FEM1A

Summary

FEM1A (fem-1 homolog A, HGNC:16934) is a protein-coding gene on chromosome 19p13.3, encoding Protein fem-1 homolog A (Q9BSK4). Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation.

Enables EP4 subtype prostaglandin E2 receptor binding activity and ubiquitin-like ligase-substrate adaptor activity. Involved in negative regulation of inflammatory response and ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Part of Cul2-RING ubiquitin ligase complex. Is active in mitochondrion.

Source: NCBI Gene 55527 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 81 total
• MANE Select transcript: NM_018708

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16934
Approved symbol	FEM1A
Name	fem-1 homolog A
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141965
Ensembl biotype	protein_coding
OMIM	613538
Entrez	55527

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000269856

RefSeq mRNA: 1 — MANE Select: NM_018708 NM_018708

CCDS: CCDS12135

Canonical transcript exons

ENST00000269856 — 1 exons

Exon	Start	End
ENSE00000951494	4791734	4801273

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 99.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.5025 / max 120.7768, expressed in 1726 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173373	5.1748	1719
173374	0.1627	62
173375	0.1184	40
173376	0.0466	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.15	gold quality
tibialis anterior	UBERON:0001385	98.71	gold quality
quadriceps femoris	UBERON:0001377	98.66	gold quality
vastus lateralis	UBERON:0001379	98.64	gold quality
biceps brachii	UBERON:0001507	98.63	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.59	gold quality
left ventricle myocardium	UBERON:0006566	97.39	gold quality
deltoid	UBERON:0001476	97.32	gold quality
body of tongue	UBERON:0011876	96.60	gold quality
skeletal muscle tissue	UBERON:0001134	96.07	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.64	gold quality
myocardium	UBERON:0002349	94.47	gold quality
upper arm skin	UBERON:0004263	94.22	gold quality
heart right ventricle	UBERON:0002080	93.48	gold quality
tongue	UBERON:0001723	92.95	gold quality
muscle tissue	UBERON:0002385	92.00	gold quality
buccal mucosa cell	CL:0002336	91.93	silver quality
tendon of biceps brachii	UBERON:0008188	91.34	gold quality
kidney epithelium	UBERON:0004819	90.77	gold quality
skeletal muscle organ	UBERON:0014892	90.01	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.82	gold quality
gingival epithelium	UBERON:0001949	89.45	silver quality
gastrocnemius	UBERON:0001388	89.22	gold quality
gingiva	UBERON:0001828	88.88	gold quality
cerebellar vermis	UBERON:0004720	88.54	silver quality
superior surface of tongue	UBERON:0007371	88.50	gold quality
oral cavity	UBERON:0000167	88.37	gold quality
esophagus squamous epithelium	UBERON:0006920	88.31	gold quality
muscle of leg	UBERON:0001383	87.97	gold quality
pharyngeal mucosa	UBERON:0000355	87.44	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-8060	yes	135.09
E-CURD-88	yes	40.13
E-MTAB-8142	yes	17.37
E-GEOD-137537	yes	4.99
E-ANND-3	yes	3.62
E-CURD-135	no	1645.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

59 targeting FEM1A, 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-4668-3P	100.00	68.74	2635
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3681-5P	99.82	66.88	387
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-6849-5P	99.64	66.00	352
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-3171	99.49	69.06	776
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-491-5P	99.13	65.98	1468

Literature-anchored findings (GeneRIF, showing 7)

• Fem1a downregulation may be involved in, and/or a marker of, an early cell fate defect fundamental to rhabdomyosarcoma pathogenesis (PMID:16254458)
• PGE(2)-EP4 signaling augments NF-kappaB1 p105 protein stability through EPRAP after proinflammatory stimulation, limiting macrophage activation. (PMID:18270204)
• This study presents evidence suggesting a role for FEM1A and FEM1B in the pathogenesis of polycystic ovary syndrome. (PMID:18757445)
• Particular genotypes of the rs12460989 and rs8111933 loci of FEM1A gene are associated with PCOS in Chinese Han. (PMID:22678803)
• FEM1 proteins are ancient regulators of Stem-Loop Binding Protein. (PMID:28118078)
• Molecular basis for arginine C-terminal degron recognition by Cul2(FEM1) E3 ligase. (PMID:33398168)
• Molecular basis for ubiquitin ligase CRL2(FEM1C)-mediated recognition of C-degron. (PMID:33398170)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fem1a	ENSMUSG00000043683
mus_musculus	Fem1al	ENSMUSG00000078157
rattus_norvegicus	Fem1a	ENSRNOG00000066151

Paralogs (4): FEM1C (ENSG00000145780), ANKRD33B (ENSG00000164236), ANKRD33 (ENSG00000167612), FEM1B (ENSG00000169018)

Protein

Protein identifiers

Protein fem-1 homolog A — Q9BSK4 (reviewed: Q9BSK4)

Alternative names: FEM1-alpha, Prostaglandin E receptor 4-associated protein

All UniProt accessions (1): Q9BSK4

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL2(FEM1A) complex specifically recognizes proteins with an arginine at the C-terminus: recognizes and binds proteins ending with -Lys/Arg-Xaa-Arg and -Lys/Arg-Xaa-Xaa-Arg C-degrons, such as SIL1 or OR51B2, leading to their ubiquitination and degradation. Promotes ubiquitination and degradation of SLBP. Involved in PGE2-EP4-mediated inhibition of inflammation of macrophages via interaction with NFKB1 and PTGER4. Promotes inflammation in brain microglia through MAP2K4/MKK4-mediated signaling.

Subunit / interactions. Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter FEM1A. Interacts with PTGER4. Interacts with NFKB1; the interaction is direct.

Subcellular location. Mitochondrion. Cytoplasm.

Tissue specificity. Present in macrophages derived from peripheral blood monocytes. Also present in atheromata (at protein level).

Post-translational modifications. Phosphorylated; highly phosphorylated in myoblasts and myotubes. Phosphorylation at Ser-108 promotes PGE2-EP4-mediated inhibition of inflammation. Dephosphorylated by protein phosphatase 2A (PP2A).

Induction. Frequently down-regulated in rhabdomyosarcoma.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the fem-1 family.

RefSeq proteins (1): NP_061178* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00023, PF12796

UniProt features (15 total): repeat 11, chain 1, region of interest 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BSK4-F1	89.28	0.77

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 (1): 108

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8951664	Neddylation

MSigDB gene sets: 160 (showing top): MODULE_97, GOBP_INFLAMMATORY_RESPONSE, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MODULE_182, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE

GO Biological Process (7): protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of inflammatory response (GO:0050728), positive regulation of inflammatory response (GO:0050729), regulation of ubiquitin-protein transferase activity (GO:0051438), ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627), MAPK cascade (GO:0000165)

GO Molecular Function (4): EP4 subtype prostaglandin E2 receptor binding (GO:0031867), molecular adaptor activity (GO:0060090), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (5): ubiquitin ligase complex (GO:0000151), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), Cul2-RING ubiquitin ligase complex (GO:0031462)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
inflammatory response	2
regulation of inflammatory response	2
binding	2
cellular anatomical structure	2
cytoplasm	2
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
ubiquitin-protein transferase activity	1
regulation of transferase activity	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
intracellular signaling cassette	1
prostanoid receptor binding	1
molecular_function	1
enzyme-substrate adaptor activity	1
intracellular protein-containing complex	1
transferase complex	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

1618 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FEM1A	PTGER4	P35408	639
FEM1A	DCUN1D2	Q6PH85	474
FEM1A	PRODH2	Q9UF12	474
FEM1A	CAPN5	O15484	472
FEM1A	DMRT1	Q9Y5R6	447
FEM1A	RNF123	Q5XPI4	440
FEM1A	IP6K2	Q9UHH9	435
FEM1A	GSTM4	Q03013	410
FEM1A	CUL2	Q13617	399
FEM1A	WWP1	Q9H0M0	394
FEM1A	NEDD4	P46934	389
FEM1A	AXDND1	Q5T1B0	387
FEM1A	PPM1F	P49593	383
FEM1A	CUL3	Q13618	379
FEM1A	ZNF584	Q8IVC4	378

IntAct

49 interactions, top by confidence:

A	B	Type	Score
CUL2	VHL	psi-mi:“MI:0914”(association)	0.940
CUL5	SOCS7	psi-mi:“MI:0914”(association)	0.640
FEM1A	KIFC3	psi-mi:“MI:0915”(physical association)	0.560
GOLGA6L9	FEM1A	psi-mi:“MI:0915”(physical association)	0.560
FEM1A	MALT1	psi-mi:“MI:0915”(physical association)	0.560
FEM1A	WWOX	psi-mi:“MI:0915”(physical association)	0.560
OGFOD1	FEM1A	psi-mi:“MI:0915”(physical association)	0.560
NDUFAB1	FEM1A	psi-mi:“MI:0915”(physical association)	0.560
MYOM3	FEM1A	psi-mi:“MI:0915”(physical association)	0.560
INCA1	FEM1A	psi-mi:“MI:0915”(physical association)	0.560
ACAA1	FEM1A	psi-mi:“MI:0915”(physical association)	0.560
DCLK1	DCX	psi-mi:“MI:0914”(association)	0.530
Kctd5		psi-mi:“MI:0914”(association)	0.350
ANLN	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Magoh	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
Kifbp	TPM1	psi-mi:“MI:0914”(association)	0.350
NLRP3	PHRF1	psi-mi:“MI:0914”(association)	0.350
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
CDK17	DHPS	psi-mi:“MI:0914”(association)	0.350
ZNF219		psi-mi:“MI:0914”(association)	0.350
TCEAL1	PDCD5	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
FEM1A	RNF113A	psi-mi:“MI:0914”(association)	0.350
NACC2	FHL2	psi-mi:“MI:0914”(association)	0.350
UBXN6	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
FEM1A	LAD1	psi-mi:“MI:0914”(association)	0.350
FEM1A	DHRS3	psi-mi:“MI:0914”(association)	0.350
DISC1	FEM1A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (116): FEM1A (Affinity Capture-MS), FEM1A (Affinity Capture-MS), FEM1A (Affinity Capture-MS), FEM1A (Affinity Capture-MS), FEM1A (Affinity Capture-MS), FEM1A (Affinity Capture-MS), FEM1A (Affinity Capture-Western), FEM1A (Affinity Capture-MS), FEM1A (Affinity Capture-MS), FEM1A (Affinity Capture-MS), FEM1A (Affinity Capture-MS), FEM1A (Affinity Capture-RNA), FEM1A (Proximity Label-MS), FEM1A (Two-hybrid), FEM1A (Two-hybrid)

ESM2 similar proteins: A0A3L7I2I8, A0FKG7, A2AGL3, A7MB89, B0LPN4, E9Q401, O60733, P30957, P42694, P49754, P97570, P97819, Q15413, Q29RM5, Q2KIX2, Q2T9K6, Q32PW3, Q3SX45, Q4V890, Q59H18, Q5F361, Q5GIG6, Q5KU39, Q5RF15, Q5U2S6, Q5ZKK2, Q66H07, Q66H63, Q6B858, Q6DFV5, Q6NYU2, Q7T3P8, Q7TQP6, Q8C0T1, Q8CEF1, Q8K0L0, Q8K114, Q8TC84, Q91W86, Q92736

Diamond homologs: A1ZBY1, A7MB89, P0C6P7, Q29RM5, Q2T9K6, Q4V890, Q5ZM55, Q6GPE5, Q6P9Z4, Q7T3P8, Q8C0T1, Q8CEF1, Q96JP0, Q9BSK4, Q9UK73, Q9VFD5, Q9Z2G0, Q9Z2G1, A2ARS0, B2RXR6, C7B178, C9JTQ0, P0C927, P19838, Q00PJ3, Q07E43, Q08353, Q21920, Q2QL84, Q337A0, Q3KP44, Q3SX00, Q3UES3, Q3UUF8, Q4FE45, Q4JHE0, Q502K3, Q5R8C8, Q5ZLC8, Q60J38

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 40 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.

GO biological processes:

GO term	Partners	Fold	FDR
protein ubiquitination	7	8.8×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4333 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:4792210:C:A	P119H	1.000
19:4792213:T:A	L120H	1.000
19:4792224:T:C	C124R	1.000
19:4792225:G:A	C124Y	1.000
19:4792226:C:G	C124W	1.000
19:4792227:T:C	F125L	1.000
19:4792229:C:A	F125L	1.000
19:4792229:C:G	F125L	1.000
19:4792295:C:A	N147K	1.000
19:4792295:C:G	N147K	1.000
19:4792311:T:C	C153R	1.000
19:4792312:G:A	C153Y	1.000
19:4792313:C:G	C153W	1.000
19:4792315:T:A	L154H	1.000
19:4792319:G:A	M155I	1.000
19:4792319:G:C	M155I	1.000
19:4792319:G:T	M155I	1.000
19:4792321:T:A	I156N	1.000
19:4792321:T:C	I156T	1.000
19:4792321:T:G	I156S	1.000
19:4792324:C:G	S157W	1.000
19:4792326:T:C	C158R	1.000
19:4792327:G:A	C158Y	1.000
19:4792328:C:G	C158W	1.000
19:4792360:T:C	L169P	1.000
19:4792411:C:A	A186D	1.000
19:4792420:A:C	D189A	1.000
19:4792420:A:G	D189G	1.000
19:4792420:A:T	D189V	1.000
19:4792421:C:A	D189E	1.000

dbSNP variants (sampled 300 via entrez): RS1000362045 (19:4797390 C>G,T), RS1000479826 (19:4797598 G>C), RS1000625232 (19:4795663 C>T), RS1000727096 (19:4800819 C>G,T), RS1000976145 (19:4795986 G>A,C), RS1002244460 (19:4791146 A>C), RS1002349557 (19:4799990 A>C,G), RS1002419802 (19:4799754 A>G), RS1002701738 (19:4790906 C>A,T), RS1002702702 (19:4798932 A>T), RS1002756614 (19:4798483 G>A,C,T), RS1002834081 (19:4795971 C>T), RS1002939962 (19:4789931 A>C,G), RS1003387294 (19:4791356 C>T), RS1003464895 (19:4790203 G>A,T)

Disease associations

OMIM: gene MIM:613538 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	increases expression	1
trichostatin A	affects expression	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
potassium chromate(VI)	affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
K 7174	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
bisphenol S	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Indomethacin	affects cotreatment, increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cyclosporine	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1X4	HAP1 FEM1A (-) 1	Cancer cell line	Male
CVCL_E1X5	HAP1 FEM1A (-) 2	Cancer cell line	Male
CVCL_E1X6	HAP1 FEM1A (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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