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Q9ULV8 (CBLC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 139. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:CBLC
Synonyms:CBL3, RNF57
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length474 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.2 Ref.4 Ref.5 Ref.6 Ref.7

Enzyme regulation

Phosphorylation at Tyr-341 is necessary and sufficient for the activation of E3 activity. Ref.6

Subunit structure

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'. Ref.2 Ref.4 Ref.5 Ref.6 Ref.7 Ref.9

Tissue specificity

Ubiquitous. Ref.2

Domain

EF-hand-like and Sh2-like domains are required for N-terminal inhibition of E3 activity (Ref.6). Ref.6

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. Ref.6

The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme By similarity. Ref.6

Post-translational modification

Phosphorylated on multiple tyrosine residues by SRC. Isoform 1, but not isoform 2, is phosphorylated on tyrosines by EGFR. Ref.2 Ref.6 Ref.7

Autoubiquitinated when phosphorylated at Tyr-341, enhanced by SRC; suggesting proteasomal degradation. Ref.2 Ref.6 Ref.7

Miscellaneous

This protein has one functional calcium-binding site.

Sequence similarities

Contains 1 Cbl-PTB (Cbl-type phosphotyrosine-binding) domain.

Contains 1 RING-type zinc finger.

Ontologies

Keywords
   Biological processUbl conjugation pathway
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainRepeat
SH3-binding
Zinc-finger
   LigandCalcium
Metal-binding
Zinc
   Molecular functionLigase
   PTMPhosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcell surface receptor signaling pathway

Inferred from electronic annotation. Source: InterPro

negative regulation of MAP kinase activity

Inferred from direct assay Ref.2. Source: BHF-UCL

negative regulation of epidermal growth factor receptor signaling pathway

Inferred from direct assay Ref.2. Source: BHF-UCL

negative regulation of epidermal growth factor-activated receptor activity

Inferred from direct assay Ref.2. Source: BHF-UCL

protein ubiquitination involved in ubiquitin-dependent protein catabolic process

Inferred from direct assay Ref.4. Source: BHF-UCL

   Cellular_componentnucleus

Inferred from electronic annotation. Source: InterPro

   Molecular_functionSH3 domain binding

Inferred from direct assay Ref.2. Source: BHF-UCL

calcium ion binding

Inferred from electronic annotation. Source: InterPro

epidermal growth factor receptor binding

Inferred from direct assay Ref.2. Source: BHF-UCL

phosphotyrosine binding

Inferred from direct assay Ref.4. Source: BHF-UCL

signal transducer activity

Inferred from electronic annotation. Source: InterPro

ubiquitin-protein transferase activity

Inferred from direct assay Ref.4. Source: BHF-UCL

zinc ion binding

Traceable author statement Ref.2. Source: ProtInc

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9ULV8-1)

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.
Isoform 2 (identifier: Q9ULV8-2)

Also known as: Short;

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 474474E3 ubiquitin-protein ligase CBL-C
PRO_0000055866

Regions

Domain7 – 321315Cbl-PTB
Calcium binding199 – 21012 Ref.9
Zinc finger351 – 39040RING-type
Region7 – 1451394H
Region146 – 21873EF-hand-like
Region219 – 321103SH2-like
Region322 – 35029Linker
Region351 – 474124Interaction with RET

Sites

Binding site2641Phosphotyrosine

Amino acid modifications

Modified residue3411Phosphotyrosine; by SRC Ref.6 Ref.7

Natural variations

Alternative sequence261 – 30646Missing in isoform 2.
VSP_005732
Natural variant4051H → Y. Ref.1 Ref.2
Corresponds to variant rs3208856 [ dbSNP | Ensembl ].
VAR_018298

Experimental info

Mutagenesis2441Y → A: Abolishes interaction with EGFR. Decreases interaction with SRC and abolishes SRC ubiquitination. Ref.9
Mutagenesis2441Y → F: No effect on interaction with EGFR and SRC as well as on SRC ubiquitination. Ref.9
Mutagenesis2641R → A: Abolishes interaction with EGFR. Decreases interaction with SRC and abolishes SRC ubiquitination. Ref.9
Mutagenesis2651P → L: Enhances interaction with EGFR and SRC as well as SRC ubiquitination. Ref.9
Mutagenesis2661S → A: Decreases interactions with EGFR and SRC as well as SRC ubiquitination. Ref.9
Mutagenesis2681T → A: Abolishes interaction with EGFR. Decreases interaction with and ubiquitination of SRC. Ref.9
Mutagenesis2761G → 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. Ref.4 Ref.5 Ref.9
Mutagenesis3411Y → E: Induces E3 activity and autoubiquitination. Releases ubiquitin-conjugating enzyme E2 UBE2D2 faster. Ref.4 Ref.6 Ref.7
Mutagenesis3411Y → F: Abolishes activation by EGF stimulation and enhancement by TGFB1I1 of E3 activity. Ref.4 Ref.6 Ref.7
Mutagenesis3411Missing: Abolishes E3 activity. Ref.4 Ref.6 Ref.7
Mutagenesis3511C → 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. Ref.4 Ref.5 Ref.7
Mutagenesis3661C → A: Abolishes interaction with TGFB1I1. Abolishes interaction with TGFB1I1; when associated with A-351. Ref.7
Sequence conflict2341N → T in BAA86298. Ref.1
Sequence conflict4131S → P in AAH28915. Ref.3

Secondary structure

.................................................... 474
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (Long) [UniParc].

Last modified February 6, 2007. Version 3.
Checksum: 202634AEDE434544

FASTA47452,456
        10         20         30         40         50         60 
MALAVAPWGR QWEEARALGR AVRMLQRLEE QCVDPRLSVS PPSLRDLLPR TAQLLREVAH 

        70         80         90        100        110        120 
SRRAAGGGGP GGPGGSGDFL LIYLANLEAK SRQVAALLPP RGRRSANDEL FRAGSRLRRQ 

       130        140        150        160        170        180 
LAKLAIIFSH MHAELHALFP GGKYCGHMYQ LTKAPAHTFW RESCGARCVL PWAEFESLLG 

       190        200        210        220        230        240 
TCHPVEPGCT ALALRTTIDL TCSGHVSIFE FDVFTRLFQP WPTLLKNWQL LAVNHPGYMA 

       250        260        270        280        290        300 
FLTYDEVQER LQACRDKPGS YIFRPSCTRL GQWAIGYVSS DGSILQTIPA NKPLSQVLLE 

       310        320        330        340        350        360 
GQKDGFYLYP DGKTHNPDLT ELGQAEPQQR IHVSEEQLQL YWAMDSTFEL CKICAESNKD 

       370        380        390        400        410        420 
VKIEPCGHLL CSCCLAAWQH SDSQTCPFCR CEIKGWEAVS IYQFHGQATA EDSGNSSDQE 

       430        440        450        460        470 
GRELELGQVP LSAPPLPPRP DLPPRKPRNA QPKVRLLKGN SPPAALGPQD PAPA 

« Hide

Isoform 2 (Short) [UniParc].

Checksum: 7070EDF530032CA0
Show »

FASTA42847,418

References

« Hide 'large scale' references
[1]"Molecular cloning and characterization of a novel cbl-family gene, cbl-c."
Kim M., Tezuka T., Suzuki Y., Sugano S., Hirai M., Yamamoto T.
Gene 239:145-154(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT TYR-405.
[2]"cbl-3: a new mammalian cbl family protein."
Keane M.M., Ettenberg S.A., Nau M.M., Banerjee P., Cuello M., Penninger J., Lipkowitz S.
Oncogene 18:3365-3375(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), VARIANT TYR-405, FUNCTION AS EGF SIGNALING NEGATIVE REGULATOR, PHOSPHORYLATION BY EGFR (ISOFORM 1), TISSUE SPECIFICITY, INTERACTION WITH CRK AND LYN.
Tissue: Pancreatic adenocarcinoma.
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Skin.
[4]"Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation."
Kim M., Tezuka T., Tanaka K., Yamamoto T.
Oncogene 23:1645-1655(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS E3 UBIQUITIN-PROTEIN LIGASE, INTERACTION WITH SRC, AUTOUBIQUITINATION, MUTAGENESIS OF GLY-276; TYR-341 AND CYS-351.
[5]"CD2AP and Cbl-3/Cbl-c constitute a critical checkpoint in the regulation of ret signal transduction."
Tsui C.C., Pierchala B.A.
J. Neurosci. 28:8789-8800(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN RET STABILITY, INTERACTION WITH RET, MUTAGENESIS OF GLY-276 AND CYS-351.
[6]"The N terminus of Cbl-c regulates ubiquitin ligase activity by modulating affinity for the ubiquitin-conjugating enzyme."
Ryan P.E., Sivadasan-Nair N., Nau M.M., Nicholas S., Lipkowitz S.
J. Biol. Chem. 285:23687-23698(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, DOMAIN, INTERACTION WITH UBE2D2 AND UBE2D3, PHOSPHORYLATION AT TYR-341, MUTAGENESIS OF TYR-341.
[7]"Cbl-c ubiquitin ligase activity is increased via the interaction of its RING finger domain with a LIM domain of the paxillin homolog, Hic 5."
Ryan P.E., Kales S.C., Yadavalli R., Nau M.M., Zhang H., Lipkowitz S.
PLoS ONE 7:E49428-E49428(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, AUTOUBIQUITINATION, PHOSPHORYLATION AT TYR-341, INTERACTION WITH TGFB1I1, MUTAGENESIS OF TYR-341; CYS-351 AND CYS-366.
[8]"Crystal structure of Cbl-c (Cbl-3) TKB domain in complex with EGFR py1069 peptide."
Structural genomics consortium (SGC)
Submitted (OCT-2010) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (2.52 ANGSTROMS) OF 9-323 IN COMPLEX WITH EGFR PEPTIDE.
[9]"Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c."
Takeshita K., Tezuka T., Isozaki Y., Yamashita E., Suzuki M., Kim M., Yamanashi Y., Yamamoto T., Nakagawa A.
J. Biochem. 152:487-495(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.52 ANGSTROMS) OF 1-323 IN COMPLEX WITH CALCIUM; SRC AND EGFR PEPTIDES, CALCIUM-BINDING, INTERACTION WITH EGFR AND SRC, MUTAGENESIS OF TYR-244; ARG-264; PRO-265; SER-266; THR-268 AND GLY-276.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB028645 mRNA. Translation: BAA86298.1.
AF117646 mRNA. Translation: AAD34341.1.
AF117647 mRNA. Translation: AAD34342.1.
BC028915 mRNA. Translation: AAH28915.1.
CCDSCCDS12643.1. [Q9ULV8-1]
CCDS46109.1. [Q9ULV8-2]
RefSeqNP_001124324.1. NM_001130852.1. [Q9ULV8-2]
NP_036248.3. NM_012116.3. [Q9ULV8-1]
UniGeneHs.466907.

3D structure databases

PDBe
RCSB-PDB
PDBj
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[»]
ProteinModelPortalQ9ULV8.
SMRQ9ULV8. Positions 10-404.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid117156. 33 interactions.
IntActQ9ULV8. 18 interactions.
MINTMINT-247027.
STRING9606.ENSP00000270279.

PTM databases

PhosphoSiteQ9ULV8.

Polymorphism databases

DMDM125987803.

Proteomic databases

MaxQBQ9ULV8.
PaxDbQ9ULV8.
PRIDEQ9ULV8.

Protocols and materials databases

DNASU23624.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000270279; ENSP00000270279; ENSG00000142273. [Q9ULV8-1]
ENST00000341505; ENSP00000340250; ENSG00000142273. [Q9ULV8-2]
GeneID23624.
KEGGhsa:23624.
UCSCuc002ozs.3. human. [Q9ULV8-1]
uc010ejt.3. human. [Q9ULV8-2]

Organism-specific databases

CTD23624.
GeneCardsGC19P045281.
H-InvDBHIX0202847.
HGNCHGNC:15961. CBLC.
HPACAB008087.
MIM608453. gene.
neXtProtNX_Q9ULV8.
PharmGKBPA26117.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG318595.
HOGENOMHOG000294176.
HOVERGENHBG005255.
InParanoidQ9ULV8.
KOK04707.
OMAWQHSDSQ.
OrthoDBEOG73BVCF.
PhylomeDBQ9ULV8.
TreeFamTF314210.

Enzyme and pathway databases

SignaLinkQ9ULV8.

Gene expression databases

BgeeQ9ULV8.
CleanExHS_CBLC.
GenevestigatorQ9ULV8.

Family and domain databases

Gene3D1.10.238.10. 1 hit.
1.20.930.20. 1 hit.
3.30.40.10. 1 hit.
3.30.505.10. 1 hit.
InterProIPR024162. 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]
PANTHERPTHR23007. PTHR23007. 1 hit.
PfamPF02262. Cbl_N. 1 hit.
PF02761. Cbl_N2. 1 hit.
PF02762. Cbl_N3. 1 hit.
[Graphical view]
SMARTSM00184. RING. 1 hit.
SM00252. SH2. 1 hit.
[Graphical view]
SUPFAMSSF47668. SSF47668. 1 hit.
SSF55550. SSF55550. 1 hit.
PROSITEPS51506. CBL_PTB. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiCBLC.
GenomeRNAi23624.
NextBio46378.
PROQ9ULV8.
SOURCESearch...

Entry information

Entry nameCBLC_HUMAN
AccessionPrimary (citable) accession number: Q9ULV8
Secondary accession number(s): Q8N1E5, Q9Y5Z2, Q9Y5Z3
Entry history
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: February 6, 2007
Last modified: July 9, 2014
This is version 139 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 19

Human chromosome 19: entries, gene names and cross-references to MIM