FOSL2

Summary

FOSL2 (FOS like 2, AP-1 transcription factor subunit, HGNC:3798) is a protein-coding gene on chromosome 2p23.2, encoding Fos-related antigen 2 (P15408). Controls osteoclast survival and size.

The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.

Source: NCBI Gene 2355 — RefSeq curated summary.

At a glance

• Gene–disease (curated): aplasia cutis-enamel dysplasia syndrome (Strong, GenCC)
• GWAS associations: 20
• Clinical variants (ClinVar): 50 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 23
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 45 downstream targets (CollecTRI)
• MANE Select transcript: NM_005253

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3798
Approved symbol	FOSL2
Name	FOS like 2, AP-1 transcription factor subunit
Location	2p23.2
Locus type	gene with protein product
Status	Approved
Aliases	FRA2, FLJ23306
Ensembl gene	ENSG00000075426
Ensembl biotype	protein_coding
OMIM	601575
Entrez	2355

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000264716, ENST00000379619, ENST00000436647, ENST00000460736, ENST00000902793, ENST00000956567

RefSeq mRNA: 1 — MANE Select: NM_005253 NM_005253

CCDS: CCDS1766

Canonical transcript exons

ENST00000264716 — 4 exons

Exon	Start	End
ENSE00000735744	28408759	28408866
ENSE00001140559	28392858	28393822
ENSE00001410491	28411930	28417317
ENSE00003508391	28404107	28404358

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 108.9044 / max 2571.1099, expressed in 1806 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
19438	79.7730	1798
19443	17.0156	1637
19444	4.6293	1368
19439	3.1277	1322
19447	2.0863	654
19442	0.7615	476
19446	0.4818	268
19445	0.3087	122
19441	0.2291	78
19455	0.1699	69

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland cortex	UBERON:0035825	98.38	gold quality
adrenal cortex	UBERON:0001235	98.33	gold quality
left adrenal gland	UBERON:0001234	98.28	gold quality
lower esophagus mucosa	UBERON:0035834	98.19	gold quality
right adrenal gland cortex	UBERON:0035827	98.11	gold quality
right adrenal gland	UBERON:0001233	98.06	gold quality
buccal mucosa cell	CL:0002336	97.92	gold quality
adrenal gland	UBERON:0002369	97.89	gold quality
mucosa of stomach	UBERON:0001199	97.85	gold quality
popliteal artery	UBERON:0002250	97.80	gold quality
tibial artery	UBERON:0007610	97.79	gold quality
vagina	UBERON:0000996	97.66	gold quality
peritoneum	UBERON:0002358	97.58	gold quality
omental fat pad	UBERON:0010414	97.58	gold quality
left ovary	UBERON:0002119	97.51	gold quality
left uterine tube	UBERON:0001303	97.39	gold quality
pericardium	UBERON:0002407	97.35	gold quality
artery	UBERON:0001637	97.29	gold quality
esophagus mucosa	UBERON:0002469	97.29	gold quality
gall bladder	UBERON:0002110	97.26	gold quality
tendon of biceps brachii	UBERON:0008188	97.21	gold quality
ectocervix	UBERON:0012249	97.14	gold quality
skin of leg	UBERON:0001511	97.04	gold quality
esophagus squamous epithelium	UBERON:0006920	97.04	gold quality
aorta	UBERON:0000947	97.01	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.91	gold quality
skin of abdomen	UBERON:0001416	96.90	gold quality
right ovary	UBERON:0002118	96.78	gold quality
endocervix	UBERON:0000458	96.43	gold quality
adrenal tissue	UBERON:0018303	96.40	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-97	yes	746.03
E-MTAB-8142	yes	81.07
E-MTAB-6678	yes	28.48
E-CURD-112	yes	13.06
E-CURD-122	yes	8.54
E-MTAB-7606	no	1014.46
E-CURD-10	no	393.18
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

45 targets.

Target	Regulation
ABCA1	Unknown
BCL6	Activation
BGLAP	Unknown
BRCA1	Activation
CCR4	Activation
CEBPA	Activation
CEBPB	Activation
CLU	Unknown
CYP11B1
DBH	Unknown
DIO2	Repression
FGF2	Activation
FOSL1	Activation
FOXC1
GCKR
GJA1
IBSP	Unknown
IL11	Activation
IL2	Activation
IL5	Unknown
IL6	Repression
ITGAX	Unknown
IVL	Unknown
LAMA3	Activation
LEP	Unknown
LIF	Activation
MDM2	Activation
MMP13	Activation
MUC5B
MYB	Activation

JASPAR motifs

Motif	Name	Family
MA0478.1	FOSL2	Fos-related
MA0478.2	FOSL2	Fos-related
MA1130.1	FOSL2::JUN	Fos-related::Jun-related
MA1130.2	FOSL2::JUN	Fos-related::Jun-related
MA1131.1	FOSL2::JUN	Fos-related::Jun-related
MA1131.2	FOSL2::JUN	Fos-related::Jun-related
MA1138.1	FOSL2::JUNB	Fos-related::Jun-related
MA1138.2	FOSL2::JUNB	Fos-related::Jun-related
MA1139.1	FOSL2::JUNB	Fos-related::Jun-related
MA1139.2	FOSL2::JUNB	Fos-related::Jun-related
MA1144.1	FOSL2::JUND	Fos-related::Jun-related
MA1144.2	FOSL2::JUND	Fos-related::Jun-related
MA1145.1	FOSL2::JUND	Fos-related::Jun-related
MA1145.2	FOSL2::JUND	Fos-related::Jun-related

JASPAR matrix evidence (PMIDs): PMID:17916232, PMID:11988758

Upstream regulators (CollecTRI, top): FOS, JUN, STAT5A

miRNA regulators (miRDB)

87 targeting FOSL2, 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-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Fra-2 overexpression is associated with a more aggressive tumor phenotype and is probably involved in breast cancer progression in vivo. (PMID:17393299)
• aberrantly expressed Fra-2 in association with JunD may play a major role in CCR4 expression and oncogenesis in adult T-cell leukemia. (PMID:18071306)
• FRA2 and AP1 have roles in development of pulmonary fibrosis (PMID:18641127)
• Genes for Fra2, Id2, and CSF1-receptor are deregulated, regardless of whether the in anaplastic large cell lymphoma contains the t(2;5). (PMID:19321746)
• Fra-2 transgenic natural killer (NK)T cells produce unusually high amounts of interleukin (IL)-2 and IL-4, and proliferate abnormally. (PMID:19620306)
• Fra-2 is present in human systemic sclerosis and may contribute to the development of microvasculopathy by inducing endothelial cell apoptosis and by reducing endothelial cell migration and chemotaxis. (PMID:19933934)
• Fra-2 is overexpressed in SSc and acts as a novel downstream mediator of the profibrotic effects of TGFbeta and PDGF. (PMID:20039427)
• Results suggest that Fra-2 protein may be more effective than ATF-2 protein in cyst formation originated from epithelial cells of dental follicles. (PMID:20675274)
• These findings reveal a novel function of Fra-2/AP-1 as a positive regulator of bone and matrix formation in mice and humans. (PMID:20837772)
• FOSL2 is a critical regulator of leptin expression in adipocytes (PMID:22326952)
• results demonstrate the presence of a common oncogenic cascade initiated by FRA2/JUND in CCR4-expressing mature T-cell malignancies such as ATLL and CTCLs (PMID:22493372)
• This study suggests that Fra-2 transgenic mice as an animal model of systemic sclerosis-associated pulmonary arterial hypertension display main characteristic features of the human disease. (PMID:22523431)
• we show that the suppression was mediated, at least in part, by a suspension culture-driven decrease in the levels of two members of the AP1 transcription factor complex, c-Jun and Fra2 (PMID:23339184)
• SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma. (PMID:23482931)
• FRA2 is a STAT5 target gene regulated by IL-2 in human CD4 T cells. (PMID:24587342)
• FOSL2 facilitates TGF-beta1-induced migration by interaction with Smad3 in non-small cell lung cancer.FOSL2 positively regulates TGF-beta1 signalling . (PMID:25375657)
• The binding and expression of c-Fos/Fra-2 increased as a function of severity of tongue lesions, yet selective participation of c-Jun appears to promote poor differentiation and aggressive tumorigenesis. (PMID:26581505)
• FOSL2 is a direct target of miR-597 in breast cancer cells. (PMID:28393251)
• Data provide evidence that FOSL2 is the target gene of miR-143 and negatively correlated with its expression. Down-regulation of FOSL2 seems to be a critical step in regulation of OS properties and the expression of miR-143 can inhibit the proliferation, migration and invasion of OS by reducing the expression of FOSL2. (PMID:29330462)
• there was a negative correlation between miR-133a and FOSL2 expression in Hepatocellular carcinoma samples. (PMID:30086463)
• Results suggest that FOSL2 is a critical regulator of colorectal cancer metastasis. (PMID:30114390)
• Fra-2 was significantly increased in kidney biopsies of lupus nephritis patients compared with healthy controls and other kidney disease in glomerular podocytes. (PMID:30296590)
• LINC00313 is upregulated in osteosarcoma (OS), and LINC00313 knockdown plays a vital anti-tumor role in OS cell progression through a miR-342-3p/FOSL2 axis. (PMID:32390359)
• microRNA-143-3p contributes to inflammatory reactions by targeting FOSL2 in PBMCs from patients with autoimmune diabetes mellitus. (PMID:32815005)
• Silencing circRNA_001937 may inhibit cutaneous squamous cell carcinoma proliferation and induce apoptosis by preventing the sponging of the miRNA5973p/FOSL2 pathway. (PMID:33000177)
• Fra-2/AP-1 regulates melanoma cell metastasis by downregulating Fam212b. (PMID:33188281)
• The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis. (PMID:33668422)
• FOSL2 promotes VEGF-independent angiogenesis by transcriptionnally activating Wnt5a in breast cancer-associated fibroblasts. (PMID:33754039)
• KLRD1, FOSL2 and LILRB3 as potential biomarkers for plaques progression in acute myocardial infarction and stable coronary artery disease. (PMID:34271875)
• LncRNA GSTM3TV2 Promotes Cell Proliferation and Invasion via miR-597/FOSL2 Axis in Hepatocellular Carcinoma. (PMID:34458365)
• Nucleolar localization of c-Jun. (PMID:34499807)
• Fra-2 overexpression upregulates pro-metastatic cell-adhesion molecules, promotes pulmonary metastasis, and reduces survival in a spontaneous xenograft model of human breast cancer. (PMID:34693476)
• Inhibition of FOSL2 aggravates the apoptosis of ovarian cancer cells by promoting the formation of inflammasomes. (PMID:34773569)
• Circ-FAT1 Up-Regulates FOSL2 Expression by Sponging miR-619-5p to Facilitate Colorectal Cancer Progression. (PMID:35034245)
• A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation. (PMID:35511484)
• Upregulation of microRNA-597 in myelodysplastic syndromes induces apoptosis through FOSL2 inhibition. (PMID:36018564)
• FOSL2 truncating variants in the last exon cause a neurodevelopmental disorder with scalp and enamel defects. (PMID:36197437)
• Circ_0005615 Regulates the Progression of Colorectal Cancer Through the miR-873-5p/FOSL2 Signaling Pathway. (PMID:36920708)
• Integration of ATAC-Seq and RNA-Seq reveals FOSL2 drives human liver progenitor-like cell aging by regulating inflammatory factors. (PMID:37173651)
• LncRNA ITGB2-AS1 promotes cisplatin resistance of non-small cell lung cancer by inhibiting ferroptosis via activating the FOSL2/NAMPT axis. (PMID:37370246)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fosl2	ENSDARG00000040623
danio_rerio	fosl2l	ENSDARG00000092174
mus_musculus	Fosl2	ENSMUSG00000029135
rattus_norvegicus	Fosl2	ENSRNOG00000068412
drosophila_melanogaster	Atf3	FBGN0028550

Paralogs (8): BATF3 (ENSG00000123685), FOSB (ENSG00000125740), JDP2 (ENSG00000140044), BATF (ENSG00000156127), ATF3 (ENSG00000162772), BATF2 (ENSG00000168062), FOS (ENSG00000170345), FOSL1 (ENSG00000175592)

Protein

Protein identifiers

Fos-related antigen 2 — P15408 (reviewed: P15408)

All UniProt accessions (2): P15408, C9JCN8

UniProt curated annotations — full annotation on UniProt →

Function. Controls osteoclast survival and size. As a dimer with JUN, activates LIF transcription. Activates CEBPB transcription in PGE2-activated osteoblasts.

Subunit / interactions. Heterodimer. Interacts with the BAF multiprotein chromatin-remodeling complex subunits SMARCB1 and SMARCD1. Interacts with ARID1A. Interacts with JUN.

Subcellular location. Nucleus.

Disease relevance. Aplasia cutis-enamel dysplasia (ACED) [MIM:620789] An autosomal dominant disorder characterized by congenital absence of a portion of skin of the scalp with or without skull defects, enamel hypoplasia, and neurodevelopmental delay with autism spectrum disorder. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the bZIP family. Fos subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P15408-1	1	yes
P15408-2	2
P15408-3	3

RefSeq proteins (1): NP_005244* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000837	AP-1	Family
IPR004827	bZIP	Domain
IPR046347	bZIP_sf	Homologous_superfamily

Pfam: PF00170

UniProt features (33 total): modified residue 8, region of interest 6, cross-link 5, splice variant 4, sequence variant 3, sequence conflict 3, compositionally biased region 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15408-F1	63.08	0.22

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 (13): 1, 104, 120, 200, 211, 230, 308, 320, 35, 104, 222, 222, 240

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 529 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARTILAGE_DEVELOPMENT, AMIT_DELAYED_EARLY_GENES, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH

GO Biological Process (57): cell morphogenesis (GO:0000902), osteoblast differentiation (GO:0001649), response to hypoxia (GO:0001666), NK T cell differentiation (GO:0001865), chondrocyte differentiation (GO:0002062), inflammatory response to antigenic stimulus (GO:0002437), keratinocyte development (GO:0003334), growth plate cartilage development (GO:0003417), regulation of transcription by RNA polymerase II (GO:0006357), cell death (GO:0008219), response to xenobiotic stimulus (GO:0009410), gene expression (GO:0010467), B cell differentiation (GO:0030183), neutrophil differentiation (GO:0030223), macrophage differentiation (GO:0030225), bone mineralization (GO:0030282), osteoclast differentiation (GO:0030316), response to lipopolysaccharide (GO:0032496), collagen biosynthetic process (GO:0032964), multicellular organism growth (GO:0035264), response to interleukin-13 (GO:0035962), chondrocyte proliferation (GO:0035988), myofibroblast differentiation (GO:0036446), regulation of multicellular organism growth (GO:0040014), B cell proliferation (GO:0042100), glucose homeostasis (GO:0042593), innate immune response (GO:0045087), fat cell differentiation (GO:0045444), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of fibroblast proliferation (GO:0048146), smooth muscle tissue development (GO:0048745), tissue remodeling (GO:0048771), homeostasis of number of cells within a tissue (GO:0048873), T cell receptor signaling pathway (GO:0050852), response to glucocorticoid (GO:0051384), lung connective tissue development (GO:0060427), fat pad development (GO:0060613), alveolar secondary septum development (GO:0061144), mucus secretion (GO:0070254), response to interleukin-7 (GO:0098760)

GO Molecular Function (10): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), transcription cis-regulatory region binding (GO:0000976), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific double-stranded DNA binding (GO:1990837)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription factor AP-1 complex (GO:0035976), RNA polymerase II transcription regulator complex (GO:0090575)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
ossification	2
cell differentiation	2
regulation of DNA-templated transcription	2
myeloid leukocyte differentiation	2
transcription cis-regulatory region binding	2
binding	2
cellular anatomical structure	2
anatomical structure morphogenesis	1
response to stress	1
response to decreased oxygen levels	1
alpha-beta T cell differentiation	1
cartilage development	1
inflammatory response	1
immune response	1
epithelial cell development	1
keratinocyte differentiation	1
endochondral bone growth	1
cartilage development involved in endochondral bone morphogenesis	1
connective tissue development	1
transcription by RNA polymerase II	1
cellular process	1
response to chemical	1
macromolecule biosynthetic process	1
lymphocyte differentiation	1
B cell activation	1
granulocyte differentiation	1
mononuclear cell differentiation	1
biomineral tissue development	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
biosynthetic process	1
collagen metabolic process	1
multicellular organismal process	1
developmental growth	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

2817 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOSL2	JUND	P17535	999
FOSL2	JUN	P05412	999
FOSL2	JUNB	P17275	996
FOSL2	FOSL1	P15407	985
FOSL2	FOSB	P53539	984
FOSL2	FOS	P01100	984
FOSL2	GLRX3	O76003	804
FOSL2	NFKB1	P19838	781
FOSL2	CEBPB	P17676	704
FOSL2	EGR1	P18146	682
FOSL2	MAF	O75444	681
FOSL2	LIFR	P42702	679
FOSL2	CREB1	P16220	664
FOSL2	EGLN1	Q9GZT9	663
FOSL2	CEBPA	P49715	625

IntAct

145 interactions, top by confidence:

A	B	Type	Score
JUN	ATF2	psi-mi:“MI:0914”(association)	0.950
JUNB	FOS	psi-mi:“MI:0914”(association)	0.950
JUN	FOSL2	psi-mi:“MI:0407”(direct interaction)	0.930
FOSL2	JUN	psi-mi:“MI:0407”(direct interaction)	0.930
JUN	FOSL2	psi-mi:“MI:0915”(physical association)	0.930
FOSL2	JUN	psi-mi:“MI:0914”(association)	0.930
JUNB	FOSL2	psi-mi:“MI:0407”(direct interaction)	0.920
FOSL2	JUNB	psi-mi:“MI:0407”(direct interaction)	0.920
FOSL2	JUNB	psi-mi:“MI:0915”(physical association)	0.920
ATF2	FOSL2	psi-mi:“MI:0407”(direct interaction)	0.810
JUND	FOSL2	psi-mi:“MI:0407”(direct interaction)	0.810
FOSL2	ATF2	psi-mi:“MI:0407”(direct interaction)	0.810
FOSL2	JUND	psi-mi:“MI:0407”(direct interaction)	0.810
ATF2	FOSL2	psi-mi:“MI:0915”(physical association)	0.810
FOSL2	CREB5	psi-mi:“MI:0915”(physical association)	0.790
CREB5	FOSL2	psi-mi:“MI:0915”(physical association)	0.790
FOSL2	DDIT3	psi-mi:“MI:0407”(direct interaction)	0.770
FOSL2	DDIT3	psi-mi:“MI:0915”(physical association)	0.770
DDIT3	FOSL2	psi-mi:“MI:0915”(physical association)	0.770
LDHC	LDHA	psi-mi:“MI:0914”(association)	0.770
FOSL2	BACH2	psi-mi:“MI:0915”(physical association)	0.740

BioGRID (175): FOSL2 (Two-hybrid), FOSL2 (Two-hybrid), TRAF1 (Two-hybrid), DNAJA3 (Two-hybrid), CREB5 (Two-hybrid), LUZP4 (Two-hybrid), GOPC (Two-hybrid), GMCL1 (Two-hybrid), FOSL2 (Affinity Capture-MS), ATF2 (Affinity Capture-MS), ATF7 (Affinity Capture-MS), CREB5 (Affinity Capture-MS), JUN (Affinity Capture-MS), JUNB (Affinity Capture-MS), JUND (Affinity Capture-MS)

ESM2 similar proteins: A0A087WPF7, A2AQ25, A8E4V2, A8MV65, B3F209, O14503, O35185, O35780, O77628, O88479, O97930, P01100, P01101, P10158, P12841, P15407, P15408, P15806, P15923, P18625, P47930, P48755, P51145, P85442, Q05AQ8, Q08E26, Q157S1, Q2VPM4, Q3LRZ1, Q3U182, Q53ET0, Q566L4, Q56TN0, Q56TT7, Q5EA15, Q5RAI7, Q68ED7, Q68FF7, Q7ZWN6, Q80TM6

Diamond homologs: D3ZLB7, O02761, O77628, O88479, O97930, P01100, P01101, P01102, P10158, P11939, P12841, P13346, P15407, P15408, P18625, P18847, P23050, P29176, P47930, P48755, P51145, P53450, P53539, P79702, Q2KII1, Q56TN0, Q56TT7, Q8HZP6, Q91496, Q9TUB3, Q9Z2Q8, A1L2X1, A8MPH9, B3MTI9, B3P5D2, B4G652, B4HZE8, B4JYN3, B4K617, B4M5T7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FOSL2	“up-regulates quantity by expression”	FOSL1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 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
NGF-stimulated transcription	5	42.0×	2e-05
TP53 Regulates Transcription of DNA Repair Genes	5	26.7×	8e-05
ESR-mediated signaling	7	26.4×	3e-06
Regulation of PD-L1(CD274) transcription	6	19.2×	7e-05
Signaling by Nuclear Receptors	6	18.0×	8e-05
Estrogen-dependent gene expression	7	15.6×	4e-05
PIP3 activates AKT signaling	6	11.8×	6e-04
Signaling by Receptor Tyrosine Kinases	6	9.1×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
integrated stress response signaling	6	87.8×	1e-08
positive regulation of miRNA transcription	5	30.3×	7e-05
cellular response to hypoxia	6	15.2×	2e-04
regulation of cell cycle	7	10.9×	3e-04
positive regulation of gene expression	8	6.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	36
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
3242357	NM_005253.4(FOSL2):c.595C>T (p.Arg199Ter)	Pathogenic
3242359	NM_005253.4(FOSL2):c.662_663del (p.Val221fs)	Pathogenic
3242360	NM_005253.4(FOSL2):c.605del (p.Pro202fs)	Pathogenic
3242361	NM_005253.4(FOSL2):c.579_589del (p.Ser194fs)	Pathogenic
1321990	NM_005253.4(FOSL2):c.810_811del (p.Pro271fs)	Likely pathogenic
3242358	NM_005253.4(FOSL2):c.619C>T (p.Gln207Ter)	Likely pathogenic

SpliceAI

999 predictions. Top by Δscore:

Variant	Effect	Δscore
2:28408749:T:TA	acceptor_gain	1.0000
2:28408750:G:A	acceptor_gain	1.0000
2:28408754:TCTA:T	acceptor_loss	1.0000
2:28408757:A:AG	acceptor_gain	1.0000
2:28408757:A:C	acceptor_loss	1.0000
2:28408757:AGCT:A	acceptor_gain	1.0000
2:28408758:G:A	acceptor_loss	1.0000
2:28408758:G:GT	acceptor_gain	1.0000
2:28408758:GC:G	acceptor_gain	1.0000
2:28408758:GCT:G	acceptor_gain	1.0000
2:28408758:GCTG:G	acceptor_gain	1.0000
2:28408758:GCTGT:G	acceptor_gain	1.0000
2:28408863:GGCG:G	donor_gain	1.0000
2:28408864:GCG:G	donor_gain	1.0000
2:28408864:GCGG:G	donor_gain	1.0000
2:28408867:G:GG	donor_gain	1.0000
2:28408868:T:A	donor_loss	1.0000
2:28392945:G:GT	donor_gain	0.9900
2:28393818:AGCAG:A	donor_loss	0.9900
2:28393819:GCAG:G	donor_gain	0.9900
2:28393820:CAGG:C	donor_loss	0.9900
2:28393821:AG:A	donor_loss	0.9900
2:28393822:GG:G	donor_loss	0.9900
2:28393824:T:A	donor_loss	0.9900
2:28404104:CAG:C	acceptor_loss	0.9900
2:28404105:A:AC	acceptor_loss	0.9900
2:28404105:A:AG	acceptor_gain	0.9900
2:28404106:G:A	acceptor_loss	0.9900
2:28404106:G:GG	acceptor_gain	0.9900
2:28404106:GA:G	acceptor_gain	0.9900

AlphaMissense

2087 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:28404143:T:C	F47L	1.000
2:28404145:C:A	F47L	1.000
2:28404145:C:G	F47L	1.000
2:28404161:G:C	A53P	1.000
2:28404165:T:A	I54N	1.000
2:28404165:T:C	I54T	1.000
2:28404165:T:G	I54S	1.000
2:28404183:T:C	L60P	1.000
2:28404188:T:A	W62R	1.000
2:28404188:T:C	W62R	1.000
2:28404190:G:C	W62C	1.000
2:28404190:G:T	W62C	1.000
2:28404192:T:C	M63T	1.000
2:28404192:T:G	M63R	1.000
2:28408783:C:A	R127S	1.000
2:28408784:G:C	R127P	1.000
2:28408787:G:C	R128P	1.000
2:28408792:C:G	R130G	1.000
2:28408793:G:C	R130P	1.000
2:28408795:C:G	R131G	1.000
2:28408796:G:C	R131P	1.000
2:28408801:A:G	R133G	1.000
2:28408801:A:T	R133W	1.000
2:28408802:G:C	R133T	1.000
2:28408802:G:T	R133M	1.000
2:28408803:G:C	R133S	1.000
2:28408803:G:T	R133S	1.000
2:28408804:A:C	N134H	1.000
2:28408804:A:G	N134D	1.000
2:28408805:A:C	N134T	1.000

dbSNP variants (sampled 300 via entrez): RS1000056026 (2:28414267 C>A), RS1000212971 (2:28403096 G>T), RS1000395338 (2:28397007 G>C), RS1000414547 (2:28403395 A>G), RS1000475229 (2:28412539 G>A), RS1000529229 (2:28391141 T>C), RS1000768014 (2:28396823 C>A,G,T), RS1000937192 (2:28401306 C>A), RS1001007465 (2:28413505 T>A), RS1001009884 (2:28395722 G>C), RS1001057386 (2:28413056 G>A), RS1001109759 (2:28413241 C>T), RS1001216884 (2:28401483 G>A), RS1001368540 (2:28395324 C>T), RS1001421145 (2:28401797 C>T)

Disease associations

OMIM: gene MIM:601575 | disease phenotypes: MIM:620789

GenCC curated gene-disease

Disease	Classification	Inheritance
aplasia cutis-enamel dysplasia syndrome	Strong	Autosomal dominant

Mondo (2): neurodevelopmental disorder (MONDO:0700092), aplasia cutis-enamel dysplasia syndrome (MONDO:0968978)

Orphanet (1): Congenital scalp aplasia cutis-enamel hypoplasia-developmental delay-intellectual disability syndrome (Orphanet:697356)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000518	Cataract
HP:0000668	Hypodontia
HP:0000684	Delayed eruption of teeth
HP:0000729	Autistic behavior
HP:0000958	Dry skin
HP:0000965	Cutis marmorata
HP:0000998	Hypertrichosis
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001320	Cerebellar vermis hypoplasia
HP:0001511	Intrauterine growth retardation
HP:0001792	Small nail
HP:0001808	Fragile nails
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0006297	Enamel hypoplasia
HP:0006480	Premature loss of teeth
HP:0007385	Aplasia cutis congenita of scalp
HP:0008070	Sparse hair
HP:0008897	Postnatal growth retardation
HP:0011463	Childhood onset
HP:0200012	Short corpus callosum

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001255_6	Type 1 diabetes	8.000000e-07
GCST001725_42	Inflammatory bowel disease	3.000000e-15
GCST003088_2	Soluble interleukin-2 receptor subunit alpha	6.000000e-06
GCST004131_95	Inflammatory bowel disease	6.000000e-11
GCST004132_72	Crohn’s disease	1.000000e-09
GCST004279_10	Systolic blood pressure	2.000000e-08
GCST005537_129	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	8.000000e-18
GCST006409_8	Allergic rhinitis	7.000000e-13
GCST006988_204	Blond vs. brown/black hair color	9.000000e-35
GCST006988_23	Blond vs. brown/black hair color	4.000000e-08
GCST007267_281	Systolic blood pressure	2.000000e-12
GCST007732_17	Allergic disease (asthma, hay fever or eczema)	9.000000e-07
GCST008074_115	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-13
GCST008074_86	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-06
GCST008083_1	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-13
GCST008083_130	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-06
GCST008087_132	Triglyceride levels in current drinkers	3.000000e-09
GCST010244_280	Triglyceride levels	8.000000e-16
GCST010984_7	Allergic disease (asthma, hay fever and/or eczema) (multivariate analysis)	3.000000e-13
GCST010985_12	Allergic disease (asthma, hay fever and/or eczema) (age of onset)	3.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007650	soluble interleukin-2 receptor subunit alpha measurement
EFO:0006335	systolic blood pressure
EFO:0003924	hair color
EFO:0004530	triglyceride measurement
EFO:0004329	alcohol drinking
EFO:0004847	age at onset

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, affects expression, affects methylation	6
Cadmium Chloride	increases expression, decreases expression, increases abundance, decreases methylation, increases methylation (+1 more)	6
Cisplatin	decreases expression, increases reaction, increases expression	3
Tetradecanoylphorbol Acetate	decreases reaction, increases expression, affects cotreatment, affects expression	3
Zinc	affects cotreatment, increases expression, affects expression, decreases expression	3
Aflatoxin B1	decreases methylation, increases expression	3
deoxynivalenol	affects cotreatment, increases expression	2
nickel sulfate	decreases expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Cadmium	increases abundance, increases expression	2
Calcitriol	increases expression	2
Curcumin	increases expression, decreases expression, decreases reaction	2
Estradiol	increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
Tretinoin	increases expression	2
Valproic Acid	decreases expression, increases expression, increases methylation	2
Asbestos, Crocidolite	increases expression	2
p-Chloromercuribenzoic Acid	increases expression, affects cotreatment	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
bisphenol F	increases expression, affects cotreatment	1
TAK-243	decreases sumoylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1V9	SEES3-1V human FOSL2, clone1	Embryonic stem cell	Male
CVCL_A1W0	SEES3-1V human FOSL2, clone2	Embryonic stem cell	Male
CVCL_A1W1	SEES3-1V human FOSL2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice