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Protein

E3 ubiquitin-protein ligase CBL-C

Gene

CBLC

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Functionally coupled with the E2 ubiquitin-protein ligases UB2D1, UB2D2 and UB2D3. Regulator of EGFR mediated signal transduction; upon EGF activation, ubiquitinates EGFR. Isoform 1, but not isoform 2, inhibits EGF stimulated MAPK1 activation. Promotes ubiquitination of SRC phosphorylated at 'Tyr-419'. In collaboration with CD2AP may act as regulatory checkpoint for Ret signaling by modulating the rate of RET degradation after ligand activation; CD2AP converts it from an inhibitor to a promoter of RET degradation; the function limits the potency of GDNF on neuronal survival.5 Publications

Enzyme regulationi

Phosphorylation at Tyr-341 is necessary and sufficient for the activation of E3 activity.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei264Phosphotyrosine1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Calcium bindingi199 – 210Add BLAST12
Zinc fingeri351 – 390RING-typePROSITE-ProRule annotationAdd BLAST40

GO - Molecular functioni

  • calcium ion binding Source: InterPro
  • epidermal growth factor receptor binding Source: BHF-UCL
  • ligase activity Source: UniProtKB-KW
  • phosphotyrosine binding Source: BHF-UCL
  • receptor tyrosine kinase binding Source: GO_Central
  • SH3 domain binding Source: BHF-UCL
  • signal transducer activity Source: InterPro
  • ubiquitin protein ligase activity Source: BHF-UCL
  • zinc ion binding Source: ProtInc

GO - Biological processi

  • cell surface receptor signaling pathway Source: InterPro
  • negative regulation of epidermal growth factor-activated receptor activity Source: BHF-UCL
  • negative regulation of epidermal growth factor receptor signaling pathway Source: BHF-UCL
  • negative regulation of MAP kinase activity Source: BHF-UCL
  • protein ubiquitination Source: BHF-UCL
  • protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: BHF-UCL
Complete GO annotation...

Keywords - Molecular functioni

Ligase

Keywords - Biological processi

Ubl conjugation pathway

Keywords - Ligandi

Calcium, Metal-binding, Zinc

Enzyme and pathway databases

BioCyciZFISH:ENSG00000142273-MONOMER.
SignaLinkiQ9ULV8.
SIGNORiQ9ULV8.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase CBL-C (EC:6.3.2.-)
Alternative name(s):
RING finger protein 57
SH3-binding protein CBL-3
SH3-binding protein CBL-C
Signal transduction protein CBL-C
Gene namesi
Name:CBLC
Synonyms:CBL3, RNF57
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:15961. CBLC.

Subcellular locationi

GO - Cellular componenti

  • extracellular exosome Source: UniProtKB
  • membrane raft Source: GO_Central
  • nucleus Source: InterPro
  • plasma membrane Source: GO_Central
Complete GO annotation...

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi244Y → A: Abolishes interaction with EGFR. Decreases interaction with SRC and abolishes SRC ubiquitination. 1 Publication1
Mutagenesisi244Y → F: No effect on interaction with EGFR and SRC as well as on SRC ubiquitination. 1 Publication1
Mutagenesisi264R → A: Abolishes interaction with EGFR. Decreases interaction with SRC and abolishes SRC ubiquitination. 1 Publication1
Mutagenesisi265P → L: Enhances interaction with EGFR and SRC as well as SRC ubiquitination. 1 Publication1
Mutagenesisi266S → A: Decreases interactions with EGFR and SRC as well as SRC ubiquitination. 1 Publication1
Mutagenesisi268T → A: Abolishes interaction with EGFR. Decreases interaction with and ubiquitination of SRC. 1 Publication1
Mutagenesisi276G → E: No effect on interaction with RET. Binds slightly to SRC, this interaction is independent of SRC phosphorylation. Strongly decreases SRC ubiquitination. Abolishes interaction with EGFR. 3 Publications1
Mutagenesisi341Y → E: Induces E3 activity and autoubiquitination. Releases ubiquitin-conjugating enzyme E2 UBE2D2 faster. 3 Publications1
Mutagenesisi341Y → F: Abolishes activation by EGF stimulation and enhancement by TGFB1I1 of E3 activity. 3 Publications1
Mutagenesisi341Missing : Abolishes E3 activity. 3 Publications1
Mutagenesisi351C → A: No effect on TGFB1I1 and SRC interactions. Abolishes SRC ubiquitination. Abolishes interaction with TGFB1I1; when associated with A-366. Abolishes interaction with RET and inhibition of RET degradation. 3 Publications1
Mutagenesisi366C → A: Abolishes interaction with TGFB1I1. Abolishes interaction with TGFB1I1; when associated with A-351. 1 Publication1

Organism-specific databases

OpenTargetsiENSG00000142273.
PharmGKBiPA26117.

Polymorphism and mutation databases

BioMutaiCBLC.
DMDMi125987803.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000558661 – 474E3 ubiquitin-protein ligase CBL-CAdd BLAST474

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei341Phosphotyrosine; by SRC2 Publications1

Post-translational modificationi

Phosphorylated on multiple tyrosine residues by SRC. Isoform 1, but not isoform 2, is phosphorylated on tyrosines by EGFR.
Autoubiquitinated when phosphorylated at Tyr-341, enhanced by SRC; suggesting proteasomal degradation.3 Publications

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ9ULV8.
PaxDbiQ9ULV8.
PeptideAtlasiQ9ULV8.
PRIDEiQ9ULV8.

PTM databases

iPTMnetiQ9ULV8.
PhosphoSitePlusiQ9ULV8.

Expressioni

Tissue specificityi

Ubiquitous.1 Publication

Gene expression databases

BgeeiENSG00000142273.
CleanExiHS_CBLC.
GenevisibleiQ9ULV8. HS.

Organism-specific databases

HPAiCAB008087.
HPA035266.

Interactioni

Subunit structurei

Interacts with ubiquitin-conjugating enzyme E2 UBE2D2 and UBE2D3. Isoform 1 interacts with EGFR (tyrosine phosphorylated). Interacts with the SH3 domain proteins LYN and CRK. Interacts (via RING-type zinc finger) with TGFB1I1 (via LIM zinc-binding domain 2); the interaction is direct and enhances the E3 activity. Interacts directly with RET (inactive) and CD2AP; dissociates from RET upon RET activation by GDNF which also increases the interaction with CD2AP suggesting dissociation as CBLC:CD2AP complex. Interacts with SRC; the interaction is enhanced when SRC is phosphorylated at 'Tyr-419'.7 Publications

GO - Molecular functioni

  • epidermal growth factor receptor binding Source: BHF-UCL
  • phosphotyrosine binding Source: BHF-UCL
  • receptor tyrosine kinase binding Source: GO_Central
  • SH3 domain binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi117156. 46 interactors.
IntActiQ9ULV8. 20 interactors.
MINTiMINT-247027.
STRINGi9606.ENSP00000270279.

Structurei

Secondary structure

1474
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi13 – 31Combined sources19
Beta strandi40 – 42Combined sources3
Helixi44 – 62Combined sources19
Beta strandi64 – 66Combined sources3
Helixi76 – 97Combined sources22
Beta strandi100 – 102Combined sources3
Helixi108 – 111Combined sources4
Helixi116 – 138Combined sources23
Helixi140 – 142Combined sources3
Turni146 – 148Combined sources3
Helixi154 – 164Combined sources11
Beta strandi168 – 171Combined sources4
Helixi172 – 179Combined sources8
Turni180 – 182Combined sources3
Helixi189 – 198Combined sources10
Beta strandi203 – 207Combined sources5
Helixi208 – 217Combined sources10
Helixi221 – 223Combined sources3
Helixi224 – 232Combined sources9
Beta strandi238 – 241Combined sources4
Helixi244 – 251Combined sources8
Helixi252 – 254Combined sources3
Beta strandi260 – 265Combined sources6
Beta strandi267 – 269Combined sources3
Beta strandi273 – 278Combined sources6
Beta strandi284 – 287Combined sources4
Helixi294 – 303Combined sources10
Helixi320 – 323Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3OP0X-ray2.52A/B9-323[»]
3VRNX-ray1.64A1-323[»]
3VROX-ray1.80A1-323[»]
3VRPX-ray1.52A1-323[»]
3VRQX-ray2.39A/B1-323[»]
3VRRX-ray2.00A1-323[»]
ProteinModelPortaliQ9ULV8.
SMRiQ9ULV8.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini7 – 321Cbl-PTBPROSITE-ProRule annotationAdd BLAST315

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni7 – 1454HAdd BLAST139
Regioni146 – 218EF-hand-likeAdd BLAST73
Regioni219 – 321SH2-likeAdd BLAST103
Regioni322 – 350LinkerAdd BLAST29
Regioni351 – 474Interaction with RET1 PublicationAdd BLAST124

Domaini

EF-hand-like and Sh2-like domains are required for N-terminal inhibition of E3 activity.1 Publication
The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain.PROSITE-ProRule annotation1 Publication
The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.By similarity

Sequence similaritiesi

Contains 1 Cbl-PTB (Cbl-type phosphotyrosine-binding) domain.PROSITE-ProRule annotation
Contains 1 RING-type zinc finger.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri351 – 390RING-typePROSITE-ProRule annotationAdd BLAST40

Keywords - Domaini

Repeat, SH3-binding, Zinc-finger

Phylogenomic databases

eggNOGiKOG1785. Eukaryota.
ENOG410YDNH. LUCA.
GeneTreeiENSGT00390000011617.
HOGENOMiHOG000294176.
HOVERGENiHBG005255.
InParanoidiQ9ULV8.
KOiK04707.
OMAiWQHSDSQ.
OrthoDBiEOG091G06R9.
PhylomeDBiQ9ULV8.
TreeFamiTF314210.

Family and domain databases

CDDicd09920. SH2_Cbl-b_TKB. 1 hit.
Gene3Di1.10.238.10. 1 hit.
1.20.930.20. 1 hit.
3.30.40.10. 1 hit.
3.30.505.10. 1 hit.
InterProiIPR024162. Adaptor_Cbl.
IPR014741. Adaptor_Cbl_EF_hand-like.
IPR003153. Adaptor_Cbl_N_hlx.
IPR014742. Adaptor_Cbl_SH2-like.
IPR024159. Cbl_PTB.
IPR011992. EF-hand-dom_pair.
IPR000980. SH2.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PANTHERiPTHR23007. PTHR23007. 1 hit.
PfamiPF02262. Cbl_N. 1 hit.
PF02761. Cbl_N2. 1 hit.
PF02762. Cbl_N3. 1 hit.
[Graphical view]
SMARTiSM00184. RING. 1 hit.
[Graphical view]
SUPFAMiSSF47473. SSF47473. 1 hit.
SSF47668. SSF47668. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEiPS51506. CBL_PTB. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9ULV8-1) [UniParc]FASTAAdd to basket
Also known as: Long

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MALAVAPWGR QWEEARALGR AVRMLQRLEE QCVDPRLSVS PPSLRDLLPR
60 70 80 90 100
TAQLLREVAH SRRAAGGGGP GGPGGSGDFL LIYLANLEAK SRQVAALLPP
110 120 130 140 150
RGRRSANDEL FRAGSRLRRQ LAKLAIIFSH MHAELHALFP GGKYCGHMYQ
160 170 180 190 200
LTKAPAHTFW RESCGARCVL PWAEFESLLG TCHPVEPGCT ALALRTTIDL
210 220 230 240 250
TCSGHVSIFE FDVFTRLFQP WPTLLKNWQL LAVNHPGYMA FLTYDEVQER
260 270 280 290 300
LQACRDKPGS YIFRPSCTRL GQWAIGYVSS DGSILQTIPA NKPLSQVLLE
310 320 330 340 350
GQKDGFYLYP DGKTHNPDLT ELGQAEPQQR IHVSEEQLQL YWAMDSTFEL
360 370 380 390 400
CKICAESNKD VKIEPCGHLL CSCCLAAWQH SDSQTCPFCR CEIKGWEAVS
410 420 430 440 450
IYQFHGQATA EDSGNSSDQE GRELELGQVP LSAPPLPPRP DLPPRKPRNA
460 470
QPKVRLLKGN SPPAALGPQD PAPA
Length:474
Mass (Da):52,456
Last modified:February 6, 2007 - v3
Checksum:i202634AEDE434544
GO
Isoform 2 (identifier: Q9ULV8-2) [UniParc]FASTAAdd to basket
Also known as: Short

The sequence of this isoform differs from the canonical sequence as follows:
     261-306: Missing.

Show »
Length:428
Mass (Da):47,418
Checksum:i7070EDF530032CA0
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti234N → T in BAA86298 (PubMed:10571044).Curated1
Sequence conflicti413S → P in AAH28915 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_018298405H → Y.2 PublicationsCorresponds to variant rs3208856dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_005732261 – 306Missing in isoform 2. 1 PublicationAdd BLAST46

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB028645 mRNA. Translation: BAA86298.1.
AF117646 mRNA. Translation: AAD34341.1.
AF117647 mRNA. Translation: AAD34342.1.
BC028915 mRNA. Translation: AAH28915.1.
CCDSiCCDS12643.1. [Q9ULV8-1]
CCDS46109.1. [Q9ULV8-2]
RefSeqiNP_001124324.1. NM_001130852.1. [Q9ULV8-2]
NP_036248.3. NM_012116.3. [Q9ULV8-1]
UniGeneiHs.466907.

Genome annotation databases

EnsembliENST00000270279; ENSP00000270279; ENSG00000142273. [Q9ULV8-1]
ENST00000341505; ENSP00000340250; ENSG00000142273. [Q9ULV8-2]
GeneIDi23624.
KEGGihsa:23624.
UCSCiuc002ozs.4. human. [Q9ULV8-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB028645 mRNA. Translation: BAA86298.1.
AF117646 mRNA. Translation: AAD34341.1.
AF117647 mRNA. Translation: AAD34342.1.
BC028915 mRNA. Translation: AAH28915.1.
CCDSiCCDS12643.1. [Q9ULV8-1]
CCDS46109.1. [Q9ULV8-2]
RefSeqiNP_001124324.1. NM_001130852.1. [Q9ULV8-2]
NP_036248.3. NM_012116.3. [Q9ULV8-1]
UniGeneiHs.466907.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3OP0X-ray2.52A/B9-323[»]
3VRNX-ray1.64A1-323[»]
3VROX-ray1.80A1-323[»]
3VRPX-ray1.52A1-323[»]
3VRQX-ray2.39A/B1-323[»]
3VRRX-ray2.00A1-323[»]
ProteinModelPortaliQ9ULV8.
SMRiQ9ULV8.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi117156. 46 interactors.
IntActiQ9ULV8. 20 interactors.
MINTiMINT-247027.
STRINGi9606.ENSP00000270279.

PTM databases

iPTMnetiQ9ULV8.
PhosphoSitePlusiQ9ULV8.

Polymorphism and mutation databases

BioMutaiCBLC.
DMDMi125987803.

Proteomic databases

EPDiQ9ULV8.
PaxDbiQ9ULV8.
PeptideAtlasiQ9ULV8.
PRIDEiQ9ULV8.

Protocols and materials databases

DNASUi23624.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000270279; ENSP00000270279; ENSG00000142273. [Q9ULV8-1]
ENST00000341505; ENSP00000340250; ENSG00000142273. [Q9ULV8-2]
GeneIDi23624.
KEGGihsa:23624.
UCSCiuc002ozs.4. human. [Q9ULV8-1]

Organism-specific databases

CTDi23624.
GeneCardsiCBLC.
H-InvDBHIX0202847.
HGNCiHGNC:15961. CBLC.
HPAiCAB008087.
HPA035266.
MIMi608453. gene.
neXtProtiNX_Q9ULV8.
OpenTargetsiENSG00000142273.
PharmGKBiPA26117.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1785. Eukaryota.
ENOG410YDNH. LUCA.
GeneTreeiENSGT00390000011617.
HOGENOMiHOG000294176.
HOVERGENiHBG005255.
InParanoidiQ9ULV8.
KOiK04707.
OMAiWQHSDSQ.
OrthoDBiEOG091G06R9.
PhylomeDBiQ9ULV8.
TreeFamiTF314210.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000142273-MONOMER.
SignaLinkiQ9ULV8.
SIGNORiQ9ULV8.

Miscellaneous databases

GeneWikiiCBLC.
GenomeRNAii23624.
PROiQ9ULV8.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000142273.
CleanExiHS_CBLC.
GenevisibleiQ9ULV8. HS.

Family and domain databases

CDDicd09920. SH2_Cbl-b_TKB. 1 hit.
Gene3Di1.10.238.10. 1 hit.
1.20.930.20. 1 hit.
3.30.40.10. 1 hit.
3.30.505.10. 1 hit.
InterProiIPR024162. Adaptor_Cbl.
IPR014741. Adaptor_Cbl_EF_hand-like.
IPR003153. Adaptor_Cbl_N_hlx.
IPR014742. Adaptor_Cbl_SH2-like.
IPR024159. Cbl_PTB.
IPR011992. EF-hand-dom_pair.
IPR000980. SH2.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PANTHERiPTHR23007. PTHR23007. 1 hit.
PfamiPF02262. Cbl_N. 1 hit.
PF02761. Cbl_N2. 1 hit.
PF02762. Cbl_N3. 1 hit.
[Graphical view]
SMARTiSM00184. RING. 1 hit.
[Graphical view]
SUPFAMiSSF47473. SSF47473. 1 hit.
SSF47668. SSF47668. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEiPS51506. CBL_PTB. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCBLC_HUMAN
AccessioniPrimary (citable) accession number: Q9ULV8
Secondary accession number(s): Q8N1E5, Q9Y5Z2, Q9Y5Z3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: February 6, 2007
Last modified: November 30, 2016
This is version 162 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Miscellaneous

This protein has one functional calcium-binding site.

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.