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   27-MAR-2024, entry version 137.
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.ENSRNOP00000074638; -.
DR   iPTMnet; Q8K4S7; -.
DR   PhosphoSitePlus; Q8K4S7; -.
DR   jPOST; Q8K4S7; -.
DR   PaxDb; 10116-ENSRNOP00000002719; -.
DR   GeneID; 171136; -.
DR   KEGG; rno:171136; -.
DR   UCSC; RGD:620535; rat.
DR   AGR; RGD:620535; -.
DR   RGD; 620535; Cblb.
DR   eggNOG; KOG1785; Eukaryota.
DR   InParanoid; Q8K4S7; -.
DR   OrthoDB; 1123734at2759; -.
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; IBA:GO_Central.
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:0035739; P:CD4-positive, alpha-beta T cell proliferation; ISO:RGD.
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:0043066; P:negative regulation of apoptotic process; IMP:RGD.
DR   GO; GO:2000562; P:negative regulation of CD4-positive, alpha-beta T cell proliferation; ISO:RGD.
DR   GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; 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:0030163; P:protein catabolic process; ISO:RGD.
DR   GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR   GO; GO:0030155; P:regulation of cell adhesion; ISO:RGD.
DR   GO; GO:2000583; P:regulation of platelet-derived growth factor receptor-alpha signaling pathway; ISS:UniProtKB.
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; IBA:GO_Central.
DR   GO; GO:0042110; P:T cell activation; ISO:RGD.
DR   GO; GO:0002870; P:T cell anergy; 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   CDD; cd14392; UBA_Cbl-b; 1.
DR   Gene3D; 1.20.930.20; Adaptor protein Cbl, N-terminal domain; 1.
DR   Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1.
DR   Gene3D; 1.10.238.10; EF-hand; 1.
DR   Gene3D; 3.30.505.10; SH2 domain; 1.
DR   Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 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; CBL; 1.
DR   PANTHER; PTHR23007:SF3; E3 UBIQUITIN-PROTEIN LIGASE CBL-B; 1.
DR   Pfam; PF02262; Cbl_N; 1.
DR   Pfam; PF02761; Cbl_N2; 1.
DR   Pfam; PF02762; Cbl_N3; 1.
DR   Pfam; PF13920; zf-C3HC4_3; 1.
DR   SMART; SM00184; RING; 1.
DR   SMART; SM00165; UBA; 1.
DR   SUPFAM; SSF47473; EF-hand; 1.
DR   SUPFAM; SSF47668; N-terminal domain of cbl (N-cbl); 1.
DR   SUPFAM; SSF57850; RING/U-box; 1.
DR   SUPFAM; SSF55550; SH2 domain; 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
//