FHL3

Summary

FHL3 (four and a half LIM domains 3, HGNC:3704) is a protein-coding gene on chromosome 1p34.3, encoding Four and a half LIM domains protein 3 (Q13643). Recruited by SOX15 to FOXK1 promoters where it acts as a transcriptional coactivator of FOXK1.

The protein encoded by this gene is a member of a family of proteins containing a four-and-a-half LIM domain, which is a highly conserved double zinc finger motif. The encoded protein has been shown to interact with the cancer developmental regulators SMAD2, SMAD3, and SMAD4, the skeletal muscle myogenesis protein MyoD, and the high-affinity IgE beta chain regulator MZF-1. This protein may be involved in tumor suppression, repression of MyoD expression, and repression of IgE receptor expression. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2275 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 53 total
• MANE Select transcript: NM_004468

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3704
Approved symbol	FHL3
Name	four and a half LIM domains 3
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	SLIM2
Ensembl gene	ENSG00000183386
Ensembl biotype	protein_coding
OMIM	602790
Entrez	2275

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 17 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000373016, ENST00000475084, ENST00000477194, ENST00000483132, ENST00000485803, ENST00000850578, ENST00000882670, ENST00000882671, ENST00000882672, ENST00000882673, ENST00000882674, ENST00000882675, ENST00000938707, ENST00000938708, ENST00000956053, ENST00000956054, ENST00000956055, ENST00000956056, ENST00000956057, ENST00000956058, ENST00000956059

RefSeq mRNA: 2 — MANE Select: NM_004468 NM_001243878, NM_004468

CCDS: CCDS30678

Canonical transcript exons

ENST00000373016 — 6 exons

Exon	Start	End
ENSE00001917363	38005357	38005514
ENSE00003521977	37998974	37999148
ENSE00003531412	37997684	37997870
ENSE00003659647	37999257	37999432
ENSE00003688546	37997963	37998132
ENSE00004282193	37996770	37997559

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 99.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.7722 / max 3188.8430, expressed in 1809 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11828	62.1401	1809
11826	0.3938	170
11829	0.1699	49
11827	0.0683	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	99.63	gold quality
gastrocnemius	UBERON:0001388	99.54	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.42	gold quality
muscle of leg	UBERON:0001383	98.25	gold quality
muscle organ	UBERON:0001630	98.10	gold quality
vastus lateralis	UBERON:0001379	97.85	gold quality
skeletal muscle tissue	UBERON:0001134	97.80	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.72	gold quality
quadriceps femoris	UBERON:0001377	97.65	gold quality
diaphragm	UBERON:0001103	97.60	gold quality
triceps brachii	UBERON:0001509	97.48	gold quality
biceps brachii	UBERON:0001507	97.34	gold quality
deltoid	UBERON:0001476	94.62	gold quality
tibialis anterior	UBERON:0001385	94.46	silver quality
muscle tissue	UBERON:0002385	93.88	gold quality
body of uterus	UBERON:0009853	93.60	gold quality
descending thoracic aorta	UBERON:0002345	93.58	gold quality
left uterine tube	UBERON:0001303	93.52	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.52	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.14	gold quality
lower esophagus	UBERON:0013473	93.12	gold quality
gluteal muscle	UBERON:0002000	93.00	gold quality
thoracic aorta	UBERON:0001515	92.99	gold quality
ascending aorta	UBERON:0001496	92.94	gold quality
granulocyte	CL:0000094	92.80	gold quality
popliteal artery	UBERON:0002250	92.69	gold quality
tibial artery	UBERON:0007610	92.68	gold quality
aorta	UBERON:0000947	92.65	gold quality
right coronary artery	UBERON:0001625	92.38	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting FHL3, 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-6740-5P	100.00	65.64	932
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-6779-3P	97.51	65.82	789
HSA-MIR-1289	97.46	65.37	655

Literature-anchored findings (GeneRIF, showing 16)

• Data show that FHL3 (human four-and-a-half LIM-only protein 3) interacts with human phosphatase CDC25B in the cell nucleus. (PMID:12681290)
• FHL2 and FHL3, respectively, are colocalized with alpha(7)beta(1) integrin receptor at the periphery of Z-discs, suggesting a role in mechanical stabilization of muscle cells (PMID:15117962)
• MZF-1 and FHL3 formed a complex of high molecular mass with some additional proteins in the nucleus. Transcriptional repression of FcepsilonRI by MZF-1 required FHL3. (PMID:15453830)
• FHL3 association with MyoD may contribute to the regulation of MyoD-dependent transcription of muscle genes and thereby myogenesis (PMID:17389685)
• Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway. (PMID:19139564)
• the second zinc finger motif in LIM4 was responsible for the auto-activation of FHL3. (PMID:20586194)
• FHL3 does not bind to HIF-1alpha or p300, indicating that it regulates transactivation by a novel molecular mechanism. (PMID:22219185)
• FHL3 suppressed anchorage-dependent and -independent growth of human breast cancer cells. (PMID:22362714)
• findings suggest that the interaction between Ang and FHL3 may provide some clues to the mechanisms of Ang-regulated cell growth and apoptosis (PMID:22633874)
• FHL3 enhances Tax1-mediated activation of the Human T-cell leukemia virus type 1 long terminal repeat (LTR) without affecting basal activity and regulates NF-kappaB activation by Tax1 in a cell-specific manner. (PMID:23616667)
• These findings suggest that functional interactions between FHL3 and MT-1X may provide some clues to the mechanisms of FHL3-regulated cell proliferation. (PMID:24690879)
• PCBP2 could bind to FHL3 mRNA 3’UTR-A and inhibited the expression of FHL3 in T98G glioms cells (PMID:24998228)
• the present study established a link between Ang and FHL3 proteins and identifies a new pathway for regulating astrocytoma progression. (PMID:25659096)
• these findings highlight the role of FHL3 as a stemness-suppressor in regulation of the Smad2/3-SOX4-SOX2 axis in glioma (PMID:29955125)
• PCBP2 promotes the development of glioma by regulating FHL3/TGF-beta/Smad signaling pathway. (PMID:31693182)
• Upregulation of FHL1, SPNS3, and MPZL2 predicts poor prognosis in pediatric acute myeloid leukemia patients with FLT3-ITD mutation. (PMID:35249471)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fhl3a	ENSDARG00000034643
danio_rerio	fhl3b	ENSDARG00000104315
mus_musculus	Fhl3	ENSMUSG00000032643
rattus_norvegicus	Fhl3	ENSRNOG00000007541
caenorhabditis_elegans	lim-9	WBGENE00006407

Paralogs (2): FHL5 (ENSG00000112214), FHL2 (ENSG00000115641)

Protein

Protein identifiers

Four and a half LIM domains protein 3 — Q13643 (reviewed: Q13643)

Alternative names: Skeletal muscle LIM-protein 2

All UniProt accessions (1): Q13643

UniProt curated annotations — full annotation on UniProt →

Function. Recruited by SOX15 to FOXK1 promoters where it acts as a transcriptional coactivator of FOXK1.

Subunit / interactions. Interacts with SOX15; the interaction recruits FHL3 to FOXK1 promoters where it acts as a transcriptional coactivator of FOXK1.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed only in skeletal muscle.

RefSeq proteins (2): NP_001230807, NP_004459* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001781	Znf_LIM	Domain
IPR056807	LIM_FHL1/2/3/5_N	Domain

Pfam: PF00412, PF25076

UniProt features (42 total): sequence conflict 11, strand 10, turn 9, domain 4, modified residue 3, helix 2, initiator methionine 1, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1WYH	SOLUTION NMR
2CUQ	SOLUTION NMR
2EHE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13643-F1	91.76	0.79

Functional residue map

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

Post-translational modifications (3): 2, 157, 235

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 142 (showing top): FXR_IR1_Q6, MAZ_Q6, AP4_Q6, TGACCTY_ERR1_Q2, TAL1ALPHAE47_01, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, EVI1_05, IRF7_01, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, MODULE_206, GATA1_01, chr1p34, GGGNNTTTCC_NFKB_Q6_01, TGANTCA_AP1_C

GO Biological Process (2): muscle organ development (GO:0007517), actin cytoskeleton organization (GO:0030036)

GO Molecular Function (5): transcription coregulator activity (GO:0003712), actin binding (GO:0003779), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): stress fiber (GO:0001725), nucleus (GO:0005634), focal adhesion (GO:0005925), Z disc (GO:0030018), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
animal organ development	1
muscle structure development	1
cytoskeleton organization	1
actin filament-based process	1
transcription regulator activity	1
cytoskeletal protein binding	1
transition metal ion binding	1
binding	1
cation binding	1
actomyosin	1
contractile actin filament bundle	1
intracellular membrane-bounded organelle	1
cell-substrate junction	1
I band	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

844 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FHL3	INPP5A	Q14642	769
FHL3	RBPJ	Q06330	548
FHL3	AAMDC	Q9H7C9	511
FHL3	ANG	P03950	474
FHL3	GSK3B	P49841	448
FHL3	FBXO32	Q969P5	377
FHL3	ISL1	P20663	355
FHL3	WIPF2	Q8TF74	347
FHL3	RGS1	Q08116	339
FHL3	RGS17	Q9UGC6	338
FHL3	HEMK1	Q9Y5R4	336
FHL3	RGS10	O43665	330
FHL3	RGS5	O15539	328
FHL3	RGS19	P49795	328
FHL3	NBPF14	Q5TI25	324

IntAct

617 interactions, top by confidence:

A	B	Type	Score
AIMP2	FHL3	psi-mi:“MI:0915”(physical association)	0.910
GCM2	FHL3	psi-mi:“MI:0915”(physical association)	0.890
FHL3	GCM2	psi-mi:“MI:0915”(physical association)	0.890
FHL3	ZNF512B	psi-mi:“MI:0915”(physical association)	0.870
ZNF512B	FHL3	psi-mi:“MI:0915”(physical association)	0.870
FHL3	KLF3	psi-mi:“MI:0915”(physical association)	0.810
KLF3	FHL3	psi-mi:“MI:0915”(physical association)	0.810
FHL3	SAXO1	psi-mi:“MI:0915”(physical association)	0.780
QRICH1	FHL3	psi-mi:“MI:0915”(physical association)	0.780
FHL3	FAM90A1	psi-mi:“MI:0915”(physical association)	0.780
CNNM3	FHL3	psi-mi:“MI:0915”(physical association)	0.780
PHF21A	FHL3	psi-mi:“MI:0915”(physical association)	0.780
FHL3	QRICH1	psi-mi:“MI:0915”(physical association)	0.780
SAXO1	FHL3	psi-mi:“MI:0915”(physical association)	0.780
GATA2	FHL3	psi-mi:“MI:0915”(physical association)	0.740
FHL3	HIPK1	psi-mi:“MI:0915”(physical association)	0.740

BioGRID (396): FHL3 (Two-hybrid), FHL3 (Two-hybrid), FOSL2 (Two-hybrid), GATA2 (Two-hybrid), LMO2 (Two-hybrid), PTPN6 (Two-hybrid), RAD21 (Two-hybrid), TRIM27 (Two-hybrid), RFX3 (Two-hybrid), SNRPG (Two-hybrid), TRO (Two-hybrid), TYK2 (Two-hybrid), UBE2I (Two-hybrid), AIMP2 (Two-hybrid), NPRL3 (Two-hybrid)

ESM2 similar proteins: A0M8R4, O04193, O35115, O70433, O80839, P21291, P29675, P47875, P50238, P50461, P50462, P50463, P50464, P53777, P63254, P63255, P67966, P67967, P97315, P97447, Q07DY3, Q07DZ4, Q09YI0, Q13642, Q13643, Q14192, Q16527, Q1ECF5, Q2IBA3, Q2KI95, Q2QLF4, Q2YDK0, Q32LE9, Q3MHY1, Q3ZBI6, Q4R7A4, Q4U0T9, Q500W4, Q56K04, Q5RC52

Diamond homologs: A0A1L8F1M4, A0M8R4, A0M8S5, A0M8U6, A1Z6W3, A8WH69, O35115, O43294, O43900, O60711, O70433, O94929, P47226, P48059, P49023, P49024, P50464, P97447, Q00PK1, Q07DW1, Q07DX3, Q07DY3, Q07DZ4, Q07E27, Q07E40, Q07E51, Q09476, Q09YI0, Q09YJ2, Q09YK3, Q09YL5, Q09YN8, Q108U9, Q13642, Q13643, Q14192, Q174I2, Q17QE2, Q28FG2, Q292U2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1052 predictions. Top by Δscore:

Variant	Effect	Δscore
1:37997668:TTG:T	donor_gain	1.0000
1:37997686:A:AC	donor_gain	1.0000
1:37997687:C:CC	donor_gain	1.0000
1:37997715:A:AC	donor_gain	1.0000
1:37997715:AGGTG:A	donor_gain	1.0000
1:37997716:G:C	donor_gain	1.0000
1:37997866:AGCGT:A	acceptor_gain	1.0000
1:37997867:GCGT:G	acceptor_gain	1.0000
1:37997868:CGT:C	acceptor_gain	1.0000
1:37997868:CGTC:C	acceptor_gain	1.0000
1:37997869:GT:G	acceptor_gain	1.0000
1:37997871:C:CC	acceptor_gain	1.0000
1:37998131:CC:C	acceptor_gain	1.0000
1:37998132:CC:C	acceptor_gain	1.0000
1:37998969:CATA:C	donor_loss	1.0000
1:37998970:ATAC:A	donor_loss	1.0000
1:37998972:A:AC	donor_gain	1.0000
1:37998973:C:CC	donor_gain	1.0000
1:37998973:CCAGG:C	donor_gain	1.0000
1:37999020:A:AC	donor_gain	1.0000
1:37999021:C:CC	donor_gain	1.0000
1:37999050:A:AC	donor_gain	1.0000
1:37999050:ACTGT:A	donor_gain	1.0000
1:37999051:C:CC	donor_gain	1.0000
1:37999051:CTGTC:C	donor_gain	1.0000
1:37999054:T:A	donor_gain	1.0000
1:37999144:AGCTC:A	acceptor_gain	1.0000
1:37999146:CTC:C	acceptor_gain	1.0000
1:37999147:TC:T	acceptor_gain	1.0000
1:37999148:CC:C	acceptor_gain	1.0000

AlphaMissense

1843 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:37999040:A:G	C89R	0.999
1:37999065:G:C	F80L	0.999
1:37999065:G:T	F80L	0.999
1:37999067:A:G	F80L	0.999
1:37997459:G:C	F263L	0.998
1:37997459:G:T	F263L	0.998
1:37997461:A:G	F263L	0.998
1:37997502:A:G	F249S	0.998
1:37997745:A:C	C209W	0.998
1:37997772:G:C	F200L	0.998
1:37997772:G:T	F200L	0.998
1:37997774:A:G	F200L	0.998
1:37997808:A:C	C188W	0.998
1:37997809:C:T	C188Y	0.998
1:37997810:A:G	C188R	0.998
1:37998041:A:C	F141L	0.998
1:37998041:A:T	F141L	0.998
1:37998043:A:G	F141L	0.998
1:37998077:G:C	C129W	0.998
1:37998079:A:G	C129R	0.998
1:37998084:A:G	F127S	0.998
1:37998086:G:C	C126W	0.998
1:37998994:C:T	C104Y	0.998
1:37999002:G:C	C101W	0.998
1:37999003:C:G	C101S	0.998
1:37999004:A:G	C101R	0.998
1:37999004:A:T	C101S	0.998
1:37999039:C:G	C89S	0.998
1:37999039:C:T	C89Y	0.998
1:37999040:A:T	C89S	0.998

dbSNP variants (sampled 300 via entrez): RS1000272678 (1:38002008 T>C), RS1000307184 (1:37997322 A>G), RS1000402425 (1:37996698 T>C,G), RS1000454231 (1:38001356 C>T), RS1000600703 (1:37997197 G>C), RS1000649837 (1:37997564 A>C,G), RS1000656740 (1:38007011 G>A,C), RS1001630823 (1:38001147 G>A), RS1001887766 (1:38006382 G>C), RS1001953022 (1:38001751 A>G), RS1002015792 (1:38000941 T>C), RS1002019337 (1:38000973 A>G), RS1002068022 (1:38000709 T>C), RS1002346380 (1:38006137 T>C), RS1002364501 (1:38001948 A>T)

Disease associations

OMIM: gene MIM:602790 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005194_115	Coronary artery disease	1.000000e-09
GCST005195_64	Coronary artery disease	4.000000e-10
GCST005196_180	Coronary artery disease	7.000000e-10
GCST007269_10	Pulse pressure	2.000000e-20
GCST010866_13	Coronary artery disease	9.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
aflatoxin B2	increases methylation	1
cupric chloride	increases expression	1
beta-methylcholine	affects expression	1
monomethylarsonous acid	increases expression	1
abrine	increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Azathioprine	increases expression	1
Cisplatin	decreases expression	1
Diazinon	increases methylation	1
Estradiol	affects cotreatment, increases expression	1
Fluorouracil	increases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Phthalic Acids	increases methylation	1
Smoke	decreases expression	1
Testosterone	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8LF	Ubigene HCT 116 FHL3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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