CBLC_RAT
ID CBLC_RAT Reviewed; 497 AA.
AC G3V8H4; Q3KRC9;
DT 22-JAN-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-NOV-2011, sequence version 1.
DT 03-AUG-2022, entry version 59.
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};
GN Name=Cblc; Synonyms=Cbl-3;
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 [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 FUNCTION IN RET STABILITY, AND INTERACTION WITH CD2AP AND RET.
RX PubMed=18753381; DOI=10.1523/jneurosci.2738-08.2008;
RA Tsui C.C., Pierchala B.A.;
RT "CD2AP and Cbl-3/Cbl-c constitute a critical checkpoint in the regulation
RT of ret signal transduction.";
RL J. Neurosci. 28:8789-8800(2008).
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. Inhibits EGF stimulated MAPK1
CC activation. Promotes ubiquitination of SRC phosphorylated at 'Tyr-419',
CC has the highest ubiquitin ligase activity among CBL family proteins. In
CC collaboration with CD2AP may act as regulatory checkpoint for Ret
CC signaling by modulating the rate of RET degradation after ligand
CC activation; CD2AP converts it from an inhibitor to a promoter of RET
CC degradation; the function limits the potency of GDNF on neuronal
CC survival. {ECO:0000269|PubMed:18753381}.
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-341 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. Interacts with EGFR (tyrosine phosphorylated). Interacts with
CC the SH3 domain proteins LYN and CRK. Interacts (via RING-type zinc
CC finger) with TGFB1I1 (via LIM zinc-binding domain 2); the interaction
CC is direct and enhances the E3 activity. Interacts directly with RET
CC (inactive) and CD2AP; dissociates from RET upon RET activation by GDNF
CC which also increases the interaction with CD2AP suggesting dissociation
CC as CBLC:CD2AP complex. Interacts with SRC; the interaction is enhanced
CC when SRC is phosphorylated at 'Tyr-419'. {ECO:0000269|PubMed:18753381}.
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 multiple tyrosine residues by SRC.
CC {ECO:0000250}.
CC -!- PTM: Autoubiquitinated, when phosphorylated at Tyr-341.
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; AABR06003893; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH473979; EDM08131.1; -; Genomic_DNA.
DR EMBL; BC105776; AAI05777.1; -; mRNA.
DR RefSeq; NP_001030092.1; NM_001034920.2.
DR AlphaFoldDB; G3V8H4; -.
DR SMR; G3V8H4; -.
DR STRING; 10116.ENSRNOP00000025829; -.
DR PaxDb; G3V8H4; -.
DR PRIDE; G3V8H4; -.
DR Ensembl; ENSRNOT00000025829; ENSRNOP00000025829; ENSRNOG00000018953.
DR GeneID; 292699; -.
DR KEGG; rno:292699; -.
DR UCSC; RGD:1307651; rat.
DR CTD; 23624; -.
DR RGD; 1307651; Cblc.
DR eggNOG; KOG1785; Eukaryota.
DR GeneTree; ENSGT00940000162336; -.
DR HOGENOM; CLU_013535_2_0_1; -.
DR InParanoid; G3V8H4; -.
DR OMA; GGTCPFC; -.
DR OrthoDB; 540689at2759; -.
DR TreeFam; TF314210; -.
DR PRO; PR:G3V8H4; -.
DR Proteomes; UP000002494; Chromosome 1.
DR Proteomes; UP000234681; Chromosome 1.
DR Bgee; ENSRNOG00000018953; Expressed in jejunum and 15 other tissues.
DR Genevisible; G3V8H4; RN.
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:0005154; F:epidermal growth factor receptor binding; ISO:RGD.
DR GO; GO:0001784; F:phosphotyrosine residue binding; ISO:RGD.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; IBA:GO_Central.
DR GO; GO:0017124; F:SH3 domain binding; ISO:RGD.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; ISO:RGD.
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:RGD.
DR GO; GO:0007175; P:negative regulation of epidermal growth factor-activated receptor activity; ISO:RGD.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; ISO:RGD.
DR GO; GO:0016567; P:protein ubiquitination; ISO:RGD.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISO:RGD.
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 Calcium; Metal-binding; Phosphoprotein; Reference proteome; SH3-binding;
KW Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..497
FT /note="E3 ubiquitin-protein ligase CBL-C"
FT /id="PRO_0000424873"
FT DOMAIN 7..321
FT /note="Cbl-PTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00839"
FT ZN_FING 351..390
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 7..145
FT /note="4H"
FT REGION 146..218
FT /note="EF-hand-like"
FT REGION 219..321
FT /note="SH2-like"
FT REGION 322..350
FT /note="Linker"
FT /evidence="ECO:0000250"
FT REGION 351..497
FT /note="Interaction with RET"
FT /evidence="ECO:0000250"
FT BINDING 199
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 201
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 210
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 264
FT /ligand="4-O-phospho-L-tyrosine"
FT /ligand_id="ChEBI:CHEBI:62338"
FT /evidence="ECO:0000250"
FT MOD_RES 341
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000250|UniProtKB:Q9ULV8"
FT CONFLICT 326
FT /note="V -> E (in Ref. 3; AAI05777)"
FT /evidence="ECO:0000305"
FT CONFLICT 453
FT /note="N -> D (in Ref. 3; AAI05777)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 497 AA; 55775 MW; C6DFE4CADD9F908E CRC64;
MAAATAPQGW QWGEPRALGR AVKLLQRLEE QCRDLRLFVG PPSLRDLLPR TAQLLREVAK
ARSDKTRGDP EGPGGAGDFL VIYLTNLEAK GRQVAELLPH RGKKDANQDV FPEGSRFRRQ
LAKLALIFSH MHAELSALFP EGKYCGHLYQ ITKGSANTFW RENCGVRCVL PWAEFQSLLC
SCHPVEPGPI MQALRSTLDL TCSGHVSVFE FDIFTRLFQP WPTLLKNWQL LAVNHPGYMA
FLTYDEVQTR LQAYRDKPGS YIFRPSCTRL GQWAIGYVSS NGSILQTIPL NKPLLQVLLK
GQKDGIFLYP DGKNHNPDLT ELCRAVLNQC IQVSQEQLQL YQAMNSTFEL CKICTERDKD
VRIEPCGHLL CSCCLAAWQH SDSQTCPFCR CEIKGREAVS ICQAQERSME VRTTAGDSGD
NCHQEAAEWK LESVTPSAPP LPPEVPCPQR PQNKGWLTLA PFTLPRLRPP LPLPKMASVL
WEVTSRPQVR EGATESS
