Tbio ITCH E3 ubiquitin-protein ligase Itchy homolog

Protein Summary

Description

Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:14602072, PubMed:17028573, PubMed:16387660, PubMed:18718448, PubMed:18718449, PubMed:11046148, PubMed:19592251, PubMed:19116316, PubMed:19881509, PubMed:20491914, PubMed:20392206, PubMed:20068034, PubMed:23146885, PubMed:24790097, PubMed:25631046). Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (PubMed:17028573, PubMed:18718448, PubMed:19131965, PubMed:19881509). Involved in the control of inflammatory signaling pathways (PubMed:19131965). Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways (PubMed:19131965). Promotes the association of the complex after TNF stimulation (PubMed:19131965). Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (PubMed:19131965). This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (PubMed:19131965). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (PubMed:19592251). Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response (PubMed:18718448, PubMed:20491914). Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (PubMed:18718448). Mediates JUN ubiquitination and degradation (By similarity). Mediates JUNB ubiquitination and degradation (PubMed:16387660). Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation (By similarity). Involved in the negative regulation of MAVS-dependent cellular antiviral responses (PubMed:19881509). Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (PubMed:19881509). Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (PubMed:23146885). Ubiquitinates PI4K2A and negatively regulates its catalytic activity (PubMed:23146885). Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (PubMed:14602072, PubMed:23146885). Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:17028573, PubMed:18628966, PubMed:23886940). Ubiquitinates SNX9 (PubMed:20491914). Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation (By similarity). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (PubMed:20068034). Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID (PubMed:20392206). Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein plays a role in multiple cellular processes including erythroid and lymphoid cell differentiation and the regulation of immune responses. Mutations in this gene are a cause of syndromic multisystem autoimmune disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

Uniprot Accession IDs

• Q96J02
• A6NEW4
• B4E234
• E1P5P3
• F5H217
• O43584
• Q5QP37
• Q5TEL0
• Q96F66
• Q9BY75
• Q9H451
• Q9H4U5
• Itch

Gene Name

• ITCH

Ensembl ID

• ENST00000262650
• ENSP00000262650
• ENSG00000078747
• ENST00000374864
• ENSP00000363998
• ENST00000535650
• ENSP00000445608

Symbol

• AIF4
• AIP4
• ADMFD
• NAPP1

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
biological process	0.99
hub protein	0.96
kinase perturbation	0.84
kinase	0.77
disease perturbation	0.74

IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 164.14   (req: < 5)

Gene RIFs: 91   (req: <= 3)

Antibodies: 276   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 164.14   (req: >= 5)

Gene RIFs: 91   (req: > 3)

Antibodies: 276   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 35

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligand: 0

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 0

Protein Sequence and Structure

Residue Counts

Protein Sequence

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Protein-Protein Interactions (467)

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1 – 10 of 467

• See Interactions on String-DB

FAM189B

Tbio

Novelty:  0.21064304

p_int:  0.999633178

p_ni:  0.000366822

Score:  0.192

Data Source:  BioPlex,STRINGDB

ARRDC1

Tbio

Novelty:  0.10481621

p_int:  0.995788269

p_ni:  0.004211731

Score:  0.741

Data Source:  BioPlex,STRINGDB

FAM189A2

Tdark

Novelty:  0.41335428

p_int:  0.989358607

p_ni:  0.010641393

Data Source:  BioPlex

SPART

Tbio

Novelty:  0.01524727

p_int:  0.987605414

p_ni:  0.012394586

Score:  0.706

Data Source:  BioPlex,STRINGDB

LDLRAD4

Tbio

Novelty:  0.04881486

p_int:  0.986764803

p_ni:  0.013235197

Score:  0.22

Data Source:  BioPlex,STRINGDB

TMEM255A

Tdark

Novelty:  1.03700118

p_int:  0.98374744

p_ni:  0.01625256

Score:  0.163

Data Source:  BioPlex,STRINGDB

ARRDC3

Tbio

Novelty:  0.04840692

p_int:  0.974832371

p_ni:  0.025167629

Score:  0.704

Data Source:  BioPlex,STRINGDB

SARAF

Tbio

Novelty:  0.0383833

p_int:  0.964623191

p_ni:  0.035376809

Data Source:  BioPlex

TIGIT

Tbio

Novelty:  0.0064542

p_int:  0.96455227

p_ni:  0.03544773

Data Source:  BioPlex

SMAD7

Tbio

Family:  TF

Novelty:  0.00116343

p_int:  0.961489627

p_ni:  0.038510373

Score:  0.803

Data Source:  BioPlex,STRINGDB

Pathways (51)

Reactome (25)

KEGG (4)

PathwayCommons (16)

UniProt (1)

WikiPathways (5)

Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Activated NOTCH1 Transmits Signal to the Nucleus	31 targets	R-HSA-2122948
Reactome	Adaptive Immune System	894 targets	R-HSA-1280218
Reactome	Antigen processing: Ubiquitination & Proteasome degradation	307 targets	R-HSA-983168
Reactome	Class I MHC mediated antigen processing & presentation	437 targets	R-HSA-983169
Reactome	DDX58/IFIH1-mediated induction of interferon-alpha/beta	77 targets	R-HSA-168928

Name	Explore in Pharos	Explore in Source
Activated NOTCH1 Transmits Signal to the Nucleus	31 targets	R-HSA-2122948
Adaptive Immune System	894 targets	R-HSA-1280218
Antigen processing: Ubiquitination & Proteasome degradation	307 targets	R-HSA-983168
Class I MHC mediated antigen processing & presentation	437 targets	R-HSA-983169
DDX58/IFIH1-mediated induction of interferon-alpha/beta	77 targets	R-HSA-168928

Gene Ontology Terms (45)

Functions (8)

Components (10)

Processes (27)

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1 – 8 of 8

GO Term	Evidence	Assigned by
ubiquitin protein ligase activity	Inferred from Direct Assay (IDA)	MGI
ubiquitin-protein transferase activity	Inferred from Direct Assay (IDA)	UniProtKB
arrestin family protein binding	Inferred from Physical Interaction (IPI)	UniProtKB
CXCR chemokine receptor binding	Inferred from Physical Interaction (IPI)	UniProtKB
ribonucleoprotein complex binding	Inferred from Physical Interaction (IPI)	UniProtKB
ubiquitin-like protein ligase binding	Inferred from Physical Interaction (IPI)	UniProtKB
ubiquitin-like protein transferase activity	Traceable Author Statement (TAS)	Reactome
ligase activity	Inferred from Electronic Annotation (IEA)	Ensembl

GWAS Traits (22)

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GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
appendicular lean mass	EFO_0004980	3	7	12		97.8
glomerular filtration rate	EFO_0005208	4	4	4		95.6
sex hormone-binding globulin measurement	EFO_0004696	6	3	6		90.5
hair color	EFO_0003924	1	1	0	1.5	85.8
creatinine measurement	EFO_0004518	2	2	2		83.2

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1 – 5 of 22

GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
appendicular lean mass	EFO_0004980	12		97.8
glomerular filtration rate	EFO_0005208	4		95.6
sex hormone-binding globulin measurement	EFO_0004696	6		90.5
hair color	EFO_0003924	0	1.5	85.8
creatinine measurement	EFO_0004518	2		83.2

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UniProt Keyword Find Similar Targets

No Header	No Header
3D-structure
Acetylation
Alternative splicing
Antiviral defense
Apoptosis
Cell membrane
Complete proteome
Cytoplasm
Direct protein sequencing
Endosome

GWAS Trait Find Similar Targets

No Header	No Header
apolipoprotein A 1 measurement
appendicular lean mass
balding measurement
BMI-adjusted hip circumference
creatinine measurement
diet measurement
feeling nervous measurement
gait measurement
glomerular filtration rate
hair color

MGI Phenotype Find Similar Targets

No Header	No Header
adipose tissue phenotype
behavior/neurological phenotype
cardiovascular system phenotype
cellular phenotype
craniofacial phenotype
growth/size/body region phenotype
hematopoietic system phenotype
homeostasis/metabolism phenotype
immune system phenotype
integument phenotype

Orthologs (12)

1 – 5 of 12

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	itchy E3 ubiquitin protein ligase	VGNC:6170	458191
Macaque	itchy E3 ubiquitin protein ligase		707640
Mouse	itchy, E3 ubiquitin protein ligase	MGI:1202301	16396
Rat	itchy E3 ubiquitin protein ligase	RGD:1359556	311567
Dog	itchy E3 ubiquitin protein ligase	VGNC:42117	477199

Species	Name	OMA	EggNOG	Inparanoid
Chimp	itchy E3 ubiquitin protein ligase
Macaque	itchy E3 ubiquitin protein ligase
Mouse	itchy, E3 ubiquitin protein ligase
Rat	itchy E3 ubiquitin protein ligase
Dog	itchy E3 ubiquitin protein ligase

Publication Statistics

PubMed Score 164.14

PubMed score by year

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PubTator Score 652.47

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