CBLB_RAT
ID CBLB_RAT Reviewed; 938 AA.
AC Q8K4S7; Q9QZ69;
DT 07-FEB-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 03-AUG-2022, entry version 128.
DE RecName: Full=E3 ubiquitin-protein ligase CBL-B;
DE EC=2.3.2.27 {ECO:0000250|UniProtKB:Q13191};
DE AltName: Full=Casitas B-lineage lymphoma proto-oncogene b;
DE AltName: Full=RING-type E3 ubiquitin transferase CBL-B {ECO:0000305};
DE AltName: Full=SH3-binding protein CBL-B;
DE AltName: Full=Signal transduction protein CBL-B;
GN Name=Cblb;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND DISEASE.
RC TISSUE=Spleen;
RX PubMed=12118252; DOI=10.1038/ng927;
RA Yokoi N., Komeda K., Wang H.-Y., Yano H., Kitada K., Saitoh Y., Seino Y.,
RA Yasuda K., Serikawa T., Seino S.;
RT "Cblb is a major susceptibility gene for rat type 1 diabetes mellitus.";
RL Nat. Genet. 31:391-394(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 738-938.
RC STRAIN=Sprague-Dawley; TISSUE=Kidney;
RA Nicolas G., Galand C., Lecomte M.-C.;
RT "Identification of cbl-b as a putative binding partner of SH3 domains of
RT erythroid and non-erythroid alpha-spectrin (alpha-fodrin).";
RL Submitted (OCT-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=14604964; DOI=10.1182/blood-2003-07-2260;
RA Qu X., Sada K., Kyo S., Maeno K., Miah S.M., Yamamura H.;
RT "Negative regulation of FcepsilonRI-mediated mast cell activation by a
RT ubiquitin-protein ligase Cbl-b.";
RL Blood 103:1779-1786(2004).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-633, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=16641100; DOI=10.1073/pnas.0600895103;
RA Hoffert J.D., Pisitkun T., Wang G., Shen R.-F., Knepper M.A.;
RT "Quantitative phosphoproteomics of vasopressin-sensitive renal cells:
RT regulation of aquaporin-2 phosphorylation at two sites.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:7159-7164(2006).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-476, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from
CC specific E2 ubiquitin-conjugating enzymes, and transfers it to
CC substrates, generally promoting their degradation by the proteasome.
CC Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and
CC FCER1 (high affinity immunoglobulin epsilon receptor) signal
CC transduction pathways. In naive T-cells, inhibits VAV1 activation upon
CC TCR engagement and imposes a requirement for CD28 costimulation for
CC proliferation and IL-2 production. Also acts by promoting PIK3R1/p85
CC ubiquitination, which impairs its recruitment to the TCR and subsequent
CC activation. In activated T-cells, inhibits PLCG1 activation and calcium
CC mobilization upon restimulation and promotes anergy. In B-cells, acts
CC by ubiquitinating SYK and promoting its proteasomal degradation.
CC Slightly promotes SRC ubiquitination. May be involved in EGFR
CC ubiquitination and internalization. May be functionally coupled with
CC the E2 ubiquitin-protein ligase UB2D3. In association with CBL,
CC required for proper feedback inhibition of ciliary platelet-derived
CC growth factor receptor-alpha (PDGFRA) signaling pathway via
CC ubiquitination and internalization of PDGFRA (By similarity).
CC {ECO:0000250|UniProtKB:Q3TTA7, ECO:0000269|PubMed:14604964}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000250|UniProtKB:Q13191};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with SH3 domain-containing proteins LCK, CRK and
CC SORBS1. Interacts with LCP2 and ZAP70. Interacts with CBL. Interacts
CC with SH3 domain-containing proteins VAV1, FYN, FGR, PLCG1, GRB2, CRKL,
CC PIK3R1 and SH3KBP1/CIN85. Identified in heterotrimeric complexes with
CC SH3KBP1/CIN85, CD2AP and ARHGEF7, where one CBLB peptide binds two
CC copies of the other protein. Interacts with poly-ubiquitinated
CC proteins. Dimerization is required for the binding of poly-ubiquitin,
CC but not for the binding of mono-ubiquitin. Interacts with EGFR
CC (phosphorylated). Interacts with IFT20. {ECO:0000250|UniProtKB:Q13191}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14604964}. Note=In
CC mast cells, translocates to lipid raft upon FCER1 engagement.
CC -!- DOMAIN: The N-terminus is composed of the phosphotyrosine binding (PTB)
CC domain, a short linker region and the RING-type zinc finger. The PTB
CC domain, which is also called TKB (tyrosine kinase binding) domain, is
CC composed of three different subdomains: a four-helix bundle (4H), a
CC calcium-binding EF hand and a divergent SH2 domain.
CC -!- DOMAIN: The RING-type zinc finger domain mediates binding to an E2
CC ubiquitin-conjugating enzyme.
CC -!- DOMAIN: The UBA domain interacts with poly-ubiquitinated proteins.
CC {ECO:0000250|UniProtKB:Q13191}.
CC -!- PTM: Phosphorylated on tyrosine and serine residues upon TCR or BCR
CC activation, and upon various types of cell stimulation.
CC {ECO:0000250|UniProtKB:Q13191}.
CC -!- PTM: Auto-ubiquitinated upon EGF-mediated cell activation or upon T-
CC cell costimulation by CD28; which promotes proteasomal degradation.
CC {ECO:0000250|UniProtKB:Q13191}.
CC -!- DISEASE: Note=Lack of Cblb expression is the cause of the Komeda
CC diabetes-prone (KDP) phenotype, characterized by autoimmune destruction
CC of pancreatic beta cells and rapid onset of overt diabetes with no sex
CC difference and no significant T-cell lymphopenia. The KPD rat is a
CC spontaneous animal model for human type 1 diabetes mellitus.
CC {ECO:0000269|PubMed:12118252}.
CC -!- MISCELLANEOUS: This protein has one functional calcium-binding site.
CC {ECO:0000250}.
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DR EMBL; AB071283; BAC05498.1; -; mRNA.
DR EMBL; AF199504; AAF13271.1; -; mRNA.
DR RefSeq; NP_598285.1; NM_133601.1.
DR AlphaFoldDB; Q8K4S7; -.
DR BMRB; Q8K4S7; -.
DR SMR; Q8K4S7; -.
DR IntAct; Q8K4S7; 6.
DR MINT; Q8K4S7; -.
DR STRING; 10116.ENSRNOP00000002719; -.
DR iPTMnet; Q8K4S7; -.
DR PhosphoSitePlus; Q8K4S7; -.
DR jPOST; Q8K4S7; -.
DR PaxDb; Q8K4S7; -.
DR GeneID; 171136; -.
DR KEGG; rno:171136; -.
DR UCSC; RGD:620535; rat.
DR CTD; 868; -.
DR RGD; 620535; Cblb.
DR eggNOG; KOG1785; Eukaryota.
DR InParanoid; Q8K4S7; -.
DR Reactome; R-RNO-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR PRO; PR:Q8K4S7; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0045121; C:membrane raft; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0001784; F:phosphotyrosine residue binding; IEA:InterPro.
DR GO; GO:0019901; F:protein kinase binding; IPI:RGD.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; IBA:GO_Central.
DR GO; GO:0017124; F:SH3 domain binding; IBA:GO_Central.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEP:RGD.
DR GO; GO:0006955; P:immune response; ISO:RGD.
DR GO; GO:0035556; P:intracellular signal transduction; ISO:RGD.
DR GO; GO:0046642; P:negative regulation of alpha-beta T cell proliferation; ISO:RGD.
DR GO; GO:0007175; P:negative regulation of epidermal growth factor-activated receptor activity; IBA:GO_Central.
DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; ISO:RGD.
DR GO; GO:0018193; P:peptidyl-amino acid modification; ISO:RGD.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; ISO:RGD.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISO:RGD.
DR GO; GO:0002669; P:positive regulation of T cell anergy; ISO:RGD.
DR GO; GO:0030155; P:regulation of cell adhesion; ISO:RGD.
DR GO; GO:0043087; P:regulation of GTPase activity; ISO:RGD.
DR GO; GO:2000583; P:regulation of platelet-derived growth factor receptor-alpha signaling pathway; ISS:UniProtKB.
DR GO; GO:0043393; P:regulation of protein binding; ISO:RGD.
DR GO; GO:0009629; P:response to gravity; IEP:RGD.
DR GO; GO:0009725; P:response to hormone; IEP:RGD.
DR GO; GO:0007165; P:signal transduction; IDA:RGD.
DR GO; GO:0042110; P:T cell activation; ISO:RGD.
DR GO; GO:0050852; P:T cell receptor signaling pathway; ISO:RGD.
DR CDD; cd16709; RING-HC_Cbl-b; 1.
DR CDD; cd09920; SH2_Cbl-b_TKB; 1.
DR Gene3D; 1.20.930.20; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR024162; Adaptor_Cbl.
DR InterPro; IPR014741; Adaptor_Cbl_EF_hand-like.
DR InterPro; IPR036537; Adaptor_Cbl_N_dom_sf.
DR InterPro; IPR003153; Adaptor_Cbl_N_hlx.
DR InterPro; IPR014742; Adaptor_Cbl_SH2-like.
DR InterPro; IPR039520; CBL-B_RING-HC.
DR InterPro; IPR024159; Cbl_PTB.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR015940; UBA.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR PANTHER; PTHR23007; PTHR23007; 2.
DR Pfam; PF02262; Cbl_N; 1.
DR Pfam; PF02761; Cbl_N2; 1.
DR Pfam; PF02762; Cbl_N3; 1.
DR SMART; SM00184; RING; 1.
DR SMART; SM00165; UBA; 1.
DR SUPFAM; SSF47473; SSF47473; 1.
DR SUPFAM; SSF47668; SSF47668; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR PROSITE; PS51506; CBL_PTB; 1.
DR PROSITE; PS50030; UBA; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Calcium; Cytoplasm; Diabetes mellitus; Metal-binding; Phosphoprotein;
KW Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..938
FT /note="E3 ubiquitin-protein ligase CBL-B"
FT /id="PRO_0000055862"
FT DOMAIN 35..343
FT /note="Cbl-PTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00839"
FT DOMAIN 887..926
FT /note="UBA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212"
FT ZN_FING 373..412
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 35..167
FT /note="4H"
FT REGION 168..240
FT /note="EF-hand-like"
FT REGION 241..343
FT /note="SH2-like"
FT REGION 344..372
FT /note="Linker"
FT REGION 465..588
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 543..567
FT /note="Interaction with VAV1"
FT /evidence="ECO:0000250"
FT REGION 702..725
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 771..885
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 847..883
FT /note="Interaction with SH3KBP1"
FT /evidence="ECO:0000250"
FT COMPBIAS 468..487
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 541..568
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 773..788
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 792..806
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 840..857
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 221
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 223
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 225
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 227
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 232
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 286
FT /ligand="4-O-phospho-L-tyrosine"
FT /ligand_id="ChEBI:CHEBI:62338"
FT /evidence="ECO:0000250"
FT MOD_RES 282
FT /note="Phosphoserine; by PKC/PRKCQ"
FT /evidence="ECO:0000250|UniProtKB:Q13191"
FT MOD_RES 363
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13191"
FT MOD_RES 476
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 480
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3TTA7"
FT MOD_RES 484
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q3TTA7"
FT MOD_RES 521
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13191"
FT MOD_RES 525
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13191"
FT MOD_RES 529
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13191"
FT MOD_RES 633
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16641100"
FT MOD_RES 664
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13191"
FT MOD_RES 708
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13191"
FT MOD_RES 845
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q3TTA7"
SQ SEQUENCE 938 AA; 104652 MW; 8316D0E7F7252EC6 CRC64;
MANSMNGRNP GGRGGNPRKG RILGIIDAIQ DAVGPPKQAA ADRRTVEKTW KLMDKVVRLC
QNPKLQLKNS PPYILDILPD TYQHLRLILS KYDDNQKLAQ LSENEYFKIY IDSLMKKSKR
AIRLFKEGKE RMYEEQSQDR RNLTKLSLIF SHMLAEIKAI FPNGQFQGDN FRITKADAAE
FWRKFFGDKT IVPWKVFRQC LHEVHQISSG LEAMALKSTI DLTCNDYISV FEFDIFTRLF
QPWGSILRNW NFLAVTHPGY MAFLTYDEVK ARLQKYSTKP GSYIFRLSCT RLGQWAIGYV
TGDGNILQTI PHNKPLFQAL IDGSREGFYL YPDGRSYNPD LTGLCEPTPH DHIKVTQEQY
ELYCEMGSTF QLCKICAEND KDVKIEPCGH LMCTSCLTAW QESDGQGCPF CRCEIKGTEP
IIVDPFDPRD EGSRCCSIID PFSIPMLDLD DDDDREESLM MNRLASVRKC TDRQNSPVTS
PGSSPLAQRR KPQPDPLQIP HLSLPPVPPR LDLIQKGIVR SPCGSPTGSP KSSPCMVRKQ
DKPLPAPPPP LRDPPPPPER PPPIPPDSRL SRHFHHGESV PSRDQPMPLE AWCPRDAFGT
NQVMGCRILG DGSPKPGVTA NSNLNGRHSR MGSDQVLMRK HRRHDLPSEG AKVFSNGHLA
PEEYDVPPRL SPPPPVTALL PSIKCTGPIA NCLSEKTRDT VEEDDDEYKI PSSHPVSLNS
QPSHCHNVKP PVRSCDNGHC ILNGTHGTPS EMKKSNIPDL GIYLKGEDAF DALPPSLPPP
PPPARHSLIE HSKPPGSSSR PSSGQDLFLL PSDPFFDPAS GQVPLPPARR APGDGVKSNR
ASQDYDQLPS SSDGSQAPAR PPKPRPRRTA PEIHHRKPHG PEAALENVDA KIAKLMGEGY
AFEEVKRALE IAQNNLEVAR SILREFAFPP PVSPRLNL
