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P22681 (CBL_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 173. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase CBL

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

Protein attributes

Sequence length906 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. 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-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. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. Ref.5 Ref.12 Ref.23 Ref.26 Ref.27 Ref.33 Ref.36 Ref.39 Ref.45

Pathway

Protein modification; protein ubiquitination.

Subunit structure

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. May interact with CBLB By similarity. 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 TEK/TIE2 (tyrosine phosphorylated). Ref.4 Ref.6 Ref.7 Ref.8 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.27 Ref.28 Ref.29 Ref.34 Ref.35 Ref.36 Ref.38 Ref.39 Ref.40 Ref.42 Ref.45

Subcellular location

Cytoplasm. Cell membrane. Note: Colocalizes with FGFR2 in lipid rafts at the cell membrane. Ref.12 Ref.36

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 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. Ref.4 Ref.7 Ref.9 Ref.11 Ref.13 Ref.19 Ref.25 Ref.26 Ref.27 Ref.28 Ref.33 Ref.38 Ref.42

Ubiquitinated, leading to its degradation via the proteasome. Ref.12 Ref.46

Involvement in disease

Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM:613563]: A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects. Some have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.49

Miscellaneous

This protein has one functional calcium-binding site.

Sequence similarities

Contains 1 Cbl-PTB (Cbl-type phosphotyrosine-binding) domain.

Contains 1 RING-type zinc finger.

Contains 1 UBA domain.

Ontologies

Keywords
   Biological processUbl conjugation pathway
   Cellular componentCell membrane
Cytoplasm
Membrane
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
Proto-oncogene
   DomainRepeat
Zinc-finger
   LigandCalcium
Metal-binding
Zinc
   Molecular functionLigase
   PTMAcetylation
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcell surface receptor signaling pathway

Traceable author statement PubMed 15465819. Source: HGNC

epidermal growth factor receptor signaling pathway

Traceable author statement PubMed 15465819. Source: HGNC

fibroblast growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

negative regulation of apoptotic process

Inferred from mutant phenotype PubMed 18070883. Source: UniProtKB

negative regulation of epidermal growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

positive regulation of phosphatidylinositol 3-kinase signaling

Inferred from mutant phenotype PubMed 17003487. Source: BHF-UCL

positive regulation of receptor-mediated endocytosis

Traceable author statement PubMed 15465819. Source: HGNC

protein ubiquitination

Traceable author statement PubMed 15465819. Source: HGNC

regulation of transcription, DNA-templated

Traceable author statement Ref.1. Source: GOC

transforming growth factor beta receptor signaling pathway

Traceable author statement. Source: Reactome

   Cellular_componentcytoplasm

Inferred from direct assay. Source: HPA

cytosol

Traceable author statement. Source: Reactome

flotillin complex

Inferred from electronic annotation. Source: Ensembl

nucleus

Inferred from electronic annotation. Source: InterPro

plasma membrane

Inferred from direct assay PubMed 15465819. Source: HGNC

   Molecular_functionSH3 domain binding

Inferred from physical interaction PubMed 9447983. Source: BHF-UCL

calcium ion binding

Inferred from electronic annotation. Source: InterPro

ephrin receptor binding

Inferred from physical interaction Ref.38. Source: UniProtKB

sequence-specific DNA binding transcription factor activity

Traceable author statement Ref.1. Source: ProtInc

signal transducer activity

Inferred from electronic annotation. Source: InterPro

ubiquitin-protein ligase activity

Traceable author statement PubMed 15465819. Source: HGNC

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 906906E3 ubiquitin-protein ligase CBL
PRO_0000055858

Regions

Domain47 – 351305Cbl-PTB
Domain856 – 89540UBA
Calcium binding227 – 24014 Ref.47
Zinc finger381 – 42040RING-type
Region1 – 357357Sufficient for interaction with EPHB1
Region47 – 1751294H
Region176 – 24873EF-hand-like
Region249 – 351103SH2-like
Region352 – 38029Linker
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 residue1411Phosphotyrosine
Modified residue1971N6-acetyllysine
Modified residue3711Phosphotyrosine; by INSR Ref.19
Modified residue4521Phosphoserine Ref.41
Modified residue4551Phosphotyrosine
Modified residue5521Phosphotyrosine
Modified residue6671Phosphoserine
Modified residue6681Phosphoserine By similarity
Modified residue6691Phosphoserine
Modified residue6741Phosphotyrosine
Modified residue6751Phosphoserine
Modified residue7001Phosphotyrosine; by ABL1 Ref.19 Ref.25
Modified residue7311Phosphotyrosine; by SRC Ref.26
Modified residue7741Phosphotyrosine Ref.19
Modified residue9001Phosphoserine Ref.32

Natural variations

Natural variant3671Q → P in NSLL; causes impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. Ref.49
VAR_064332
Natural variant3821K → E in NSLL; causes impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. Ref.49
VAR_064333
Natural variant3901D → Y in NSLL; causes impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. Ref.49
VAR_064334
Natural variant4201R → Q in NSLL; causes impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion as well as constitutive ERK phosphorylation. Ref.49
VAR_064335
Natural variant6201L → F.
Corresponds to variant rs2227988 [ dbSNP | Ensembl ].
VAR_057211
Natural variant7821P → L.
Corresponds to variant rs2229073 [ dbSNP | Ensembl ].
VAR_057212
Natural variant9041V → I.
Corresponds to variant rs17122769 [ dbSNP | Ensembl ].
VAR_057213

Experimental info

Mutagenesis801S → D: Abolishes interaction with ZAP70. Ref.47
Mutagenesis821P → A: Abolishes interaction with ZAP70. Ref.47
Mutagenesis2291D → Q: Abolishes interaction with ZAP70. Ref.47
Mutagenesis2401E → S: Abolishes interaction with ZAP70. Ref.47
Mutagenesis2941R → K: Abolishes interaction with ZAP70. Ref.47
Mutagenesis3061G → E: Abolishes interaction with ZAP70 and EPHB1, but does not affect interaction with SLA. Ref.16 Ref.47
Mutagenesis3711Y → F: Strongly reduces tyrosine phosphorylation by INSR; when associated with F-700 and F-774. Ref.19
Mutagenesis3811C → A: Loss of ubiquitin ligase activity. Ref.12
Mutagenesis7001Y → F: Strongly reduces tyrosine phosphorylation by INSR; when associated with F-371 and F-774. Ref.19
Mutagenesis7311Y → F: No effect on tyrosine phosphorylation by INSR. Loss of phosphorylation by SRC. Inhibition of bone resorption. Abolishes interaction with PIK3R1. Ref.19 Ref.26
Mutagenesis7741Y → F: Strongly reduces tyrosine phosphorylation by INSR; when associated with F-371 and F-700. Ref.19
Sequence conflict151S → T in CAA40393. Ref.1

Secondary structure

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

Details...

Sequences

Sequence LengthMass (Da)Tools
P22681 [UniParc].

Last modified July 7, 2009. Version 2.
Checksum: 1AA6BF67377322CA

FASTA90699,633
        10         20         30         40         50         60 
MAGNVKKSSG AGGGSGSGGS 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 

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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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Human chromosome 11 DNA sequence and analysis including novel gene identification."
Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. expand/collapse author list , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y.
Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]"The proto-oncogene p120(Cbl) is a downstream substrate of the Hck protein-tyrosine kinase."
Howlett C.J., Bisson S.A., Resek M.E., Tigley A.W., Robbins S.M.
Biochem. Biophys. Res. Commun. 257:129-138(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY HCK, INTERACTION WITH HCK.
[5]"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] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"The protein product of the c-cbl protooncogene is the 120-kDa tyrosine-phosphorylated protein in Jurkat cells activated via the T cell antigen receptor."
Donovan J.A., Wange R.L., Langdon W.Y., Samelson L.E.
J. Biol. Chem. 269:22921-22924(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH BLK.
[7]"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] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY EGFR, INTERACTION WITH EGFR.
[8]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ZAP70.
[9]"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] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY SYK AND FYN.
[10]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LAT2.
[11]"C-Cbl binds the CSF-1 receptor at tyrosine 973, a novel phosphorylation site in the receptor's carboxy-terminus."
Wilhelmsen K., Burkhalter S., van der Geer P.
Oncogene 21:1079-1089(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CSF1R, PHOSPHORYLATION.
[12]"Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation."
Howlett C.J., Robbins S.M.
Oncogene 21:1707-1716(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION, MUTAGENESIS OF CYS-381, INTERACTION WITH HCK.
[13]"Fgr but not Syk tyrosine kinase is a target for beta 2 integrin-induced c-Cbl-mediated ubiquitination in adherent human neutrophils."
Melander F., Andersson T., Dib K.
Biochem. J. 370:687-694(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH FGR, PHOSPHORYLATION BY FGR.
[14]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SH2B2.
[15]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SH2B2.
[16]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SLA AND ZAP70, MUTAGENESIS OF GLY-306.
[17]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SLA2.
[18]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CD2AP.
[19]"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] [Europe PMC] [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.
[20]"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] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH INPPL1.
[21]"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] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[22]"Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry."
Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., Peters E.C.
Anal. Chem. 76:2763-2772(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[23]"Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation."
Kim M., Tezuka T., Tanaka K., Yamamoto T.
Oncogene 23:1645-1655(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[24]"Signal transduction via the stem cell factor receptor/c-Kit."
Ronnstrand L.
Cell. Mol. Life Sci. 61:2535-2548(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ROLE IN KIT SIGNALING AND KIT DEGRADATION.
[25]"Catalytic domains of tyrosine kinases determine the phosphorylation sites within c-Cbl."
Grossmann A.H., Kolibaba K.S., Willis S.G., Corbin A.S., Langdon W.S., Deininger M.W., Druker B.J.
FEBS Lett. 577:555-562(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-700.
[26]"Src kinase activity is essential for osteoclast function."
Miyazaki T., Sanjay A., Neff L., Tanaka S., Horne W.C., Baron R.
J. Biol. Chem. 279:17660-17666(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT TYR-731, MUTAGENESIS OF TYR-731.
[27]"Cbl-mediated degradation of Lyn and Fyn induced by constitutive fibroblast growth factor receptor-2 activation supports osteoblast differentiation."
Kaabeche K., Lemonnier J., Le Mee S., Caverzasio J., Marie P.J.
J. Biol. Chem. 279:36259-36267(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION, INTERACTION WITH FGFR2; LYN AND FYN.
[28]"ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth."
Motegi A., Fujimoto J., Kotani M., Sakuraba H., Yamamoto T.
J. Cell Sci. 117:3319-3329(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ALK, PHOSPHORYLATION BY ALK.
[29]"Effects of Gas6 and hydrogen peroxide in Axl ubiquitination and downregulation."
Valverde P.
Biochem. Biophys. Res. Commun. 333:180-185(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AXL.
[30]"Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor."
Roskoski R. Jr.
Biochem. Biophys. Res. Commun. 337:1-13(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ROLE IN KIT SIGNALING AND KIT DEGRADATION.
[31]"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] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[32]"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] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-900, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[33]"The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor."
Bonaventure J., Horne W.C., Baron R.
FEBS J. 274:3078-3093(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION.
[34]"Binding of Cbl to a phospholipase Cgamma1-docking site on platelet-derived growth factor receptor beta provides a dual mechanism of negative regulation."
Reddi A.L., Ying G., Duan L., Chen G., Dimri M., Douillard P., Druker B.J., Naramura M., Band V., Band H.
J. Biol. Chem. 282:29336-29347(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PDGFRB.
[35]"Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells."
Wu J., Meng F., Lu H., Kong L., Bornmann W., Peng Z., Talpaz M., Donato N.J.
Blood 111:3821-3829(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LYN.
[36]"FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival."
Dufour C., Guenou H., Kaabeche K., Bouvard D., Sanjay A., Marie P.J.
Bone 42:1032-1039(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH FGFR2, SUBCELLULAR LOCATION.
[37]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[38]"Ligand binding induces Cbl-dependent EphB1 receptor degradation through the lysosomal pathway."
Fasen K., Cerretti D.P., Huynh-Do U.
Traffic 9:251-266(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH EPHB1, PHOSPHORYLATION.
[39]"Angiopoietin-1-induced ubiquitylation of Tie2 by c-Cbl is required for internalization and degradation."
Wehrle C., Van Slyke P., Dumont D.J.
Biochem. J. 423:375-380(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TEK/TIE2, FUNCTION.
[40]"An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase controlling EGFR endocytosis."
Tarcic G., Boguslavsky S.K., Wakim J., Kiuchi T., Liu A., Reinitz F., Nathanson D., Takahashi T., Mischel P.S., Ng T., Yarden Y.
Curr. Biol. 19:1788-1798(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH EGFR.
[41]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-452, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[42]"Mutation of tyrosine residue 857 in the PDGF beta-receptor affects cell proliferation but not migration."
Wardega P., Heldin C.H., Lennartsson J.
Cell. Signal. 22:1363-1368(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PDGFRB, PHOSPHORYLATION.
[43]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[44]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[45]"The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination."
Severe N., Miraoui H., Marie P.J.
J. Biol. Chem. 286:24443-24450(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH FGFR2.
[46]"Fibroblast growth factor signalling: from development to cancer."
Turner N., Grose R.
Nat. Rev. Cancer 10:116-129(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION IN FGF SIGNALING, UBIQUITINATION OF FGFR1.
[47]"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] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 47-350 IN COMPLEX WITH ZAP70 PEPTIDE AND CALCIUM IONS, CALCIUM-BINDING SITE, MUTAGENESIS OF SER-80; PRO-82; ASP-229; GLU-240; ARG-294 AND GLY-306.
[48]"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] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 47-434 IN COMPLEX WITH ZAP70 AND UBE2L3.
[49]"Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype."
Martinelli S., De Luca A., Stellacci E., Rossi C., Checquolo S., Lepri F., Caputo V., Silvano M., Buscherini F., Consoli F., Ferrara G., Digilio M.C., Cavaliere M.L., van Hagen J.M., Zampino G., van der Burgt I., Ferrero G.B., Mazzanti L. expand/collapse author list , Screpanti I., Yntema H.G., Nillesen W.M., Savarirayan R., Zenker M., Dallapiccola B., Gelb B.D., Tartaglia M.
Am. J. Hum. Genet. 87:250-257(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS NSLL PRO-367; GLU-382; TYR-390 AND GLN-420, CHARACTERIZATION OF VARIANTS NSLL PRO-367; GLU-382; TYR-390 AND GLN-420.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X57110 mRNA. Translation: CAA40393.1.
AP002956 Genomic DNA. No translation available.
BC132733 mRNA. Translation: AAI32734.1.
BC136463 mRNA. Translation: AAI36464.1.
PIRA43817.
RefSeqNP_005179.2. NM_005188.3.
UniGeneHs.504096.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1B47X-ray2.20A/B/C47-350[»]
1FBVX-ray2.90A47-434[»]
1YVHX-ray2.05A25-351[»]
2CBLX-ray2.10A47-351[»]
2JUJNMR-A851-906[»]
2K4DNMR-A358-437[»]
2OO9X-ray2.10A/B/C856-895[»]
2Y1MX-ray2.67A/B/C/D/E/F47-435[»]
2Y1NX-ray2.00A/C47-435[»]
3BUMX-ray2.00B25-351[»]
3BUNX-ray2.00B25-351[»]
3BUOX-ray2.60B/D25-351[»]
3BUWX-ray1.45B/D25-351[»]
3BUXX-ray1.35B/D25-351[»]
3OB1X-ray2.20B25-351[»]
3OB2X-ray2.10B25-351[»]
3PLFX-ray1.92B/D25-351[»]
4A49X-ray2.21A354-435[»]
4A4BX-ray2.79A47-435[»]
4A4CX-ray2.70A47-435[»]
4GPLX-ray3.00B47-351[»]
ProteinModelPortalP22681.
SMRP22681. Positions 48-435, 851-906.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107315. 214 interactions.
DIPDIP-189N.
IntActP22681. 61 interactions.
MINTMINT-109040.
STRING9606.ENSP00000264033.

PTM databases

PhosphoSiteP22681.

Polymorphism databases

DMDM251757253.

Proteomic databases

PaxDbP22681.
PRIDEP22681.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000264033; ENSP00000264033; ENSG00000110395.
GeneID867.
KEGGhsa:867.
UCSCuc001pwe.4. human.

Organism-specific databases

CTD867.
GeneCardsGC11P119110.
HGNCHGNC:1541. CBL.
HPACAB004350.
HPA027956.
MIM165360. gene.
613563. phenotype.
neXtProtNX_P22681.
Orphanet86834. Juvenile myelomonocytic leukemia.
363972. Noonan syndrome-like disorder with juvenile myelomonocytic leukemia.
PharmGKBPA26115.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG242251.
HOGENOMHOG000294176.
HOVERGENHBG005255.
InParanoidP22681.
KOK04707.
OMATTNFTEG.
OrthoDBEOG7M0NQX.
PhylomeDBP22681.
TreeFamTF314210.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.
SignaLinkP22681.
UniPathwayUPA00143.

Gene expression databases

BgeeP22681.
CleanExHS_CBL.
GenevestigatorP22681.

Family and domain databases

Gene3D1.10.238.10. 1 hit.
1.20.930.20. 1 hit.
3.30.40.10. 1 hit.
3.30.505.10. 1 hit.
InterProIPR024162. 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.
IPR009060. UBA-like.
IPR015940. UBA/transl_elong_EF1B_N_euk.
IPR000449. UBA/Ts_N.
IPR018957. Znf_C3HC4_RING-type.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PANTHERPTHR23007. PTHR23007. 1 hit.
PfamPF02262. Cbl_N. 1 hit.
PF02761. Cbl_N2. 1 hit.
PF02762. Cbl_N3. 1 hit.
PF00627. UBA. 1 hit.
PF00097. zf-C3HC4. 1 hit.
[Graphical view]
SMARTSM00184. RING. 1 hit.
SM00165. UBA. 1 hit.
[Graphical view]
SUPFAMSSF46934. SSF46934. 1 hit.
SSF47668. SSF47668. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEPS51506. CBL_PTB. 1 hit.
PS50030. UBA. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP22681.
GeneWikiCBL_(gene).
GenomeRNAi867.
NextBio3618.
PMAP-CutDBP22681.
PROP22681.
SOURCESearch...

Entry information

Entry nameCBL_HUMAN
AccessionPrimary (citable) accession number: P22681
Secondary accession number(s): A3KMP8
Entry history
Integrated into UniProtKB/Swiss-Prot: August 1, 1991
Last sequence update: July 7, 2009
Last modified: April 16, 2014
This is version 173 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

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

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM