CBLC_MOUSE
ID CBLC_MOUSE Reviewed; 496 AA.
AC Q80XL1; Q99PB6; Q9D6L2; Q9D7A9;
DT 16-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 16-AUG-2005, sequence version 2.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=E3 ubiquitin-protein ligase CBL-C;
DE EC=2.3.2.27 {ECO:0000250|UniProtKB:Q9ULV8};
DE AltName: Full=RING-type E3 ubiquitin transferase CBL-C {ECO:0000305};
DE AltName: Full=SH3-binding protein CBL-3;
DE AltName: Full=SH3-binding protein CBL-C;
DE AltName: Full=Signal transduction protein CBL-C;
GN Name=Cblc; Synonyms=Cbl3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP DEVELOPMENTAL STAGE.
RC STRAIN=C57BL/6J;
RX PubMed=11162497; DOI=10.1006/bbrc.2000.4116;
RA Fiore F., Ollendorff V., Birnbaum D.;
RT "Characterization of the mouse Cblc/Cbl3 gene.";
RL Biochem. Biophys. Res. Commun. 280:182-187(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J; TISSUE=Tongue;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=FVB/N; TISSUE=Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=14560016; DOI=10.1128/mcb.23.21.7708-7718.2003;
RA Griffiths E.K., Sanchez O., Mill P., Krawczyk C., Hojilla C.V., Rubin E.,
RA Nau M.M., Khokha R., Lipkowitz S., Hui C.C., Penninger J.M.;
RT "Cbl-3-deficient mice exhibit normal epithelial development.";
RL Mol. Cell. Biol. 23:7708-7718(2003).
CC -!- FUNCTION: Acts as an E3 ubiquitin-protein ligase, which accepts
CC ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then
CC transfers it to substrates promoting their degradation by the
CC proteasome. Functionally coupled with the E2 ubiquitin-protein ligases
CC UB2D1, UB2D2 and UB2D3. Regulator of EGFR mediated signal transduction;
CC upon EGF activation, ubiquitinates EGFR. Isoform 1, but not isoform 2,
CC inhibits EGF stimulated MAPK1 activation. Promotes ubiquitination of
CC SRC phosphorylated at 'Tyr-424', has the highest ubiquitin ligase
CC activity among CBL family proteins. In collaboration with CD2AP may act
CC as regulatory checkpoint for Ret signaling by modulating the rate of
CC RET degradation after ligand activation; CD2AP converts it from an
CC inhibitor to a promoter of RET degradation; the function limits the
CC potency of GDNF on neuronal survival. {ECO:0000250|UniProtKB:Q9ULV8}.
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:Q9ULV8};
CC -!- ACTIVITY REGULATION: Phosphorylation at Tyr-340 is necessary and
CC sufficient for the activation of E3 activity.
CC {ECO:0000250|UniProtKB:Q9ULV8}.
CC -!- SUBUNIT: Interacts with Ubiquitin-conjugating enzyme E2 UBE2D2 and
CC UBE2D3. Isoform 1 interacts with EGFR (tyrosine phosphorylated).
CC Interacts with the SH3 domain proteins LYN and CRK. Interacts (via
CC RING-type zinc finger) with TGFB1I1 (via LIM zinc-binding domain 2);
CC the interaction is direct and enhances the E3 activity. Interacts
CC directly with RET (inactive) and CD2AP; dissociates from RET upon RET
CC activation by GDNF which also increases the interaction with CD2AP
CC suggesting dissociation as CBLC:CD2AP complex. Interacts with SRC; the
CC interaction is enhanced when SRC is phosphorylated at 'Tyr-419'.
CC {ECO:0000250|UniProtKB:Q9ULV8}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q80XL1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q80XL1-2; Sequence=VSP_014946, VSP_014947;
CC -!- TISSUE SPECIFICITY: Widely expressed in tissues, where the expression
CC is restricted to epithelial cells (at protein level).
CC {ECO:0000269|PubMed:11162497, ECO:0000269|PubMed:14560016}.
CC -!- DEVELOPMENTAL STAGE: Expressed at 14.5 dpc in liver, lung and brain.
CC {ECO:0000269|PubMed:11162497}.
CC -!- DOMAIN: EF-hand-like and Sh2-like domains are required for N-terminal
CC inhibition of E3 activity. {ECO:0000250|UniProtKB:Q9ULV8}.
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 {ECO:0000255|PROSITE-ProRule:PRU00839}.
CC -!- DOMAIN: The RING-type zinc finger domain mediates binding to an E2
CC ubiquitin-conjugating enzyme. {ECO:0000250}.
CC -!- PTM: Phosphorylated on tyrosines by EGFR. {ECO:0000250}.
CC -!- PTM: Phosphorylated on multiple tyrosine residues by SRC. Isoform 1,
CC but not isoform 2, is phosphorylated on tyrosines by EGFR.
CC {ECO:0000250|UniProtKB:Q9ULV8}.
CC -!- PTM: Autoubiquitinated, when phosphorylated at Tyr-340.
CC {ECO:0000250|UniProtKB:Q9ULV8}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype.
CC {ECO:0000269|PubMed:14560016}.
CC -!- MISCELLANEOUS: This protein has one functional calcium-binding site.
CC {ECO:0000250}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF319956; AAK01405.1; -; mRNA.
DR EMBL; AK009399; BAB26265.1; -; mRNA.
DR EMBL; AK010228; BAB26782.1; -; mRNA.
DR EMBL; BC046337; AAH46337.1; -; mRNA.
DR CCDS; CCDS39804.1; -. [Q80XL1-1]
DR RefSeq; NP_075713.3; NM_023224.5. [Q80XL1-1]
DR AlphaFoldDB; Q80XL1; -.
DR SMR; Q80XL1; -.
DR BioGRID; 219812; 2.
DR STRING; 10090.ENSMUSP00000039955; -.
DR PhosphoSitePlus; Q80XL1; -.
DR PaxDb; Q80XL1; -.
DR PRIDE; Q80XL1; -.
DR ProteomicsDB; 265279; -. [Q80XL1-1]
DR ProteomicsDB; 265280; -. [Q80XL1-2]
DR Antibodypedia; 3762; 391 antibodies from 31 providers.
DR DNASU; 80794; -.
DR Ensembl; ENSMUST00000043822; ENSMUSP00000039955; ENSMUSG00000040525. [Q80XL1-1]
DR GeneID; 80794; -.
DR KEGG; mmu:80794; -.
DR UCSC; uc009fnh.2; mouse. [Q80XL1-1]
DR UCSC; uc009fni.2; mouse. [Q80XL1-2]
DR CTD; 23624; -.
DR MGI; MGI:1931457; Cblc.
DR VEuPathDB; HostDB:ENSMUSG00000040525; -.
DR eggNOG; KOG1785; Eukaryota.
DR GeneTree; ENSGT00940000162336; -.
DR HOGENOM; CLU_013535_2_0_1; -.
DR InParanoid; Q80XL1; -.
DR OMA; GGTCPFC; -.
DR OrthoDB; 540689at2759; -.
DR PhylomeDB; Q80XL1; -.
DR TreeFam; TF314210; -.
DR BioGRID-ORCS; 80794; 5 hits in 76 CRISPR screens.
DR ChiTaRS; Cblc; mouse.
DR PRO; PR:Q80XL1; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q80XL1; protein.
DR Bgee; ENSMUSG00000040525; Expressed in duodenum and 120 other tissues.
DR ExpressionAtlas; Q80XL1; baseline and differential.
DR Genevisible; Q80XL1; MM.
DR GO; GO:0045121; C:membrane raft; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0000151; C:ubiquitin ligase complex; ISO:MGI.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0005154; F:epidermal growth factor receptor binding; ISO:MGI.
DR GO; GO:0001784; F:phosphotyrosine residue binding; ISO:MGI.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; IBA:GO_Central.
DR GO; GO:0017124; F:SH3 domain binding; ISO:MGI.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; ISO:MGI.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IEA:InterPro.
DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; ISO:MGI.
DR GO; GO:0007175; P:negative regulation of epidermal growth factor-activated receptor activity; ISO:MGI.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; ISO:MGI.
DR GO; GO:0016567; P:protein ubiquitination; ISO:MGI.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISO:MGI.
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; IPR024159; Cbl_PTB.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR PANTHER; PTHR23007; PTHR23007; 1.
DR Pfam; PF02262; Cbl_N; 1.
DR Pfam; PF02761; Cbl_N2; 1.
DR Pfam; PF02762; Cbl_N3; 1.
DR SMART; SM00184; RING; 1.
DR SUPFAM; SSF47473; SSF47473; 1.
DR SUPFAM; SSF47668; SSF47668; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR PROSITE; PS51506; CBL_PTB; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calcium; Metal-binding; Phosphoprotein;
KW Reference proteome; Repeat; SH3-binding; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..496
FT /note="E3 ubiquitin-protein ligase CBL-C"
FT /id="PRO_0000055867"
FT DOMAIN 7..320
FT /note="Cbl-PTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00839"
FT ZN_FING 350..389
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 7..144
FT /note="4H"
FT REGION 145..217
FT /note="EF-hand-like"
FT REGION 218..320
FT /note="SH2-like"
FT REGION 321..349
FT /note="Linker"
FT /evidence="ECO:0000250"
FT REGION 350..494
FT /note="Interaction with RET"
FT /evidence="ECO:0000250"
FT REGION 432..453
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 198
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 200
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 202
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 209
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 263
FT /ligand="4-O-phospho-L-tyrosine"
FT /ligand_id="ChEBI:CHEBI:62338"
FT /evidence="ECO:0000250"
FT MOD_RES 340
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV8"
FT VAR_SEQ 259
FT /note="S -> R (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_014946"
FT VAR_SEQ 260..496
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_014947"
FT CONFLICT 8
FT /note="R -> Q (in Ref. 1; AAK01405)"
FT /evidence="ECO:0000305"
FT CONFLICT 371
FT /note="S -> G (in Ref. 1; AAK01405)"
FT /evidence="ECO:0000305"
FT CONFLICT 375
FT /note="A -> S (in Ref. 2; BAB26782)"
FT /evidence="ECO:0000305"
FT CONFLICT 416
FT /note="G -> D (in Ref. 3; AAH46337)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 496 AA; 55715 MW; 4DBE4A14C3D1BF57 CRC64;
MAAAAAPRGW QRGEPRALSR AVKLLQRLEE QCRDPRMVTG PPSLRDLLPR TAQLLGEVAK
ARREAREDPE GPGGADDFLA IYLANLEVKG RQVAELLPPR GKKDVNQDVF REGSRFRRQL
AKLALIFSHM HAELSALFPA GKYCGHLYQL TKGSAHIFWR QNCGVRCVLP WAEFQSLLCA
CHPVEPGPTM QALRSTLDLT CNGHVSVFEF DVFTRLFQPW PTLLRNWQLL AVNHPGYMAF
LTYDEVQTRL QAYRDKPGSY IFRPSCTRLG QWAIGYVSSD GSILQTIPLN KPLLQVLLKG
QKDGIFLFPD GKKHNPDLTE LCRVEPYQRI QVSEEQLLLY QAMNSTFQLC KICAERDKDV
RIEPCGHLLC SCCLAAWQDS DSQTCPFCRC EIKGREAVSI CQAQERPTEV RTAADGSRDN
CHQEAAEQKL GPVIPSAPSL LPEDQFPQGP QDKGWLTLAP LALPRLRPPL PLPKMASVLW
EVTSRPRARE EATESS
