FRS3

Summary

FRS3 (fibroblast growth factor receptor substrate 3, HGNC:16970) is a protein-coding gene on chromosome 6p21.1, encoding Fibroblast growth factor receptor substrate 3 (O43559). Adapter protein that links FGF and NGF receptors to downstream signaling pathways.

This gene encodes a substrate for the fibroblast growth factor receptor. The encoded protein is found in the peripheral plasma membrane and links fibroblast growth factor receptor stimulation to activators of Ras. The encoded protein down-regulates extracellular regulated kinase 2 through direct binding.

Source: NCBI Gene 10817 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 102 total — 1 likely-pathogenic
• MANE Select transcript: NM_006653

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16970
Approved symbol	FRS3
Name	fibroblast growth factor receptor substrate 3
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	SNT-2, FRS2beta, FRS2B
Ensembl gene	ENSG00000137218
Ensembl biotype	protein_coding
OMIM	607744
Entrez	10817

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000259748, ENST00000373018, ENST00000422888, ENST00000426290, ENST00000466420, ENST00000930712, ENST00000930713, ENST00000930714, ENST00000930715, ENST00000957913, ENST00000957914, ENST00000957915

RefSeq mRNA: 1 — MANE Select: NM_006653 NM_006653

CCDS: CCDS4860

Canonical transcript exons

ENST00000373018 — 7 exons

Exon	Start	End
ENSE00000929687	41770176	41771533
ENSE00000929688	41771816	41771964
ENSE00000929689	41772798	41772959
ENSE00000929690	41775419	41775605
ENSE00001459315	41778033	41778176
ENSE00001459317	41779816	41779900
ENSE00003535106	41776922	41777010

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 88.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.4349 / max 30.4939, expressed in 1257 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73569	2.2747	1226
73570	0.1603	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	88.89	gold quality
anterior cingulate cortex	UBERON:0009835	88.18	gold quality
cingulate cortex	UBERON:0003027	88.15	gold quality
cerebellar hemisphere	UBERON:0002245	87.87	gold quality
cerebellar cortex	UBERON:0002129	87.71	gold quality
prefrontal cortex	UBERON:0000451	87.08	gold quality
cerebellum	UBERON:0002037	86.82	gold quality
right frontal lobe	UBERON:0002810	86.76	gold quality
cortical plate	UBERON:0005343	86.31	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.59	gold quality
neocortex	UBERON:0001950	85.49	gold quality
frontal cortex	UBERON:0001870	85.34	gold quality
frontal lobe	UBERON:0016525	85.34	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.26	gold quality
hypothalamus	UBERON:0001898	85.12	gold quality
amygdala	UBERON:0001876	84.50	gold quality
cerebral cortex	UBERON:0000956	84.12	gold quality
right testis	UBERON:0004534	83.28	gold quality
apex of heart	UBERON:0002098	83.09	gold quality
left testis	UBERON:0004533	83.06	gold quality
substantia nigra	UBERON:0002038	83.02	gold quality
telencephalon	UBERON:0001893	82.87	gold quality
brain	UBERON:0000955	82.70	gold quality
substantia nigra pars reticulata	UBERON:0001966	82.49	gold quality
midbrain	UBERON:0001891	82.48	gold quality
forebrain	UBERON:0001890	82.35	gold quality
lateral nuclear group of thalamus	UBERON:0002736	82.29	gold quality
substantia nigra pars compacta	UBERON:0001965	82.21	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	82.15	gold quality
Ammon’s horn	UBERON:0001954	81.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting FRS3, 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-5692A	100.00	74.40	6850
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-4709-5P	98.51	67.25	1335
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-6847-5P	97.93	66.74	1808

Literature-anchored findings (GeneRIF, showing 6)

• FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors (PMID:11877385)
• FRS2beta can compensate for the loss of FRS2alpha for activation of MAP kinase when expressed in fibroblasts (PMID:15094036)
• SNT-2 negatively regulates ERK2 signaling activated via EGF stimulation through direct binding to ERK2 (PMID:15485655)
• Novel mechanism of negative control of EGFR tyrosine kinase activity with SNT-2 by recruiting ERK2. (PMID:16702953)
• Mechanisms by which FRS2beta acts as a feedback inhibitor of EGFR family members and suggest a role for FRS2beta as a tumor suppressor. (PMID:20228838)
• an FRS2beta-CIN85/CD2AP-Cbl axis for downregulation of ErbB2 may regulate ErbB2 protein levels in physiological and pathological settings (PMID:23279575)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	frs3	ENSDARG00000078688
mus_musculus	Frs3	ENSMUSG00000023266
rattus_norvegicus	Frs3	ENSRNOG00000014328
drosophila_melanogaster	Dok	FBGN0029944
drosophila_melanogaster	CG13398	FBGN0032042
caenorhabditis_elegans		WBGENE00018819

Paralogs (7): DOK5 (ENSG00000101134), DOK1 (ENSG00000115325), DOK4 (ENSG00000125170), DOK3 (ENSG00000146094), DOK2 (ENSG00000147443), FRS2 (ENSG00000166225), DOK6 (ENSG00000206052)

Protein

Protein identifiers

Fibroblast growth factor receptor substrate 3 — O43559 (reviewed: O43559)

Alternative names: FGFR-signaling adaptor SNT2, Suc1-associated neurotrophic factor target 2

All UniProt accessions (4): O43559, A0A0A0MSM8, A0A140VJJ7, A6PVU0

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that links FGF and NGF receptors to downstream signaling pathways. Involved in the activation of MAP kinases. Down-regulates ERK2 signaling by interfering with the phosphorylation and nuclear translocation of ERK2.

Subunit / interactions. Binds NTRK1. Binds FGFR1, NGFR, GRB2, PTPN11 and ERK2.

Subcellular location. Membrane.

Post-translational modifications. Phosphorylated by ULK2 in vitro. Phosphorylated on tyrosine residues upon stimulation by BFGF or NGFB.

RefSeq proteins (1): NP_006644* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002404	IRS_PTB	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR038742	FRS2_PTB	Domain
IPR050996	Docking_Protein_DOK	Family

Pfam: PF02174

UniProt features (20 total): strand 10, region of interest 3, helix 2, initiator methionine 1, chain 1, domain 1, lipid moiety-binding region 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2KUP	SOLUTION NMR
2KUQ	SOLUTION NMR
2YS5	SOLUTION NMR
2YT2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43559-F1	56.94	0.15

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): 2

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654700	FRS-mediated FGFR2 signaling
R-HSA-5654706	FRS-mediated FGFR3 signaling
R-HSA-5654712	FRS-mediated FGFR4 signaling
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-9028731	Activated NTRK2 signals through FRS2 and FRS3
R-HSA-9696270	RND2 GTPase cycle
R-HSA-9696273	RND1 GTPase cycle
R-HSA-9725370	Signaling by ALK fusions and activated point mutants

MSigDB gene sets: 121 (showing top): PID_SHP2_PATHWAY, TGCGCANK_UNKNOWN, REACTOME_SIGNALING_BY_FGFR, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_RESPONSE_TO_FIBROBLAST_GROWTH_FACTOR, GOBP_RESPONSE_TO_GROWTH_FACTOR, RYTTCCTG_ETS2_B, GOBP_FIBROBLAST_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOMF_SIGNALING_RECEPTOR_BINDING, ACEVEDO_LIVER_CANCER_UP, GOBP_CELL_SURFACE_RECEPTOR_PROTEIN_TYROSINE_KINASE_SIGNALING_PATHWAY, GOMF_FIBROBLAST_GROWTH_FACTOR_RECEPTOR_BINDING, NFAT_Q6, PID_TRKR_PATHWAY, GOMF_GROWTH_FACTOR_RECEPTOR_BINDING

GO Biological Process (2): signal transduction (GO:0007165), fibroblast growth factor receptor signaling pathway (GO:0008543)

GO Molecular Function (4): transmembrane receptor protein tyrosine kinase adaptor activity (GO:0005068), fibroblast growth factor receptor binding (GO:0005104), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
RHO GTPase cycle	2
Downstream signaling of activated FGFR1	1
Downstream signaling of activated FGFR2	1
Downstream signaling of activated FGFR3	1
Downstream signaling of activated FGFR4	1
MAPK1/MAPK3 signaling	1
Signaling by NTRK2 (TRKB)	1
Signaling by ALK in cancer	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor protein tyrosine kinase signaling pathway	2
cellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to fibroblast growth factor stimulus	1
signaling receptor complex adaptor activity	1
receptor tyrosine kinase binding	1
growth factor receptor binding	1
protein binding	1
binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

572 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRS3	PTPN11	Q06124	984
FRS3	GRB2	P29354	892
FRS3	FGFR1	P11362	695
FRS3	FGFR2	P18443	607
FRS3	USP49	Q70CQ1	485
FRS3	FLOT1	O75955	483
FRS3	TENM2	Q9NT68	428
FRS3	PRICKLE4	Q2TBC4	418
FRS3	FRS2	Q8WU20	399
FRS3	LETM2	Q2VYF4	397
FRS3	FGF18	O76093	369
FRS3	FGF20	Q9NP95	366
FRS3	SHB	Q15464	365
FRS3	FGF9	P31371	359
FRS3	FGF17	O60258	358

IntAct

345 interactions, top by confidence:

A	B	Type	Score
TRIP6	FRS3	psi-mi:“MI:0915”(physical association)	0.720
FRS3	RFX6	psi-mi:“MI:0915”(physical association)	0.720
FRS3	TRIP6	psi-mi:“MI:0915”(physical association)	0.720
RFX6	FRS3	psi-mi:“MI:0915”(physical association)	0.720
FRS3	FRS3	psi-mi:“MI:0915”(physical association)	0.700
PIK3R3	FRS3	psi-mi:“MI:0915”(physical association)	0.570
PLSCR1	FRS3	psi-mi:“MI:0915”(physical association)	0.560
FRS3	SPRY2	psi-mi:“MI:0915”(physical association)	0.560
TCF4	FRS3	psi-mi:“MI:0915”(physical association)	0.560
FRS3	GATA1	psi-mi:“MI:0915”(physical association)	0.560
FRS3	TLE5	psi-mi:“MI:0915”(physical association)	0.560
ADAMTSL4	FRS3	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	FRS3	psi-mi:“MI:0915”(physical association)	0.560
FRS3	CBY2	psi-mi:“MI:0915”(physical association)	0.560
FRS3	PLSCR1	psi-mi:“MI:0915”(physical association)	0.560
FRS3	TCF4	psi-mi:“MI:0915”(physical association)	0.560
GATA1	FRS3	psi-mi:“MI:0915”(physical association)	0.560
TLE5	FRS3	psi-mi:“MI:0915”(physical association)	0.560
FRS3	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.560
CBY2	FRS3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (127): SH3KBP1 (Affinity Capture-Western), CD2AP (Affinity Capture-Western), CBL (Affinity Capture-Western), ERBB2 (Affinity Capture-Western), FRS3 (Two-hybrid), FRS3 (Two-hybrid), FRS3 (Two-hybrid), FRS3 (Two-hybrid), FRS3 (Two-hybrid), FRS3 (Two-hybrid), ADAMTSL4 (Two-hybrid), SPERT (Two-hybrid), RFX6 (Two-hybrid), NOTCH2NL (Two-hybrid), MATK (Two-hybrid)

ESM2 similar proteins: A0A8I5KY20, A4IHR5, A7UKY7, A8IHN8, D3YYI7, G3V9M2, O43559, P39881, P49796, Q13387, Q14DQ1, Q2TAM9, Q32KV8, Q3UPL5, Q4VA45, Q5VUJ9, Q5VV17, Q5XKK7, Q62392, Q673H1, Q6NV74, Q6PJ61, Q6QHK4, Q6UXB0, Q7Z6J2, Q80TE3, Q86SH2, Q8BWU3, Q8CE64, Q8IWP9, Q8N554, Q8NFT6, Q8R4T5, Q8TC41, Q8VCC6, Q8WV24, Q96HA4, Q96IQ9, Q96SQ7, Q96T92

Diamond homologs: A3R064, A7MBB8, B2RYG7, O43559, O60496, O70469, P97465, Q4QQV2, Q52RG8, Q5EA84, Q7L591, Q8C180, Q8WU20, Q91WJ0, Q99704, Q9QZK7, Q5RA30, Q8TEW6, Q99KE3, Q2MHE5, Q6PKX4, Q91ZM9, Q9P104

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NTRK2	“up-regulates activity”	FRS3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 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
Keratinization	11	10.9×	7e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	86
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
518451	t(6;17)(p21.1;q24.3)	Likely pathogenic

SpliceAI

2462 predictions. Top by Δscore:

Variant	Effect	Δscore
6:41771534:C:CC	acceptor_gain	1.0000
6:41772792:CCTCA:C	donor_loss	1.0000
6:41772793:CTCAC:C	donor_loss	1.0000
6:41772794:TCACC:T	donor_loss	1.0000
6:41772795:CACCA:C	donor_loss	1.0000
6:41772796:ACCAT:A	donor_loss	1.0000
6:41772797:C:CA	donor_loss	1.0000
6:41772836:G:C	donor_gain	1.0000
6:41772955:TATTC:T	acceptor_gain	1.0000
6:41772957:TTC:T	acceptor_gain	1.0000
6:41772958:TCC:T	acceptor_loss	1.0000
6:41772959:CCT:C	acceptor_loss	1.0000
6:41772961:T:A	acceptor_loss	1.0000
6:41775415:TCACC:T	donor_loss	1.0000
6:41775416:CACC:C	donor_loss	1.0000
6:41775417:A:AC	donor_gain	1.0000
6:41775417:AC:A	donor_gain	1.0000
6:41775417:ACC:A	donor_gain	1.0000
6:41775418:C:CC	donor_gain	1.0000
6:41775418:CC:C	donor_gain	1.0000
6:41775418:CCC:C	donor_gain	1.0000
6:41775418:CCCT:C	donor_gain	1.0000
6:41775418:CCCTG:C	donor_gain	1.0000
6:41775601:GTCAC:G	acceptor_gain	1.0000
6:41775602:TCAC:T	acceptor_gain	1.0000
6:41775603:CAC:C	acceptor_gain	1.0000
6:41775603:CACC:C	acceptor_gain	1.0000
6:41775604:AC:A	acceptor_gain	1.0000
6:41775605:CC:C	acceptor_gain	1.0000
6:41775605:CCTG:C	acceptor_loss	1.0000

AlphaMissense

3207 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:41772947:A:G	F89S	1.000
6:41772952:A:C	F87L	1.000
6:41772952:A:T	F87L	1.000
6:41772954:A:G	F87L	1.000
6:41775451:A:G	F74S	1.000
6:41775457:A:G	F72S	1.000
6:41775503:A:G	W57R	1.000
6:41775503:A:T	W57R	1.000
6:41772911:A:G	L101P	0.999
6:41772919:G:C	F98L	0.999
6:41772919:G:T	F98L	0.999
6:41772921:A:G	F98L	0.999
6:41772942:A:G	C91R	0.999
6:41772946:A:C	F89L	0.999
6:41772946:A:T	F89L	0.999
6:41772948:A:G	F89L	0.999
6:41772953:A:G	F87S	0.999
6:41775434:A:G	C80R	0.999
6:41775444:A:C	S76R	0.999
6:41775444:A:T	S76R	0.999
6:41775446:T:G	S76R	0.999
6:41775450:A:C	F74L	0.999
6:41775450:A:T	F74L	0.999
6:41775452:A:G	F74L	0.999
6:41775460:A:G	L71P	0.999
6:41775475:C:T	G66D	0.999
6:41775479:A:C	Y65D	0.999
6:41775487:A:G	L62S	0.999
6:41775501:C:A	W57C	0.999
6:41775501:C:G	W57C	0.999

dbSNP variants (sampled 300 via entrez): RS1000013226 (6:41774282 C>T), RS1000089694 (6:41773144 C>G,T), RS1000699759 (6:41774710 G>A), RS1000991174 (6:41776723 G>A,C), RS1001140650 (6:41774790 G>A), RS1001295107 (6:41781253 G>A), RS1001519293 (6:41774354 G>A), RS1002048778 (6:41769984 G>A), RS1002804714 (6:41776282 G>A,C), RS1003087196 (6:41776407 G>A), RS1003099003 (6:41777273 A>G), RS1003137849 (6:41777657 G>A,T), RS1003367764 (6:41772059 G>A,T), RS1003424569 (6:41777951 T>C), RS1003441712 (6:41770937 A>C,T)

Disease associations

OMIM: gene MIM:607744 | disease phenotypes: MIM:114290

GenCC curated gene-disease

Mondo (1): campomelic dysplasia (MONDO:0007251)

Orphanet (1): Campomelic dysplasia (Orphanet:140)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002541_21	Menarche (age at onset)	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D055036	Campomelic Dysplasia	C05.660.142; C16.131.621.142

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
decabromobiphenyl ether	affects expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases abundance, increases expression	1
bleomycetin	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
ICG 001	increases expression	1
jinfukang	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Dimethyl Sulfoxide	affects expression	1
Manganese	increases abundance, increases expression	1
Phenytoin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Acrylamide	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06529848	Not specified	RECRUITING	Impact of Exercise Training on Ischemia With Non-Obstructive Coronary Arteries (INOCA): The ExINOCA Study