FRAT2

Summary

FRAT2 (FRAT regulator of Wnt signaling pathway 2, HGNC:16048) is a protein-coding gene on chromosome 10q24.1, encoding GSK-3-binding protein FRAT2 (O75474). Positively regulates the Wnt signaling pathway by stabilizing beta-catenin through the association with GSK-3.

The protein encoded by this intronless gene belongs to the GSK-3-binding protein family. Studies show that this protein plays a role as a positive regulator of the WNT signaling pathway. It may be upregulated in tumor progression.

Source: NCBI Gene 23401 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 42 total
• MANE Select transcript: NM_012083

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16048
Approved symbol	FRAT2
Name	FRAT regulator of Wnt signaling pathway 2
Location	10q24.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000181274
Ensembl biotype	protein_coding
OMIM	605006
Entrez	23401

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000371019

RefSeq mRNA: 1 — MANE Select: NM_012083 NM_012083

CCDS: CCDS7456

Canonical transcript exons

ENST00000371019 — 1 exons

Exon	Start	End
ENSE00001454131	97332497	97334729

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 96.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.9508 / max 907.3634, expressed in 1716 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110925	11.6016	1604
110924	3.3492	918

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	96.93	gold quality
monocyte	CL:0000576	95.35	gold quality
leukocyte	CL:0000738	95.26	gold quality
granulocyte	CL:0000094	95.25	gold quality
mononuclear cell	CL:0000842	95.13	gold quality
secondary oocyte	CL:0000655	94.39	gold quality
oocyte	CL:0000023	91.00	gold quality
mucosa of transverse colon	UBERON:0004991	90.90	gold quality
bone marrow	UBERON:0002371	90.10	gold quality
trabecular bone tissue	UBERON:0002483	88.97	gold quality
jejunal mucosa	UBERON:0000399	88.68	gold quality
duodenum	UBERON:0002114	88.24	gold quality
palpebral conjunctiva	UBERON:0001812	88.10	gold quality
esophagus squamous epithelium	UBERON:0006920	86.62	gold quality
bone marrow cell	CL:0002092	85.88	gold quality
spleen	UBERON:0002106	85.65	gold quality
rectum	UBERON:0001052	84.65	gold quality
colonic mucosa	UBERON:0000317	84.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.34	gold quality
epithelium of esophagus	UBERON:0001976	83.94	silver quality
endometrium epithelium	UBERON:0004811	83.87	silver quality
mucosa of sigmoid colon	UBERON:0004993	83.80	gold quality
skin of leg	UBERON:0001511	83.47	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.28	gold quality
transverse colon	UBERON:0001157	83.14	gold quality
skin of abdomen	UBERON:0001416	83.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	83.03	silver quality
upper leg skin	UBERON:0004262	82.49	gold quality
right lobe of liver	UBERON:0001114	82.31	gold quality
zone of skin	UBERON:0000014	82.07	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	7.38
E-ANND-3	yes	3.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

66 targeting FRAT2, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-150-5P	99.99	66.69	1976
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-22-3P	99.93	68.13	917
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-4251	99.40	69.19	3363

Literature-anchored findings (GeneRIF, showing 3)

• FRAT-2 enhances glycogen synthase kinase 3 beta-mediated phosphorylation of a primed substrate to a greater extent than an unprimed substrate (PMID:15522877)
• It suggests that activation of GSK-3 inhibits PP-2A through up-regulation of I(2)(PP-2A) with hnRNP A18-involved mechanism. (PMID:17433504)
• The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells. (PMID:36153370)

Cross-species orthologs

0 orthologs

Paralogs (1): FRAT1 (ENSG00000165879)

Protein

Protein identifiers

GSK-3-binding protein FRAT2 — O75474 (reviewed: O75474)

Alternative names: Frequently rearranged in advanced T-cell lymphomas 2

All UniProt accessions (1): O75474

UniProt curated annotations — full annotation on UniProt →

Function. Positively regulates the Wnt signaling pathway by stabilizing beta-catenin through the association with GSK-3.

Subunit / interactions. Binds GSK-3 and prevents GSK-3-dependent phosphorylation.

Similarity. Belongs to the GSK-3-binding protein family.

RefSeq proteins (1): NP_036215* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008014	GSK3-bd	Family

Pfam: PF05350

UniProt features (6 total): region of interest 3, chain 1, compositionally biased region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75474-F1	63.17	0.17

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-196299	Beta-catenin phosphorylation cascade
R-HSA-4641262	Disassembly of the destruction complex and recruitment of AXIN to the membrane

MSigDB gene sets: 246 (showing top): GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_REGULATION_OF_PROTEIN_EXPORT_FROM_NUCLEUS, GOBP_NUCLEAR_TRANSPORT, GOBP_REGULATION_OF_NUCLEOCYTOPLASMIC_TRANSPORT, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, GOBP_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, TCCAGAT_MIR5165P, BENPORATH_NOS_TARGETS, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, FISCHER_DREAM_TARGETS, GOBP_NUCLEAR_EXPORT, GOBP_REGULATION_OF_TRANSPORT

GO Biological Process (3): regulation of protein export from nucleus (GO:0046825), canonical Wnt signaling pathway (GO:0060070), Wnt signaling pathway (GO:0016055)

GO Molecular Function (0):

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

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Degradation of beta-catenin by the destruction complex	1
TCF dependent signaling in response to WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein export from nucleus	1
regulation of intracellular protein transport	1
regulation of nucleocytoplasmic transport	1
Wnt signaling pathway	1
cell surface receptor signaling pathway	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

662 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRAT2	GSK3B	P49841	709
FRAT2	CTNNB1	P35222	568
FRAT2	FZD10	Q9ULW2	548
FRAT2	LRP6	O75581	485
FRAT2	PLPPR2	Q96GM1	483
FRAT2	TMEM125	Q96AQ2	475
FRAT2	PHLDA1	Q8WV24	468
FRAT2	EPM2A	O95278	437
FRAT2	GYS1	P13807	432
FRAT2	NHLRC1	Q6VVB1	430
FRAT2	SCN4B	Q8IWT1	426
FRAT2	MAPK6	Q16659	425
FRAT2	CLDN19	Q8N6F1	412
FRAT2	CD244	Q9BZW8	411
FRAT2	IER2	Q9BTL4	409
FRAT2	FZD4	Q9ULV1	409

IntAct

19 interactions, top by confidence:

A	B	Type	Score
GSK3B	AXIN1	psi-mi:“MI:0914”(association)	0.980
FRAT2	BUB1	psi-mi:“MI:0915”(physical association)	0.370
FRAT2	CDKN2A	psi-mi:“MI:0915”(physical association)	0.370
FRAT2	CTNNA1	psi-mi:“MI:0915”(physical association)	0.370
FRAT2	EGFR	psi-mi:“MI:0915”(physical association)	0.370
ERBB2	FRAT2	psi-mi:“MI:0915”(physical association)	0.370
KRAS	FRAT2	psi-mi:“MI:0915”(physical association)	0.370
MCC	FRAT2	psi-mi:“MI:0915”(physical association)	0.370
FRAT2	MLH1	psi-mi:“MI:0915”(physical association)	0.370
MLH3	FRAT2	psi-mi:“MI:0915”(physical association)	0.370
FRAT2	NRAS	psi-mi:“MI:0915”(physical association)	0.370
PTPN12	FRAT2	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
S100A2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CEP170P1	DAPK3	psi-mi:“MI:0914”(association)	0.350
FRAT2	GSK3A	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): FRAT2 (Affinity Capture-MS), FRAT2 (Two-hybrid), FRAT2 (Two-hybrid), FRAT2 (Two-hybrid), FRAT2 (Two-hybrid), FRAT2 (Two-hybrid), FRAT2 (Two-hybrid), FRAT2 (Two-hybrid), FRAT2 (Two-hybrid), FRAT2 (Two-hybrid), FRAT2 (Two-hybrid), FRAT2 (Two-hybrid), DACH1 (Affinity Capture-MS), C17orf70 (Affinity Capture-MS), CEP170 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RRK4, A0A1W2PPE3, A0A1W2PR82, A0A2Z4LIS9, A2VE02, A4D1S0, A5PKC7, A5PL33, A6H7B4, A6NEL2, A6QP24, A6QPM6, A8MTW9, A8MYA2, D3ZAQ5, D4AAA5, E7EW31, O75474, O75638, O89113, O94850, P0C7X2, P14652, P50617, P70339, Q2KIS6, Q3UN58, Q5JPB2, Q5VZ46, Q6GQX2, Q6NZ36, Q6ZSJ8, Q6ZW13, Q76NI1, Q7TNS8, Q80TS7, Q86UU5, Q8IWN7, Q8N6K4, Q8N944

Diamond homologs: O75474, O93343, P70339, Q8K025, Q92837

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FRAT2	“down-regulates activity”	GSK3B	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 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
SHC1 events in ERBB2 signaling	5	148.7×	3e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

193 predictions. Top by Δscore:

Variant	Effect	Δscore
10:97334001:T:TA	donor_gain	0.7200
10:97333438:C:CT	acceptor_gain	0.6300
10:97333439:A:T	acceptor_gain	0.6100
10:97334400:T:TA	donor_gain	0.5800
10:97334544:T:TA	donor_gain	0.5400
10:97333996:CGG:C	donor_gain	0.5100
10:97333964:A:AT	donor_gain	0.4900
10:97334550:T:TA	donor_gain	0.4800
10:97333837:AGCGG:A	donor_gain	0.4700
10:97334482:A:AC	donor_gain	0.4700
10:97334483:C:CC	donor_gain	0.4700
10:97333947:G:A	donor_gain	0.4500
10:97334475:G:GC	donor_gain	0.4500
10:97334412:T:TA	donor_gain	0.4400
10:97333123:TTGGA:T	acceptor_gain	0.4300
10:97333853:T:TA	donor_gain	0.4300
10:97333891:GCT:G	acceptor_gain	0.4300
10:97333123:T:C	acceptor_gain	0.4200
10:97334483:CTG:C	donor_gain	0.4200
10:97332895:A:T	acceptor_gain	0.4100
10:97333193:T:TG	acceptor_gain	0.4100
10:97333674:TCTCC:T	donor_gain	0.4100
10:97333863:GGCC:G	acceptor_loss	0.4000
10:97333866:C:CA	acceptor_loss	0.4000
10:97333867:T:A	acceptor_loss	0.4000
10:97334474:CG:C	donor_gain	0.4000
10:97333751:C:A	donor_gain	0.3900
10:97333868:G:C	acceptor_loss	0.3900
10:97333873:A:T	acceptor_loss	0.3900
10:97333892:C:A	acceptor_gain	0.3900

AlphaMissense

1437 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:97334003:C:A	K190N	0.997
10:97334003:C:G	K190N	0.997
10:97334007:A:G	I189T	0.995
10:97334007:A:T	I189N	0.995
10:97334016:C:A	G186V	0.995
10:97334007:A:C	I189S	0.993
10:97334016:C:T	G186E	0.993
10:97333999:C:G	A192P	0.992
10:97334010:A:G	L188P	0.990
10:97334004:T:A	K190M	0.988
10:97334028:A:G	L182P	0.987
10:97334017:C:G	G186R	0.986
10:97334017:C:T	G186R	0.986
10:97334433:A:C	I47S	0.985
10:97333986:A:G	L196P	0.984
10:97334012:G:C	N187K	0.983
10:97334012:G:T	N187K	0.983
10:97334433:A:T	I47N	0.982
10:97334010:A:T	L188H	0.981
10:97334002:C:T	E191K	0.979
10:97334037:A:T	L179H	0.979
10:97333986:A:T	L196H	0.978
10:97333998:G:T	A192D	0.978
10:97334005:T:C	K190E	0.969
10:97334028:A:T	L182H	0.969
10:97334433:A:G	I47T	0.969
10:97334013:T:A	N187I	0.968
10:97334037:A:G	L179P	0.968
10:97333988:T:A	R195S	0.967
10:97333988:T:G	R195S	0.967

dbSNP variants (sampled 300 via entrez): RS1000163584 (10:97335157 G>A), RS1002266811 (10:97332808 C>G,T), RS1002299431 (10:97332514 A>C,G), RS1002726820 (10:97334336 C>A,G,T), RS1003082835 (10:97334144 C>A,G), RS1003308158 (10:97335492 T>C), RS1003681428 (10:97332850 G>C), RS1004091112 (10:97335521 G>C), RS1004138652 (10:97333047 T>TC), RS1004172045 (10:97335625 C>A), RS1005066302 (10:97334723 C>T), RS1005159671 (10:97334828 A>C,G,T), RS1005736269 (10:97334954 G>A,T), RS1005767524 (10:97334746 G>A,T), RS1007440822 (10:97333465 G>T)

Disease associations

OMIM: gene MIM:605006 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004904_162	Body mass index	7.000000e-09
GCST007325_61	General risk tolerance (MTAG)	7.000000e-20
GCST90002393_337	Monocyte count	2.000000e-35
GCST90013407_178	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008579	risk-taking behaviour
EFO:0005091	monocyte count
EFO:0004532	serum gamma-glutamyl transferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, affects expression, increases abundance	3
Cyclosporine	decreases expression	3
entinostat	increases expression, affects cotreatment	2
Particulate Matter	decreases expression, increases abundance	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases 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
dorsomorphin	affects cotreatment, increases expression	1
PKF115-584	affects expression	1
PCI 5002	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Benzene	increases expression	1
Carbamazepine	affects expression	1
Niclosamide	increases expression	1
Ozone	increases abundance, affects expression	1
Quercetin	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	decreases methylation	1
Zinc	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
Palmitic Acid	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7Q6	Ubigene A-549 FRAT2 KO	Cancer cell line	Male
CVCL_D8LL	Ubigene HCT 116 FRAT2 KO	Cancer cell line	Male
CVCL_D9F3	Ubigene HEK293 FRAT2 KO	Transformed cell line	Female
CVCL_E0DB	Ubigene HeLa FRAT2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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