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Reviewed, UniProtKB/Swiss-Prot P22681 (CBL_HUMAN)

Last modified June 16, 2009. Version 119. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    E3 ubiquitin-protein ligase CBL
    EC=6.3.2.-
Alternative name(s):
    Signal transduction protein CBL
    Proto-oncogene c-CBL
    Casitas B-lineage lymphoma proto-oncogene
    RING finger protein 55
Gene names
Name: CBL
Synonyms: CBL2, RNF55
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length906 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Participates in signal transduction in hematopoietic cells. Adapter protein that functions as a negative regulator of many signaling pathways that start from receptors at the cell surface. 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 PDGFA, EGF and CSF1, and terminates signaling. Ref.2

Pathway

Protein modification; protein ubiquitination.

Subunit structure

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. May interact with CBLB By similarity.

Subcellular location

Cytoplasm.

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.

Post-translational modification

Phosphorylated on tyrosine residues by EGFR, SYK, FYN and ZAP70 By similarity. Phosphorylated on tyrosine residues by INSR.

Involvement in disease

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

Miscellaneous

This protein has one functional calcium-binding site.

Sequence similarities

Contains 1 CBL N-terminal domain.

Contains 2 EF-hand-like domains.

Contains 1 RING-type zinc finger.

Contains 1 SH2 domain.

Contains 1 UBA domain.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

EGFRP005331EBI-518228,EBI-297353
KHDRBS1Q076661EBI-518228,EBI-1364

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 906906E3 ubiquitin-protein ligase CBL
PRO_0000055858

Regions

Domain46 – 357312CBL N-terminal
Domain212 – 2209EF-hand-like 1
Domain229 – 24012EF-hand-like 2
Domain267 – 34175SH2; atypical
Domain856 – 89540UBA
Zinc finger381 – 42040RING-type
Region46 – 1771324H
Region342 – 38039Linker
Region648 – 906259Interaction with CD2AP
Compositional bias357 – 476120Asp/Glu-rich (acidic)
Compositional bias477 – 688212Pro-rich
Compositional bias689 – 834146Asp/Glu-rich (acidic)

Sites

Binding site2941Phosphotyrosine By similarity

Amino acid modifications

Modified residue3711Phosphotyrosine; by INSR Ref.13 Ref.15
Modified residue5521Phosphotyrosine Ref.15
Modified residue6671Phosphoserine Ref.17
Modified residue6681Phosphoserine By similarity
Modified residue6691Phosphoserine Ref.7
Modified residue6741Phosphotyrosine Ref.7 Ref.16
Modified residue6751Phosphoserine Ref.17
Modified residue7001Phosphotyrosine Ref.13
Modified residue7741Phosphotyrosine Ref.13
Modified residue9001Phosphoserine Ref.18

Experimental info

Mutagenesis801S → D: Abolishes interaction with ZAP70. Ref.20
Mutagenesis821P → A: Abolishes interaction with ZAP70. Ref.20
Mutagenesis2291D → Q: Abolishes interaction with ZAP70. Ref.20
Mutagenesis2401E → S: Abolishes interaction with ZAP70. Ref.20
Mutagenesis2941R → K: Abolishes interaction with ZAP70. Ref.20
Mutagenesis3061G → E: Abolishes interaction with ZAP70, but does not affect interaction with SLA. Ref.20 Ref.10
Mutagenesis3711Y → F: Strongly reduces tyrosine phosphorylation by INSR; when associated with F-700 and F-774. Ref.13
Mutagenesis7001Y → F: Strongly reduces tyrosine phosphorylation by INSR; when associated with F-371 and F-774. Ref.13
Mutagenesis7311Y → F: No effect on tyrosine phosphorylation by INSR. Ref.13
Mutagenesis7741Y → F: Strongly reduces tyrosine phosphorylation by INSR; when associated with F-371 and F-700. Ref.13

Secondary structure

.................................................................. 906
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P22681-1 [UniParc].

Last modified August 1, 1991. Version 1.
Checksum: 7D686B050204AD8F

FASTA90699,647
        10         20         30         40         50         60 
MAGNVKKSSG AGGGTGSGGS GSGGLIGLMK DAFQPHHHHH HHLSPHPPGT VDKKMVEKCW 

        70         80         90        100        110        120 
KLMDKVVRLC QNPKLALKNS PPYILDLLPD TYQHLRTILS RYEGKMETLG ENEYFRVFME 

       130        140        150        160        170        180 
NLMKKTKQTI SLFKEGKERM YEENSQPRRN LTKLSLIFSH MLAELKGIFP SGLFQGDTFR 

       190        200        210        220        230        240 
ITKADAAEFW RKAFGEKTIV PWKSFRQALH EVHPISSGLE AMALKSTIDL TCNDYISVFE 

       250        260        270        280        290        300 
FDIFTRLFQP WSSLLRNWNS LAVTHPGYMA FLTYDEVKAR LQKFIHKPGS YIFRLSCTRL 

       310        320        330        340        350        360 
GQWAIGYVTA DGNILQTIPH NKPLFQALID GFREGFYLFP DGRNQNPDLT GLCEPTPQDH 

       370        380        390        400        410        420 
IKVTQEQYEL YCEMGSTFQL CKICAENDKD VKIEPCGHLM CTSCLTSWQE SEGQGCPFCR 

       430        440        450        460        470        480 
CEIKGTEPIV VDPFDPRGSG SLLRQGAEGA PSPNYDDDDD ERADDTLFMM KELAGAKVER 

       490        500        510        520        530        540 
PPSPFSMAPQ ASLPPVPPRL DLLPQRVCVP SSASALGTAS KAASGSLHKD KPLPVPPTLR 

       550        560        570        580        590        600 
DLPPPPPPDR PYSVGAESRP QRRPLPCTPG DCPSRDKLPP VPSSRLGDSW LPRPIPKVPV 

       610        620        630        640        650        660 
SAPSSSDPWT GRELTNRHSL PFSLPSQMEP RPDVPRLGST FSLDTSMSMN SSPLVGPECD 

       670        680        690        700        710        720 
HPKIKPSSSA NAIYSLAARP LPVPKLPPGE QCEGEEDTEY MTPSSRPLRP LDTSQSSRAC 

       730        740        750        760        770        780 
DCDQQIDSCT YEAMYNIQSQ APSITESSTF GEGNLAAAHA NTGPEESENE DDGYDVPKPP 

       790        800        810        820        830        840 
VPAVLARRTL SDISNASSSF GWLSLDGDPT TNVTEGSQVP ERPPKPFPRR INSERKAGSC 

       850        860        870        880        890        900 
QQGSGPAASA ATASPQLSSE IENLMSQGYS YQDIQKALVI AQNNIEMAKN ILREFVSISS 


PAHVAT 

« Hide

References

« Hide 'large scale' references
[1]"The sequences of the human and mouse c-cbl proto-oncogenes show v-cbl was generated by a large truncation encompassing a proline-rich domain and a leucine zipper-like motif."
Blake T.J., Shapiro M., Morse H.C. III, Langdon W.Y.
Oncogene 6:653-657(1991) [PubMed: 2030914] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase."
Joazeiro C.A., Wing S.S., Huang H.-K., Leverson J.D., Hunter T., Liu Y.-C.
Science 286:309-312(1999) [PubMed: 10514377] [Abstract]
Cited for: FUNCTION.
[3]"Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation."
Galisteo M.L., Dikic I., Batzer A.G., Langdon W.Y., Schlessinger J.
J. Biol. Chem. 270:20242-20245(1995) [PubMed: 7657591] [Abstract]
Cited for: PHOSPHORYLATION BY EGFR.
[4]"The Cbl phosphotyrosine-binding domain selects a D(N/D)XpY motif and binds to the Tyr292 negative regulatory phosphorylation site of ZAP-70."
Lupher M.L. Jr., Songyang Z., Shoelson S.E., Cantley L.C., Band H.
J. Biol. Chem. 272:33140-33144(1997) [PubMed: 9407100] [Abstract]
Cited for: INTERACTION WITH ZAP70.
[5]"Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases."
Deckert M., Elly C., Altman A., Liu Y.C.
J. Biol. Chem. 273:8867-8874(1998) [PubMed: 9535867] [Abstract]
Cited for: PHOSPHORYLATION BY SYK AND FYN.
[6]"Non-T cell activation linker (NTAL): a transmembrane adaptor protein involved in immunoreceptor signaling."
Brdicka T., Imrich M., Angelisova P., Brdickova N., Horvath O., Spicka J., Hilgert I., Luskova P., Draber P., Novak P., Engels N., Wienands J., Simeoni L., Oesterreicher J., Aguado E., Malissen M., Schraven B., Horejsi V.
J. Exp. Med. 196:1617-1626(2002) [PubMed: 12486104] [Abstract]
Cited for: INTERACTION WITH LAT2.
[7]"Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry."
Salomon A.R., Ficarro S.B., Brill L.M., Brinker A., Phung Q.T., Ericson C., Sauer K., Brock A., Horn D.M., Schultz P.G., Peters E.C.
Proc. Natl. Acad. Sci. U.S.A. 100:443-448(2003) [PubMed: 12522270] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-669 AND TYR-674, MASS SPECTROMETRY.
[8]"APS, an adaptor protein containing pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl."
Wakioka T., Sasaki A., Mitsui K., Yokouchi M., Inoue A., Komiya S., Yoshimura A.
Leukemia 13:760-767(1999) [PubMed: 10374881] [Abstract]
Cited for: INTERACTION WITH SH2B2.
[9]"APS, an adaptor protein containing PH and SH2 domains, is associated with the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis."
Yokouchi M., Wakioka T., Sakamoto H., Yasukawa H., Ohtsuka S., Sasaki A., Ohtsubo M., Valius M., Inoue A., Komiya S., Yoshimura A.
Oncogene 18:759-767(1999) [PubMed: 9989826] [Abstract]
Cited for: INTERACTION WITH SH2B2.
[10]"SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling."
Tang J., Sawasdikosol S., Chang J.-H., Burakoff S.J.
Proc. Natl. Acad. Sci. U.S.A. 96:9775-9780(1999) [PubMed: 10449770] [Abstract]
Cited for: INTERACTION WITH SLA AND ZAP70, MUTAGENESIS OF GLY-306.
[11]"Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel inhibitor of antigen receptor signaling."
Holland S.J., Liao X.C., Mendenhall M.K., Zhou X., Pardo J., Chu P., Spencer C., Fu A.C., Sheng N., Yu P., Pali E., Nagin A., Shen M., Yu S., Chan E., Wu X., Li C., Woisetschlager M. expand/collapse author list , Aversa G., Kolbinger F., Bennett M.K., Molineaux S., Luo Y., Payan D.G., Mancebo H.S.Y., Wu J.
J. Exp. Med. 194:1263-1276(2001) [PubMed: 11696592] [Abstract]
Cited for: INTERACTION WITH SLA2.
[12]"The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction."
Kirsch K.H., Georgescu M.M., Shishido T., Langdon W.Y., Birge R.B., Hanafusa H.
J. Biol. Chem. 276:4957-4963(2001) [PubMed: 11067845] [Abstract]
Cited for: INTERACTION WITH CD2AP.
[13]"APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes."
Liu J., Kimura A., Baumann C.A., Saltiel A.R.
Mol. Cell. Biol. 22:3599-3609(2002) [PubMed: 11997497] [Abstract]
Cited for: INTERACTION WITH SH2B2, MUTAGENESIS OF TYR-371; TYR-700; TYR-731 AND TYR-774, PHOSPHORYLATION AT TYR-371; TYR-700 AND TYR-774.
[14]"The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2."
Vandenbroere I., Paternotte N., Dumont J.E., Erneux C., Pirson I.
Biochem. Biophys. Res. Commun. 300:494-500(2003) [PubMed: 12504111] [Abstract]
Cited for: INTERACTION WITH INPPL1.
[15]"Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules."
Zhang Y., Wolf-Yadlin A., Ross P.L., Pappin D.J., Rush J., Lauffenburger D.A., White F.M.
Mol. Cell. Proteomics 4:1240-1250(2005) [PubMed: 15951569] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-371 AND TYR-552, MASS SPECTROMETRY.
Tissue: Epithelium.
[16]"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."
Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J.
Nat. Biotechnol. 23:94-101(2005) [PubMed: 15592455] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-674, MASS SPECTROMETRY.
[17]"Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry."
Tao W.A., Wollscheid B., O'Brien R., Eng J.K., Li X.-J., Bodenmiller B., Watts J.D., Hood L., Aebersold R.
Nat. Methods 2:591-598(2005) [PubMed: 16094384] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-667 AND SER-675, MASS SPECTROMETRY.
Tissue: T-cell.
[18]"A probability-based approach for high-throughput protein phosphorylation analysis and site localization."
Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.
Nat. Biotechnol. 24:1285-1292(2006) [PubMed: 16964243] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-900, MASS SPECTROMETRY.
Tissue: Epithelium.
[19]Colinge J., Superti-Furga G., Bennett K.L.
Submitted (OCT-2008) to UniProtKB
Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[20]"Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase."
Meng W., Sawasdikosol S., Burakoff S.J., Eck M.J.
Nature 398:84-90(1999) [PubMed: 10078535] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 47-350, CALCIUM-BINDING SITE, MUTAGENESIS OF SER-80; PRO-82; ASP-229; GLU-240; ARG-294 AND GLY-306.
[21]"Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases."
Zheng N., Wang P., Jeffrey P.D., Pavletich N.P.
Cell 102:533-539(2000) [PubMed: 10966114] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 47-434 IN COMPLEX WITH ZAP70 AND UBE2L3.
+Additional computationally mapped references.

Cross-references

Sequence databases

X57110 mRNA. Translation: CAA40393.1.
IPIIPI00027269.
PIRA43817.
RefSeqNP_005179.2.
UniGeneHs.504096

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
1B47X-ray2.20A/B/C47-350[»]
1FBVX-ray2.90A47-434[»]
1YVHX-ray2.05A23-351[»]
2CBLX-ray2.10A47-351[»]
2JUJNMR-A851-906[»]
2OO9X-ray2.10A/B/C856-899[»]
3BUMX-ray2.00B23-351[»]
3BUNX-ray2.00B23-351[»]
3BUOX-ray2.60B/D23-351[»]
3BUWX-ray1.45B/D23-351[»]
3BUXX-ray1.35B/D23-351[»]
ModBaseSearch...

Protein-protein interaction databases

DIPDIP:189N.
IntActP22681. 2 interactions.

PTM databases

PhosphoSiteP22681.

Proteomic databases

PRIDEP22681.

Genome annotation databases

EnsemblENSG00000110395. Homo sapiens. [Contig view]
GeneID867.
KEGGhsa:867.

Organism-specific databases

GeneCardsGC11P118582.
H-InvDBHIX0010191.
HGNCHGNC:1541. CBL.
HPACAB004350.
MIM165360. gene.
PharmGKBPA26115.
GenAtlasSearch...

Phylogenomic databases

HOGENOMP22681.
HOVERGENP22681.

Enzyme and pathway databases

Pathway_Interaction_DBepha_fwdpathway. EPHA forward signaling.
epha2_fwdpathway. EPHA2 forward signaling.
epopathway. EPO signaling pathway.
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
fgf_pathway. FGF signaling pathway.
ifngpathway. IFN-gamma pathway.
il4_2pathway. IL4-mediated signaling events.
insulin_pathway. Insulin Pathway.
avb3_integrin_pathway. Integrins in angiogenesis.
a4b1_paxdep_pathway. Paxillin-dependent events mediated by a4b1.
a4b1_paxindep_pathway. Paxillin-independent events mediated by a4b1 and a4b7.
pdgfrbpathway. PDGFR-beta signaling pathway.
reelinpathway. Reelin signaling pathway.
met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met).
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).
tcrpathway. TCR signaling in naive CD4+ T cells.
cd8tcrpathway. TCR signaling in naive CD8+ T cells.
vegfr1_pathway. VEGFR1 specific signals.
ReactomeREACT_9417. Signaling by EGFR.

Gene expression databases

ArrayExpressP22681.
BgeeP22681.
CleanExHS_CBL.
GermOnlineENSG00000110395. Homo sapiens.

Family and domain databases

InterProIPR014741. Adaptor_Cbl_EF_Hand-like.
IPR003153. Adaptor_Cbl_N.
IPR014742. Adaptor_Cbl_SH2-like.
IPR011992. EF-Hand_type.
IPR000449. UBA/transl_elong_EF1B_N.
IPR015940. UBA/transl_elong_EF1B_N_euk.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
Gene3DG3DSA:1.20.930.20. Adaptor_Cbl_N. 1 hit.
G3DSA:1.10.238.10. EF-Hand_type. 1 hit.
G3DSA:3.30.40.10. Znf_RING/FYVE/PHD. 1 hit.
PfamPF02262. Cbl_N. 1 hit.
PF02761. Cbl_N2. 1 hit.
PF02762. Cbl_N3. 1 hit.
PF00627. UBA. 1 hit.
[Graphical view]
SMARTSM00184. RING. 1 hit.
SM00165. UBA. 1 hit.
[Graphical view]
PROSITEPS50001. SH2. False negative.
PS50030. UBA. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio3618.
SOURCESearch...

Entry information

Entry nameCBL_HUMAN
AccessionPrimary (citable) accession number: P22681
Entry history
Integrated into UniProtKB/Swiss-Prot: August 1, 1991
Last sequence update: August 1, 1991
Last modified: June 16, 2009
This is version 119 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

Relevant documents

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PATHWAY comments

Index of metabolic and biosynthesis pathways

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents