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   27-MAR-2024, entry version 68.
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}.
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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.ENSRNOP00000070090; -.
DR   PhosphoSitePlus; G3V8H4; -.
DR   PaxDb; 10116-ENSRNOP00000025829; -.
DR   Ensembl; ENSRNOT00000025829.8; ENSRNOP00000025829.4; ENSRNOG00000018953.8.
DR   Ensembl; ENSRNOT00060057189; ENSRNOP00060047268; ENSRNOG00060032969.
DR   Ensembl; ENSRNOT00065057110; ENSRNOP00065047004; ENSRNOG00065033207.
DR   GeneID; 292699; -.
DR   KEGG; rno:292699; -.
DR   UCSC; RGD:1307651; rat.
DR   AGR; RGD:1307651; -.
DR   RGD; 1307651; Cblc.
DR   eggNOG; KOG1785; Eukaryota.
DR   GeneTree; ENSGT00940000162336; -.
DR   HOGENOM; CLU_013535_2_0_1; -.
DR   InParanoid; G3V8H4; -.
DR   OMA; CAMDSTF; -.
DR   OrthoDB; 1123734at2759; -.
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 cell types or tissues.
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: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; cd16710; RING-HC_Cbl-c; 1.
DR   CDD; cd09920; SH2_Cbl-b_TKB; 1.
DR   Gene3D; 1.20.930.20; Adaptor protein Cbl, N-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; 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; CBL; 1.
DR   PANTHER; PTHR23007:SF12; E3 UBIQUITIN-PROTEIN LIGASE CBL-C; 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   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; PS00518; ZF_RING_1; 1.
DR   PROSITE; PS50089; ZF_RING_2; 1.
DR   Genevisible; G3V8H4; RN.
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
//