TRIB1

Summary

TRIB1 (tribbles pseudokinase 1, HGNC:16891) is a protein-coding gene on chromosome 8q24.13, encoding Tribbles homolog 1 (Q96RU8). Adapter protein involved in protein degradation by interacting with COP1 ubiquitin ligase.

Enables RNA polymerase II-specific DNA-binding transcription factor binding activity; mitogen-activated protein kinase kinase binding activity; and protein kinase inhibitor activity. Involved in several processes, including JNK cascade; negative regulation of lipopolysaccharide-mediated signaling pathway; and regulation of protein kinase activity. Located in cytoplasm and nucleus.

Source: NCBI Gene 10221 — RefSeq curated summary.

At a glance

• GWAS associations: 220
• Clinical variants (ClinVar): 44 total
• Druggable target: yes
• MANE Select transcript: NM_025195

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16891
Approved symbol	TRIB1
Name	tribbles pseudokinase 1
Location	8q24.13
Locus type	gene with protein product
Status	Approved
Aliases	C8FW, GIG2, TRB1
Ensembl gene	ENSG00000173334
Ensembl biotype	protein_coding
OMIM	609461
Entrez	10221

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000311922, ENST00000519576, ENST00000520847, ENST00000521778

RefSeq mRNA: 2 — MANE Select: NM_025195 NM_001282985, NM_025195

CCDS: CCDS6357, CCDS64971

Canonical transcript exons

ENST00000311922 — 3 exons

Exon	Start	End
ENSE00001236574	125430358	125431262
ENSE00001303838	125436006	125438403
ENSE00003610439	125433317	125433609

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 67.6075 / max 2781.1658, expressed in 1801 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
90573	63.5836	1797
90574	2.1744	861
90584	0.3985	179
90583	0.3471	145
90585	0.3183	124
90575	0.2668	125
90582	0.2642	98
90576	0.1533	58
90581	0.1013	43

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of urinary bladder	UBERON:0001259	99.02	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.57	gold quality
visceral pleura	UBERON:0002401	97.50	gold quality
gall bladder	UBERON:0002110	97.20	gold quality
cervix squamous epithelium	UBERON:0006922	97.15	gold quality
cauda epididymis	UBERON:0004360	96.84	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.84	gold quality
parotid gland	UBERON:0001831	96.69	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.69	gold quality
pleura	UBERON:0000977	96.63	gold quality
nephron tubule	UBERON:0001231	96.48	gold quality
thyroid gland	UBERON:0002046	96.47	gold quality
left lobe of thyroid gland	UBERON:0001120	96.35	gold quality
mammary duct	UBERON:0001765	96.35	gold quality
bone marrow cell	CL:0002092	96.33	gold quality
right lobe of thyroid gland	UBERON:0001119	96.33	gold quality
lower lobe of lung	UBERON:0008949	96.32	gold quality
epithelium of mammary gland	UBERON:0003244	96.29	gold quality
parietal pleura	UBERON:0002400	96.25	gold quality
biceps brachii	UBERON:0001507	96.16	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.08	gold quality
colonic mucosa	UBERON:0000317	95.92	gold quality
esophagus squamous epithelium	UBERON:0006920	95.72	gold quality
bone marrow	UBERON:0002371	95.54	gold quality
epithelium of nasopharynx	UBERON:0001951	95.51	gold quality
rectum	UBERON:0001052	95.37	gold quality
pigmented layer of retina	UBERON:0001782	95.20	gold quality
upper leg skin	UBERON:0004262	95.18	gold quality
cartilage tissue	UBERON:0002418	95.17	gold quality
caput epididymis	UBERON:0004358	94.99	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	178.31
E-MTAB-9467	yes	53.41
E-HCAD-4	yes	44.85
E-CURD-122	yes	38.66
E-MTAB-9543	yes	12.75
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB, RARA

miRNA regulators (miRDB)

117 targeting TRIB1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-3919	99.87	69.45	2489

Literature-anchored findings (GeneRIF, showing 40)

• Tribbles controls both the extent and the specificity of MAPK kinase activation of MAPK (PMID:15299019)
• used chemical shift perturbation experiments to show the possible SKIP binding interface on PPIL1 (PMID:16595688)
• trb-1 has an important role in vascular smooth muscle cell biology (PMID:17452330)
• Data show that SNPs associated with TG in normolipidemic samples, including APOA5, TRIB1, TBL2, GCKR, GALNT2 and ANGPTL3 were significantly associated with HLP types 2B, 3, 4 and 5. (PMID:19656773)
• low trb-1 expression was associated with inactive C/EBPalpha (PMID:20005259)
• Trib1 may be a key mediator between the RTK-MAPK pathway and the C/EBP transcription factor in myeloid leukemogenesis. (PMID:20610816)
• genetic association studies in Spain: A TRIB1 SNP (rs17321515) is associated with familial hypercholesterolemia. Smoking status and presence of arcus cornealis modulate effect of this TRIB1 SNP on plasma lipid levels in such patients. (PMID:20692138)
• Tribbles homolog 1 (Trib1) functions as a negative regulator of retinoic acid receptors. (PMID:21053424)
• TRIB1 polymorphisms were associated with increased risk of ischemic heart disease and myocardial infarction. (PMID:21071687)
• Data show no differences in triglyceride or total cholesterol levels in relation to any allelic variants of ANGPTL3, CILP2, or TRIB1 SNPs. (PMID:21691831)
• The associations of TRIB1 rs17321515 SNP and serum lipid levels are different between the Mulao and Han populations. (PMID:22145581)
• Studies indicate tribbles 1 and tribbles 3 as regulators of lipid level and disease susceptibility genes in metabolic syndrome and type 2 diabetes. (PMID:22274752)
• TRIB1 R107L gain-of-function mutation is associated with acute megakaryocytic leukemia. (PMID:22294728)
• Studies indicate that three loci for lipid levels identified by GWAS has identified functional genes GALNT2, TRIB1, and SORT1, and a functional variant at SORT1. (PMID:22418572)
• Allelic variants of TRIB1 are independently involved in regulation of lipid metabolism and sleep. (PMID:22832862)
• tribbles-1 is a novel binding partner of Foxp3 in regulatory T cells (PMID:23417677)
• We discuss the role of Tribs as central signaling mediators in different subtypes of acute leukemia and propose that inhibition of dysregulated Trib signaling may be therapeutically beneficial. (PMID:23550039)
• Trib1 acts as an activator of the MAPK pathway. (PMID:24161842)
• High TRIB1 expression is associated with prostate cancer. (PMID:24382668)
• These data suggested that the modulation of TRIB1 expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions. (PMID:24389359)
• genetic association studies in Japan: Data suggest SNPs in TRIB1 (rs2954021), GCKR (glucokinase regulatory protein, rs780094), and PNPLA3 (patatin-like phospholipase domain containing 3, rs738409) are associated with nonalcoholic fatty liver disease. (PMID:24785259)
• association with plasma triglyceride concentrations (PMID:24895164)
• The TRIB1 rs2954029 is associated with serum triglyceride concentrations in Japanese community-dwelling women. (PMID:24910200)
• trait-specific genetic risk scores are robustly associated with 10-yr changes in lipid levels and three individual SNPs in APOE, TRIB1, and APOA1 were strongly associated with 10-yr changes in lipid levels (PMID:24922540)
• TRIB1 was related to endoplasmic reticulum (ER) pathways. (PMID:24962028)
• our study indicated that the TRIB1 gene, especially the rs2980879 polymorphism, is related to the development of pancreatic cancer in the Chinese Han population. (PMID:25117373)
• TRB1 negatively regulates tumor-suppressor activity of p53 through p53 deacetylation (PMID:25832642)
• These studies indicated that SAP18 expression enhanced the recruitment of mSin3A in coordination with TRIB1 to MTTP regulatory elements and increased MTTP expression. (PMID:25921304)
• SNP rs17321515 associated with plasma triglycerides level and increasing risk of coronary heart disease in male Chinese Han population (PMID:25986010)
• Studies indicate that tribbles homolog 1 (Drosophila) protein appear to be involved in some of the most common diseases, such as cancer, metabolic disease and hyperlipidaemia. (PMID:26517921)
• Studies suggest that pseudo-kinase family of tribbles (TRIB) proteins TRIB1, TRIB2 and TRIB3 play roles in pathogenesis of rheumatoid arthritis (RA) and osteoarthritis. (PMID:26517922)
• Studies indicate that the minor allele of a single nucleotide polymorphism (SNP, rs6982502) in the regulatory sequence reduces the activity of the tribbles homolog 1 (Drosophila) protein (TRIB1) promoter. (PMID:26517924)
• Studies suggest that pseudo-kinase family of tribbles (TRIB) proteins TRIB1, TRIB2 and TRIB3 were involved in the pathogenesis of inflammation. (PMID:26517925)
• Studies indicate that tribbles homolog 1 (Drosophila) protein (TRIB1) interacts with the master molecule of Tregs, forkhead box P3 (FOXP3), a transcription factor essential for Treg suppressive activity. (PMID:26517926)
• Studies indicate that tribbles homolog 1 (Drosophila) protein (tribbles-1; TRIB1) is an important modulator of human energy metabolism and metabolic syndromes. (PMID:26517927)
• Studies indicate that small molecules can reveal rate-limiting signalling outputs and functions of pseudo-kinase family of tribbles (TRIB) proteins TRIB1, TRIB2 and TRIB3 in cells and intact organisms, serving as guides for the development of new drugs. (PMID:26517930)
• Studies indicate that overexpression of the wild-type tribbles homolog 1 (Drosophila) protein (Trib1) gene effectively induces leukaemia. (PMID:26517931)
• Studies show that TRIB1 and TRIB2 are highly expressed in molecularly-defined sub-types of acute myeloid leukemia (AML). (PMID:26517933)
• Studies show a remarkable reduction in tribbles 2 protein (Trib2) expression during oocyte maturation whereas tribbles 1 protein (Trib1) and tribbles 3 protein (Trib3) expression was significantly increased during this process. (PMID:26517934)
• Trib1 formed a complex with pHDAC1. (PMID:26521947)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	trib1	ENSDARG00000110963
mus_musculus	Trib1	ENSMUSG00000032501
rattus_norvegicus	Trib1	ENSRNOG00000004100
drosophila_melanogaster	trbl	FBGN0028978

Paralogs (3): TRIB2 (ENSG00000071575), TRIB3 (ENSG00000101255), STK40 (ENSG00000196182)

Protein

Protein identifiers

Tribbles homolog 1 — Q96RU8 (reviewed: Q96RU8)

Alternative names: G-protein-coupled receptor-induced gene 2 protein, SKIP1

All UniProt accessions (2): E5RFH4, Q96RU8

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein involved in protein degradation by interacting with COP1 ubiquitin ligase. The COP1-binding motif is masked by autoinhibitory interactions with the protein kinase domain. Serves to alter COP1 substrate specificity by directing the activity of COP1 toward CEBPA. Binds selectively the recognition sequence of CEBPA. Regulates myeloid cell differentiation by altering the expression of CEBPA in a COP1-dependent manner. Controls macrophage, eosinophil and neutrophil differentiation via the COP1-binding domain. Interacts with MAPK kinases and regulates activation of MAP kinases, but has no kinase activity.

Subunit / interactions. Monomer. Interacts (via protein kinase domain) with CEBPA. Interacts with COP1.

Tissue specificity. Expressed in most human tissues with the highest levels in skeletal muscle, thyroid gland, pancreas, peripheral blood leukocytes, and bone marrow.

Domain organisation. The protein kinase active site is incompatible with ATP binding and is inactive. The C-terminus (351-372) is required for interaction with COP1. The COP1-binding motif (355-360) is required for regulation activity.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. Tribbles subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96RU8-1	1	yes
Q96RU8-2	2

RefSeq proteins (2): NP_001269914, NP_079471* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR024104	Tribbles/Ser_Thr_kinase_40	Family
IPR024105	TRB1_pseudokinase_dom	Domain

Pfam: PF00069

UniProt features (50 total): helix 13, strand 12, sequence variant 7, mutagenesis site 7, region of interest 2, sequence conflict 2, turn 2, chain 1, domain 1, short sequence motif 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5IGO	X-RAY DIFFRACTION	1.6
5CEM	X-RAY DIFFRACTION	2.1
5CEK	X-RAY DIFFRACTION	2.8
6DC0	X-RAY DIFFRACTION	2.8
5IGQ	X-RAY DIFFRACTION	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RU8-F1	78.38	0.61

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (7):

Position	Phenotype
355	decreased interaction with cop1.
356	decreased interaction with cop1.
357	decreased interaction with cop1.
358	loss of interaction with cop1.
359	strongly decreased interaction with cop1.
360	decreased interaction with cop1.
361	no effect on interaction with cop1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9031628	NGF-stimulated transcription

MSigDB gene sets: 592 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, RNGTGGGC_UNKNOWN, AP1_01, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, HNF3ALPHA_Q6, MCLACHLAN_DENTAL_CARIES_UP, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, BOYAULT_LIVER_CANCER_SUBCLASS_G56_DN, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_CELLULAR_RESPONSE_TO_LIPID

GO Biological Process (14): negative regulation of transcription by RNA polymerase II (GO:0000122), negative regulation of smooth muscle cell migration (GO:0014912), negative regulation of lipopolysaccharide-mediated signaling pathway (GO:0031665), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), response to lipopolysaccharide (GO:0032496), regulation of MAP kinase activity (GO:0043405), negative regulation of MAPK cascade (GO:0043409), positive regulation of eosinophil differentiation (GO:0045645), positive regulation of macrophage differentiation (GO:0045651), negative regulation of neutrophil differentiation (GO:0045659), negative regulation of JNK cascade (GO:0046329), negative regulation of smooth muscle cell proliferation (GO:0048662), protein phosphorylation (GO:0006468), regulation of protein modification process (GO:0031399)

GO Molecular Function (12): protein kinase inhibitor activity (GO:0004860), protein kinase binding (GO:0019901), mitogen-activated protein kinase kinase binding (GO:0031434), ubiquitin protein ligase binding (GO:0031625), ubiquitin-protein transferase regulator activity (GO:0055106), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), transcription regulator inhibitor activity (GO:0140416), protein kinase activity (GO:0004672), protein binding (GO:0005515), ATP binding (GO:0005524), enzyme binding (GO:0019899), enzyme regulator activity (GO:0030234)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nuclear Events (kinase and transcription factor activation)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification process	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
smooth muscle cell migration	1
regulation of smooth muscle cell migration	1
negative regulation of cell migration	1
negative regulation of response to biotic stimulus	1
negative regulation of signal transduction	1
lipopolysaccharide-mediated signaling pathway	1
regulation of lipopolysaccharide-mediated signaling pathway	1
negative regulation of response to external stimulus	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
MAP kinase activity	1
regulation of protein serine/threonine kinase activity	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
eosinophil differentiation	1
positive regulation of granulocyte differentiation	1
regulation of eosinophil differentiation	1
positive regulation of myeloid leukocyte differentiation	1
macrophage differentiation	1
regulation of macrophage differentiation	1
neutrophil differentiation	1
negative regulation of granulocyte differentiation	1
regulation of neutrophil differentiation	1
JNK cascade	1
negative regulation of MAPK cascade	1
regulation of JNK cascade	1
negative regulation of cell population proliferation	1
smooth muscle cell proliferation	1
regulation of smooth muscle cell proliferation	1

Protein interactions and networks

STRING

2193 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIB1	MAP2K1	Q02750	951
TRIB1	RIBC2	Q9H4K1	930
TRIB1	CEBPA	P49715	823
TRIB1	ANGPTL3	Q9Y5C1	703
TRIB1	APOB	P04114	651
TRIB1	GALNT2	Q10471	620
TRIB1	APOA5	Q6Q788	612
TRIB1	CILP2	Q8IUL8	580
TRIB1	MLXIPL	Q9NP71	555
TRIB1	CEBPB	P17676	549
TRIB1	PPP1R3B	Q86XI6	540
TRIB1	MMAB	Q96EY8	528
TRIB1	FOSB	P53539	526
TRIB1	SORT1	Q99523	517
TRIB1	LIPC	P11150	510

IntAct

59 interactions, top by confidence:

A	B	Type	Score
FOSL2	JUN	psi-mi:“MI:0914”(association)	0.930
STK40	TRIB1	psi-mi:“MI:0915”(physical association)	0.740
FOSB	JUN	psi-mi:“MI:0914”(association)	0.690
TRIB1	DET1	psi-mi:“MI:0914”(association)	0.640
TRIB2	POTEF	psi-mi:“MI:0914”(association)	0.530
FOSL2	ZZEF1	psi-mi:“MI:0914”(association)	0.530
TRIB1	UBE2E1	psi-mi:“MI:0914”(association)	0.530
STK40	COP1	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
COP1	ETS2	psi-mi:“MI:0914”(association)	0.460
MAP2K1	TRIB1	psi-mi:“MI:0915”(physical association)	0.400
TRIB1	MAP2K4	psi-mi:“MI:0915”(physical association)	0.400
ALOX12	TRIB1	psi-mi:“MI:0915”(physical association)	0.370
CEBPB	TRIB1	psi-mi:“MI:0915”(physical association)	0.370
TRIB1	CEBPB	psi-mi:“MI:0915”(physical association)	0.370
HNRNPA1L2	STX18	psi-mi:“MI:0914”(association)	0.350
SLAIN2	TACC2	psi-mi:“MI:0914”(association)	0.350
MORC3	RDH10	psi-mi:“MI:0914”(association)	0.350
PCDH1	DBI	psi-mi:“MI:0914”(association)	0.350
LLGL1	ALDH1B1	psi-mi:“MI:0914”(association)	0.350
RASSF8	TCOF1	psi-mi:“MI:0914”(association)	0.350
STK17B	REV3L	psi-mi:“MI:0914”(association)	0.350
BECN1	TCOF1	psi-mi:“MI:0914”(association)	0.350
FOS	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
JUNB	PPP1R12A	psi-mi:“MI:0914”(association)	0.350

BioGRID (74): STK40 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), TRIB1 (Affinity Capture-MS), RFWD2 (Affinity Capture-Western), TRIB1 (Protein-peptide), TRIB1 (Co-crystal Structure)

ESM2 similar proteins: A0AUV4, A1A5Q6, A1A5R7, A2KF29, B1WAS2, C0HKC8, C0HKC9, O60285, O74536, O88831, O88866, P35125, P51956, P57058, Q20443, Q28283, Q2T9U5, Q4R9F7, Q5GLH2, Q5R669, Q5R7G9, Q5XHI9, Q66HE5, Q68UT7, Q6P431, Q6VZ17, Q7TNJ7, Q7TNL4, Q8BHI9, Q8BZN4, Q8C078, Q8C0N0, Q8C0V7, Q8C0X8, Q8K4K4, Q8NE63, Q8WP28, Q91VB2, Q92519, Q96L34

Diamond homologs: A7E3X2, A8BPK8, A8X0C4, B0WAU8, D2I3C6, D4AE59, O75914, O80902, O88643, P18431, P35465, P35509, P36003, P36005, P39745, P40417, P62345, Q08E52, Q10452, Q13153, Q15772, Q15831, Q17850, Q21017, Q28283, Q39027, Q39193, Q40517, Q40884, Q4R9A9, Q54C77, Q54DF2, Q54LR6, Q54MV2, Q54PX0, Q54QB1, Q54VV7, Q54XQ2, Q55GS4, Q5GLH2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 58 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by Interleukins	6	10.1×	4e-03
Diseases of signal transduction by growth factor receptors and second messengers	6	9.0×	6e-03
Cytokine Signaling in Immune system	8	8.6×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
integrated stress response signaling	5	63.8×	8e-06
cellular response to epidermal growth factor stimulus	6	34.7×	8e-06
positive regulation of miRNA transcription	6	31.7×	9e-06
cellular response to calcium ion	5	18.2×	1e-03
positive regulation of ERK1 and ERK2 cascade	7	10.8×	7e-04
response to xenobiotic stimulus	7	8.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

44 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

316 predictions. Top by Δscore:

Variant	Effect	Δscore
8:125431259:CAAGG:C	donor_loss	1.0000
8:125431261:AGG:A	donor_loss	1.0000
8:125431262:GGT:G	donor_loss	1.0000
8:125431263:G:C	donor_loss	1.0000
8:125431264:T:A	donor_loss	1.0000
8:125433312:TACA:T	acceptor_loss	1.0000
8:125433314:CA:C	acceptor_loss	1.0000
8:125433315:A:AC	acceptor_loss	1.0000
8:125433315:A:AG	acceptor_gain	1.0000
8:125433315:AG:A	acceptor_gain	1.0000
8:125433316:G:GC	acceptor_loss	1.0000
8:125433316:G:GG	acceptor_gain	1.0000
8:125433316:GG:G	acceptor_gain	1.0000
8:125433316:GGT:G	acceptor_gain	1.0000
8:125433316:GGTGT:G	acceptor_gain	1.0000
8:125433583:G:GT	donor_gain	1.0000
8:125433607:GAG:G	donor_gain	1.0000
8:125433607:GAGGT:G	donor_loss	1.0000
8:125436002:GCAG:G	acceptor_loss	1.0000
8:125436003:CAGA:C	acceptor_loss	1.0000
8:125436004:A:AC	acceptor_loss	1.0000
8:125436004:A:AG	acceptor_gain	1.0000
8:125436005:G:GC	acceptor_gain	1.0000
8:125436005:GA:G	acceptor_gain	1.0000
8:125436005:GAA:G	acceptor_gain	1.0000
8:125436005:GAACC:G	acceptor_gain	1.0000
8:125431258:GCAAG:G	donor_gain	0.9900
8:125431263:G:GG	donor_gain	0.9900
8:125432130:T:G	donor_gain	0.9900
8:125433313:A:AG	acceptor_gain	0.9900

AlphaMissense

2401 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:125433544:C:G	C196W	1.000
8:125433575:A:G	K207E	1.000
8:125433577:G:C	K207N	1.000
8:125433577:G:T	K207N	1.000
8:125433594:T:C	F213S	1.000
8:125436085:T:C	C245R	1.000
8:125436094:T:C	Y248H	1.000
8:125436100:A:C	S250R	1.000
8:125436102:C:A	S250R	1.000
8:125436102:C:G	S250R	1.000
8:125436104:C:A	P251H	1.000
8:125436113:T:A	L254H	1.000
8:125436154:T:A	W268R	1.000
8:125436154:T:C	W268R	1.000
8:125436156:G:C	W268C	1.000
8:125436156:G:T	W268C	1.000
8:125436163:G:A	G271R	1.000
8:125436163:G:C	G271R	1.000
8:125436163:G:T	G271W	1.000
8:125436164:G:A	G271E	1.000
8:125436164:G:T	G271V	1.000
8:125436196:T:C	Y282H	1.000
8:125436199:C:T	P283S	1.000
8:125436200:C:A	P283H	1.000
8:125436202:T:A	F284I	1.000
8:125436202:T:C	F284L	1.000
8:125436203:T:C	F284S	1.000
8:125436204:C:A	F284L	1.000
8:125436204:C:G	F284L	1.000
8:125436239:T:C	I296T	1.000

dbSNP variants (sampled 300 via entrez): RS1000292679 (8:125431794 A>G), RS1000830202 (8:125431454 G>A), RS1000882327 (8:125431710 G>A), RS1001007333 (8:125437394 A>G), RS1001459755 (8:125437758 A>G), RS1001523284 (8:125438451 A>G), RS1001654251 (8:125432397 C>G), RS1001704480 (8:125432561 A>G), RS1001989436 (8:125431108 C>T), RS1002046869 (8:125437658 G>T), RS1002066041 (8:125431049 C>T), RS1002076370 (8:125437372 G>A,C), RS1002178794 (8:125436986 A>G), RS1002274200 (8:125430852 C>T), RS1002559560 (8:125435829 T>A)

Disease associations

OMIM: gene MIM:609461 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

220 associations (top):

Study	Trait	p-value
GCST000138_2	Triglycerides	4.000000e-17
GCST000139_4	Triglycerides	7.000000e-13
GCST000282_7	LDL cholesterol	3.000000e-06
GCST000285_15	Cholesterol, total	3.000000e-09
GCST000286_3	Triglycerides	3.000000e-19
GCST000533_22	Lipid metabolism phenotypes	7.000000e-12
GCST000533_23	Lipid metabolism phenotypes	1.000000e-09
GCST000584_5	Triglycerides	3.000000e-07
GCST000635_6	Response to statin therapy	7.000000e-06
GCST000755_3	HDL cholesterol	6.000000e-19
GCST000758_22	Triglycerides	3.000000e-55
GCST000759_29	LDL cholesterol	3.000000e-29
GCST000760_9	Cholesterol, total	5.000000e-36
GCST000807_6	LDL cholesterol	1.000000e-07
GCST000809_3	Triglycerides	2.000000e-11
GCST001004_3	Triglycerides-Blood Pressure (TG-BP)	9.000000e-09
GCST001005_5	HDL Cholesterol - Triglycerides (HDLC-TG)	8.000000e-09
GCST001275_1	Liver enzyme levels (alanine transaminase)	5.000000e-09
GCST001276_13	Liver enzyme levels (alkaline phosphatase)	2.000000e-13
GCST001463_4	Adiponectin levels	1.000000e-09
GCST001465_11	Adiponectin levels	7.000000e-09
GCST001725_97	Inflammatory bowel disease	8.000000e-20
GCST001762_193	Obesity-related traits	3.000000e-06
GCST002216_7	Triglycerides	1.000000e-107
GCST002221_43	Cholesterol, total	2.000000e-65
GCST002222_2	LDL cholesterol	2.000000e-50
GCST002223_58	HDL cholesterol	3.000000e-29
GCST002321_9	Lipid traits	8.000000e-07
GCST002468_6	Triglycerides	7.000000e-09
GCST002896_8	Cholesterol, total	1.000000e-38

EFO canonical traits (31, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004529	lipid measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0004502	adiponectin measurement
EFO:0005112	gestational age
EFO:0004458	C-reactive protein measurement
EFO:0004318	smoking behavior
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008378	mosquito bite reaction size measurement
EFO:0004344	birth weight
EFO:0009180	rosacea severity measurement
EFO:0005090	basophil count
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004285	albuminuria
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0009767	glycine measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0004329	alcohol drinking
EFO:0010460	anthranilic acid measurement
EFO:0000195	metabolic syndrome
EFO:0006527	smoking status measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004459	ferritin measurement
EFO:0004736	aspartate aminotransferase measurement
EFO:0010821	liver fat measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4524042 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Trbl family

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.00	IC50	1000	nM	TP-030n

CTD chemical–gene interactions

119 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	6
Estradiol	affects binding, decreases expression, increases expression	4
Valproic Acid	affects cotreatment, decreases expression, affects expression	4
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	3
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases expression	3
Tobacco Smoke Pollution	decreases methylation, increases expression	3
Tretinoin	affects expression, increases expression	3
Cyclosporine	increases expression	3
Aflatoxin B1	affects expression, increases expression, increases methylation	3
bisphenol A	affects cotreatment, decreases expression, affects expression	2
Arsenic	affects expression, affects methylation, increases abundance, increases expression	2
Cisplatin	affects cotreatment, decreases expression	2
Formaldehyde	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
methylselenic acid	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
diethyl maleate	increases expression	1
beta-lapachone	increases expression	1
arsenite	decreases methylation	1
afimoxifene	decreases response to substance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
nickel chloride	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4885528	Binding	Trb1(TRI1PARP) Takeda global kinase panel	Data for DCP probe TP-030-1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TT74	HAP1 TRIB1 (-) 1	Cancer cell line	Male
CVCL_TT75	HAP1 TRIB1 (-) 2	Cancer cell line	Male
CVCL_TT76	HAP1 TRIB1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.