P22682 · CBL_MOUSE
- ProteinE3 ubiquitin-protein ligase CBL
- GeneCbl
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids913 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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. Ubiquitinates SPRY2 (By similarity).
Ubiquitinates EGFR (By similarity).
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).
Ubiquitinates EGFR (By similarity).
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).
Miscellaneous
This protein has one functional calcium-binding site.
Catalytic activity
Pathway
Protein modification; protein ubiquitination.
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 227 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 229 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: T | ||||||
Binding site | 231 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: N | ||||||
Binding site | 233 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: Y | ||||||
Binding site | 238 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 292 | 4-O-phospho-L-tyrosine (UniProtKB | ChEBI) | ||||
Sequence: R |
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameE3 ubiquitin-protein ligase CBL
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionP22682
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Colocalizes with FGFR2 in lipid rafts at the cell membrane.
Keywords
- Cellular component
Phenotypes & Variants
Involvement in disease
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 304 | Abolishes interaction with ZAP70, but does not affect interaction with SLA. | ||||
Sequence: G → E | ||||||
Natural variant | 364-380 | in oncogenic variant 70Z/3 | ||||
Sequence: Missing |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 48 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
PTM/Processing
Features
Showing features for chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000055859 | 1-913 | E3 ubiquitin-protein ligase CBL | |||
Sequence: MAGNVKKSSGAGGGGSGGSGAGGLIGLMKDAFQPHHHHHHLSPHPPCTVDKKMVEKCWKLMDKVVRLCQNPKLALKNSPPYILDLLPDTYQHLRTVLSRYEGKMETLGENEYFRVFMENLMKKTKQTISLFKEGKERMYEENSQPRRNLTKLSLIFSHMLAELKGIFPSGLFQGDTFRITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLFQPWSSLLRNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREGFYLFPDGRNQNPDLTGLCEPTPQDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPFDPRGSGSLLRQGAEGAPSPNYDDDDDERADDSLFMMKELAGAKVERPSSPFSMAPQASLPPVPPRLDLLQQRAPVPASTSVLGTASKAASGSLHKDKPLPIPPTLRDLPPPPPPDRPYSVGAETRPQRRPLPCTPGDCPSRDKLPPVPSSRPGDSWLSRPIPKVPVATPNPGDPWNGRELTNRHSLPFSLPSQMEPRADVPRLGSTFSLDTSMTMNSSPVAGPESEHPKIKPSSSANAIYSLAARPLPMPKLPPGEQGESEEDTEYMTPTSRPVGVQKPEPKRPLEATQSSRACDCDQQIDSCTYEAMYNIQSQALSVAENSASGEGNLATAHTSTGPEESENEDDGYDVPKPPVPAVLARRTLSDISNASSSFGWLSLDGDPTNFNEGSQVPERPPKPFPRRINSERKASSYQQGGGATANPVATAPSPQLSSEIERLMSQGYSYQDIQKALVIAHNNIEMAKNILREFVSISSPAHVAT | ||||||
Modified residue | 369 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Modified residue | 437 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 450 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 481 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 617 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 640 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 666 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 667 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 672 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Modified residue | 692 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 698 | Phosphotyrosine; by ABL1 | ||||
Sequence: Y | ||||||
Modified residue | 737 | Phosphotyrosine; by SRC | ||||
Sequence: Y | ||||||
Modified residue | 780 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Modified residue | 907 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
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
Phosphorylated on tyrosine residues in response to CSF1R, FLT1 and KIT signaling. Phosphorylated on tyrosine residues by HCK
Ubiquitinated, leading to its degradation via the proteasome. Ubiquitination is negatively regulated by IFT20.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Gene expression databases
Interaction
Subunit
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 (PubMed:18602463).
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).
Interacts with SPRY2; the interaction inhibits CBL-mediated ubiquitination of EGFR (By similarity).
Interacts (phosphorylated at Tyr-780) with tensin TNS4 (via SH2 domain); the interaction is enhanced in the presence of EGF and reduces interaction of CBL with EGFR (By similarity).
Interacts with EGFR; the interaction is reduced in the presence of TNS4 (By similarity).
Interacts with CD5 (By similarity).
Interacts with CD93 (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 (PubMed:18602463).
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).
Interacts with SPRY2; the interaction inhibits CBL-mediated ubiquitination of EGFR (By similarity).
Interacts (phosphorylated at Tyr-780) with tensin TNS4 (via SH2 domain); the interaction is enhanced in the presence of EGF and reduces interaction of CBL with EGFR (By similarity).
Interacts with EGFR; the interaction is reduced in the presence of TNS4 (By similarity).
Interacts with CD5 (By similarity).
Interacts with CD93 (By similarity).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P22682 | Cd2ap Q9JLQ0 | 5 | EBI-640919, EBI-644807 | |
BINARY | P22682 | Cd5 P13379 | 5 | EBI-640919, EBI-12600513 | |
BINARY | P22682 | Egfr Q01279 | 2 | EBI-640919, EBI-6296235 | |
XENO | P22682 | EGFR P00533 | 2 | EBI-640919, EBI-297353 | |
BINARY | P22682 | Fyn P39688 | 5 | EBI-640919, EBI-524514 | |
BINARY | P22682 | Met P16056 | 2 | EBI-640919, EBI-1798780 | |
BINARY | P22682 | Rigi Q6Q899 | 3 | EBI-640919, EBI-6841237 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, domain, zinc finger, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-355 | Sufficient for interaction with EPHB1 | ||||
Sequence: MAGNVKKSSGAGGGGSGGSGAGGLIGLMKDAFQPHHHHHHLSPHPPCTVDKKMVEKCWKLMDKVVRLCQNPKLALKNSPPYILDLLPDTYQHLRTVLSRYEGKMETLGENEYFRVFMENLMKKTKQTISLFKEGKERMYEENSQPRRNLTKLSLIFSHMLAELKGIFPSGLFQGDTFRITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLFQPWSSLLRNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREGFYLFPDGRNQNPDLTGLCEPTP | ||||||
Region | 45-173 | 4H | ||||
Sequence: PPCTVDKKMVEKCWKLMDKVVRLCQNPKLALKNSPPYILDLLPDTYQHLRTVLSRYEGKMETLGENEYFRVFMENLMKKTKQTISLFKEGKERMYEENSQPRRNLTKLSLIFSHMLAELKGIFPSGLFQ | ||||||
Domain | 45-349 | Cbl-PTB | ||||
Sequence: PPCTVDKKMVEKCWKLMDKVVRLCQNPKLALKNSPPYILDLLPDTYQHLRTVLSRYEGKMETLGENEYFRVFMENLMKKTKQTISLFKEGKERMYEENSQPRRNLTKLSLIFSHMLAELKGIFPSGLFQGDTFRITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLFQPWSSLLRNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREGFYLFPDGRNQNPDLTG | ||||||
Region | 174-246 | EF-hand-like | ||||
Sequence: GDTFRITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLF | ||||||
Region | 247-349 | SH2-like | ||||
Sequence: QPWSSLLRNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREGFYLFPDGRNQNPDLTG | ||||||
Region | 350-378 | Linker | ||||
Sequence: LCEPTPQDHIKVTQEQYELYCEMGSTFQL | ||||||
Region | 356-913 | Required for ubiquitination of SPRED2 | ||||
Sequence: QDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPFDPRGSGSLLRQGAEGAPSPNYDDDDDERADDSLFMMKELAGAKVERPSSPFSMAPQASLPPVPPRLDLLQQRAPVPASTSVLGTASKAASGSLHKDKPLPIPPTLRDLPPPPPPDRPYSVGAETRPQRRPLPCTPGDCPSRDKLPPVPSSRPGDSWLSRPIPKVPVATPNPGDPWNGRELTNRHSLPFSLPSQMEPRADVPRLGSTFSLDTSMTMNSSPVAGPESEHPKIKPSSSANAIYSLAARPLPMPKLPPGEQGESEEDTEYMTPTSRPVGVQKPEPKRPLEATQSSRACDCDQQIDSCTYEAMYNIQSQALSVAENSASGEGNLATAHTSTGPEESENEDDGYDVPKPPVPAVLARRTLSDISNASSSFGWLSLDGDPTNFNEGSQVPERPPKPFPRRINSERKASSYQQGGGATANPVATAPSPQLSSEIERLMSQGYSYQDIQKALVIAHNNIEMAKNILREFVSISSPAHVAT | ||||||
Zinc finger | 379-418 | RING-type | ||||
Sequence: CKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCR | ||||||
Region | 430-460 | Disordered | ||||
Sequence: DPFDPRGSGSLLRQGAEGAPSPNYDDDDDER | ||||||
Region | 476-613 | Disordered | ||||
Sequence: VERPSSPFSMAPQASLPPVPPRLDLLQQRAPVPASTSVLGTASKAASGSLHKDKPLPIPPTLRDLPPPPPPDRPYSVGAETRPQRRPLPCTPGDCPSRDKLPPVPSSRPGDSWLSRPIPKVPVATPNPGDPWNGRELT | ||||||
Compositional bias | 505-519 | Polar residues | ||||
Sequence: APVPASTSVLGTASK | ||||||
Compositional bias | 534-551 | Pro residues | ||||
Sequence: PPTLRDLPPPPPPDRPYS | ||||||
Region | 646-913 | Interaction with CD2AP | ||||
Sequence: TMNSSPVAGPESEHPKIKPSSSANAIYSLAARPLPMPKLPPGEQGESEEDTEYMTPTSRPVGVQKPEPKRPLEATQSSRACDCDQQIDSCTYEAMYNIQSQALSVAENSASGEGNLATAHTSTGPEESENEDDGYDVPKPPVPAVLARRTLSDISNASSSFGWLSLDGDPTNFNEGSQVPERPPKPFPRRINSERKASSYQQGGGATANPVATAPSPQLSSEIERLMSQGYSYQDIQKALVIAHNNIEMAKNILREFVSISSPAHVAT | ||||||
Region | 647-727 | Disordered | ||||
Sequence: MNSSPVAGPESEHPKIKPSSSANAIYSLAARPLPMPKLPPGEQGESEEDTEYMTPTSRPVGVQKPEPKRPLEATQSSRACD | ||||||
Compositional bias | 750-769 | Polar residues | ||||
Sequence: VAENSASGEGNLATAHTSTG | ||||||
Region | 750-787 | Disordered | ||||
Sequence: VAENSASGEGNLATAHTSTGPEESENEDDGYDVPKPPV | ||||||
Region | 814-863 | Disordered | ||||
Sequence: DPTNFNEGSQVPERPPKPFPRRINSERKASSYQQGGGATANPVATAPSPQ | ||||||
Compositional bias | 839-863 | Polar residues | ||||
Sequence: ERKASSYQQGGGATANPVATAPSPQ | ||||||
Domain | 863-902 | UBA | ||||
Sequence: QLSSEIERLMSQGYSYQDIQKALVIAHNNIEMAKNILREF |
Domain
The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.
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.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length913
- Mass (Da)100,564
- Last updated2011-07-27 v3
- Checksum22F8A5C29F0262B8
Computationally mapped potential isoform sequences
There are 6 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A0U1RQ85 | A0A0U1RQ85_MOUSE | Cbl | 896 | ||
A0A0U1RP95 | A0A0U1RP95_MOUSE | Cbl | 79 | ||
A0A0U1RNF1 | A0A0U1RNF1_MOUSE | Cbl | 69 | ||
A0A0U1RP47 | A0A0U1RP47_MOUSE | Cbl | 895 | ||
A0A0U1RP17 | A0A0U1RP17_MOUSE | Cbl | 51 | ||
A0A0X1KG61 | A0A0X1KG61_MOUSE | Cbl | 869 |
Features
Showing features for sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 72-73 | in Ref. 1; CAA40394 | ||||
Sequence: KL → NV | ||||||
Sequence conflict | 218 | in Ref. 2; BAC26087 | ||||
Sequence: E → D | ||||||
Compositional bias | 505-519 | Polar residues | ||||
Sequence: APVPASTSVLGTASK | ||||||
Compositional bias | 534-551 | Pro residues | ||||
Sequence: PPTLRDLPPPPPPDRPYS | ||||||
Sequence conflict | 592 | in Ref. 1; CAA40394 | ||||
Sequence: P → T | ||||||
Sequence conflict | 742 | in Ref. 1; CAA40394 | ||||
Sequence: N → T | ||||||
Compositional bias | 750-769 | Polar residues | ||||
Sequence: VAENSASGEGNLATAHTSTG | ||||||
Compositional bias | 839-863 | Polar residues | ||||
Sequence: ERKASSYQQGGGATANPVATAPSPQ |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
X57111 EMBL· GenBank· DDBJ | CAA40394.1 EMBL· GenBank· DDBJ | mRNA | ||
AK028730 EMBL· GenBank· DDBJ | BAC26087.1 EMBL· GenBank· DDBJ | mRNA | ||
AK153915 EMBL· GenBank· DDBJ | BAE32253.1 EMBL· GenBank· DDBJ | mRNA | ||
BC125285 EMBL· GenBank· DDBJ | AAI25286.1 EMBL· GenBank· DDBJ | mRNA |