TRIB1 (tribbles pseudokinase 1)

2015-03-01   Jessica Johnston , Endre Kiss-Toth 

Department of Cardiovascular Science, University of Sheffield, Sheffield, Beech Hill Road, Sheffield S10 2RX, United Kingdom

Identity

HGNC
LOCATION
8q24.13
LOCUSID
ALIAS
C8FW,GIG-2,GIG2,SKIP1,TRB-1,TRB1
FUSION GENES

Abstract

Review on TRIB1, with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Atlas Image
There are two validated transcripts of TRIB1 (NM_025195 and NM_001282985) coding for isoforms 1 and 2 respectively. Isoform 2 has a shorter 5UTR (untranslated region) and 5 coding region compared to isoform 1 and initiates translation further downstream. UTRs and exons are represented by the red and grey boxes respectively. Image drawn by FancyGene (Rambaldi and Ciccarelli 2009).

Transcription

There are two protein coding transcripts of TRIB1; TRIB1-001 and TRIB1-002.
TRIB1-001 (Isoform 1); Transcript size: 3,635bp; Exon count: 3.
TRIB1-002 (Isoform 2); Transcript size: 1,332 bp; Exon count: 2

Proteins

Note

TRIB1-001: 372 amino acids; TRIB1-002: 206 amino acids
Atlas Image
Protein structure of Tribbles 1: TRIB1 has a N terminal, pseudokinase and C terminal domains. It contains four protein motifs; a putative PEST sequence, a kinase dead catalytic loop, a MEK1 binding and COP1 binding motif. The characteristic amino acid sequence for each motif is shown along with location.

Description

TRIB1 contain a N terminal (NT) domain of 60-80 residues and a C-terminal domain of 35-40 residues and a characteristic single central Ser/Thr kinase-like (pseudokinase) domain. TRIB1 contains features consistent with its emerging role as a protein adaptor in signalling pathways.
N-Terminal Domain The NT fragment of TRIB1 is proline and serine rich, mostly in the sequence adjacent to the kinase-like domain. The abundance of these amino acids are a characteristic of PEST proteins that are involved in controlling the half life of proteins by altering their susceptibility to degradation. Other functions of these types of proteins include the anchoring of SH3 or WW domains of other proteins or acting as a substrate for proline dependent phosphorylation. TRIB1 contains possible phosphorylation sites for proline-dependent kinases (Hegedus, et al 2007).
TRIB1 also contains two evolutionary conserved motifs. The first consists of a putative nuclear localisation signal, [K/R]2X2[D/E]X[D/E]. The second motif contains a G-S-P consensus pattern found close to the kinase-like domain. The G-S-P motif is present in human SNIP1 (Smad nuclear interacting protein) which functionally associates with BGR1, which interacts with the Drosophila homologue of Slbo, C/EBP transcription factors (Beausoleil, et al 2004, Kadam, et al 2000). C/EBP transcription factors have been shown to functionally and physically interact with TRIB1 promoting their degradation (Yoshida, et al 2013).
Kinase-like domain TRIB1 contains a Ser/Thr kinase-like domain that is composed of some of the motifs present in catalytically active kinases such as a Lysine crucial for ATP binding whilst others are missing. Despite this evidence would suggest TRIB1 no to possess kinase activity. However this domain is highly conserved during evolution suggesting it is important for the role of TRIB1(Hegedus, et al 2007).
C-Terminal Domain The CT domain is around 35-45 amino acids long and is rich in charged amino acids important for protein interactions. Two important motifs have been identified in the CT domain; a hexapeptide motif [D/E]QXVP[D/E] as a COP1 (E3 ubiqutin ligase) binding site, essential for proteasome mediated degradation of C/EBPα family members and a MEK 1 binding site (ILLHPWF) (Hegedus, et al 2007).
Post translational modifications Several post translational modifications of TRIB1 have been reported and validated by mass spectrometry and listed in the PhosphoSitePlus database (Hornbeck, et al 2012).

Expression

TRIB1 expression is ubiquitious with highest expression in the thyroid and myeloid cells (Figure?). TRIB1 is thought to expressed in a cell-type specific manner (Sung, et al 2006).
Atlas Image
The tissue specific expression of human TRIB1 mRNA is shown. Data and figure taken from BioGPS. Additional microarray expression data from the Human Gene Expression Atlas from the Genomics Institute of the Novartis Research Foundation (GNF) can be found on the UCSC browser ( http://genome.ucsc.edu/) (Su, et al 2004, Wu, et al 2009).

Localisation

Numerous over-expression experiments have shown TRIB1 to be located in the nucleus. It contains a putative nuclear localisation signal (Yokoyama, et al 2010).
Atlas Image

Function

TRIB1 has been shown to interact with a number of proteins as detailed herein (Table1):
MEK-1 and MKK4 Co-immunoprecipitation experiments have shown specific interactions with MEK1 (an ERK activator MAPKK) and MKK4 (a JNK activator MAPKK). Interactions with Tribbles control the extent and specificity of MAPK activation and are dependent on levels of TRIB expression (Kiss-Toth, et al 2004, Sung, et al 2007).
MEK1 phosphorylates ERK which in turn promotes cell proliferation and suppression of apoptosis. The interaction between TRIB1 (via ILLHPWF motif) and MEK1
enhances ERK phosphorylation as mutants lacking the motif were unable to do so (Yokoyama, et al 2010) .
TRIB1 also interacts with MKK4, a JNK activator and implicated in the migration and proliferation of smooth muscle and involved in the pathogenesis of atherosclerosis. The nuclear localisation of TRIB1-MKK4 complex is dependent on the NT domain of TRIB1, however the central kinase-like domain of TRIB1 is sufficient for its interaction with MKK4 but the interaction is no longer preferentially nuclear (Sung, et al 2007).
COP1 AND C/EBPalpha TRIB1 contains a COP1 binding site at the carboxy terminus. COP1 is an E3 ubiquitin ligase that promotes the transfer of ubiquitin to target substrates for degradation via the proteasome. One of the prinicipal targets of COP1 are the family of transcription proteins CCAT/enhancer binding proteins (C/EBPs). It is thought TRIB1 acts to negatively regulate C/EBP proteins by acting as adaptors to recruit COP1 to C/EBP family members thereby promoting ubiquitination and degradation. Studies have shown that COP1 requires TRIB1 for its action of α (Yoshida, et al 2013).

Homology

TRIB1 homologues have been indentified in different species including mouse, frog and zebrafish. Table 2 illustrates some of the TRIB1 homologues.
Atlas Image
Table 2: % protein and DNA identity of human TRIB1 vs other species. Data taken from Homologene and NCBI.

Mutations

Note

A somatic point mutation of TRIB1 has been reported in Down syndrome (DS)- related acute megakaryocytic leukaemia (AMKL) (Yokoyama, et al 2012). A G:T point mutation was found in the pseudokinase domain resulting in an amino acid change from arginine to leucine (R107L). When the mutation was expressed in mouse bone marrow cells and transferred into lethally irradiated recipient mice there was a more rapid development of AML and enhancement of ERK phosporylation suggesting a gain of function mutation. Yokoyama, et al (2012) suggests that the mutation of TRIB1 is an early event in leukaemogenesis.
A wide range of allelic variants of TRIB1 have been reported. There are several genetic and protein variations of TRIB1 listed on Ensembl.
Table (3) shows the types of genetic variation of TRIB1. Data taken from: http://Feb2014.archive.ensembl.org/Homo_sapiens/Gene/Variation_Gene/Table?db=core;g=ENSG00000173334;r=8:126442563-126450647
Protein variants of TRIB1: Table 4 shows the protein variants of TRIB1. Each variant is listed in order according to residue number. The table also lists SIFT and Poly-Phen scores for the variations. SIFT predicts whether an amino acid substitution is likely to affect protein function based on the sequence homology and the physico-chemical similarity between the alternate amino acids. Each variant is accompanied with a score and predictive consequence that is based on the probability that the amino acid change is tolerable. A score closer to 0 is more likely to be deleterious. A score of
Atlas Image
Table 3: Genetic variations of TRIB1

Implicated in

Entity
Smooth muscle cells
Note
TRIB1 is selectively over-expressed in chronically inflamed human atherosclerotic arteries and regulates vascular smooth muscle cell (VSMC) chemotaxis and proliferation, a characteristic feature of atherosclerosis via the JNK pathway (Sung, et al 2007).
Entity
Macrophages
Note
Trib1 is expressed in plaque resident macrophages in murine experimental atherosclerosis. The expression of Trib1 could be upregulated by IL-1, a major contributor to plaque development as the percentage of Trib1 expressing macrophages significantly decreases in ApoE -/- IL1R-/- double knockout mice compared to ApoE-/- controls. Overexpression of Trib1 in macrophages in vitro also leads to a significant attenuation (~70%) of IL-6 production and suppressed IL-12 expression induced with a pro-inflammatory stimulus (Sung, et al 2012).
It has also been shown that TRIB1 is involved in macrophage migration through interactions with C/EBP β and TNF- α. Knockdown of TRIB1 in RAW246.7 cells resulted in an increase in TNF- α production and C/EBPβ expression suggesting TRIB1 may modulate TNF- α through C/EBP β (Liu, et al 2013).
Trib1 has been shown to also be involved with adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue M2-like macrophages. Trib1 deficiency results in a significant reduction of M2-like macrophages. Mice lacking Trib1 in haematopoietic cells show a reduced adipocyte tissue mass and have evidence of increased lipolysis even on a normal diet. Supplementation of M2-like macrophages causes rescue suggesting the lack of these M2-like macrophages are responsible for lipolysis. When mice are fed a high fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance and a pro-inflammatory cytokine induction (Satoh, et al 2013).
Entity
Cancer
Note
TRIB1 has been associated with the development of cancer and is considered as a leukaemia disease gene. It was identified as a collaborator of Hoxa9 and Meis1 in myeloid leukaemogenesis (Jin, et al 2007). Cooperative genes for Hoxa9/Meis1 were identified as common targets for retroviral integration, where TRIB1 was identified as the most frequent common site for integration in AML (Nakamura 2005). Table 5 shows the common integration sites and candidate cooperative genes in TRIB1-induced AML (Yokoyama and Nakamura 2011). TRIB1 alone is a transforming gene for myeloid cells and also significantly accelerates the development of Hoxa9/Meis1 AML.
Atlas Image
Table 5: Common integration sites and candidate cooperative genes in TRIB1-induced AML.
Oncogenesis
Phosphorylation of ERK is enhanced in TRIB1 transfected HeLa and Baf3 cells and leukaemia cells derived from TRIB1-induced AML upon cytokine stimulation (Jin, et al 2007).
MEK1 and enhancement of MEK/ERK phosporylation is required for reactivity. Mutant lacking MEK1 binding site is unable to enhance phosphorylation of ERK or extend self renewal in bone marrow cells or induce AML/accelerate Hoxa9/Meis1 induced AML (Yokoyama, et al 2010).
TRB1 has been implicated in human AML. TRIB1 is found on chromosome 8q24, 1.5Mb away from c-MYC, the target of AML amplification. TRIB1 is over-expressed even in some cases of AML when c-MYC amplification is not detected (Roethlisberger, et al 2007, Storlazzi, et al 2006)
Entity
Cardiovascular Disease and Atherosclerosis
Note
Emerging evidence from several genome-wide association studies (GWAS) has implicated TRIB1 in the risk of cardiovascular disease and events specifically due to the levels of circulating lipids (Kathiresan, et al 2008, Willer, et al 2008).
Two SNPs (rs2954029 and rs17321515) near the TRIB1 gene have been implicated with triglyceride, LDL and HDL levels. A minor G allele at rs17321515 was associated with lower triglyceride and LDL cholesterol and higher HDL cholesterol levels. A TT -> TA -> AA genotypes at rs2954029 were associated with step wise increases in the levels of triglyceride, remnant cholesterol and apo-lipoprotein B, the primary apolipoproteins present on LDLs. Likewise HDL cholesterol levels decreased step-wise through the genotypes. Additionally the genotypes were found to be significantly associated with increased risk of ischemic heart disease (IHD) and increased risk of MI
Further bivariate analysis showed TRIB1 expression to be significantly associated with triglyceride/ elevated blood pressure and triglyceride/HDL-cholesterol suggesting TRIB1 may be involved in a specific feature of lipid homeostasis (Kraja, et al 2011).
These genetic studies were further validated in in vivo models. Specific hepatic over-expression of Trib1 using an adenovirus vector reduced lipid plasma levels in a dose-dependent manner due to reduced VLDL production. Equally the opposite was seen in Trib1- knockout mice due to increased VLDL production. Interestingly when hepatic expression was reconstituted in knockout mice, VLDL-triglyceride production decreased to levels found in control mice (Burkhardt, et al 2010). The precise mechanisms of Trib1 involvement in lipid metabolism however are unknown.
Burkhardt, et al (2010) further investigated by examining the mRNA levels of genes associated with lipid metabolism in the livers of Trib1 over-expressing and Trib1- deficient mice. A significant decrease was found for genes involved in fatty acid oxidation such as Cpt1a (carnitine palmitoyltransferase 1A), Cpt2, and Acox1 (acyl-Coenzyme A oxidase 1) in Trib1 -/- mice. A significant up-regulation of key lipogeneic genes was also found such as Acc1 (acetyl-Coenzyme A carboxylase), fatty acid synthesis (Fasn) and stearoyl-Coenzyme A desaturase 1(Scd1). Significant downregulation of these genes were found in Trib1-over expressing mice. These genes have been noted to have effects on VLDL secretion and plasma triglyceride and cholesterol levels.
TRIB1 may also have a further role in lipogenesis. TRIB1 over-expression resulted in a significant decrease in 35S-methionine labelled apoB secretion in HepG2 cells (human liver carcinoma cell line). The authors speculate that TRIB1-mediated regulation of hepatic lipid availability might alter the secretion of apoB particles via a mechanism involving ER-associated degradation (ERAD) as previous data has shown a reduced availability or synthesis of lipid for apoB lipidation leads to co-translational targeting of apoB for ERAD (Ginsberg, et al 2009).
Entity
Type 2 Diabetes
Note
Trib1 has been hypothesised to have a regulatory role in inflammation in adipoctyes that may contribute towards obesity related type 2 diabetes. Trib1 is specifically up-regulated during acute and chronic inflammation in white adipose tissue in mice. Trib1 knockout mice show it to be a key regulator of inflammatory cytokines such as TNF-a and are protected from high fat diet induced obesity (Ostertag, et al 2010). It is proposed that Trib1 is pro-inflammatory in the adipose by acting as a co-activator for NF-kB inducing the expression of proinflammatory cytokines.

Bibliography

Pubmed IDLast YearTitleAuthors
203545122010A method and server for predicting damaging missense mutations.Adzhubei IA et al
153029352004Large-scale characterization of HeLa cell nuclear phosphoproteins.Beausoleil SA et al
210847522010Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice.Burkhardt R et al
213039022011Dense genotyping of candidate gene loci identifies variants associated with high-density lipoprotein cholesterol.Edmondson AC et al
214579092011Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel.González-Pérez A et al
108504942000A genetic link between morphogenesis and cell division during formation of the ventral furrow in Drosophila.Grosshans J et al
169632282007Tribbles: a family of kinase-like proteins with potent signalling regulatory function.Hegedus Z et al
172278322007Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis.Jin G et al
110180122000Functional selectivity of recombinant mammalian SWI/SNF subunits.Kadam S et al
170975622006Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia.Keeshan K et al
152990192004Human tribbles, a protein family controlling mitogen-activated protein kinase cascades.Kiss-Toth E et al
213860852011A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium.Kraja AT et al
195615902009Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.Kumar P et al
238104192013Macrophage migration is controlled by Tribbles 1 through the interaction between C/EBPβ and TNF-α.Liu YH et al
108504932000Tribbles coordinates mitosis and morphogenesis in Drosophila by regulating string/CDC25 proteolysis.Mata J et al
221352962012VectorBase: improvements to a bioinformatics resource for invertebrate vector genomics.Megy K et al
175767712007TRB2, a mouse Tribbles ortholog, suppresses adipocyte differentiation by inhibiting AKT and C/EBPbeta.Naiki T et al
205226002010Control of adipose tissue inflammation through TRB1.Ostertag A et al
167940742006TRB3 links the E3 ubiquitin ligase COP1 to lipid metabolism.Qi L et al
195421502009FancyGene: dynamic visualization of gene structures and protein domain architectures on genomic loci.Rambaldi D et al
235151632013Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages.Satoh T et al
164521262006MYC-containing double minutes in hematologic malignancies: evidence in favor of the episome model and exclusion of MYC as the target gene.Storlazzi CT et al
150753902004A gene atlas of the mouse and human protein-encoding transcriptomes.Su AI et al
163644542006Regulation of expression and signalling modulator function of mammalian tribbles is cell-type specific.Sung HY et al
174523302007Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways.Sung HY et al
22947281990The use of anabolic steroids in high school students.Terney R et al
210716872011TRIB1 and GCKR polymorphisms, lipid levels, and risk of ischemic heart disease in the general population.Varbo A et al
199196822009BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources.Wu C et al
213384412011Tribbles in disease: Signaling pathways important for cellular function and neoplastic transformation.Yokoyama T et al
238848582013COP1 targets C/EBPα for degradation and induces acute myeloid leukemia via Trib1.Yoshida A et al

Other Information

Locus ID:

NCBI: 10221
MIM: 609461
HGNC: 16891
Ensembl: ENSG00000173334

Variants:

dbSNP: 10221
ClinVar: 10221
TCGA: ENSG00000173334
COSMIC: TRIB1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000173334ENST00000311922Q96RU8
ENSG00000173334ENST00000519576E5RFH4
ENSG00000173334ENST00000520847Q96RU8

Expression (GTEx)

0
50
100
150
200

References

Pubmed IDYearTitleCitations
181930432008Newly identified loci that influence lipid concentrations and risk of coronary artery disease.690
181930442008Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.575
152990192004Human tribbles, a protein family controlling mitogen-activated protein kinase cascades.110
191482832009Genetic differences between the determinants of lipid profile phenotypes in African and European Americans: the Jackson Heart Study.56
185960512008Polygenic determinants of severe hypertriglyceridemia.45
194875392009Large scale replication analysis of loci associated with lipid concentrations in a Japanese population.35
243826682014MicroRNA-224 inhibits progression of human prostate cancer by downregulating TRIB1.34
174523302007Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways.31
206108162010Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis.31
205717542010Evaluating the discriminative power of multi-trait genetic risk scores for type 2 diabetes in a northern Swedish population.26

Citation

Jessica Johnston ; Endre Kiss-Toth

TRIB1 (tribbles pseudokinase 1)

Atlas Genet Cytogenet Oncol Haematol. 2015-03-01

Online version: http://atlasgeneticsoncology.org/gene/43539/trib1