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Q3TTA7 (CBLB_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 95. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase CBL-B

EC=6.3.2.-
Alternative name(s):
Casitas B-lineage lymphoma proto-oncogene b
SH3-binding protein CBL-B
Signal transduction protein CBL-B
Gene names
Name:Cblb
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

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

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. Slightly promotes SRC ubiquitination. May be involved in EGFR ubiquitination and internalization. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. Ref.3 Ref.4 Ref.5 Ref.6 Ref.9 Ref.10

Pathway

Protein modification; protein ubiquitination.

Subunit structure

Interacts with SH3 domain-containing proteins LCK, CRK and SORBS1. Interacts with LCP2 and ZAP70. May interact with CBL. Interacts with SH3 domain-containing proteins VAV1, FYN, FGR, PLCG1, 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. Interacts with EGFR (phosphorylated). Ref.4 Ref.8

Subcellular location

Cytoplasm. Note: In adipocytes, translocates to the plasma membrane upon insulin stimulation. Ref.8

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 and serine residues upon TCR or BCR activation. Phosphorylated on Tyr-664 and Tyr-708 in adipocytes following insulin stimulation. Ref.8 Ref.9

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.5

Miscellaneous

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

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 componentCytoplasm
   Coding sequence diversityAlternative splicing
   DomainRepeat
Zinc-finger
   LigandCalcium
Metal-binding
Zinc
   Molecular functionLigase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processT cell activation

Inferred from mutant phenotype Ref.3. Source: MGI

cell surface receptor signaling pathway

Inferred from electronic annotation. Source: InterPro

immune response

Inferred from mutant phenotype Ref.3. Source: MGI

intracellular signal transduction

Inferred from mutant phenotype Ref.3. Source: MGI

negative regulation of T cell receptor signaling pathway

Inferred from mutant phenotype PubMed 14738763. Source: MGI

negative regulation of alpha-beta T cell proliferation

Inferred from mutant phenotype PubMed 14973438. Source: MGI

positive regulation of T cell anergy

Inferred from mutant phenotype PubMed 14973438. Source: MGI

positive regulation of protein catabolic process

Inferred from mutant phenotype PubMed 14973438. 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: InterPro

protein binding

Inferred from physical interaction PubMed 20639876. Source: IntAct

signal transducer activity

Inferred from electronic annotation. Source: InterPro

ubiquitin-protein transferase activity

Inferred from electronic annotation. Source: InterPro

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Myd88P223662EBI-3649276,EBI-525108
Ticam1Q80UF72EBI-3649276,EBI-3649271

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.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

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

Regions

Domain35 – 343309Cbl-PTB
Domain931 – 97040UBA
Calcium binding219 – 23214 By similarity
Zinc finger373 – 41240RING-type
Region35 – 1671334H
Region168 – 24073EF-hand-like
Region241 – 343103SH2-like
Region344 – 37229Linker
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 residue2821Phosphoserine; by PKC/PRKCQ By similarity
Modified residue5211Phosphoserine By similarity
Modified residue5251Phosphoserine By similarity
Modified residue5291Phosphoserine By similarity
Modified residue6331Phosphoserine By similarity
Modified residue6641Phosphotyrosine Ref.8
Modified residue7081Phosphotyrosine Ref.8
Modified residue8891Phosphotyrosine Ref.11

Natural variations

Alternative sequence1 – 152152Missing in isoform 2.
VSP_017222

Experimental info

Sequence conflict1761A → T in BAE36418. Ref.1

Sequences

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

Last modified July 27, 2011. Version 3.
Checksum: 14B55C4106F84A86

FASTA982109,092
        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 FRITKADAAE 

       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 [UniParc].

Checksum: AD8C574827907824
Show »

FASTA83091,524

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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
Strain: C57BL/6J.
Tissue: Testis.
[2]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6J.
[3]"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] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[4]"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] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH PIK3R1; LCP2; ZAP70; LCK; PLCG1 AND VAV1.
[5]"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] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[6]"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] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[7]"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] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION.
[8]"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] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-664 AND TYR-708, INTERACTION WITH CBL; CRK AND SORBS1, SUBCELLULAR LOCATION.
[9]"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] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION, FUNCTION.
[10]"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] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[11]"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: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-889, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AK147367 mRNA. No translation available.
AK161486 mRNA. Translation: BAE36418.1.
AC117780 Genomic DNA. No translation available.
AC154251 Genomic DNA. No translation available.
AC154478 Genomic DNA. No translation available.
RefSeqNP_001028410.1. NM_001033238.1.
XP_006522010.1. XM_006521947.1. [Q3TTA7-1]
XP_006522011.1. XM_006521948.1. [Q3TTA7-1]
XP_006522012.1. XM_006521949.1. [Q3TTA7-1]
XP_006522013.1. XM_006521950.1. [Q3TTA7-1]
XP_006522015.1. XM_006521952.1.
UniGeneMm.328206.

3D structure databases

ProteinModelPortalQ3TTA7.
SMRQ3TTA7. Positions 38-427, 929-972.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid229001. 17 interactions.
IntActQ3TTA7. 4 interactions.
MINTMINT-5042139.
STRING10090.ENSMUSP00000023313.

PTM databases

PhosphoSiteQ3TTA7.

Proteomic databases

PaxDbQ3TTA7.
PRIDEQ3TTA7.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID208650.
KEGGmmu:208650.
UCSCuc007zlf.1. mouse. [Q3TTA7-1]

Organism-specific databases

CTD868.
MGIMGI:2146430. Cblb.

Phylogenomic databases

eggNOGNOG242251.
HOGENOMHOG000294176.
HOVERGENHBG005255.
InParanoidQ3TTA7.
KOK04707.

Enzyme and pathway databases

UniPathwayUPA00143.

Gene expression databases

CleanExMM_CBLB.
GenevestigatorQ3TTA7.

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.
IPR015940. UBA/transl_elong_EF1B_N_euk.
IPR000449. UBA/Ts_N.
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.
[Graphical view]
SMARTSM00184. RING. 1 hit.
SM00252. SH2. 1 hit.
SM00165. UBA. 1 hit.
[Graphical view]
SUPFAMSSF47668. 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

NextBio372367.
PROQ3TTA7.
SOURCESearch...

Entry information

Entry nameCBLB_MOUSE
AccessionPrimary (citable) accession number: Q3TTA7
Secondary accession number(s): E9QMY2
Entry history
Integrated into UniProtKB/Swiss-Prot: February 7, 2006
Last sequence update: July 27, 2011
Last modified: July 9, 2014
This is version 95 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PATHWAY comments

Index of metabolic and biosynthesis pathways

MGD cross-references

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