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Reviewed, UniProtKB/Swiss-Prot Q3TTA7 (CBLB_MOUSE)

Last modified January 19, 2010. Version 49. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein namesRecommended name:
    E3 ubiquitin-protein ligase CBL-B
    EC=6.3.2.-
Alternative name(s):
    Signal transduction protein CBL-B
    SH3-binding protein CBL-B
    Casitas B-lineage lymphoma proto-oncogene b
Gene names
Name: Cblb
OrganismMus musculus (Mouse)
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

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Protein attributes

Sequence length982 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level.

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General annotation (Comments)

Function

E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T-cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. May also be involved in EGFR ubiquitination and internalization. Ref.2 Ref.3 Ref.4 Ref.5 Ref.8 Ref.9

Pathway

Protein modification; protein ubiquitination.

Subunit structure

Interacts with SH3 domain-containing proteins FYN, FGR, GRB2, CRKL, PIK3R1 and SH3KBP1/CIN85. Identified in heterotrimeric complexes with SH3KBP1/CIN85, CD2AP and ARHGEF7, where one CBLB peptide binds two copies of the other protein. Interacts with poly-ubiquitinated proteins. Dimerization is required for the binding of poly-ubiquitin, but not for the binding of mono-ubiquitin By similarity. Interacts with SH3 domain-containing proteins VAV1, PLCG1, PIK3R1, LCK, CRK and SORBS1. May interact with CBL. Interacts with LCP2 and ZAP70. Ref.3 Ref.7

Subcellular location

Cytoplasm. Note: In adipocytes, translocates to the plasma membrane upon insulin stimulation. Ref.7

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.

The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.

The UBA domain interacts with poly-ubiquitinated proteins By similarity.

Post-translational modification

Phosphorylated on tyrosine residues upon TCR or BCR activation. Phosphorylated on Tyr-664 and Tyr-708 in adipocytes following insulin stimulation. Ref.8 Ref.7 Ref.10

Auto-ubiquitinated upon EGF-mediated cell activation or upon T-cell costimulation by CD28; which promotes proteasomal degradation.

Disruption phenotype

Mice are fertile and grossly normal. However, they show a high sensitivity to autoimmune diseases and may develop a spontaneous generalized autoimmune disorder characterized by auto-antibody production, infiltration of activated T- and B-lymphocytes into various organs and parenchymal damage. Ref.4

Miscellaneous

This protein has one functional calcium-binding site By similarity.

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.

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Ontologies

Keywords
   Biological processImmune response
Ubl conjugation pathway
   Cellular componentCytoplasm
   Coding sequence diversityAlternative splicing
   DomainRepeat
SH2 domain
Zinc-finger
   LigandCalcium
Metal-binding
Zinc
   Molecular functionLigase
   PTMPhosphoprotein
Ubl conjugation
Gene Ontology (GO)
   Biological processT cell activation Ref.2

Inferred from mutant phenotype. Source: MGI

cell surface receptor linked signal transduction

Inferred from electronic annotation. Source: InterPro

immune response Ref.2

Inferred from mutant phenotype. Source: MGI

intracellular signaling cascade Ref.2

Inferred from mutant phenotype. Source: MGI

modification-dependent protein catabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of T cell receptor signaling pathway

Inferred from mutant phenotype. Source: MGI

negative regulation of alpha-beta T cell proliferation

Inferred from mutant phenotype. Source: MGI

positive regulation of T cell anergy

Inferred from mutant phenotype. Source: MGI

positive regulation of protein catabolic process

Inferred from mutant phenotype. Source: MGI

   Cellular componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from electronic annotation. Source: InterPro

   Molecular functioncalcium ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

ligase activity

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from electronic annotation. Source: InterPro

signal transducer activity

Inferred from electronic annotation. Source: InterPro

zinc ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

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Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q3TTA7-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q3TTA7-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-152: Missing.

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 982982E3 ubiquitin-protein ligase CBL-B
PRO_0000055861

Regions

Domain36 – 349314CBL N-terminal
Domain204 – 2129EF-hand-like 1
Domain221 – 23212EF-hand-like 2
Domain259 – 33375SH2; atypical
Domain931 – 97040UBA
Zinc finger373 – 41240RING-type
Region36 – 1691344H
Region334 – 37239Linker
Region543 – 56725Interaction with VAV1 By similarity
Region891 – 92737Interaction with SH3KBP1 By similarity
Compositional bias477 – 56690Pro-rich
Compositional bias672 – 6754Poly-Pro
Compositional bias775 – 87197Pro-rich

Sites

Binding site2861Phosphotyrosine By similarity

Amino acid modifications

Modified residue3631Phosphotyrosine By similarity
Modified residue4801Phosphoserine By similarity
Modified residue4841Phosphoserine By similarity
Modified residue5211Phosphoserine By similarity
Modified residue5251Phosphoserine By similarity
Modified residue5291Phosphoserine By similarity
Modified residue6131Phosphoserine By similarity
Modified residue6641Phosphotyrosine Ref.7
Modified residue7081Phosphotyrosine Ref.7
Modified residue8891Phosphotyrosine Ref.10

Natural variations

Alternative sequence1 – 152152Missing in isoform 2.
VSP_017222

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Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified February 7, 2006. Version 2.
Checksum: F541B486324B2826

FASTA982109,122
        10         20         30         40         50         60 
MANSMNGRNP GGRGGNPRKG RILGIIDAIQ DAVGPPKQAA ADRRTVEKTW KLMDKVVRLC 

        70         80         90        100        110        120 
QNPKLQLKNS PPYILDILPD TYQHLRLILS KYDDNQKLAQ LSENEYFKIY IDSLMKKSKR 

       130        140        150        160        170        180 
AIRLFKEGKE RMYEEQSQDR RNLTKLSLIF SHMLAEIKAI FPNGQFQGDN FRITKTDAAE 

       190        200        210        220        230        240 
FWRKFFGDKT IVPWKVFRQC LHEVHQISSG LEAMALKSTI DLTCNDYISV FEFDIFTRLF 

       250        260        270        280        290        300 
QPWGSILRNW NFLAVTHPGY MAFLTYDEVK ARLQKYSTKP GSYIFRLSCT RLGQWAIGYV 

       310        320        330        340        350        360 
TGDGNILQTI PHNKPLFQAL IDGSREGFYL YPDGRSYNPD LTGLCEPTPH DHIKVTQEQY 

       370        380        390        400        410        420 
ELYCEMGSTF QLCKICAEND KDVKIEPCGH LMCTSCLTAW QESDGQGCPF CRCEIKGTEP 

       430        440        450        460        470        480 
IIVDPFDPRD EGSRCCSIID PFSIPMLDLD DDDDREESLM MNRLASVRKC TDRQNSPVTS 

       490        500        510        520        530        540 
PGSSPLAQRR KPQPDPLQIP HLSLPPVPPR LDLIQKGIVR SPCGSPTGSP KSSPCMVRKQ 

       550        560        570        580        590        600 
DKPLPAPPPP LRDPPPPPER PPPIPPDNRL SRHFHHGESV PSRDQPMPLE AWCPRDAFGT 

       610        620        630        640        650        660 
NQVMGCRILG DGSPKPGVTA NSSLNGRHSR MGSEQVLMRK HRRHDLPSEG AKVFSNGHLA 

       670        680        690        700        710        720 
TEEYDVPPRL SPPPPVTTLL PSIKCTGPLA NCLSEKTRDT VEDDDDEYKI PSSHPVSLNS 

       730        740        750        760        770        780 
QPSHCHNVKA PVRSCDNGHC ILNGTHGAPS EMKKSNIPDL GIYLKGGGSD SASDPVPLPP 

       790        800        810        820        830        840 
ARPPPRDSPK HGSSVNRTPS DYDLLIPPLG EDAFDALPPS LPPPPPPARH SLIEHSKPPG 

       850        860        870        880        890        900 
SSSRPSSGQD LFLLPSDPFF DPTSGQVPLP PARRAAGDSG KANRASQDYD QLPSSSDGSQ 

       910        920        930        940        950        960 
APARPPKPRP RRTAPEIHHR KPHGPEAALE NVDAKIAKLM GEGYAFEEVK RALEIAQNNV 

       970        980 
EVARSILREF AFPPPVSPRL NL

« Hide

Isoform 2.

Checksum: 4C78BF8F13231A84
Show »

FASTA83091,554

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References

« Hide 'large scale' references
[1]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
Strain: C57BL/6J.
Tissue: Testis.
[2]"Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells."
Krawczyk C., Bachmaier K., Sasaki T., Jones R.G., Snapper S.B., Bouchard D., Kozieradzki I., Ohashi P.S., Alt F.W., Penninger J.M.
Immunity 13:463-473(2000) [PubMed: 11070165] [Abstract]
Cited for: FUNCTION.
[3]"Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b."
Bachmaier K., Krawczyk C., Kozieradzki I., Kong Y.-Y., Sasaki T., Oliveira-dos-Santos A., Mariathasan S., Bouchard D., Wakeham A., Itie A., Le J., Ohashi P.S., Sarosi I., Nishina H., Lipkowitz S., Penninger J.M.
Nature 403:211-216(2000) [PubMed: 10646608] [Abstract]
Cited for: FUNCTION, INTERACTION WITH PIK3R1; LCP2; ZAP70; LCK; PLCG1 AND VAV1.
[4]"Cbl-b regulates the CD28 dependence of T-cell activation."
Chiang Y.J., Kole H.K., Brown K., Naramura M., Fukuhara S., Hu R.-J., Jang I.K., Gutkind J.S., Shevach E., Gu H.
Nature 403:216-220(2000) [PubMed: 10646609] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[5]"Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells."
Fang D., Liu Y.-C.
Nat. Immunol. 2:870-875(2001) [PubMed: 11526404] [Abstract]
Cited for: FUNCTION.
[6]"Regulation of T cell activation threshold by CD28 costimulation through targeting Cbl-b for ubiquitination."
Zhang J., Bardos T., Li D., Gal I., Vermes C., Xu J., Mikecz K., Finnegan A., Lipkowitz S., Glant T.T.
J. Immunol. 169:2236-2240(2002) [PubMed: 12193687] [Abstract]
Cited for: UBIQUITINATION.
[7]"The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport."
Liu J., DeYoung S.M., Hwang J.B., O'Leary E.E., Saltiel A.R.
J. Biol. Chem. 278:36754-36762(2003) [PubMed: 12842890] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-664 AND TYR-708, INTERACTION WITH CBL; CRK AND SORBS1, SUBCELLULAR LOCATION.
[8]"Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk."
Sohn H.W., Gu H., Pierce S.K.
J. Exp. Med. 197:1511-1524(2003) [PubMed: 12771181] [Abstract]
Cited for: PHOSPHORYLATION, FUNCTION.
[9]"Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction."
Jeon M.-S., Atfield A., Venuprasad K., Krawczyk C., Sarao R., Elly C., Yang C., Arya S., Bachmaier K., Su L., Bouchard D., Jones R., Gronski M., Ohashi P., Wada T., Bloom D., Fathman C.G., Liu Y.-C., Penninger J.M.
Immunity 21:167-177(2004) [PubMed: 15308098] [Abstract]
Cited for: FUNCTION.
[10]"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-889, MASS SPECTROMETRY.
+Additional computationally mapped references.

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Cross-references

Sequence databases

EMBL
GenBank
DDBJ		AK147367 mRNA. No translation available.
AK161486 mRNA. Translation: BAE36418.1.
IPIIPI00266006.
IPI00660894.
RefSeqNP_001028410.1.
UniGeneMm.328206

3D structure databases

SMRQ3TTA7. Positions 35-426, 929-972.
ModBaseSearch...

Protein-protein interaction databases

STRINGQ3TTA7.

PTM databases

PhosphoSiteQ3TTA7.

Proteomic databases

PRIDEQ3TTA7.

Genome annotation databases

EnsemblENSMUST00000023313; ENSMUSP00000023313; ENSMUSG00000022637; Mus musculus. [Genome view]
GeneID208650.
KEGGmmu:208650.
UCSCuc007zle.1. mouse.

Organism-specific databases

CTD208650.
MGIMGI:2146430. Cblb.

Phylogenomic databases

eggNOGroNOG15295.
HOGENOMHBG715842.
HOVERGENQ3TTA7.
InParanoidQ3TTA7.

Gene expression databases

ArrayExpressQ3TTA7.
BgeeQ3TTA7.
CleanExMM_CBLB.
GenevestigatorQ3TTA7.
GermOnlineENSMUSG00000022637. Mus musculus.

Family and domain databases

InterProIPR014741. Adaptor_Cbl_EF_Hand-like.
IPR003153. Adaptor_Cbl_N.
IPR014742. Adaptor_Cbl_SH2-like.
IPR011992. EF-hand-like_dom.
IPR000980. SH2.
IPR000449. UBA/transl_elong_EF1B_N.
IPR015940. UBA/transl_elong_EF1B_N_euk.
IPR018957. Znf_C3HC4_RING-type.
IPR001841. Znf_RING.
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:3.30.505.10. SH2. 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.
SM00252. SH2. 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

SOURCESearch...

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Entry information

Entry nameCBLB_MOUSE
AccessionPrimary (citable) accession number: Q3TTA7
Entry history
Integrated into UniProtKB/Swiss-Prot: February 7, 2006
Last sequence update: February 7, 2006
Last modified: January 19, 2010
This is version 49 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

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Relevant documents

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot

PATHWAY comments

Index of metabolic and biosynthesis pathways

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents