FOXR2

Summary

FOXR2 (forkhead box R2, HGNC:30469) is a protein-coding gene on chromosome Xp11.21, encoding Forkhead box protein R2 (Q6PJQ5).

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm.

Source: NCBI Gene 139628 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 40 total
• MANE Select transcript: NM_198451

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30469
Approved symbol	FOXR2
Name	forkhead box R2
Location	Xp11.21
Locus type	gene with protein product
Status	Approved
Aliases	MGC21658, FOXN6
Ensembl gene	ENSG00000189299
Ensembl biotype	protein_coding
OMIM	300949
Entrez	139628

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000339140

RefSeq mRNA: 1 — MANE Select: NM_198451 NM_198451

CCDS: CCDS35308

Canonical transcript exons

ENST00000339140 — 1 exons

Exon	Start	End
ENSE00001371789	55623400	55626192

Expression profiles

Bgee: expression breadth tissue_specific, 6 present calls, max score 82.00.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.00	silver quality
buccal mucosa cell	CL:0002336	61.18	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	55.58	silver quality
lower lobe of lung	UBERON:0008949	49.27	silver quality
tendon of biceps brachii	UBERON:0008188	47.25	gold quality
right testis	UBERON:0004534	45.38	gold quality
testis	UBERON:0000473	44.90	gold quality
left testis	UBERON:0004533	44.40	gold quality
lateral globus pallidus	UBERON:0002476	44.30	gold quality
upper leg skin	UBERON:0004262	43.71	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
substantia nigra pars reticulata	UBERON:0001966	42.03	gold quality
parietal pleura	UBERON:0002400	41.69	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
middle temporal gyrus	UBERON:0002771	41.09	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
epithelium of nasopharynx	UBERON:0001951	40.45	gold quality
myocardium	UBERON:0002349	40.45	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality
jejunum	UBERON:0002115	40.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

79 targeting FOXR2, 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-513A-5P	100.00	69.77	2465
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-4666A-3P	99.96	71.71	3434
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-7153-5P	99.94	68.89	1006
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-448	99.79	72.37	2103

Literature-anchored findings (GeneRIF, showing 19)

• Human FOXN6 gene was identified within human genome sequence RP11-167P23 ( (PMID:15202009)
• we observed that the highly expressed FOXR2 in breast and overexpression of FOXR2 was positively associated with the progression and poor prognosis in patients with breast cancer, which indicated that FOXR2 might serve as a valuable prognosis biomarker for breast cancer individuals. (PMID:26596836)
• FOXR2 is frequently upregulated in hepatocellular carcinoma specimens compared with neighboring non-cancerous tissues in both messenger RNA and protein. It promoted cell growth and colony formation, and it facilitated tumor xenograft growth. beta-catenin, Skp2, c-Myc, and Gli-1 are the potential downstream effectors of FOXR2. (PMID:26846213)
• FOXR2 acts with MYC to promote cancer cell proliferation, which is a potential tumor-specific target for therapeutic intervention against MYC-driven cancers. (PMID:27346356)
• Knockdown of FOXR2 significantly down-regulated the protein expression levels of beta-catenin. (PMID:28068638)
• our data suggested that FOXR2 significantly promoted proliferation, invasion, and EMT of CRC cells. All these findings provided evidence for the role of FOXR2 as an oncogene in CRC development. (PMID:28548041)
• FOXR2 was up-regulated and significantly associated with poor endometrial adenocarcinoma prognosis. FOXR2 is a target gene of miR-202. (PMID:28827892)
• FOXR2 might be considered as a promising therapeutic target for non-small cell lung cancer treatment. (PMID:29634928)
• Study found that FoxR2 is frequently upregulated in ovarian cancer (OC) and associated with worse histologic grade and poor survival. FOXR2 expression was related to cell growth, migration, and epithelial-mesenchymal transition, whereas its silencing suppressed the malignant phenotype. Angiogenesis was also stimulated by FoxR2 overexpression by enhancing VEGF expression. (PMID:29943836)
• CircABCB10 promotes non-small cell lung cancer cell proliferation and migration by regulating the miR-1252/FOXR2 axis. (PMID:30417418)
• FOXR2 up-regulation can promote the proliferation and inhibit the apoptosis of prostate cancer cells because that HOTAIR restrains the expression of miR-152 (PMID:31269585)
• Down-regulation of FOXR2 inhibits hypoxia-driven ROS-induced migration and invasion of thyroid cancer cells via regulation of the hedgehog pathway. (PMID:32068268)
• The tumor suppressor NOR1 suppresses cell growth, invasiveness, and tumorigenicity in glioma. (PMID:32241159)
• The Relationship of FOXR2 Gene Expression Profile with Epithelial-Mesenchymal Transition Related Markers in Epithelial Ovarian Cancer. (PMID:32683876)
• Long noncoding RNA LINC00520 accelerates lung adenocarcinoma progression via miR-1252-5p/FOXR2 pathway. (PMID:33464477)
• Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation. (PMID:33536079)
• E3 ubiquitin ligase PJA1 regulates lung adenocarcinoma apoptosis and invasion through promoting FOXR2 degradation. (PMID:33839405)
• FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits. (PMID:35802025)
• Insights into the molecular roles of FOXR2 in the pathology of primary pediatric brain tumors. (PMID:37879492)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxr1	ENSDARG00000004864
mus_musculus	Foxr2	ENSMUSG00000071665
rattus_norvegicus	Foxr2	ENSRNOG00000076722

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXH1 (ENSG00000160973), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXE3 (ENSG00000186790), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXI3 (ENSG00000214336), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Forkhead box protein R2 — Q6PJQ5 (reviewed: Q6PJQ5)

Alternative names: Forkhead box protein N6

All UniProt accessions (1): Q6PJQ5

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Nucleus.

Tissue specificity. Expressed in breast cancer cell lines and primary cancer.

RefSeq proteins (1): NP_940853* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR052328	FOX_transcription_regulators	Family

Pfam: PF00250

UniProt features (8 total): compositionally biased region 3, region of interest 2, chain 1, DNA-binding region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PJQ5-F1	65.41	0.31

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 35 (showing top): GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MIKKELSEN_IPS_LCP_WITH_H3K4ME3, chrXp11, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, MIR3680_3P, MIR4666A_3P, MIR450B_5P, MIR448, MIR153_3P, MIR889_3P, MIR4528, MIR1303, MIR302F, MIR6830_3P, MIR122B_3P

GO Biological Process (2): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (6): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
cellular anatomical structure	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

624 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXR2	FOXB2	Q5VYV0	461
FOXR2	JMJD1C	Q15652	458
FOXR2	FOXI2	Q6ZQN5	450
FOXR2	MN1	Q10571	445
FOXR2	ZFTA	C9JLR9	421
FOXR2	GRIPAP1	Q4V328	418
FOXR2	CTNNB1	P35222	400
FOXR2	FOXB1	Q99853	399
FOXR2	SOX5	P35711	394
FOXR2	ARHGEF9	O43307	389
FOXR2	FOXD4	Q12950	387
FOXR2	CLCN5	P51795	383
FOXR2	FOXN1	O15353	379
FOXR2	AMER1	Q5JTC6	377
FOXR2	TBC1D8B	Q0IIM8	375

IntAct

22 interactions, top by confidence:

A	B	Type	Score
FOXR2	PEF1	psi-mi:“MI:0915”(physical association)	0.780
PEF1	FOXR2	psi-mi:“MI:0915”(physical association)	0.780
KRT76	FOXR2	psi-mi:“MI:0915”(physical association)	0.560
POLR1C	FOXR2	psi-mi:“MI:0915”(physical association)	0.560
CCNC	FOXR2	psi-mi:“MI:0915”(physical association)	0.560
FOXR2	MYC	psi-mi:“MI:0914”(association)	0.530
FOXR2	NME2P1	psi-mi:“MI:0914”(association)	0.530
FOXN3	FOXR2	psi-mi:“MI:0915”(physical association)	0.400
FOXR2	SUV39H1	psi-mi:“MI:0915”(physical association)	0.370
KRT76	FOXR2	psi-mi:“MI:0915”(physical association)	0.000
POLR1C	FOXR2	psi-mi:“MI:0915”(physical association)	0.000
PEF1	FOXR2	psi-mi:“MI:0915”(physical association)	0.000
CCNC	FOXR2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (97): PEF1 (Two-hybrid), RUVBL1 (Affinity Capture-MS), EP400 (Affinity Capture-MS), MEAF6 (Affinity Capture-MS), EPC1 (Affinity Capture-MS), EPC2 (Affinity Capture-MS), DMAP1 (Affinity Capture-MS), TRRAP (Affinity Capture-MS), TXNRD2 (Affinity Capture-MS), BRD8 (Affinity Capture-MS), ARHGAP1 (Affinity Capture-MS), ING3 (Affinity Capture-MS), VPS72 (Affinity Capture-MS), EIF2B1 (Affinity Capture-MS), MYC (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTS1, A0A1B0GWH4, A1A4L6, A1YGI6, A6NDR6, B8QB46, F1MJR8, F1QDF8, O35892, O35893, P09015, P15036, P15037, P23497, P52729, P59598, Q32NH9, Q3KRF1, Q3UM89, Q4G112, Q4V7E1, Q5M7N6, Q5ND04, Q5XIV2, Q5ZHX5, Q66IG8, Q6P1R3, Q6PCX9, Q6PJQ5, Q708W2, Q76I76, Q76I79, Q76N89, Q7M6U3, Q8AXQ4, Q8BVK9, Q8IUE0, Q8IUE1, Q8IWB6, Q8IXJ9

Diamond homologs: A0A078BQN7, A0A8V0YY16, A1L1S5, A2BGM5, A8XJN7, O00358, O00409, O08696, O15353, O17617, O54743, O60129, O70220, O93529, P14734, P25364, P32027, P32314, P39521, P42128, P55316, P56260, P85037, P91278, P97691, Q00939, Q08050, Q10924, Q12946, Q12947, Q12948, Q17241, Q19802, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q28BS5

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

101 predictions. Top by Δscore:

Variant	Effect	Δscore
X:55624272:G:GT	donor_gain	0.9200
X:55623548:G:GG	donor_gain	0.5800
X:55623547:A:AG	donor_gain	0.5500
X:55624302:T:TA	donor_gain	0.5400
X:55624303:A:AA	donor_gain	0.5400
X:55623950:T:G	donor_gain	0.5300
X:55624399:T:TA	acceptor_gain	0.5300
X:55624282:C:T	donor_gain	0.5100
X:55624046:A:AG	acceptor_gain	0.4700
X:55624047:G:GG	acceptor_gain	0.4700
X:55624255:C:T	donor_gain	0.4200
X:55624968:GAGA:G	acceptor_gain	0.3900
X:55623948:G:GT	donor_gain	0.3800
X:55623954:G:A	donor_gain	0.3800
X:55624400:G:T	acceptor_gain	0.3800
X:55623706:G:GG	donor_gain	0.3700
X:55624183:GAGGC:G	donor_gain	0.3700
X:55624186:GC:G	donor_gain	0.3700
X:55624300:T:G	donor_gain	0.3700
X:55624400:G:A	acceptor_gain	0.3700
X:55624534:G:GT	donor_gain	0.3700
X:55623705:A:AG	donor_gain	0.3600
X:55623746:AT:A	donor_gain	0.3600
X:55624404:A:AG	acceptor_gain	0.3600
X:55624405:G:GG	acceptor_gain	0.3600
X:55623552:G:GT	donor_gain	0.3500
X:55624405:GCTCC:G	acceptor_gain	0.3500
X:55624118:G:GG	donor_gain	0.3400
X:55624419:G:GT	donor_gain	0.3400
X:55624042:CCTCA:C	acceptor_loss	0.3300

AlphaMissense

2090 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:55624372:T:C	F221L	0.961
X:55624374:C:A	F221L	0.961
X:55624374:C:G	F221L	0.961
X:55624459:T:C	F250L	0.959
X:55624461:T:A	F250L	0.959
X:55624461:T:G	F250L	0.959
X:55624387:T:C	F226L	0.957
X:55624389:C:A	F226L	0.957
X:55624389:C:G	F226L	0.957
X:55624396:T:C	F229L	0.936
X:55624398:C:A	F229L	0.936
X:55624398:C:G	F229L	0.936
X:55624636:T:C	F309L	0.932
X:55624638:T:A	F309L	0.932
X:55624638:T:G	F309L	0.932
X:55624388:T:C	F226S	0.923
X:55624549:T:C	F280L	0.909
X:55624551:T:A	F280L	0.909
X:55624551:T:G	F280L	0.909
X:55624521:G:C	W270C	0.905
X:55624521:G:T	W270C	0.905
X:55624393:T:C	F228L	0.904
X:55624395:T:A	F228L	0.904
X:55624395:T:G	F228L	0.904
X:55624417:T:A	W236R	0.904
X:55624417:T:C	W236R	0.904
X:55624322:C:A	A204E	0.898
X:55624373:T:C	F221S	0.897
X:55624519:T:A	W270R	0.895
X:55624519:T:C	W270R	0.895

dbSNP variants (sampled 300 via entrez): RS1001112405 (X:55622259 C>A), RS1001144956 (X:55622770 A>G), RS1001777481 (X:55626201 C>G,T), RS1003912782 (X:55623545 T>A,C), RS1003946794 (X:55623898 A>G), RS1004921246 (X:55621715 A>G), RS1005589260 (X:55625641 A>T), RS1005615401 (X:55626042 C>A,T), RS1006052809 (X:55622118 C>A), RS1007073908 (X:55621529 C>T), RS1007445098 (X:55623298 T>C), RS1008477441 (X:55623143 G>A,T), RS1010253655 (X:55626289 C>T), RS1010569764 (X:55624852 G>A), RS1012840051 (X:55622143 G>A,T)

Disease associations

OMIM: gene MIM:300949 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006011_35	Mean corpuscular volume	3.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

Clinical trials (associated diseases)

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