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Protein

E3 ubiquitin-protein ligase CBL

Gene

Cbl

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 UB2D3.5 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

Complete GO annotation...

Keywords - Molecular functioni

Ligase

Keywords - Biological processi

Ubl conjugation pathway

Keywords - Ligandi

Calcium, 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.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase CBL (EC:6.3.2.-)
Alternative name(s):
Casitas B-lineage lymphoma proto-oncogene
Proto-oncogene c-Cbl
Signal transduction protein CBL
Gene namesi
Name:Cbl
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:88279. Cbl.

Subcellular locationi

  • Cytoplasm
  • Cell membrane By similarity

  • Note: Colocalizes with FGFR2 in lipid rafts at the cell membrane.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, 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.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP22682.
MaxQBiP22682.
PaxDbiP22682.
PeptideAtlasiP22682.
PRIDEiP22682.

PTM databases

iPTMnetiP22682.
PhosphoSitePlusiP22682.

Expressioni

Gene expression databases

BgeeiENSMUSG00000034342.
CleanExiMM_CBL.
ExpressionAtlasiP22682. baseline and differential.
GenevisibleiP22682. MM.

Interactioni

Subunit structurei

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. May interact 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).By similarity13 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Ddx58Q6Q8993EBI-640919,EBI-6841237
EGFRP005332EBI-640919,EBI-297353From a different organism.
EgfrQ012792EBI-640919,EBI-6296235
MetP160562EBI-640919,EBI-1798780

GO - Molecular functioni

  • cadherin binding involved in cell-cell adhesion Source: MGI
  • ephrin receptor binding Source: UniProtKB
  • receptor tyrosine kinase binding Source: GO_Central
  • SH3 domain binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi198527. 55 interactors.
DIPiDIP-33472N.
IntActiP22682. 16 interactors.
MINTiMINT-255892.
STRINGi10090.ENSMUSP00000041902.

Structurei

Secondary structure

1913
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi865 – 874Combined sources10
Helixi878 – 887Combined sources10
Turni888 – 890Combined sources3
Helixi892 – 902Combined sources11

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...

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.

Sequence similaritiesi

Contains 1 Cbl-PTB (Cbl-type phosphotyrosine-binding) domain.PROSITE-ProRule annotation
Contains 1 RING-type zinc finger.PROSITE-ProRule annotation
Contains 1 UBA domain.PROSITE-ProRule annotation

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.
OMAiEQCESEE.
OrthoDBiEOG091G0GPE.
TreeFamiTF314210.

Family and domain databases

CDDicd09920. SH2_Cbl-b_TKB. 1 hit.
Gene3Di1.10.238.10. 1 hit.
1.20.930.20. 1 hit.
3.30.40.10. 1 hit.
3.30.505.10. 1 hit.
InterProiIPR024162. Adaptor_Cbl.
IPR014741. Adaptor_Cbl_EF_hand-like.
IPR003153. Adaptor_Cbl_N_hlx.
IPR014742. Adaptor_Cbl_SH2-like.
IPR024159. Cbl_PTB.
IPR011992. EF-hand-dom_pair.
IPR000980. SH2.
IPR015940. UBA.
IPR009060. UBA-like.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PANTHERiPTHR23007. PTHR23007. 1 hit.
PfamiPF02262. Cbl_N. 1 hit.
PF02761. Cbl_N2. 1 hit.
PF02762. Cbl_N3. 1 hit.
PF00627. UBA. 1 hit.
[Graphical view]
SMARTiSM00184. RING. 1 hit.
SM00165. UBA. 1 hit.
[Graphical view]
SUPFAMiSSF46934. SSF46934. 1 hit.
SSF47473. SSF47473. 1 hit.
SSF47668. SSF47668. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEiPS51506. CBL_PTB. 1 hit.
PS50030. UBA. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

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

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. 55 interactors.
DIPiDIP-33472N.
IntActiP22682. 16 interactors.
MINTiMINT-255892.
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.
OMAiEQCESEE.
OrthoDBiEOG091G0GPE.
TreeFamiTF314210.

Enzyme and pathway databases

UniPathwayiUPA00143.
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.
PROiP22682.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000034342.
CleanExiMM_CBL.
ExpressionAtlasiP22682. baseline and differential.
GenevisibleiP22682. MM.

Family and domain databases

CDDicd09920. SH2_Cbl-b_TKB. 1 hit.
Gene3Di1.10.238.10. 1 hit.
1.20.930.20. 1 hit.
3.30.40.10. 1 hit.
3.30.505.10. 1 hit.
InterProiIPR024162. Adaptor_Cbl.
IPR014741. Adaptor_Cbl_EF_hand-like.
IPR003153. Adaptor_Cbl_N_hlx.
IPR014742. Adaptor_Cbl_SH2-like.
IPR024159. Cbl_PTB.
IPR011992. EF-hand-dom_pair.
IPR000980. SH2.
IPR015940. UBA.
IPR009060. UBA-like.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PANTHERiPTHR23007. PTHR23007. 1 hit.
PfamiPF02262. Cbl_N. 1 hit.
PF02761. Cbl_N2. 1 hit.
PF02762. Cbl_N3. 1 hit.
PF00627. UBA. 1 hit.
[Graphical view]
SMARTiSM00184. RING. 1 hit.
SM00165. UBA. 1 hit.
[Graphical view]
SUPFAMiSSF46934. SSF46934. 1 hit.
SSF47473. SSF47473. 1 hit.
SSF47668. SSF47668. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEiPS51506. CBL_PTB. 1 hit.
PS50030. UBA. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCBL_MOUSE
AccessioniPrimary (citable) accession number: P22682
Secondary accession number(s): Q3U527, Q8CEA1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 1, 1991
Last sequence update: July 27, 2011
Last modified: November 30, 2016
This is version 176 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

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

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
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.