UniProt Accession

 CBL_HUMAN; P22681; A3KMP8 

Genbank Protein ID

 X57110; AP002956; BC132733; BC136463 

Genbank Nucleotide ID

 CAA40393.1; AAI32734.1; AAI36464.1 

Protein Name

 E3 ubiquitin-protein ligase CBL 

Protein Synonyms/Alias

 Casitas B-lineage lymphoma proto-oncogene; Proto-oncogene c-Cbl; RING finger protein 55; Signal transduction protein CBL 

Gene Name

 CBL 

Gene Synonyms/Alias

 CBL2; RNF55 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
7	*MAGNVKKSSGAGGG	ubiquitination	[1]
74	VRLCQNPKLALKNSP	ubiquitination	[1, 2]
105	ILSRYEGKMETLGEN	ubiquitination	[1]
197	WRKAFGEKTIVPWKS	acetylation	[3]
203	EKTIVPWKSFRQALH	ubiquitination	[1, 4]
424	PFCRCEIKGTEPIVV	ubiquitination	[1]
521	SALGTASKAASGSLH	ubiquitination	[1]

Reference

 [1] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [2] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [3] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
 [4] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724] 

Functional Description

 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 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-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. 

Sequence Annotation

 DOMAIN 47 351 Cbl-PTB.
 DOMAIN 856 895 UBA.
 ZN_FING 381 420 RING-type.
 REGION 1 357 Sufficient for interaction with EPHB1.
 REGION 47 175 4H.
 REGION 176 248 EF-hand-like.
 REGION 249 351 SH2-like.
 REGION 352 380 Linker.
 REGION 648 906 Interaction with CD2AP.
 BINDING 294 294 Phosphotyrosine (By similarity).
 MOD_RES 141 141 Phosphotyrosine.
 MOD_RES 197 197 N6-acetyllysine.
 MOD_RES 371 371 Phosphotyrosine; by INSR.
 MOD_RES 452 452 Phosphoserine.
 MOD_RES 455 455 Phosphotyrosine.
 MOD_RES 552 552 Phosphotyrosine.
 MOD_RES 667 667 Phosphoserine.
 MOD_RES 668 668 Phosphoserine (By similarity).
 MOD_RES 669 669 Phosphoserine.
 MOD_RES 674 674 Phosphotyrosine.
 MOD_RES 675 675 Phosphoserine.
 MOD_RES 700 700 Phosphotyrosine; by ABL1.
 MOD_RES 731 731 Phosphotyrosine; by SRC.
 MOD_RES 774 774 Phosphotyrosine.
 MOD_RES 900 900 Phosphoserine.  

Keyword

 3D-structure; Acetylation; Calcium; Cell membrane; Complete proteome; Cytoplasm; Disease mutation; Ligase; Membrane; Metal-binding; Phosphoprotein; Polymorphism; Proto-oncogene; Reference proteome; Repeat; Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 906 AA 

Protein Sequence

Gene Ontology

 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0016600; C:flotillin complex; IEA:Compara.
 GO:0005634; C:nucleus; IEA:InterPro.
 GO:0005886; C:plasma membrane; IDA:HGNC.
 GO:0005509; F:calcium ion binding; IEA:InterPro.
 GO:0003700; F:sequence-specific DNA binding transcription factor activity; TAS:ProtInc.
 GO:0004871; F:signal transducer activity; IEA:InterPro.
 GO:0004842; F:ubiquitin-protein ligase activity; TAS:HGNC.
 GO:0008270; F:zinc ion binding; IEA:InterPro.
 GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:HGNC.
 GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
 GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
 GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome.
 GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase cascade; IMP:BHF-UCL.
 GO:0048260; P:positive regulation of receptor-mediated endocytosis; TAS:HGNC. 

Interpro

 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.
 IPR009060; UBA-like.
 IPR000449; UBA/transl_elong_EF1B_N.
 IPR015940; UBA/transl_elong_EF1B_N_euk.
 IPR018957; Znf_C3HC4_RING-type.
 IPR001841; Znf_RING.
 IPR013083; Znf_RING/FYVE/PHD.
 IPR017907; Znf_RING_CS. 

Pfam

 PF02262; Cbl_N
 PF02761; Cbl_N2
 PF02762; Cbl_N3
 PF00627; UBA
 PF00097; zf-C3HC4 

SMART

 SM00184; RING
 SM00165; UBA 

PROSITE

 PS51506; CBL_PTB
 PS50030; UBA
 PS00518; ZF_RING_1
 PS50089; ZF_RING_2 

PRINTS