SPRED3

Summary

SPRED3 (sprouty related EVH1 domain containing 3, HGNC:31041) is a protein-coding gene on chromosome 19q13, encoding Sprouty-related, EVH1 domain-containing protein 3 (Q2MJR0). Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase.

This gene encodes a protein with a C-terminal Sprouty-like cysteine-rich domain (SRY) and an N-terminal Ena/Vasodilator-stimulated phosphoprotein (VASP) homology-1 (EVH-1) domain. The encoded protein is a member of a family of proteins that negatively regulates mitogen-activated protein (MAP) kinase signaling, particularly during organogenesis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 399473 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 77 total
• MANE Select transcript: NM_001394336

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31041
Approved symbol	SPRED3
Name	sprouty related EVH1 domain containing 3
Location	19q13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000188766
Ensembl biotype	protein_coding
OMIM	609293
Entrez	399473

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000338502, ENST00000586301, ENST00000586958, ENST00000587013, ENST00000587564, ENST00000587947, ENST00000590962, ENST00000691638, ENST00000921746, ENST00000921747

RefSeq mRNA: 4 — MANE Select: NM_001394336 NM_001042522, NM_001394336, NM_001394337, NM_001394338

CCDS: CCDS42560

Canonical transcript exons

ENST00000691638 — 6 exons

Exon	Start	End
ENSE00001366465	38394643	38394786
ENSE00001389754	38395480	38399587
ENSE00003513664	38390299	38390479
ENSE00003531567	38392212	38392288
ENSE00003638155	38391946	38392114
ENSE00003931145	38388697	38388807

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 97.63.

FANTOM5 (CAGE): breadth broad, TPM avg 1.1492 / max 19.2564, expressed in 671 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175629	1.1492	671

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	97.63	silver quality
parotid gland	UBERON:0001831	94.66	silver quality
lateral nuclear group of thalamus	UBERON:0002736	94.26	silver quality
vena cava	UBERON:0004087	93.60	silver quality
epithelial cell of pancreas	CL:0000083	92.90	silver quality
lateral globus pallidus	UBERON:0002476	92.63	silver quality
heart right ventricle	UBERON:0002080	91.96	silver quality
substantia nigra pars reticulata	UBERON:0001966	91.09	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.85	silver quality
body of tongue	UBERON:0011876	90.56	silver quality
pons	UBERON:0000988	90.35	silver quality
dorsal plus ventral thalamus	UBERON:0001897	90.32	silver quality
subthalamic nucleus	UBERON:0001906	90.25	silver quality
substantia nigra pars compacta	UBERON:0001965	89.91	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.80	silver quality
biceps brachii	UBERON:0001507	88.37	silver quality
cerebellar vermis	UBERON:0004720	88.25	silver quality
pericardium	UBERON:0002407	88.12	silver quality
tendon of biceps brachii	UBERON:0008188	88.12	silver quality
pylorus	UBERON:0001166	88.09	silver quality
tongue	UBERON:0001723	87.81	silver quality
inferior vagus X ganglion	UBERON:0005363	87.78	silver quality
ventral tegmental area	UBERON:0002691	87.70	silver quality
medulla oblongata	UBERON:0001896	87.55	silver quality
pharyngeal mucosa	UBERON:0000355	87.25	silver quality
superior vestibular nucleus	UBERON:0007227	87.06	gold quality
entorhinal cortex	UBERON:0002728	86.78	gold quality
trachea	UBERON:0003126	86.51	silver quality
globus pallidus	UBERON:0001875	85.63	silver quality
saphenous vein	UBERON:0007318	85.63	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.54
E-GEOD-36552	no	11.18

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

173 targeting SPRED3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3180-5P	99.82	69.12	2422

Literature-anchored findings (GeneRIF, showing 4)

• The finding of Spred-3 revealed the presence of a novel family of regulators for the Ras/MAP kinase pathway, each member of which may have different specificities for extracellular signals. [Spred-3] (PMID:12646235)
• Eve-3 may act as an inhibitor of proliferation pathways in the mature liver and be involved in modulating the unique regenerative capacity of this organ (PMID:16478641)
• Bioinformatics analysis for the identification of Sprouty-related EVH1 domain-containing protein 3 expression and its clinical significance in thyroid carcinoma. (PMID:38402263)
• SPRED3 regulates the NF-kappaB signaling pathway in thyroid cancer and promotes the proliferation. (PMID:39227612)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	spred3	ENSDARG00000040358
mus_musculus	Spred3	ENSMUSG00000037239
rattus_norvegicus	Spred3	ENSRNOG00000051915
drosophila_melanogaster	ena	FBGN0000578
drosophila_melanogaster	Spred	FBGN0020767
caenorhabditis_elegans		WBGENE00006770

Paralogs (5): VASP (ENSG00000125753), ENAH (ENSG00000154380), SPRED1 (ENSG00000166068), EVL (ENSG00000196405), SPRED2 (ENSG00000198369)

Protein

Protein identifiers

Sprouty-related, EVH1 domain-containing protein 3 — Q2MJR0 (reviewed: Q2MJR0)

All UniProt accessions (4): Q2MJR0, K7EKP4, K7EPT9, K7EPU5

UniProt curated annotations — full annotation on UniProt →

Function. Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase. Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2. Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells.

Subunit / interactions. Interacts with palmitoyltransferase ZDHHC17/HIP14; the interaction leads to palmitoylation of SPRED3.

Subcellular location. Cell membrane.

Post-translational modifications. Phosphorylated on tyrosine. Palmitoylated by ZDHHC17/HIP14. Ubiquitinated.

Isoforms (2)

UniProt ID	Names	Canonical?
Q2MJR0-1	1	yes
Q2MJR0-2	2, EVE-3

RefSeq proteins (4): NP_001035987, NP_001381265, NP_001381266, NP_001381267 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000697	WH1/EVH1_dom	Domain
IPR007875	Sprouty	Family
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR023337	KBD	Domain
IPR041937	SPRE_EVH1	Domain

Pfam: PF00568, PF05210

UniProt features (13 total): domain 3, compositionally biased region 3, modified residue 2, splice variant 2, region of interest 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2MJR0-F1	66.28	0.25

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 (2): 248, 240

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5658442	Regulation of RAS by GAPs
R-HSA-6802953	RAS signaling downstream of NF1 loss-of-function variants
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-6802957	Oncogenic MAPK signaling

MSigDB gene sets: 105 (showing top): GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_MESENCHYMAL_CELL_DIFFERENTIATION, KOYAMA_SEMA3B_TARGETS_UP, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA_STIMULUS, GOBP_RESPONSE_TO_GROWTH_FACTOR

GO Biological Process (7): negative regulation of epithelial to mesenchymal transition (GO:0010719), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of ERK1 and ERK2 cascade (GO:0070373), negative regulation of lens fiber cell differentiation (GO:1902747), multicellular organism development (GO:0007275), regulation of signal transduction (GO:0009966), negative regulation of intracellular signal transduction (GO:1902532)

GO Molecular Function (1): protein kinase binding (GO:0019901)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
RAF/MAP kinase cascade	1
Oncogenic MAPK signaling	1
Disease	1
MAPK1/MAPK3 signaling	1
Signal Transduction	1
MAPK family signaling cascades	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of multicellular organismal process	2
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
negative regulation of epithelial cell differentiation	1
lens fiber cell differentiation	1
regulation of lens fiber cell differentiation	1
multicellular organismal process	1
anatomical structure development	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
negative regulation of signal transduction	1
intracellular signal transduction	1
regulation of intracellular signal transduction	1
kinase binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

557 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPRED3	SH3D19	Q5HYK7	575
SPRED3	KIT	P10721	497
SPRED3	HSPB3	Q12988	490
SPRED3	SMIM3	Q9BZL3	490
SPRED3	ACTMAP	Q5BKX5	489
SPRED3	TRIM42	Q8IWZ5	454
SPRED3	NUDT6	P53370	444
SPRED3	AFG2A	Q8NB90	426
SPRED3	KCTD14	Q9BQ13	415
SPRED3	STAM2	O75886	413
SPRED3	STAM	Q92783	389
SPRED3	HAO1	Q9UJM8	382
SPRED3	CCDC177	Q9NQR7	381
SPRED3	SPRY4	Q9C004	359
SPRED3	CYYR1	Q96J86	358

IntAct

0 interactions, top by confidence:

BioGRID (1): ZDHHC17 (Affinity Capture-Western)

ESM2 similar proteins: A2A9Q0, A5PKD8, A9JSM3, D4A2Q0, E7ERA6, F1SAM7, F2Z333, P0CG25, Q07303, Q0IIA6, Q1RMK9, Q24JP5, Q2MJR0, Q2WF71, Q3MIP1, Q3UV16, Q3ZCQ3, Q504Y2, Q5EBM0, Q5GH56, Q5GH64, Q5GH72, Q5RJI4, Q5SZI1, Q641Q3, Q6IEE6, Q6IQX7, Q6P6N5, Q6UKI2, Q6ZMC9, Q6ZVW7, Q86UD0, Q8IUW3, Q8IZ52, Q8K064, Q8N4K4, Q8NAC3, Q8NBR0, Q8NCL9, Q8NFR9

Diamond homologs: A2VDU1, A5D992, O43597, O43609, O43610, O44783, Q08E39, Q1L0X2, Q2MJR0, Q2PFN5, Q3C2P8, Q3UUD2, Q5R959, Q5RDN2, Q5Y171, Q6NYK3, Q6P6N5, Q7Z698, Q7Z699, Q866R9, Q924S7, Q924S8, Q9C004, Q9PTL1, Q9PTL2, Q9QXV8, Q9QXV9, Q9WTP2, Q66JG9, O08719, P50551, P50552, P70429, P70460, Q03173, Q2TA49, Q5R896, Q5TJ65, Q64GL0, Q8N8S7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

947 predictions. Top by Δscore:

Variant	Effect	Δscore
19:38391936:T:TA	acceptor_gain	1.0000
19:38391941:CTCAG:C	acceptor_loss	1.0000
19:38391943:CAGA:C	acceptor_loss	1.0000
19:38391944:A:AG	acceptor_gain	1.0000
19:38391944:AGAC:A	acceptor_loss	1.0000
19:38391945:G:GT	acceptor_gain	1.0000
19:38391945:GA:G	acceptor_gain	1.0000
19:38391945:GAC:G	acceptor_gain	1.0000
19:38391945:GACA:G	acceptor_gain	1.0000
19:38391945:GACAA:G	acceptor_gain	1.0000
19:38392110:TCG:T	donor_gain	1.0000
19:38392111:CGAG:C	donor_loss	1.0000
19:38392113:AG:A	donor_loss	1.0000
19:38392115:G:T	donor_loss	1.0000
19:38394641:A:AG	acceptor_gain	1.0000
19:38394642:G:GA	acceptor_gain	1.0000
19:38394642:GTCC:G	acceptor_gain	1.0000
19:38394642:GTCCC:G	acceptor_gain	1.0000
19:38394784:CAGGT:C	donor_loss	1.0000
19:38394785:AGG:A	donor_loss	1.0000
19:38394786:GGTG:G	donor_loss	1.0000
19:38394787:G:GA	donor_loss	1.0000
19:38389738:G:GG	donor_gain	0.9900
19:38390476:GAAA:G	donor_gain	0.9900
19:38390480:G:GG	donor_gain	0.9900
19:38392115:G:GG	donor_gain	0.9900
19:38394638:TCCA:T	acceptor_loss	0.9900
19:38394641:AGT:A	acceptor_loss	0.9900
19:38394642:G:C	acceptor_loss	0.9900
19:38394642:GT:G	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000265697 (19:38387887 T>C,G), RS1000495198 (19:38388820 G>A,C,T), RS1000674996 (19:38388072 C>A), RS1001012869 (19:38394889 A>T), RS1001576983 (19:38390190 G>A,T), RS1002117862 (19:38387356 T>C,G), RS1002147536 (19:38387584 C>G), RS1002456043 (19:38396454 A>G), RS1002530902 (19:38391454 G>C), RS1002575105 (19:38391178 C>G), RS1003048979 (19:38397993 T>G), RS1003427735 (19:38398267 C>A,T), RS1003575311 (19:38396697 A>G), RS1003932715 (19:38396447 A>G), RS1004126456 (19:38396423 C>A)

Disease associations

OMIM: gene MIM:609293 | 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

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
sodium arsenite	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
sulforaphane	increases expression	1
tobacco tar	decreases reaction, increases expression	1
diallyl disulfide	decreases reaction, increases expression	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
eprenetapopt	affects expression, affects reaction	1
jinfukang	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases expression, increases abundance	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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