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Details on Person UniProt:P22681 CBL
| Class:Id | ReferenceGeneProduct:51488 |
|---|---|
| _chainChangeLog | chain:1-906 added on Fri February 6 2015 |
| _displayName | UniProt:P22681 CBL |
| _timestamp | 2026-02-20 22:41:36 |
| chain | chain:1-906 |
| checksum | 1AA6BF67377322CA |
| comment | FUNCTION E3 ubiquitin-protein ligase that acts as a negative regulator of many signaling pathways by mediating ubiquitination of cell surface receptors (PubMed:10514377, PubMed:11896602, PubMed:14661060, PubMed:14739300, PubMed:15190072, PubMed:17509076, PubMed:18374639, PubMed:19689429, PubMed:21596750, PubMed:28381567, PubMed:40101708). Accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome (PubMed:10514377, PubMed:14661060, PubMed:14739300, PubMed:17094949, PubMed:17509076, PubMed:17974561). Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, CSF1R, EPHA8 and KDR and mediates their ubiquitination to terminate signaling (PubMed:15190072, PubMed:18374639, PubMed:21596750). Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation (PubMed:11896602). Ubiquitinates EGFR and SPRY2 (PubMed:17094949, PubMed:17974561). Involved in LAG3-mediated inhibition of TCR signaling: following ligand-binding to LAG3, catalyzes 'Lys-63'-linked ubiquitination of LAG3, unleashing the LAG3 C-terminus from the membrane, and initiating a signaling that prevents TCR activation (PubMed:40101708). Ubiquitinates NECTIN1 following association between NECTIN1 and herpes simplex virus 1/HHV-1 envelope glycoprotein D, leading to NECTIN1 removal from cell surface (PubMed:28381567). Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis (PubMed:15190072, PubMed:18374639). Essential for osteoclastic bone resorption (PubMed:14739300). 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 (PubMed:14739300). 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 (By similarity).CATALYTIC ACTIVITY S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Forms homodimers; IFT20 promotes the formation of stable homodimers (PubMed:29237719). Interacts (phosphorylated at Tyr-731) with PIK3R1. 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. Also interacts with SORBS1 and INPPL1/SHIP2. Interacts with phosphorylated LAT2 (By similarity). Interacts with CBLB (PubMed:29237719). Interacts with ALK, AXL, BLK, FGR and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates receptor degradation through ubiquitination. Interacts with HCK and LYN. Interacts with ATX2 (By similarity). Interacts with TEK/TIE2 (tyrosine phosphorylated). Interacts with SH3KBP1 and this interaction is inhibited in the presence of SHKBP1 or ARAP1 (By similarity). Interacts with SIGLEC10 (By similarity). Interacts with IFT20 (PubMed:29237719). Interacts with SPRY2; the interaction inhibits CBL-mediated ubiquitination of EGFR (PubMed:17974561). Interacts (phosphorylated at Tyr-774) with tensin TNS4 (via SH2 domain); the interaction is enhanced in the presence of EGF and reduces interaction of CBL with EGFR (PubMed:23774213). Interacts with EGFR; the interaction is reduced in the presence of TNS4 (PubMed:23774213). Interacts with CD5 (PubMed:23376399). Interacts with CD93 (PubMed:26848865).SUBUNIT (Microbial infection) Interacts with M.tuberculosis LpqN, which influences the balance between intrinsic antibacterial and antiviral defense.INTERACTION Colocalizes with FGFR2 in lipid rafts at the cell membrane.DOMAIN The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.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.PTM Phosphorylated on tyrosine residues by ALK, EGFR, SYK, FYN and ZAP70 (By similarity). Phosphorylated on tyrosine residues in response to FLT1 and KIT signaling. Phosphorylated on tyrosine residues by INSR and FGR. Phosphorylated on several tyrosine residues by constitutively activated FGFR3. Not phosphorylated at Tyr-731 by FGFR3. Phosphorylated on tyrosine residues by activated CSF1R, PDGFRA and PDGFRB. Phosphorylated on tyrosine residues by HCK.PTM Ubiquitinated, leading to its degradation via the proteasome (PubMed:11896602, PubMed:20094046). Ubiquitination is negatively regulated by IFT20 (PubMed:29237719).DISEASE The disease is caused by variants affecting the gene represented in this entry.MISCELLANEOUS This protein has one functional calcium-binding site. |
| description | recommendedName: E3 ubiquitin-protein ligase CBL ecNumber evidence="11 21 28 48"2.3.2.27 alternativeName: Casitas B-lineage lymphoma proto-oncogene alternativeName: Proto-oncogene c-Cbl alternativeName: RING finger protein 55 alternativeName: fullName evidence="54"RING-type E3 ubiquitin transferase CBL alternativeName: Signal transduction protein CBL |
| geneName | CBL CBL2 RNF55 |
| identifier | P22681 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Calcium Cell membrane Cell projection Cytoplasm Disease variant Golgi apparatus Membrane Metal-binding Phosphoprotein Proteomics identification Proto-oncogene Reference proteome Repeat Transferase Ubl conjugation Ubl conjugation pathway Zinc Zinc-finger |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9948485] Weiser, Joel, 2025-05-21 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | CBL |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8997049] ENSEMBL:ENSG00000110395 CBL [Homo sapiens] |
| secondaryIdentifier | CBL_HUMAN A3KMP8 |
| sequenceLength | 906 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:112175] CBL [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:112192] CBL [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:112199] CBL [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:182923] p-Y371-CBL [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:182940] p-Y371-CBL [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:912656] p-Y700,Y731,Y774-CBL [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:8848826] PolyUb,p-Y700,Y731,Y774-CBL [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:8875457] p-Y-CBL [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9706176] CBL del366-477 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9706179] CBL E366_Q409del [cytosol] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:182913] O4'-phospho-L-tyrosine at 371 [ModifiedResidue:912617] O4'-phospho-L-tyrosine at 731 [ModifiedResidue:912781] O4'-phospho-L-tyrosine at 700 [ModifiedResidue:912785] O4'-phospho-L-tyrosine at 774 [GroupModifiedResidue:8848828] ubiquitinylated lysine (polyubiquitin chain [cytosol]) at unknown position [ModifiedResidue:8875455] O4'-phospho-L-tyrosine at unknown position [FragmentDeletionModification:9706024] Deletion of residues 366 to 380 [FragmentDeletionModification:9706026] Deletion of residues 366 to 409 [FragmentDeletionModification:9706028] Deletion of residues 366 to 477 [ReplacedResidue:9706031] L-arginine 420 replaced with L-leucine |
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No pathways have been reviewed or authored by UniProt:P22681 CBL (51488)
