TRABD2B

Summary

TRABD2B (TraB domain containing 2B, HGNC:44200) is a protein-coding gene on chromosome 1p33, encoding Metalloprotease TIKI2 (A6NFA1). Metalloprotease that acts as a negative regulator of the Wnt signaling pathway by mediating the cleavage of the 8 N-terminal residues of a subset of Wnt proteins.

Enables Wnt-protein binding activity and metalloendopeptidase activity. Involved in several processes, including negative regulation of Wnt signaling pathway; positive regulation of protein oxidation; and positive regulation of protein-containing complex assembly. Located in nucleoplasm; organelle membrane; and plasma membrane.

Source: NCBI Gene 388630 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 71 total
• MANE Select transcript: NM_001194986

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:44200
Approved symbol	TRABD2B
Name	TraB domain containing 2B
Location	1p33
Locus type	gene with protein product
Status	Approved
Aliases	TIKI2
Ensembl gene	ENSG00000269113
Ensembl biotype	protein_coding
OMIM	614913
Entrez	388630

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000435576, ENST00000606738, ENST00000878671, ENST00000878672, ENST00000878673, ENST00000878674

RefSeq mRNA: 1 — MANE Select: NM_001194986 NM_001194986

CCDS: CCDS58000

Canonical transcript exons

ENST00000606738 — 7 exons

Exon	Start	End
ENSE00001606776	47775170	47775439
ENSE00001656855	47994034	47994597
ENSE00001667318	47794586	47794760
ENSE00002607792	47996688	47997385
ENSE00003668316	47778454	47778544
ENSE00003688282	47801473	47801619
ENSE00003697971	47760528	47766106

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 91.63.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8922 / max 78.8251, expressed in 499 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12244	1.1198	384
12245	0.4445	220
12241	0.1229	73
12242	0.0722	38
12240	0.0564	21
12246	0.0467	24
12243	0.0298	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	91.63	gold quality
tibial artery	UBERON:0007610	91.60	gold quality
right coronary artery	UBERON:0001625	87.85	gold quality
left coronary artery	UBERON:0001626	87.71	gold quality
aorta	UBERON:0000947	87.63	gold quality
coronary artery	UBERON:0001621	85.17	gold quality
ascending aorta	UBERON:0001496	82.97	gold quality
thoracic aorta	UBERON:0001515	82.90	gold quality
descending thoracic aorta	UBERON:0002345	81.06	gold quality
right atrium auricular region	UBERON:0006631	80.81	gold quality
cardiac atrium	UBERON:0002081	78.74	gold quality
adult mammalian kidney	UBERON:0000082	78.43	gold quality
metanephros cortex	UBERON:0010533	74.54	gold quality
sural nerve	UBERON:0015488	74.41	gold quality
right lobe of liver	UBERON:0001114	74.39	gold quality
tibial nerve	UBERON:0001323	73.82	gold quality
lower esophagus muscularis layer	UBERON:0035833	73.81	gold quality
lower esophagus	UBERON:0013473	73.76	gold quality
mucosa of stomach	UBERON:0001199	73.47	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	72.59	gold quality
ectocervix	UBERON:0012249	69.24	gold quality
kidney	UBERON:0002113	69.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.03	gold quality
omental fat pad	UBERON:0010414	68.74	gold quality
cortex of kidney	UBERON:0001225	68.72	gold quality
peritoneum	UBERON:0002358	68.66	gold quality
endocervix	UBERON:0000458	68.60	gold quality
heart	UBERON:0000948	68.49	gold quality
muscle layer of sigmoid colon	UBERON:0035805	68.24	gold quality
left uterine tube	UBERON:0001303	67.77	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

332 targeting TRABD2B, 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-7110-3P	100.00	73.18	2486
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-128-3P	99.95	71.17	2484

Literature-anchored findings (GeneRIF, showing 3)

• provided evidence that reduced expression of TIKI family protein in osteosarcoma may participate in the progression of osteosarcoma and restoring its expression was able to impair the growth of osteosarcoma (PMID:24771064)
• examination of the structural prediction and identification of the active site residues of human TIKI2 (PMID:26631728)
• Results of the present study indicate that TIKI2 is upregulated in renal cell carcinoma tissues and plays an oncogenic role in renal cell carcinoma (PMID:26942462)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Trabd2b	ENSMUSG00000070867
rattus_norvegicus	Trabd2b	ENSRNOG00000029141

Paralogs (1): TRABD2A (ENSG00000186854)

Protein

Protein identifiers

Metalloprotease TIKI2 — A6NFA1 (reviewed: A6NFA1)

Alternative names: Heart, kidney and adipose-enriched transmembrane protein homolog, TRAB domain-containing protein 2B

All UniProt accessions (1): A6NFA1

UniProt curated annotations — full annotation on UniProt →

Function. Metalloprotease that acts as a negative regulator of the Wnt signaling pathway by mediating the cleavage of the 8 N-terminal residues of a subset of Wnt proteins. Following cleavage, Wnt proteins become oxidized and form large disulfide-bond oligomers, leading to their inactivation. Able to cleave WNT3A, WNT5, but not WNT11. Required for head formation.

Subcellular location. Cell membrane.

Activity regulation. Inhibited by 1,10-phenanthroline, a metalloprotease inhibitor which is a divalent metal chelator. Also inhibited by EDTA. Not inhibited by Bestatin, an aminopeptidase inhibitor, nor to a mixture of inhibitors for serine, cysteine, and aspartic proteases and aminopeptidases.

Cofactor. Divalent metal cations. Mn(2+) or Co(2+).

Miscellaneous. Was named TIKI in reference to large-headed humanoid in Polynesian mythology.

Similarity. Belongs to the TIKI family.

RefSeq proteins (1): NP_001181915* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002816	TraB/PrgY/GumN_fam	Family
IPR040230	TIKI1/2-like	Family

Pfam: PF01963

UniProt features (13 total): compositionally biased region 3, region of interest 3, glycosylation site 2, topological domain 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NFA1-F1	70.11	0.38

Functional residue map

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

Glycosylation sites (2): 228, 335

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 122 (showing top): GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, HOOI_ST7_TARGETS_DN, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR, GOBP_NEGATIVE_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_PROTEOLYSIS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_G_UP, GOMF_WNT_PROTEIN_BINDING, GOMF_PEPTIDASE_ACTIVITY, GSE13522_CTRL_VS_T_CRUZI_BRAZIL_STRAIN_INF_SKIN_DN, ZNF561_TARGET_GENES

GO Biological Process (4): proteolysis (GO:0006508), Wnt signaling pathway (GO:0016055), negative regulation of Wnt signaling pathway (GO:0030178), positive regulation of protein-containing complex assembly (GO:0031334)

GO Molecular Function (8): metalloendopeptidase activity (GO:0004222), Wnt-protein binding (GO:0017147), metal ion binding (GO:0046872), endopeptidase activity (GO:0004175), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleoplasm (GO:0005654), plasma membrane (GO:0005886), organelle membrane (GO:0031090), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	2
cellular anatomical structure	2
membrane	2
protein metabolic process	1
cell surface receptor signaling pathway	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
regulation of protein-containing complex assembly	1
positive regulation of cellular component biogenesis	1
positive regulation of cellular component organization	1
protein-containing complex assembly	1
endopeptidase activity	1
metallopeptidase activity	1
protein binding	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
nuclear lumen	1
cell periphery	1
membrane-bounded organelle	1

Protein interactions and networks

STRING

236 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRABD2B	AADAT	Q8N5Z0	660
TRABD2B	KYAT1	Q16773	583
TRABD2B	SLC5A9	Q2M3M2	460
TRABD2B	SLITRK6	Q9H5Y7	443
TRABD2B	SHISA3	A0PJX4	418
TRABD2B	KYAT3	Q6YP21	403
TRABD2B	NUS1	Q96E22	396
TRABD2B	TRABD	Q9H4I3	385
TRABD2B	UPK1B	O75841	383
TRABD2B	TCTA	P57738	371
TRABD2B	CFAP298	P57076	370
TRABD2B	OR52A5	Q9H2C5	370
TRABD2B	SESTD1	Q86VW0	369
TRABD2B	EDA2R	Q9HAV5	321
TRABD2B	NOTUM	Q6P988	315

IntAct

17 interactions, top by confidence:

A	B	Type	Score
TRABD2B	Wnt3a	psi-mi:“MI:0570”(protein cleavage)	0.540
TRABD2B	Wnt3a	psi-mi:“MI:0915”(physical association)	0.540
TRABD2B	WNT3A	psi-mi:“MI:0194”(cleavage reaction)	0.520
TRABD2B	WNT5A	psi-mi:“MI:0194”(cleavage reaction)	0.520
FZD7	TRABD2B	psi-mi:“MI:0194”(cleavage reaction)	0.520
FZD7	TRABD2B	psi-mi:“MI:0914”(association)	0.520
TRABD2B	FZD7	psi-mi:“MI:0914”(association)	0.520
FZD5	TRABD2B	psi-mi:“MI:0403”(colocalization)	0.430
FZD5	TRABD2B	psi-mi:“MI:0914”(association)	0.430
TRABD2B	wnt8	psi-mi:“MI:0915”(physical association)	0.400
Wnt5a	TRABD2B	psi-mi:“MI:0915”(physical association)	0.400
TRABD2B	wnt11b	psi-mi:“MI:0915”(physical association)	0.400
TRABD2B	CD99L2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (3): TRABD2B (Proximity Label-MS), TRABD2B (Proximity Label-MS), TRABD2B (Co-fractionation)

ESM2 similar proteins: A2RRU4, A4Q9F3, A6NFA1, A6QM06, B1ATG9, D4A6L0, E1BBQ2, E7F4V6, E7F6V0, E9Q6C8, F1LQY6, F6PTN1, O02695, O09010, O35245, P0DJQ9, P56726, P97260, P97698, Q12770, Q13563, Q3TMX7, Q58CS8, Q5BK01, Q5GH57, Q5JXM2, Q5MNU5, Q5QQ49, Q5QQ50, Q5QQ51, Q5T848, Q6GQT6, Q6NW40, Q6ZRP7, Q7TQ33, Q86V40, Q8C419, Q8CCB5, Q8IZP7, Q8TCT7

Diamond homologs: A6NFA1, A7RX69, B1ATG9, E7F4V6, E7F6V0, F6PTN1, I1FQB6, P0DJQ9, Q17678, Q86V40

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3114 predictions. Top by Δscore:

Variant	Effect	Δscore
1:47778448:GCTTA:G	donor_loss	1.0000
1:47778449:CTTA:C	donor_loss	1.0000
1:47778450:TTAC:T	donor_loss	1.0000
1:47778451:TACCT:T	donor_loss	1.0000
1:47778452:A:C	donor_loss	1.0000
1:47778453:C:CA	donor_loss	1.0000
1:47794662:ATT:A	donor_gain	1.0000
1:47801467:CCTCA:C	donor_loss	1.0000
1:47801468:CTCA:C	donor_loss	1.0000
1:47801469:TCA:T	donor_loss	1.0000
1:47801470:CA:C	donor_loss	1.0000
1:47801471:ACCT:A	donor_loss	1.0000
1:47801472:C:CT	donor_loss	1.0000
1:47801626:C:CT	acceptor_gain	1.0000
1:47801627:G:T	acceptor_gain	1.0000
1:47994030:CTACC:C	donor_loss	1.0000
1:47994031:TA:T	donor_loss	1.0000
1:47994032:A:AT	donor_loss	1.0000
1:47994593:CTCTG:C	acceptor_gain	1.0000
1:47994595:CTG:C	acceptor_gain	1.0000
1:47994596:TG:T	acceptor_gain	1.0000
1:47778452:A:AC	donor_gain	0.9900
1:47778453:C:CC	donor_gain	0.9900
1:47778540:GTGAC:G	acceptor_gain	0.9900
1:47778541:TGAC:T	acceptor_gain	0.9900
1:47778542:GAC:G	acceptor_gain	0.9900
1:47778545:C:CC	acceptor_gain	0.9900
1:47778545:CTGGA:C	acceptor_loss	0.9900
1:47778546:T:G	acceptor_loss	0.9900
1:47794580:CCAAA:C	donor_loss	0.9900

AlphaMissense

3374 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:47778520:A:T	V338D	0.999
1:47794597:G:T	A326D	0.999
1:47794662:A:C	N304K	0.999
1:47794662:A:T	N304K	0.999
1:47794663:T:A	N304I	0.999
1:47794666:C:A	R303M	0.999
1:47801606:A:G	L227P	0.999
1:47994120:C:G	A194P	0.999
1:47994226:C:A	W158C	0.999
1:47994226:C:G	W158C	0.999
1:47994228:A:G	W158R	0.999
1:47994228:A:T	W158R	0.999
1:47994295:C:A	W135C	0.999
1:47994295:C:G	W135C	0.999
1:47994443:A:G	L86P	0.999
1:47994445:C:A	E85D	0.999
1:47994445:C:G	E85D	0.999
1:47994505:C:A	W65C	0.999
1:47994505:C:G	W65C	0.999
1:47994528:G:C	H58D	0.999
1:47794664:T:A	N304Y	0.998
1:47794665:C:A	R303S	0.998
1:47794665:C:G	R303S	0.998
1:47794678:A:G	L299P	0.998
1:47801594:A:G	L231P	0.998
1:47994068:C:G	C211S	0.998
1:47994069:A:G	C211R	0.998
1:47994069:A:T	C211S	0.998
1:47994131:A:G	L190P	0.998
1:47994140:T:A	D187V	0.998

dbSNP variants (sampled 300 via entrez): RS1000051836 (1:47812588 A>C), RS1000059633 (1:47908944 G>A), RS1000070687 (1:47771824 T>C), RS1000077716 (1:47827298 G>A), RS1000099261 (1:47851863 C>A,T), RS1000113728 (1:47984330 A>C), RS1000115362 (1:47867560 G>C), RS1000118779 (1:47787567 A>G), RS1000126100 (1:47771625 C>G,T), RS1000129694 (1:47827668 G>A,C), RS1000157267 (1:47771832 T>G), RS1000166054 (1:47811763 G>C), RS1000184955 (1:47850614 C>T), RS1000197412 (1:47961460 C>T), RS1000256748 (1:47971608 C>T)

Disease associations

OMIM: gene MIM:614913 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST004860_121	Alcoholic chronic pancreatitis	8.000000e-06
GCST006463_1	Urinary albumin excretion (no hypertensive medication)	3.000000e-13
GCST006586_43	Urinary albumin excretion	1.000000e-19
GCST006979_976	Heel bone mineral density	2.000000e-09
GCST007021_5	Type 2 diabetes nephropathy	3.000000e-06
GCST008529_40	Tea consumption	2.000000e-07
GCST010002_358	Refractive error	3.000000e-10
GCST011387_1	Vaginal microbiome composition (L. iners)	7.000000e-07
GCST011826_6	Computer vision syndrome	2.000000e-07
GCST012017_6	Mastocytosis (KIT D816V positive)	2.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004285	albuminuria
EFO:0009270	heel bone mineral density
EFO:0010091	tea consumption measurement
EFO:0011013	vaginal microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
ormosil	affects binding, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
DEET	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Polyethylene Glycols	affects binding, increases expression	1
Rotenone	increases expression	1
Silicon Dioxide	increases expression	1
Triclosan	decreases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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