FRS2

Summary

FRS2 (fibroblast growth factor receptor substrate 2, HGNC:16971) is a protein-coding gene on chromosome 12q15, encoding Fibroblast growth factor receptor substrate 2 (Q8WU20). Adapter protein that links activated FGR and NGF receptors to downstream signaling pathways.

Enables fibroblast growth factor receptor binding activity and neurotrophin TRKA receptor binding activity. Involved in negative regulation of cardiac muscle cell differentiation. Acts upstream of or within fibroblast growth factor receptor signaling pathway. Located in adherens junction. Biomarker of renal cell carcinoma.

Source: NCBI Gene 10818 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 70 total
• Druggable target: yes
• MANE Select transcript: NM_001278356

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16971
Approved symbol	FRS2
Name	fibroblast growth factor receptor substrate 2
Location	12q15
Locus type	gene with protein product
Status	Approved
Aliases	SNT-1, FRS2alpha, SNT1, FRS2A
Ensembl gene	ENSG00000166225
Ensembl biotype	protein_coding
OMIM	607743
Entrez	10818

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 26 protein_coding

ENST00000397997, ENST00000547219, ENST00000547414, ENST00000548154, ENST00000549092, ENST00000549921, ENST00000550169, ENST00000550316, ENST00000550389, ENST00000550937, ENST00000551325, ENST00000872616, ENST00000872617, ENST00000872618, ENST00000872619, ENST00000872620, ENST00000872621, ENST00000872622, ENST00000934305, ENST00000934306, ENST00000934307, ENST00000934308, ENST00000934309, ENST00000948178, ENST00000948179, ENST00000948180

RefSeq mRNA: 8 — MANE Select: NM_001278356 NM_001042555, NM_001278351, NM_001278353, NM_001278354, NM_001278355, NM_001278356, NM_001278357, NM_006654

CCDS: CCDS41809

Canonical transcript exons

ENST00000549921 — 9 exons

Exon	Start	End
ENSE00001101177	69570331	69570517
ENSE00001101184	69572118	69572281
ENSE00001101187	69569005	69569096
ENSE00001101189	69571276	69571434
ENSE00001206504	69562180	69562274
ENSE00001720664	69530865	69530960
ENSE00001724775	69532014	69532056
ENSE00002359773	69470388	69470530
ENSE00002386257	69574005	69579793

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 95.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.3596 / max 3050.4609, expressed in 1795 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126709	20.3431	1795
206791	0.0165	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	95.12	gold quality
adrenal tissue	UBERON:0018303	94.83	gold quality
tendon	UBERON:0000043	90.04	gold quality
endothelial cell	CL:0000115	89.93	silver quality
ventricular zone	UBERON:0003053	87.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.76	gold quality
cortical plate	UBERON:0005343	86.55	gold quality
colonic epithelium	UBERON:0000397	86.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.53	gold quality
ganglionic eminence	UBERON:0004023	84.33	gold quality
islet of Langerhans	UBERON:0000006	84.20	gold quality
stromal cell of endometrium	CL:0002255	83.95	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.74	gold quality
corpus epididymis	UBERON:0004359	83.49	gold quality
gall bladder	UBERON:0002110	83.15	gold quality
medial globus pallidus	UBERON:0002477	83.07	gold quality
corpus callosum	UBERON:0002336	82.67	gold quality
tendon of biceps brachii	UBERON:0008188	81.99	gold quality
monocyte	CL:0000576	81.66	gold quality
mononuclear cell	CL:0000842	81.37	gold quality
spinal cord	UBERON:0002240	81.28	gold quality
leukocyte	CL:0000738	81.18	gold quality
primary visual cortex	UBERON:0002436	80.91	gold quality
rectum	UBERON:0001052	80.33	gold quality
secondary oocyte	CL:0000655	80.21	gold quality
popliteal artery	UBERON:0002250	80.21	gold quality
tibial artery	UBERON:0007610	80.21	gold quality
tibial nerve	UBERON:0001323	79.77	gold quality
descending thoracic aorta	UBERON:0002345	79.58	gold quality
prefrontal cortex	UBERON:0000451	79.50	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	1303.05
E-ANND-3	yes	5.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

255 targeting FRS2, 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-98-3P	100.00	74.08	3907
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AA	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 40)

• FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors (PMID:11877385)
• FRS2 has a role in fibroblast growth factor-2-induced signaling (PMID:12571252)
• findings support a broader role of FRS2 in EGFR-controlled signaling pathways in A-431 cells and provide insight into a molecular mechanism for ligand-stimulated feedback regulation with FRS2 as a central regulatory switch point (PMID:12974390)
• FRS2-dependent SRC activation is required for FGFR-induced phosphorylation of Sprouty and suppression of ERK activity (PMID:15564375)
• Bisindolylmaleimide I does not inhibit FGF2-induced tyrosine phosphorylation of Frs2. (PMID:17145761)
• an important function for FRS2 is to concentrate RET in membrane foci, leading to an engagement of specific signaling complexes localized in these membrane domains (PMID:18189271)
• a dual mechanism where deletion of the 770YXXL773 motif promotes FGFR2 IIIb C3 transforming activity by causing aberrant receptor recycling and stability and persistent FRS2-dependent signaling. (PMID:19103595)
• Mechanical wounding induces significant ROS generation at the wound edge which, in turn, induced ligand-independent KGFR and FRS2 activation via c-Src kinase signaling. (PMID:19111446)
• Phosphorylation of Fibroblast growth factor receptor substrate 2alpha may function as a molecular switch in the FGF pathway, sensing and participating in crosstalk with other signaling pathways. (PMID:19652666)
• The signaling complex appears to integrate the input from FGFR and EphA4, and release the output signal through FRS2alpha. (PMID:20184660)
• Microdeformations produced by the combination of polyurethane foam and suction are associated with increased fibroblast proliferation and up-regulation of gene expressions in fibroblasts (PMID:21233699)
• Validated FRS2 amplification in both Well-differentiated liposarcoma and dedifferentiated liposarcoma. (PMID:21793095)
• Patient with pigmentation disorders and vitiligo show decreased expression of mRNA. (PMID:22151832)
• a novel signaling network containing FRS2, CAP and flotillin-1 (PMID:22235335)
• Data indicate that the FGFR/FRS2 signaling axis was generally activated in about 75% of FRS2-positive high-grade liposarcomas. (PMID:23393200)
• These results establish the Frs2alpha-Shp2 complex as the key mediator of FGF signaling in lens development. (PMID:24284065)
• The docking protein FRS2alpha is a critical regulator of VEGF receptors signaling. (PMID:24706887)
• Results identify FRS2 as an oncogene in a subset of high-grade serous ovarian cancers that harbor FRS2 amplifications. (PMID:25368431)
• Increased expression of FRS2alpha (and FGFR1) was associated with decreased progression-free survival among patients with metastatic renal cell carcinoma treated with sorafenib. (PMID:25900027)
• They also demonstrate the potential of overexpressed FRS2alpha as a biomarker for prostate cancer diagnosis, prognosis and response to therapies. (PMID:26096936)
• MiR-4653-3p and its target gene FRS2 are may have roles in response of hormone receptor positive breast cancer patients to tamoxifen (PMID:27533459)
• we report for the first time that PKD1 was tightly regulated by androgen at the transcriptional level in prostate cancer cells and was a novel androgen-repressed gene. Further analysis identified FRS2 as a novel mediator of androgen-induced PKD1 repression. (PMID:28077787)
• These findings suggest that FRS2 is amplified consistently in liposarcoma. (PMID:29368794)
• loss of myristoylation of fibroblast growth factor receptor substrate 2 (FRS2alpha), a scaffold protein essential for FGFR signaling, inhibits FGF/FGFR-mediated oncogenic signaling and FGF10-induced tumorigenesis. Moreover, a previously synthesized myristoyl-CoA analog, B13, which targets the activity of N-myristoyltransferases. (PMID:29540482)
• the FRS2 gene is consistently amplified in classic and dedifferentiated low-grade osteosarcomas (PMID:30001240)
• Authors find recurrent ADGRG6 enhancer mutations and FRS2 duplications which are associated with higher protein expression in the tumor and poor prognosis. Functional assays demonstrate that depletion of ADGRG6 or FRS2 expression in UBC cells compromise their abilities to recruit endothelial cells and induce tube formation. (PMID:30755618)
• inhibition of FGF signaling by silencing FGF receptor substrate 2 (FRS2) decreased the protein expression levels of various chemokines (PMID:31115530)
• Results found that FRS2 expression was downregulated in nephroblastoma tissues and cell lines. Furthermore, its expression was directly regulated by miR-200c. (PMID:31194576)
• Genomic coamplification of CDK4/MDM2/FRS2 is associated with very poor prognosis and atypical clinical features in neuroblastoma patients. (PMID:31756773)
• MiR-140-5p and miR-92a-3p suppress the cell proliferation, migration and invasion and promoted apoptosis in Wilms’ tumor by targeting FRS2. (PMID:31957822)
• LncRNA ANRIL regulates cell proliferation and migration via sponging miR-339-5p and regulating FRS2 expression in atherosclerosis. (PMID:32141564)
• Upregulation of lncRNA ZFAS1 promotes lung adenocarcinoma progression by sponging miR-1271-5p and upregulating FRS2. (PMID:32515146)
• MiR-96 promotes apoptosis of nucleus pulpous cells by targeting FRS2. (PMID:32578051)
• Circular RNA circUBR4 regulates ox-LDL-induced proliferation and migration of vascular smooth muscle cells through miR-185-5p/FRS2 axis. (PMID:34159479)
• Long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) regulates fibroblast growth factor receptor substrate 2 (FRS2) by targeting microRNA (miR)-29-3p in hypertrophic scar fibroblasts. (PMID:34414852)
• Expression of FRS2 in atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma: an immunohistochemical analysis of 182 cases with genetic data. (PMID:34696768)
• Hsa_circ_0093741 competes with FRS2 for miR-562 binding sites to promote nephroblastoma progression. (PMID:36286392)
• Over-expression of microRNA-145 Elevating Autophagy Activities via Downregulating FRS2 Expression. (PMID:37264620)
• Expression of fibroblast growth factor receptor substrate 2 (FRS2) in primary retroperitoneal liposarcoma and its clinical implications. (PMID:37458641)
• FRS2 regulated by miR-429 and miR-206 promotes angiogenesis in osteosarcoma. (PMID:38159618)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	frs2b	ENSDARG00000037353
danio_rerio	frs2a	ENSDARG00000045873
mus_musculus	Frs2	ENSMUSG00000020170
rattus_norvegicus	Frs2	ENSRNOG00000005642
drosophila_melanogaster	Dok	FBGN0029944
drosophila_melanogaster	CG13398	FBGN0032042
caenorhabditis_elegans		WBGENE00018819

Paralogs (7): DOK5 (ENSG00000101134), DOK1 (ENSG00000115325), DOK4 (ENSG00000125170), FRS3 (ENSG00000137218), DOK3 (ENSG00000146094), DOK2 (ENSG00000147443), DOK6 (ENSG00000206052)

Protein

Protein identifiers

Fibroblast growth factor receptor substrate 2 — Q8WU20 (reviewed: Q8WU20)

Alternative names: FGFR-signaling adaptor SNT, Suc1-associated neurotrophic factor target 1

All UniProt accessions (10): A0A0G2JL00, Q8WU20, F8VP54, F8VS98, F8VW66, F8VX65, F8VYZ7, F8VZ12, F8VZI4, L7RTG7

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that links activated FGR and NGF receptors to downstream signaling pathways. Plays an important role in the activation of MAP kinases and in the phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, in response to ligand-mediated activation of FGFR1. Modulates signaling via SHC1 by competing for a common binding site on NTRK1.

Subunit / interactions. Part of a complex containing FRS2, GRB2, GAB1, PIK3R1 and SOS1. Part of a complex containing GRB2 and CBL. Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Binds RET. Binds ALK, FGFR1, CKS2, MAPK1/ERK2, MAPK3/ERK1 and SRC. The tyrosine-phosphorylated protein binds the SH2 domains of GRB2 and PTPN11. Interacts with NTRK1, NTRK2 and NTRK3 (phosphorylated upon ligand-binding).

Subcellular location. Endomembrane system.

Tissue specificity. Highly expressed in heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis.

Post-translational modifications. Phosphorylated by ULK2 in vitro. Phosphorylated on tyrosine residues upon stimulation by NGF or FGF2. Phosphorylated on tyrosine residues by activated ALK and FGFR1. Phosphorylated on tyrosine residues upon activation of FGFR2 and FGFR3. Phosphorylated on threonine residues by MAP kinases; this inhibits tyrosine phosphorylation, and thereby down-regulates FRS2-mediated activation of MAP kinases. Ubiquitinated when tyrosine phosphorylated and in a complex with GRB2. The unphosphorylated form is not subject to ubiquitination.

RefSeq proteins (8): NP_001036020, NP_001265280, NP_001265282, NP_001265283, NP_001265284, NP_001265285, NP_001265286, NP_006645 (=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 (39 total): modified residue 10, strand 8, region of interest 7, compositionally biased region 4, turn 3, sequence variant 2, initiator methionine 1, chain 1, domain 1, lipid moiety-binding region 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1XR0	SOLUTION NMR
2MFQ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WU20-F1	57.98	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 (11): 177, 196, 211, 221, 306, 349, 365, 392, 436, 471, 2

Function

Pathways and Gene Ontology

Reactome pathways

28 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-170968	Frs2-mediated activation
R-HSA-201556	Signaling by ALK
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5654689	PI-3K cascade:FGFR1
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654695	PI-3K cascade:FGFR2
R-HSA-5654700	FRS-mediated FGFR2 signaling
R-HSA-5654706	FRS-mediated FGFR3 signaling
R-HSA-5654710	PI-3K cascade:FGFR3
R-HSA-5654712	FRS-mediated FGFR4 signaling
R-HSA-5654720	PI-3K cascade:FGFR4
R-HSA-5654726	Negative regulation of FGFR1 signaling
R-HSA-5654727	Negative regulation of FGFR2 signaling
R-HSA-5654732	Negative regulation of FGFR3 signaling
R-HSA-5654733	Negative regulation of FGFR4 signaling
R-HSA-5655253	Signaling by FGFR2 in disease
R-HSA-5655291	Signaling by FGFR4 in disease
R-HSA-5655302	Signaling by FGFR1 in disease
R-HSA-5655332	Signaling by FGFR3 in disease
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8853659	RET signaling
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: 371 (showing top): PID_SHP2_PATHWAY, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_AXIS_SPECIFICATION, GOBP_GLAND_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_PROSTATE_GLAND_MORPHOGENESIS, GOBP_EMBRYONIC_AXIS_SPECIFICATION, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_EPITHELIAL_CELL_DEVELOPMENT

GO Biological Process (19): gastrulation with mouth forming second (GO:0001702), organ induction (GO:0001759), ventricular septum development (GO:0003281), cell surface receptor protein tyrosine phosphatase signaling pathway (GO:0007185), G protein-coupled receptor signaling pathway (GO:0007186), neuroblast proliferation (GO:0007405), fibroblast growth factor receptor signaling pathway (GO:0008543), anterior/posterior axis specification, embryo (GO:0008595), forebrain development (GO:0030900), regulation of apoptotic process (GO:0042981), positive regulation of MAPK cascade (GO:0043410), lens placode formation involved in camera-type eye formation (GO:0046619), regulation of epithelial cell proliferation (GO:0050678), prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis (GO:0060527), lens fiber cell development (GO:0070307), regulation of ERK1 and ERK2 cascade (GO:0070372), negative regulation of cardiac muscle cell differentiation (GO:2000726), lens development in camera-type eye (GO:0002088), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169)

GO Molecular Function (5): transmembrane receptor protein tyrosine kinase adaptor activity (GO:0005068), fibroblast growth factor receptor binding (GO:0005104), neurotrophin TRKA receptor binding (GO:0005168), phosphatase activator activity (GO:0019211), protein binding (GO:0005515)

GO Cellular Component (7): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), adherens junction (GO:0005912), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Signaling by FGFR in disease	3
Downstream signaling of activated FGFR1	2
Downstream signaling of activated FGFR2	2
Downstream signaling of activated FGFR3	2
Downstream signaling of activated FGFR4	2
IRS-mediated signalling	1
Intracellular signaling by second messengers	1
Prolonged ERK activation events	1
Signaling by Receptor Tyrosine Kinases	1
PI3K/AKT Signaling in Cancer	1
Signaling by FGFR1	1
Signaling by FGFR2	1
Signaling by FGFR3	1
Signaling by FGFR4	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
enzyme-linked receptor protein signaling pathway	2
cell surface receptor protein tyrosine kinase signaling pathway	2
anatomical structure development	2
regulation of MAPK cascade	2
gastrulation	1
regulation of animal organ formation	1
specification of animal organ identity	1
developmental induction	1
positive regulation of animal organ morphogenesis	1
cardiac ventricle development	1
cardiac septum development	1
G protein-coupled receptor activity	1
signal transduction	1
generation of neurons	1
neural precursor cell proliferation	1
cellular response to fibroblast growth factor stimulus	1
embryonic axis specification	1
tripartite regional subdivision	1
anterior/posterior axis specification	1
brain development	1
apoptotic process	1
regulation of programmed cell death	1
MAPK cascade	1
positive regulation of intracellular signal transduction	1
lens placode formation	1
embryonic camera-type eye formation	1
regulation of cell population proliferation	1
epithelial cell proliferation	1
branching involved in prostate gland morphogenesis	1
prostate glandular acinus morphogenesis	1
epithelial cell development	1
lens fiber cell differentiation	1
ERK1 and ERK2 cascade	1
negative regulation of striated muscle cell differentiation	1
cardiac muscle cell differentiation	1
negative regulation of cardiocyte differentiation	1
regulation of cardiac muscle cell differentiation	1
camera-type eye development	1
signaling receptor complex adaptor activity	1

Protein interactions and networks

STRING

1142 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FRS2	GRB2	P29354	998
FRS2	PTPN11	Q06124	995
FRS2	FGFR1	P11362	987
FRS2	CRK	P46108	972
FRS2	SOS1	Q07889	962
FRS2	FGFR2	P18443	928
FRS2	GAB1	Q13480	911
FRS2	SOS2	Q07890	902
FRS2	SHC1	P29353	892
FRS2	FGFR4	P22455	890
FRS2	SRC	P12931	864
FRS2	FGF10	O15520	843
FRS2	FGF20	Q9NP95	838
FRS2	FGF6	P10767	838
FRS2	FGF9	P31371	825

IntAct

41 interactions, top by confidence:

A	B	Type	Score
PTPN11	FRS2	psi-mi:“MI:2364”(proximity)	0.650
PTPN11	FRS2	psi-mi:“MI:0915”(physical association)	0.650
PTPN11	FRS2	psi-mi:“MI:0914”(association)	0.650
FRS2	FGFR1	psi-mi:“MI:0914”(association)	0.570
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
BECN1	FRS2	psi-mi:“MI:0915”(physical association)	0.370
FRS2	RPS6	psi-mi:“MI:0915”(physical association)	0.370
FRS2	iglC2	psi-mi:“MI:0915”(physical association)	0.370
SH2B1	Fgfr1	psi-mi:“MI:0914”(association)	0.350
suc1	SOS1	psi-mi:“MI:0914”(association)	0.350
Coro1c	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
FGFR1	NDUFA4	psi-mi:“MI:0914”(association)	0.350
NTRK2	GNAI3	psi-mi:“MI:0914”(association)	0.350
NTRK3	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC16A10	STXBP3	psi-mi:“MI:0914”(association)	0.350
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
CDH1	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
KCNJ2	PIK3R2	psi-mi:“MI:2364”(proximity)	0.270
ALK	NUDT19	psi-mi:“MI:2364”(proximity)	0.270
EGFR	FAM171A2	psi-mi:“MI:2364”(proximity)	0.270
EPHA4	FAM171A2	psi-mi:“MI:2364”(proximity)	0.270
FGFR1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
FGFR2	APBB1	psi-mi:“MI:2364”(proximity)	0.270
FGFR3	AIP	psi-mi:“MI:2364”(proximity)	0.270
FGFR4	SH3PXD2B	psi-mi:“MI:2364”(proximity)	0.270
LTK	AIP	psi-mi:“MI:2364”(proximity)	0.270
NTRK1	C1orf226	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (165): BECN1 (Two-hybrid), RPS6 (Two-hybrid), FRS2 (Proximity Label-MS), FRS2 (Affinity Capture-MS), GRB2 (Affinity Capture-Western), PTPN11 (Affinity Capture-Western), FRS2 (Affinity Capture-Western), FRS2 (Affinity Capture-Western), Ptpn11 (Affinity Capture-Western), Grb2 (Affinity Capture-Western), Gab1 (Affinity Capture-Western), FRS2 (Proximity Label-MS), FRS2 (Biochemical Activity), FRS2 (Affinity Capture-RNA), FGFR2 (Affinity Capture-Western)

ESM2 similar proteins: A5PMU4, A6QLU3, O89032, P35568, P35569, P35570, P81122, P84770, Q06649, Q13094, Q13191, Q13480, Q13625, Q1LY51, Q1LYG0, Q28224, Q3TTA7, Q4KM52, Q5NBX1, Q5RJW5, Q5TCZ1, Q60787, Q62415, Q6DFR2, Q6GQL0, Q6P4Y6, Q6ZNC4, Q80UZ0, Q8BM65, Q8BSM5, Q8C180, Q8CG79, Q8IVF5, Q8TEW8, Q8WU20, Q8WV28, Q8WWW8, Q91615, Q93073, Q96KQ4

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

11 interactions.

A	Effect	B	Mechanism
RET	up-regulates	FRS2	binding
INSR	“up-regulates activity”	FRS2	phosphorylation
FGFR1	“up-regulates activity”	FRS2	phosphorylation
FRS2	up-regulates	PTPN11	phosphorylation
NTRK1	up-regulates	FRS2	binding
CBL	down-regulates	FRS2	ubiquitination
FRS2	up-regulates	GRAP	binding
FGFR2	“up-regulates activity”	FRS2	phosphorylation
FRS2	“up-regulates activity”	GRB2	binding
FGFR4	“up-regulates activity”	FRS2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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
PI3K Cascade	7	46.4×	2e-08
Constitutive Signaling by Aberrant PI3K in Cancer	10	30.9×	3e-10
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	10	23.6×	2e-09
PIP3 activates AKT signaling	10	16.3×	4e-08
RAF/MAP kinase cascade	9	13.4×	2e-06
RAC1 GTPase cycle	5	7.5×	4e-03
Diseases of signal transduction by growth factor receptors and second messengers	5	6.9×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
fibroblast growth factor receptor signaling pathway	7	46.5×	5e-08
epidermal growth factor receptor signaling pathway	5	28.8×	6e-05
cell surface receptor protein tyrosine kinase signaling pathway	6	24.2×	2e-05
positive regulation of neuron projection development	7	22.3×	6e-06
protein autophosphorylation	6	20.3×	4e-05
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	10	18.2×	5e-08
positive regulation of ERK1 and ERK2 cascade	7	13.9×	5e-05
positive regulation of MAPK cascade	7	13.1×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	63
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2367 predictions. Top by Δscore:

Variant	Effect	Δscore
12:69561664:T:A	acceptor_gain	1.0000
12:69562175:TTTA:T	acceptor_loss	1.0000
12:69562177:TA:T	acceptor_loss	1.0000
12:69562178:A:AG	acceptor_gain	1.0000
12:69562178:AGGT:A	acceptor_loss	1.0000
12:69562179:G:A	acceptor_loss	1.0000
12:69562179:G:GA	acceptor_gain	1.0000
12:69562179:GGT:G	acceptor_gain	1.0000
12:69562179:GGTT:G	acceptor_gain	1.0000
12:69562179:GGTTA:G	acceptor_gain	1.0000
12:69562270:TCTAG:T	donor_gain	1.0000
12:69562271:CTAGG:C	donor_loss	1.0000
12:69562272:TAGG:T	donor_loss	1.0000
12:69562275:G:GG	donor_gain	1.0000
12:69562275:GTA:G	donor_loss	1.0000
12:69562276:T:A	donor_loss	1.0000
12:69568999:A:AG	acceptor_gain	1.0000
12:69568999:AT:A	acceptor_gain	1.0000
12:69569000:T:G	acceptor_gain	1.0000
12:69569000:T:TA	acceptor_gain	1.0000
12:69569001:GTA:G	acceptor_loss	1.0000
12:69569002:TA:T	acceptor_loss	1.0000
12:69569003:A:AC	acceptor_loss	1.0000
12:69569003:A:AG	acceptor_gain	1.0000
12:69569003:AGT:A	acceptor_gain	1.0000
12:69569004:G:GT	acceptor_gain	1.0000
12:69569004:GT:G	acceptor_gain	1.0000
12:69569004:GTG:G	acceptor_gain	1.0000
12:69569004:GTGC:G	acceptor_gain	1.0000
12:69569004:GTGCA:G	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000003443 (12:69515133 A>G), RS1000014146 (12:69556011 G>C,T), RS1000029367 (12:69579343 T>A,C), RS1000037503 (12:69493906 A>G), RS1000047638 (12:69522319 A>G), RS1000052036 (12:69472174 A>G), RS1000056667 (12:69479948 G>A), RS1000129951 (12:69479610 A>T), RS1000194298 (12:69529640 A>T), RS1000230360 (12:69558115 T>C), RS1000247824 (12:69491492 G>A), RS1000250629 (12:69532958 T>A), RS1000262975 (12:69562000 A>G,T), RS1000274166 (12:69575923 A>G,T), RS1000280071 (12:69503647 T>C)

Disease associations

OMIM: gene MIM:607743 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000175_26	Height	3.000000e-06
GCST000208_1	Response to diuretic therapy	3.000000e-07
GCST000817_190	Height	2.000000e-20
GCST001956_55	Height	7.000000e-15
GCST002647_49	Height	4.000000e-29
GCST002702_99	Height	7.000000e-07
GCST004067_122	Hip circumference adjusted for BMI	9.000000e-07
GCST004067_8	Hip circumference adjusted for BMI	4.000000e-09
GCST006979_1068	Heel bone mineral density	3.000000e-09
GCST007006_11	Logical memory (delayed recall) in normal cognition	4.000000e-07
GCST007061_1	Response to antidepressants (symptom remission)	4.000000e-06
GCST007424_1	Complete remission in asthma	5.000000e-07
GCST008790_45	Urinary albumin-to-creatinine ratio	4.000000e-14
GCST008791_16	Microalbuminuria	3.000000e-11
GCST008839_58	Height	6.000000e-18
GCST010653_21	Thyroid stimulating hormone levels	2.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0009270	heel bone mineral density
EFO:0004874	memory performance
EFO:0009785	remission
EFO:0007778	urinary albumin to creatinine ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291586 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.23	IC50	59	nM	CHEMBL3964954
7.05	IC50	89	nM	CHEMBL3964954
7.03	IC50	93	nM	CHEMBL3964954

PubChem BioAssay actives

3 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[3-(2,4-difluorophenyl)-5-[5-(1-methylpyrazol-4-yl)benzimidazol-1-yl]phenyl]cyclopropanesulfonamide	1937903: Inhibition of FRS2 phosphorylation at Tyr196 residue in human SNU-16 cells incubated for 20 mins by electrochemiluminescence method	ic50	0.0590	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression	3
Valproic Acid	decreases expression, increases expression	3
Formaldehyde	decreases expression, increases expression	2
Quercetin	increases expression, increases phosphorylation	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
potassium chromate(VI)	affects cotreatment, increases expression	1
coumarin	decreases phosphorylation	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
monomethylarsonous acid	increases expression	1
abrine	increases expression	1
pyrachlostrobin	decreases expression	1
jinfukang	decreases expression	1
picoxystrobin	decreases expression	1
PCI 5002	increases expression, affects cotreatment	1
AZD4547	increases phosphorylation	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5241396	Binding	Inhibition of FRS2 phosphorylation at Tyr196 residue in human NCI-H1581 cells incubated for 20 mins by electrochemiluminescence method	Recent advances of dual FGFR inhibitors as a novel therapy for cancer. — Eur J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1XT	HAP1 FRS2 (-) 1	Cancer cell line	Male
CVCL_E1XU	HAP1 FRS2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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