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Protein

Tribbles homolog 3

Gene

TRIB3

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

Functioni

Disrupts insulin signaling by binding directly to Akt kinases and blocking their activation. May bind directly to and mask the 'Thr-308' phosphorylation site in AKT1. Binds to ATF4 and inhibits its transcriptional activation activity. Interacts with the NF-kappa-B transactivator p65 RELA and inhibits its phosphorylation and thus its transcriptional activation activity. Interacts with MAPK kinases and regulates activation of MAP kinases. May play a role in programmed neuronal cell death but does not appear to affect non-neuronal cells. Does not display kinase activity. Inhibits the transcriptional activity of DDIT3/CHOP and is involved in DDIT3/CHOP-dependent cell death during ER stress. Can inhibit APOBEC3A editing of nuclear DNA.5 Publications

Caution

The role of this protein in Akt activation has been demonstrated by Du et al (PubMed:12791994) for the mouse ortholog but Iynedjian (PubMed:15469416) has not been able to reproduce the result in rat hepatocytes.Curated

GO - Molecular functioni

  • ATP binding Source: InterPro
  • mitogen-activated protein kinase kinase binding Source: GO_Central
  • protein kinase binding Source: UniProtKB
  • protein kinase inhibitor activity Source: UniProtKB-KW
  • transcription corepressor activity Source: UniProtKB
  • ubiquitin protein ligase binding Source: BHF-UCL
  • ubiquitin-protein transferase regulator activity Source: BHF-UCL

GO - Biological processi

Keywordsi

Molecular functionProtein kinase inhibitor
Biological processApoptosis, Stress response, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-1257604 PIP3 activates AKT signaling
R-HSA-165158 Activation of AKT2
R-HSA-1989781 PPARA activates gene expression
R-HSA-199418 Negative regulation of the PI3K/AKT network
R-HSA-389357 CD28 dependent PI3K/Akt signaling
R-HSA-5218920 VEGFR2 mediated vascular permeability
SignaLinkiQ96RU7
SIGNORiQ96RU7

Names & Taxonomyi

Protein namesi
Recommended name:
Tribbles homolog 3
Short name:
TRB-3
Alternative name(s):
Neuronal cell death-inducible putative kinase
SINK
p65-interacting inhibitor of NF-kappa-B
Gene namesi
Name:TRIB3
Synonyms:C20orf97, NIPK, SKIP3, TRB3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 20

Organism-specific databases

EuPathDBiHostDB:ENSG00000101255.10
HGNCiHGNC:16228 TRIB3
MIMi607898 gene
neXtProtiNX_Q96RU7

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Organism-specific databases

DisGeNETi57761
OpenTargetsiENSG00000101255
PharmGKBiPA25804

Polymorphism and mutation databases

BioMutaiTRIB3
DMDMi28201830

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001318661 – 358Tribbles homolog 3Add BLAST358

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei12PhosphoserineCombined sources1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ96RU7
MaxQBiQ96RU7
PaxDbiQ96RU7
PeptideAtlasiQ96RU7
PRIDEiQ96RU7
ProteomicsDBi78040

PTM databases

iPTMnetiQ96RU7
PhosphoSitePlusiQ96RU7

Expressioni

Tissue specificityi

Highest expression in liver, pancreas, peripheral blood leukocytes and bone marrow. Also highly expressed in a number of primary lung, colon and breast tumors. Expressed in spleen, thymus, and prostate and is undetectable in other examined tissues, including testis, ovary, small intestine, colon, leukocyte, heart, brain, placenta, lung, skeletal muscle, and kidney.3 Publications

Inductioni

By hypoxia, TNF, and by nutrient starvation. Expression is PI 3-kinase and/or NF-kappa-B-dependent. Induced by ER stress via ATF4-DDIT3/CHOP pathway and can downregulate its own induction by repression of ATF4-DDIT3/CHOP functions.4 Publications

Gene expression databases

BgeeiENSG00000101255 Expressed in 163 organ(s), highest expression level in liver
CleanExiHS_TRIB3
ExpressionAtlasiQ96RU7 baseline and differential
GenevisibleiQ96RU7 HS

Interactioni

Subunit structurei

Interacts with AKT1, AKT2, ATF4, MAP2K1 and MAP2K7. Interacts with DDIT3/CHOP and inhibits its interaction with EP300/P300. Interacts (via N-terminus) with APOBEC3A. Interacts with APOBEC3C.6 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi121756, 36 interactors
CORUMiQ96RU7
IntActiQ96RU7, 79 interactors
MINTiQ96RU7
STRINGi9606.ENSP00000217233

Structurei

3D structure databases

ProteinModelPortaliQ96RU7
SMRiQ96RU7
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini68 – 316Protein kinasePROSITE-ProRule annotationAdd BLAST249

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 127Interaction with DDIT3/CHOPAdd BLAST127

Domaini

The protein kinase domain is predicted to be catalytically inactive.

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0583 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00930000150878
HOGENOMiHOG000231872
HOVERGENiHBG067729
InParanoidiQ96RU7
KOiK19518
PhylomeDBiQ96RU7
TreeFamiTF329785

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR024104 Tribbles/Ser_Thr_kinase_40
IPR024106 Tribbles_TRB3
PANTHERiPTHR22961 PTHR22961, 1 hit
PTHR22961:SF14 PTHR22961:SF14, 1 hit
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50011 PROTEIN_KINASE_DOM, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 3 potential isoforms that are computationally mapped.Show allAlign All

Q96RU7-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MRATPLAAPA GSLSRKKRLE LDDNLDTERP VQKRARSGPQ PRLPPCLLPL
60 70 80 90 100
SPPTAPDRAT AVATASRLGP YVLLEPEEGG RAYQALHCPT GTEYTCKVYP
110 120 130 140 150
VQEALAVLEP YARLPPHKHV ARPTEVLAGT QLLYAFFTRT HGDMHSLVRS
160 170 180 190 200
RHRIPEPEAA VLFRQMATAL AHCHQHGLVL RDLKLCRFVF ADRERKKLVL
210 220 230 240 250
ENLEDSCVLT GPDDSLWDKH ACPAYVGPEI LSSRASYSGK AADVWSLGVA
260 270 280 290 300
LFTMLAGHYP FQDSEPVLLF GKIRRGAYAL PAGLSAPARC LVRCLLRREP
310 320 330 340 350
AERLTATGIL LHPWLRQDPM PLAPTRSHLW EAAQVVPDGL GLDEAREEEG

DREVVLYG
Length:358
Mass (Da):39,578
Last modified:February 1, 2003 - v2
Checksum:iCE15FD89A81E8D63
GO

Computationally mapped potential isoform sequencesi

There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
J3KR25J3KR25_HUMAN
Tribbles homolog 3
TRIB3
385Annotation score:
B0QYQ2B0QYQ2_HUMAN
Tribbles homolog 3
TRIB3
271Annotation score:
A0A087WTX3A0A087WTX3_HUMAN
Tribbles homolog 3
TRIB3
130Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti24N → D in CAG33647 (Ref. 7) Curated1
Sequence conflicti105L → P in BAB15597 (PubMed:14702039).Curated1
Sequence conflicti105L → P in BAD96557 (Ref. 8) Curated1
Sequence conflicti114L → V in AAK58175 (PubMed:15299019).Curated1
Sequence conflicti194 – 195ER → DREK in AAK58175 (PubMed:15299019).Curated2

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04237260T → I in a glioblastoma multiforme sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs757496714Ensembl.1
Natural variantiVAR_02396584Q → R2 PublicationsCorresponds to variant dbSNP:rs2295490Ensembl.1
Natural variantiVAR_042373153R → H1 PublicationCorresponds to variant dbSNP:rs35051116Ensembl.1
Natural variantiVAR_042374274R → H1 PublicationCorresponds to variant dbSNP:rs56291463Ensembl.1
Natural variantiVAR_042375347E → K1 PublicationCorresponds to variant dbSNP:rs56342286Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF250311 mRNA Translation: AAK58175.1
AJ697936 mRNA Translation: CAG27047.1
AY247738 mRNA Translation: AAP04407.1
AK026945 mRNA Translation: BAB15597.1
CR457366 mRNA Translation: CAG33647.1
AK222837 mRNA Translation: BAD96557.1
AL034548 Genomic DNA No translation available.
BC019363 mRNA Translation: AAH19363.1
BC027484 mRNA Translation: AAH27484.1
CCDSiCCDS12997.1
RefSeqiNP_001288117.1, NM_001301188.1
NP_001288119.1, NM_001301190.1
NP_001288122.1, NM_001301193.1
NP_001288125.1, NM_001301196.1
NP_001288130.1, NM_001301201.1
NP_066981.2, NM_021158.4
UniGeneiHs.516826

Genome annotation databases

EnsembliENST00000217233; ENSP00000217233; ENSG00000101255
GeneIDi57761
KEGGihsa:57761
UCSCiuc002wdm.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF250311 mRNA Translation: AAK58175.1
AJ697936 mRNA Translation: CAG27047.1
AY247738 mRNA Translation: AAP04407.1
AK026945 mRNA Translation: BAB15597.1
CR457366 mRNA Translation: CAG33647.1
AK222837 mRNA Translation: BAD96557.1
AL034548 Genomic DNA No translation available.
BC019363 mRNA Translation: AAH19363.1
BC027484 mRNA Translation: AAH27484.1
CCDSiCCDS12997.1
RefSeqiNP_001288117.1, NM_001301188.1
NP_001288119.1, NM_001301190.1
NP_001288122.1, NM_001301193.1
NP_001288125.1, NM_001301196.1
NP_001288130.1, NM_001301201.1
NP_066981.2, NM_021158.4
UniGeneiHs.516826

3D structure databases

ProteinModelPortaliQ96RU7
SMRiQ96RU7
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121756, 36 interactors
CORUMiQ96RU7
IntActiQ96RU7, 79 interactors
MINTiQ96RU7
STRINGi9606.ENSP00000217233

PTM databases

iPTMnetiQ96RU7
PhosphoSitePlusiQ96RU7

Polymorphism and mutation databases

BioMutaiTRIB3
DMDMi28201830

Proteomic databases

EPDiQ96RU7
MaxQBiQ96RU7
PaxDbiQ96RU7
PeptideAtlasiQ96RU7
PRIDEiQ96RU7
ProteomicsDBi78040

Protocols and materials databases

DNASUi57761
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000217233; ENSP00000217233; ENSG00000101255
GeneIDi57761
KEGGihsa:57761
UCSCiuc002wdm.4 human

Organism-specific databases

CTDi57761
DisGeNETi57761
EuPathDBiHostDB:ENSG00000101255.10
GeneCardsiTRIB3
HGNCiHGNC:16228 TRIB3
MIMi607898 gene
neXtProtiNX_Q96RU7
OpenTargetsiENSG00000101255
PharmGKBiPA25804
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0583 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00930000150878
HOGENOMiHOG000231872
HOVERGENiHBG067729
InParanoidiQ96RU7
KOiK19518
PhylomeDBiQ96RU7
TreeFamiTF329785

Enzyme and pathway databases

ReactomeiR-HSA-1257604 PIP3 activates AKT signaling
R-HSA-165158 Activation of AKT2
R-HSA-1989781 PPARA activates gene expression
R-HSA-199418 Negative regulation of the PI3K/AKT network
R-HSA-389357 CD28 dependent PI3K/Akt signaling
R-HSA-5218920 VEGFR2 mediated vascular permeability
SignaLinkiQ96RU7
SIGNORiQ96RU7

Miscellaneous databases

ChiTaRSiTRIB3 human
GeneWikiiTRIB3
GenomeRNAii57761
PROiPR:Q96RU7
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000101255 Expressed in 163 organ(s), highest expression level in liver
CleanExiHS_TRIB3
ExpressionAtlasiQ96RU7 baseline and differential
GenevisibleiQ96RU7 HS

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR024104 Tribbles/Ser_Thr_kinase_40
IPR024106 Tribbles_TRB3
PANTHERiPTHR22961 PTHR22961, 1 hit
PTHR22961:SF14 PTHR22961:SF14, 1 hit
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50011 PROTEIN_KINASE_DOM, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiTRIB3_HUMAN
AccessioniPrimary (citable) accession number: Q96RU7
Secondary accession number(s): Q53GU4
, Q53ZW7, Q6I9Y9, Q8TAI6, Q9H5M8, Q9NUD2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 2003
Last sequence update: February 1, 2003
Last modified: November 7, 2018
This is version 168 of the entry and version 2 of the sequence. See 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

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  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. Human chromosome 20
    Human chromosome 20: entries, gene names and cross-references to MIM
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
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Main funding by: National Institutes of Health

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