UniProt functional annotation for Q9ULV8



	UniProt functional annotation for Q9ULV8

UniProt code: Q9ULV8.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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. {ECO:0000269|PubMed:10362357, ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:18753381, ECO:0000269|PubMed:20525694, ECO:0000269|PubMed:23145173}.

Catalytic activity: Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; EC=2.3.2.27; Evidence={ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:20525694, ECO:0000269|PubMed:23145173};

Activity regulation: Phosphorylation at Tyr-341 is necessary and sufficient for the activation of E3 activity. {ECO:0000269|PubMed:20525694}.

Subunit: 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'. {ECO:0000269|PubMed:10362357, ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:18753381, ECO:0000269|PubMed:20525694, ECO:0000269|PubMed:22888118, ECO:0000269|PubMed:23145173, ECO:0000269|Ref.8}.

Tissue specificity: Ubiquitous. {ECO:0000269|PubMed:10362357}.

Domain: EF-hand-like and Sh2-like domains are required for N-terminal inhibition of E3 activity. {ECO:0000269|PubMed:20525694}.

Domain: 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. {ECO:0000255|PROSITE-ProRule:PRU00839, ECO:0000269|PubMed:20525694}.

Domain: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme. {ECO:0000250}.

Ptm: Phosphorylated on multiple tyrosine residues by SRC. Isoform 1, but not isoform 2, is phosphorylated on tyrosines by EGFR.

Ptm: Autoubiquitinated when phosphorylated at Tyr-341, enhanced by SRC; suggesting proteasomal degradation. {ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:20525694, ECO:0000269|PubMed:23145173}.

Miscellaneous: This protein has one functional calcium-binding site.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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. {ECO:0000269\|PubMed:10362357, ECO:0000269\|PubMed:14661060, ECO:0000269\|PubMed:18753381, ECO:0000269\|PubMed:20525694, ECO:0000269\|PubMed:23145173}.


Catalytic activity:		Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; EC=2.3.2.27; Evidence={ECO:0000269\|PubMed:14661060, ECO:0000269\|PubMed:20525694, ECO:0000269\|PubMed:23145173};
Activity regulation:		Phosphorylation at Tyr-341 is necessary and sufficient for the activation of E3 activity. {ECO:0000269\|PubMed:20525694}.
Subunit:		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'. {ECO:0000269\|PubMed:10362357, ECO:0000269\|PubMed:14661060, ECO:0000269\|PubMed:18753381, ECO:0000269\|PubMed:20525694, ECO:0000269\|PubMed:22888118, ECO:0000269\|PubMed:23145173, ECO:0000269\|Ref.8}.
Tissue specificity:		Ubiquitous. {ECO:0000269\|PubMed:10362357}.
Domain:		EF-hand-like and Sh2-like domains are required for N-terminal inhibition of E3 activity. {ECO:0000269\|PubMed:20525694}.
Domain:		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. {ECO:0000255\|PROSITE-ProRule:PRU00839, ECO:0000269\|PubMed:20525694}.
Domain:		The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme. {ECO:0000250}.
Ptm:		Phosphorylated on multiple tyrosine residues by SRC. Isoform 1, but not isoform 2, is phosphorylated on tyrosines by EGFR.
Ptm:		Autoubiquitinated when phosphorylated at Tyr-341, enhanced by SRC; suggesting proteasomal degradation. {ECO:0000269\|PubMed:14661060, ECO:0000269\|PubMed:20525694, ECO:0000269\|PubMed:23145173}.
Miscellaneous:		This protein has one functional calcium-binding site.