A0U1RP95A0A0U1RP95_MOUSE
E3 ubiquitin-protein ligase CBL
Cbl
79Annotation score:
A0A0U1RNF1A0A0U1RNF1_MOUSE
E3 ubiquitin-protein ligase CBL
Cbl
69Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti72 – 73KL → NV in CAA40394 (PubMed:2030914).Curated2
Sequence conflicti218E → D in BAC26087 (PubMed:16141072).Curated1
Sequence conflicti592P → T in CAA40394 (PubMed:2030914).Curated1
Sequence conflicti742N → T in CAA40394 (PubMed:2030914).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti364 – 380Missing in oncogenic variant 70Z/3. Add BLAST17

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X57111 mRNA Translation: CAA40394.1
AK028730 mRNA Translation: BAC26087.1
AK153915 mRNA Translation: BAE32253.1
BC125285 mRNA Translation: AAI25286.1
CCDSiCCDS40598.1
PIRiB43817
RefSeqiNP_031645.2, NM_007619.2
UniGeneiMm.266871

Genome annotation databases

EnsembliENSMUST00000206720; ENSMUSP00000146244; ENSMUSG00000034342
GeneIDi12402
KEGGimmu:12402
UCSCiuc009pce.1 mouse

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X57111 mRNA Translation: CAA40394.1
AK028730 mRNA Translation: BAC26087.1
AK153915 mRNA Translation: BAE32253.1
BC125285 mRNA Translation: AAI25286.1
CCDSiCCDS40598.1
PIRiB43817
RefSeqiNP_031645.2, NM_007619.2
UniGeneiMm.266871

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2D9SNMR-A/B863-902[»]
ProteinModelPortaliP22682
SMRiP22682
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198527, 54 interactors
CORUMiP22682
DIPiDIP-33472N
IntActiP22682, 111 interactors
MINTiP22682
STRINGi10090.ENSMUSP00000041902

PTM databases

iPTMnetiP22682
PhosphoSitePlusiP22682

Proteomic databases

EPDiP22682
MaxQBiP22682
PaxDbiP22682
PeptideAtlasiP22682
PRIDEiP22682

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000206720; ENSMUSP00000146244; ENSMUSG00000034342
GeneIDi12402
KEGGimmu:12402
UCSCiuc009pce.1 mouse

Organism-specific databases

CTDi867
MGIiMGI:88279 Cbl

Phylogenomic databases

eggNOGiKOG1785 Eukaryota
ENOG410YDNH LUCA
GeneTreeiENSGT00390000011617
HOGENOMiHOG000294176
HOVERGENiHBG005255
InParanoidiP22682
KOiK04707
OrthoDBiEOG091G0GPE
TreeFamiTF314210

Enzyme and pathway databases

UniPathwayi
UPA00143

BRENDAi6.3.2.19 3474
ReactomeiR-MMU-1059683 Interleukin-6 signaling
R-MMU-1295596 Spry regulation of FGF signaling
R-MMU-1433559 Regulation of KIT signaling
R-MMU-182971 EGFR downregulation
R-MMU-2173789 TGF-beta receptor signaling activates SMADs
R-MMU-5654726 Negative regulation of FGFR1 signaling
R-MMU-5654727 Negative regulation of FGFR2 signaling
R-MMU-5654732 Negative regulation of FGFR3 signaling
R-MMU-5654733 Negative regulation of FGFR4 signaling
R-MMU-6807004 Negative regulation of MET activity
R-MMU-8849469 PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1
R-MMU-8856825 Cargo recognition for clathrin-mediated endocytosis
R-MMU-8856828 Clathrin-mediated endocytosis
R-MMU-912631 Regulation of signaling by CBL
R-MMU-983695 Antigen activates B Cell Receptor (BCR) leading to generation of second messengers

Miscellaneous databases

ChiTaRSiCbl mouse
EvolutionaryTraceiP22682
PROiPR:P22682
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000034342 Expressed in 271 organ(s), highest expression level in thymus
CleanExiMM_CBL
ExpressionAtlasiP22682 baseline and differential
GenevisibleiP22682 MM

Family and domain databases

CDDicd16709 RING-HC_Cbl-b, 1 hit
cd09920 SH2_Cbl-b_TKB, 1 hit
Gene3Di1.20.930.20, 1 hit
3.30.40.10, 1 hit
3.30.505.10, 1 hit
InterProiView protein in InterPro
IPR024162 Adaptor_Cbl
IPR014741 Adaptor_Cbl_EF_hand-like
IPR036537 Adaptor_Cbl_N_dom_sf
IPR003153 Adaptor_Cbl_N_hlx
IPR014742 Adaptor_Cbl_SH2-like
IPR039520 CBL-B_RING-HC
IPR024159 Cbl_PTB
IPR011992 EF-hand-dom_pair
IPR036860 SH2_dom_sf
IPR015940 UBA
IPR009060 UBA-like_sf
IPR001841 Znf_RING
IPR013083 Znf_RING/FYVE/PHD
IPR017907 Znf_RING_CS
PANTHERiPTHR23007 PTHR23007, 1 hit
PfamiView protein in Pfam
PF02262 Cbl_N, 1 hit
PF02761 Cbl_N2, 1 hit
PF02762 Cbl_N3, 1 hit
PF00627 UBA, 1 hit
SMARTiView protein in SMART
SM00184 RING, 1 hit
SM00165 UBA, 1 hit
SUPFAMiSSF46934 SSF46934, 1 hit
SSF47473 SSF47473, 1 hit
SSF47668 SSF47668, 1 hit
SSF55550 SSF55550, 1 hit
PROSITEiView protein in PROSITE
PS51506 CBL_PTB, 1 hit
PS50030 UBA, 1 hit
PS00518 ZF_RING_1, 1 hit
PS50089 ZF_RING_2, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiCBL_MOUSE
AccessioniPrimary (citable) accession number: P22682
Secondary accession number(s): Q3U527, Q8CEA1
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1991
Last sequence update: July 27, 2011
Last modified: November 7, 2018
This is version 193 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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