SPRY2

Summary

SPRY2 (sprouty RTK signaling antagonist 2, HGNC:11270) is a protein-coding gene on chromosome 13q31.1, encoding Protein sprouty homolog 2 (O43597). Antagonist of fibroblast growth factor (FGF) pathways via inhibition of FGF-mediated phosphorylation of ERK1/2.

This gene encodes a protein belonging to the sprouty family. The encoded protein contains a carboxyl-terminal cysteine-rich domain essential for the inhibitory activity on receptor tyrosine kinase signaling proteins and is required for growth factor stimulated translocation of the protein to membrane ruffles. In primary dermal endothelial cells this gene is transiently upregulated in response to fibroblast growth factor two. This protein is indirectly involved in the non-cell autonomous inhibitory effect on fibroblast growth factor two signaling. The protein interacts with Cas-Br-M (murine) ectropic retroviral transforming sequence, and can function as a bimodal regulator of epidermal growth factor receptor/mitogen-activated protein kinase signaling. This protein may play a role in alveoli branching during lung development as shown by a similar mouse protein.

Source: NCBI Gene 10253 — RefSeq curated summary.

At a glance

• Gene–disease (curated): IgA nephropathy, susceptibility to, 3 (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 37
• Clinical variants (ClinVar): 44 total
• Phenotypes (HPO): 9
• MANE Select transcript: NM_005842

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11270
Approved symbol	SPRY2
Name	sprouty RTK signaling antagonist 2
Location	13q31.1
Locus type	gene with protein product
Status	Approved
Aliases	hSPRY2
Ensembl gene	ENSG00000136158
Ensembl biotype	protein_coding
OMIM	602466
Entrez	10253

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 20 protein_coding

ENST00000377102, ENST00000377104, ENST00000909616, ENST00000909617, ENST00000909618, ENST00000909619, ENST00000909620, ENST00000909621, ENST00000909622, ENST00000919040, ENST00000919041, ENST00000919042, ENST00000919043, ENST00000919044, ENST00000919045, ENST00000919046, ENST00000919047, ENST00000960175, ENST00000960176, ENST00000960177

RefSeq mRNA: 4 — MANE Select: NM_005842 NM_001318536, NM_001318537, NM_001318538, NM_005842

CCDS: CCDS9463

Canonical transcript exons

ENST00000377104 — 2 exons

Exon	Start	End
ENSE00001472795	80335976	80337756
ENSE00001472796	80340622	80341126

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 97.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.9310 / max 332.0976, expressed in 1723 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137743	16.4986	1523
137746	12.4419	1663
137742	1.6402	846
137744	1.0168	563
137745	0.3298	171
137741	0.2934	117
137737	0.1728	67
137739	0.1574	58
137736	0.1514	60
137738	0.1344	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	97.84	gold quality
tibial nerve	UBERON:0001323	95.89	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.31	gold quality
cerebellar hemisphere	UBERON:0002245	95.19	gold quality
cerebellar cortex	UBERON:0002129	95.15	gold quality
omental fat pad	UBERON:0010414	95.02	gold quality
peritoneum	UBERON:0002358	94.98	gold quality
cerebellum	UBERON:0002037	94.93	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.71	gold quality
left uterine tube	UBERON:0001303	94.58	gold quality
ventricular zone	UBERON:0003053	94.58	gold quality
pericardium	UBERON:0002407	94.41	gold quality
parotid gland	UBERON:0001831	94.13	gold quality
right lung	UBERON:0002167	94.07	gold quality
pigmented layer of retina	UBERON:0001782	93.71	gold quality
heart right ventricle	UBERON:0002080	93.71	gold quality
cerebellar vermis	UBERON:0004720	93.60	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.40	gold quality
adult organism	UBERON:0007023	93.27	gold quality
adipose tissue	UBERON:0001013	92.81	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.69	gold quality
left coronary artery	UBERON:0001626	92.36	gold quality
cardiac ventricle	UBERON:0002082	92.33	gold quality
connective tissue	UBERON:0002384	92.33	gold quality
heart left ventricle	UBERON:0002084	92.28	gold quality
ganglionic eminence	UBERON:0004023	92.23	gold quality
mucosa of stomach	UBERON:0001199	92.22	gold quality
mammary duct	UBERON:0001765	92.07	gold quality
thoracic mammary gland	UBERON:0005200	92.04	gold quality
colonic mucosa	UBERON:0000317	91.97	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.51
E-GEOD-81547	yes	8.81
E-MTAB-6075	no	335.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, ETS1, FOXO1, FOXO4, HIF1A, SP1, TFAP2A, TXK

miRNA regulators (miRDB)

138 targeting SPRY2, 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-3163	100.00	77.23	8605
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-98-3P	100.00	74.08	3907
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4482-3P	99.98	72.50	3147
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-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434

Literature-anchored findings (GeneRIF, showing 40)

• The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins (PMID:11983899)
• Data show that human sprouty2 potentiates epidermal growth factor receptor signalling by specifically intercepting c-Cbl-mediated effects on receptor down-regulation. (PMID:12234920)
• Targeting of human Sprouty2 to PtdIns(4,5)P(2) was shown to be essential for the down-regulation of Ras/MAPK signaling. (PMID:12391162)
• Spry1 and Spry2 function in a negative feedback mechanism in which the inhibitor activity is controlled rapidly and reversibly by post-translational mechanisms (PMID:12402043)
• Data show that an increase in soluble protein-tyrosine phosphatase 1B activity contributes to the anti-migratory, but not anti-mitogenic, actions of human Sprouty 2. (PMID:12414790)
• targeted to the ubiquitin-dependent proteasome pathway by c-Cbl (PMID:12593796)
• tyrosine phosphorylation “activates” hSpry2 by enhancing its interaction with c-Cbl and this interaction is critical for its physiological function in a signal-specific context (PMID:12815057)
• Overexpression of SPRY2 inhibits HGF/SF-mediated cell growth, invasion, migration, and cytokinesis. (PMID:15122328)
• Sprouty proteins regulate ureteric branching by coordinating reciprocal epithelial Wnt11, mesenchymal Gdnf and stromal Fgf7 signalling during kidney development (PMID:15201220)
• Data suggest that SPRY2, an inhibitor of ERK signaling, may be bypassed in melanoma cells either by down-regulation of its expression in WT BRAF cells, or by the presence of the BRAF mutation. (PMID:15313890)
• SPRY2 mediates its anti-migratory actions by inhibiting Rac1 activation (PMID:15351707)
• FRS2-dependent SRC activation is required for FGFR-induced phosphorylation of Sprouty and suppression of ERK activity (PMID:15564375)
• hSPRY2 inhibits growth and migration of vascular smooth muscle cells, and can decrease neointimal growth after blood vessel injury (PMID:15653567)
• hSPRY2 is a potential tumor suppressor locus in a prostate cancer cell line. (PMID:15735753)
• Spry 1, 2 and 3 expression was observed in placental tissue from all three trimesters (PMID:15950061)
• Sprouty2 acts as an inducible inhibitor of EGFR downregulation by targeting both the Cbl and CIN85 pathways. (PMID:15962011)
• This work is the first evidence of a key role for Sprouty-2 in skeletal muscle cells, modulating fibroblast growth factor signaling and allowing terminal myogenic differentiation. (PMID:16000370)
• Detection of Sprouty-2 mRNA and protein in human granulosa-lutein cells may suggest a role for Sprouty-2 during the final stages of follicle maturation and corpus luteum formation. (PMID:16126775)
• SPRY2 mediates its anti-proliferative actions by altering PTEN content and activity (PMID:16371366)
• Mnk1-mediated serine phosphorylation of Spry2 constitutes a regulatory mechanism to extend the temporal range of Spry2 activity. (PMID:16479008)
• Spry2 inhibits both extracellular signal-regulated kinase signaling as well as proliferation in hepatocellular carcinoma cell lines, whereas knocking down Spry2 levels in NIH3T3 cells causes mild transformation. (PMID:16489004)
• the Sprouty/Caveolin-1 interaction modulates signaling in a growth factor- and Sprouty isoform-specific manner (PMID:16877379)
• No hypermethylation was found to accompany down-regulation of SPRY2 in prostate cancer tissues and cell lines. (PMID:16954433)
• PP2A binding to Sprouty2 and phosphorylation changes are a prerequisite for ERK inhibition downstream of FGFR stimulation (PMID:17255109)
• interferes with the trafficking of activated EGFR specifically at the step of progression from early to late endosomes. (PMID:17320394)
• our results suggest that SPRY2 regulates GDNF-dependent proliferation and differentiation of TGW neuroblastoma cells mediated by RET tyrosine kinase. (PMID:17388787)
• Trophoblast outgrowth and invasion (part of placental villi sprouting) at the fetal maternal interface is in part under delicate control of FGF 10 and Sprouty 2. (PMID:17496316)
• Spry2 plays a role as tumor suppressor in NSCLC by antagonizing receptor tyrosine kinase-induced signaling at different levels. (PMID:17510316)
• These results are evidence that the Sprouty2 mechanism of ERK inhibition is independent of Grb2 binding. (PMID:17689925)
• Although Spry2 transgenic lines express reduced levels of Spry2, Spry2 transgenic lines completely rescue defective facial and palate development in deletion mutant mice. (PMID:17693063)
• H-Ras interacts with Spry2-binding partners, c-Cbl and CIN85, in a Spry2-dependent manner. (PMID:18048363)
• endogenous hSPRY2-mediated regulation of apoptosis requires c-Cbl and is manifested by the ability of hSPRY2 to sequester c-Cbl and thereby augment signaling via growth factor receptors (PMID:18070883)
• may function as a candidate tumor suppressor for hepatocellular carcinoma development (PMID:18214995)
• detected that hSpry2 promoter hypermethylation was associated with a significant decrease in the 5-year survival rate in B-cell diffuse lymphoma (PMID:18427547)
• results suggest that activated Spry2 may interfere with c-Cbl-mediated ubiquitination of FGFR3 by sequestering c-Cbl. (PMID:18485666)
• Ablation of Sprouty2 with RNA interference can block the KAI1/CD82-induced suppression of hepatoma cell migration and downregulation of SphK1 expression (PMID:18622748)
• Sprouty 2 is present in the synaptic plasma membrane fraction of crude synaptosomal preparations (PMID:18678649)
• phosphorylation analysis of human Sprouty2, a regulator of receptor tyrosine kinase signaling: fifteen sites of phosphorylation were identified, 11 of which are novel (PMID:18683950)
• Spry2 inhibits apoptosis in response to DNA damage by regulating Akt, HDM2, and p53, by a process mediated partly by Rac1 (PMID:19008219)
• ZIC2, SPRY2, and GPC5 genes are candidate genes suspected to explain the malformations associated with cerebral anomalies in the hypothesis of a contiguous gene syndrome in 13q deletion syndrome (PMID:19022413)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	spry2	ENSDARG00000078308
mus_musculus	Spry2	ENSMUSG00000022114
rattus_norvegicus	Spry2	ENSRNOG00000010058
drosophila_melanogaster	sty	FBGN0014388

Paralogs (3): SPRY1 (ENSG00000164056), SPRY3 (ENSG00000168939), SPRY4 (ENSG00000187678)

Protein

Protein identifiers

Protein sprouty homolog 2 — O43597 (reviewed: O43597)

All UniProt accessions (1): O43597

UniProt curated annotations — full annotation on UniProt →

Function. Antagonist of fibroblast growth factor (FGF) pathways via inhibition of FGF-mediated phosphorylation of ERK1/2. Thereby acts as an antagonist of FGF-induced retinal lens fiber differentiation, may inhibit limb bud outgrowth and may negatively modulate respiratory organogenesis. Inhibits TGFB-induced epithelial-to-mesenchymal transition in retinal lens epithelial cells. Inhibits CBL/C-CBL-mediated EGFR ubiquitination.

Subunit / interactions. Forms heterodimers with SPRY1. Forms a tripartite complex containing GAB1, METTL13 and SPRY2. Within the complex interacts with METTL13. Interacts with RAF1. Interacts (via C-terminus) with TESK1 (via C-terminus); the interaction disrupts SPRY2 interaction with GRB2, potentially via disruption of SPRY2 serine dephosphorylation. Interacts with PPP2R1A/PP2A-A and PPP2CA/PP2A-C; the interaction with PPP2CA/PP2A-C is inhibited by interaction with TESK1, possibly by vesicular sequestration of SPRY2. Inhibition of the interaction with the serine/threonine-protein phosphatase 2A (PP2A) holoenzyme results in loss of PP2A-mediated dephosphorylation, resulting in the loss of SPRY2 interaction with GRB2. Interacts with GRB2. Interacts with CBL/C-CBL; the interaction inhibits CBL-mediated ubiquitination of EGFR. Interacts (via C-terminus) with CAV1 (via C-terminus).

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Ruffle membrane.

Post-translational modifications. Cleaved at Pro-144 by the prolyl endopeptidase FAP (seprase) activity (in vitro).

Disease relevance. IgA nephropathy 3 (IGAN3) [MIM:616818] A form of IgA nephropathy, a common primary glomerulonephritis characterized by glomerular sclerosis, interstitial fibrosis, and mesangial glomerular deposits of immunoglobulin A and immunoglobulin G visible on renal biopsies. IgA nephropathy is associated with renal insufficiency that can progress to end-stage renal disease. Proteinuria and hematuria are characteristic clinical presentations. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Domain organisation. The Cys-rich domain is responsible for the localization of the protein to the membrane ruffles.

Similarity. Belongs to the sprouty family.

RefSeq proteins (4): NP_001305465, NP_001305466, NP_001305467, NP_005833* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007875	Sprouty	Family
IPR051192	Sprouty_domain	Family

Pfam: PF05210

UniProt features (17 total): region of interest 4, mutagenesis site 3, compositionally biased region 3, sequence variant 2, chain 1, domain 1, sequence conflict 1, turn 1, site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5HKY	X-RAY DIFFRACTION	1.8
5HKZ	X-RAY DIFFRACTION	1.8
3BUM	X-RAY DIFFRACTION	2
3OB1	X-RAY DIFFRACTION	2.2
5HL0	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43597-F1	62.57	0.13

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 144–145 (cleavage; by fap)

Mutagenesis-validated functional residues (3):

Position	Phenotype
115	abolishes interaction with grb2.
144	inhibits cleavage by the prolyl endopeptidase fap.
252	abolishes interaction with cav1.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-1295596	Spry regulation of FGF signaling
R-HSA-182971	EGFR downregulation
R-HSA-162582	Signal Transduction
R-HSA-177929	Signaling by EGFR
R-HSA-190236	Signaling by FGFR
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-5654736	Signaling by FGFR1
R-HSA-5654738	Signaling by FGFR2
R-HSA-5654741	Signaling by FGFR3
R-HSA-5654743	Signaling by FGFR4
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 514 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, LEE_SP4_THYMOCYTE, 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, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, PAX4_01, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (37): establishment of mitotic spindle orientation (GO:0000132), sensory perception of sound (GO:0007605), negative regulation of cell population proliferation (GO:0008285), fibroblast growth factor receptor signaling pathway (GO:0008543), positive regulation of gene expression (GO:0010628), negative regulation of epithelial to mesenchymal transition (GO:0010719), negative regulation of angiogenesis (GO:0016525), positive regulation of cell migration (GO:0030335), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of cell projection organization (GO:0031345), negative regulation of protein ubiquitination (GO:0031397), positive regulation of peptidyl-serine phosphorylation (GO:0033138), cellular response to vascular endothelial growth factor stimulus (GO:0035924), negative regulation of fibroblast growth factor receptor signaling pathway (GO:0040037), negative regulation of epidermal growth factor receptor signaling pathway (GO:0042059), inner ear morphogenesis (GO:0042472), negative regulation of apoptotic process (GO:0043066), cell fate commitment (GO:0045165), positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742), negative regulation of Ras protein signal transduction (GO:0046580), animal organ development (GO:0048513), negative regulation of neurotrophin TRK receptor signaling pathway (GO:0051387), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), lung growth (GO:0060437), bud elongation involved in lung branching (GO:0060449), ERK1 and ERK2 cascade (GO:0070371), negative regulation of ERK1 and ERK2 cascade (GO:0070373), positive regulation of ERK1 and ERK2 cascade (GO:0070374), negative regulation of vascular endothelial growth factor signaling pathway (GO:1900747), negative regulation of lens fiber cell differentiation (GO:1902747), cellular response to leukemia inhibitory factor (GO:1990830), multicellular organism development (GO:0007275), regulation of signal transduction (GO:0009966), lung development (GO:0030324), branching morphogenesis of an epithelial tube (GO:0048754), lung morphogenesis (GO:0060425), respiratory system development (GO:0060541)

GO Molecular Function (6): protein kinase binding (GO:0019901), protein serine/threonine kinase inhibitor activity (GO:0030291), protein serine/threonine kinase activator activity (GO:0043539), ubiquitin-protein transferase inhibitor activity (GO:0055105), protein binding (GO:0005515), molecular function inhibitor activity (GO:0140678)

GO Cellular Component (12): nucleus (GO:0005634), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), ruffle membrane (GO:0032587), microtubule end (GO:1990752), cytoplasm (GO:0005737), microtubule (GO:0005874), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Signaling by FGFR	4
Signaling by Receptor Tyrosine Kinases	2
Negative regulation of FGFR1 signaling	1
Negative regulation of FGFR2 signaling	1
Negative regulation of FGFR3 signaling	1
Negative regulation of FGFR4 signaling	1
Signaling by EGFR	1
Signaling by FGFR1	1
Signaling by FGFR2	1
Signaling by FGFR3	1
Signaling by FGFR4	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
epidermal growth factor receptor signaling pathway	2
regulation of epidermal growth factor receptor signaling pathway	2
protein serine/threonine kinase activity	2
cytoskeleton	2
mitotic cell cycle	1
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
sensory perception of mechanical stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	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
cell projection organization	1
regulation of cell projection organization	1
negative regulation of cellular component organization	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
positive regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
cellular response to growth factor stimulus	1

Protein interactions and networks

STRING

1513 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPRY2	GRB2	P29354	889
SPRY2	CBL	P22681	837
SPRY2	DUSP6	Q16828	776
SPRY2	FRS2	Q8WU20	733
SPRY2	FGF8	P55075	717
SPRY2	FGF10	O15520	701
SPRY2	FGF3	P11487	667
SPRY2	FGF9	P31371	656
SPRY2	FGF6	P10767	638
SPRY2	IL17RD	Q8NFM7	636
SPRY2	DUSP5	Q16690	635
SPRY2	EGFR	P00533	627
SPRY2	RAF1	P04049	611
SPRY2	FGF18	O76093	603
SPRY2	BRAF	P15056	603

IntAct

252 interactions, top by confidence:

A	B	Type	Score
SPRY2	LCE1B	psi-mi:“MI:0915”(physical association)	0.740
LCE1B	SPRY2	psi-mi:“MI:0915”(physical association)	0.740
SPRY2	PRKAB2	psi-mi:“MI:0915”(physical association)	0.670
SPRY2	OTX1	psi-mi:“MI:0915”(physical association)	0.670
SPRY2	UBASH3A	psi-mi:“MI:0915”(physical association)	0.670
ZDHHC17	SPRY2	psi-mi:“MI:0915”(physical association)	0.670
KRTAP4-12	SPRY2	psi-mi:“MI:0915”(physical association)	0.670
OTX1	SPRY2	psi-mi:“MI:0915”(physical association)	0.670
SPRY2	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.670
SPRY2	KRTAP4-12	psi-mi:“MI:0915”(physical association)	0.670
PRKAB2	SPRY2	psi-mi:“MI:0915”(physical association)	0.670
UBASH3A	SPRY2	psi-mi:“MI:0915”(physical association)	0.670
FRS3	SPRY2	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	SPRY2	psi-mi:“MI:0915”(physical association)	0.560
SPRY2		psi-mi:“MI:0915”(physical association)	0.560
	SPRY2	psi-mi:“MI:0915”(physical association)	0.560
SPRY2	GRAP2	psi-mi:“MI:0915”(physical association)	0.560
SPRY2	MDFI	psi-mi:“MI:0915”(physical association)	0.560
SPRY2	SPRY1	psi-mi:“MI:0915”(physical association)	0.560
SPRY2	NCK2	psi-mi:“MI:0915”(physical association)	0.560
SPRY2	MAPKBP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (230): SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid), SPRY2 (Two-hybrid)

ESM2 similar proteins: A0A1B0GVS7, A2CE83, A2VDU1, A5D992, A8KBE0, O43597, O43609, O43610, P28290, Q02223, Q08AD1, Q08E39, Q14CH0, Q1L0X2, Q2PFN5, Q2TBG9, Q3UUD2, Q4R815, Q5R959, Q5RGQ8, Q5TB30, Q66H35, Q6AYK4, Q6DD45, Q6GPM0, Q6NRB7, Q6P995, Q6PEM6, Q6ZUJ8, Q7ZX27, Q866R9, Q86VY9, Q8BGN6, Q8C3K5, Q8C817, Q8IYD9, Q8N957, Q96HH4, Q9BZD6, Q9C004

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, P50551, O08719, P50552, P70429, P70460, Q03173, Q2TA49, Q64GL0, Q8N8S7, Q8T4F7

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
SRC	up-regulates	SPRY2	phosphorylation
DYRK1A	down-regulates	SPRY2	phosphorylation
MKNK1	down-regulates	SPRY2	phosphorylation
NEDD4	“down-regulates quantity by destabilization”	SPRY2	polyubiquitination
PRKD1	“down-regulates quantity by destabilization”	SPRY2	phosphorylation
SPRY2	down-regulates	CBLB	binding
SPRY2	down-regulates	CBLC
SPRY2	up-regulates	PTPN1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 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	15	21.4×	1e-14
Formation of the cornified envelope	5	11.3×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
keratinization	5	22.1×	1e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

344 predictions. Top by Δscore:

Variant	Effect	Δscore
13:80337754:CTC:C	acceptor_gain	1.0000
13:80337755:TC:T	acceptor_gain	0.9900
13:80337756:CC:C	acceptor_gain	0.9900
13:80337757:CT:C	acceptor_loss	0.9800
13:80337758:T:C	acceptor_loss	0.9800
13:80337767:C:T	acceptor_gain	0.9800
13:80337768:A:T	acceptor_gain	0.9800
13:80339461:A:AC	donor_gain	0.9800
13:80339462:C:CC	donor_gain	0.9800
13:80337752:AACTC:A	acceptor_gain	0.9700
13:80337753:ACTC:A	acceptor_gain	0.9700
13:80337753:ACTCC:A	acceptor_gain	0.9700
13:80337754:CTCC:C	acceptor_gain	0.9700
13:80337755:TCCTG:T	acceptor_gain	0.9700
13:80337757:C:CC	acceptor_gain	0.9700
13:80337767:C:CT	acceptor_gain	0.9700
13:80337754:CTCCT:C	acceptor_gain	0.9600
13:80339443:T:A	donor_gain	0.9600
13:80339454:A:AC	donor_gain	0.9500
13:80339455:C:CC	donor_gain	0.9500
13:80339461:ACT:A	donor_gain	0.9300
13:80339462:CTC:C	donor_gain	0.9300
13:80338618:T:C	donor_gain	0.9200
13:80338884:A:AC	donor_gain	0.9200
13:80339256:G:A	donor_gain	0.9200
13:80339338:G:A	donor_gain	0.9200
13:80338639:T:TA	donor_gain	0.9100
13:80338738:T:C	donor_gain	0.9000
13:80339131:T:TA	donor_gain	0.9000
13:80338737:AT:A	donor_gain	0.8900

AlphaMissense

2047 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:80336834:C:G	C291S	0.999
13:80336835:A:G	C291R	0.999
13:80336835:A:T	C291S	0.999
13:80336913:A:G	C265R	0.999
13:80336949:A:G	W253R	0.999
13:80336949:A:T	W253R	0.999
13:80337054:A:G	C218R	0.999
13:80337140:C:G	C189S	0.999
13:80337141:A:T	C189S	0.999
13:80337155:C:G	C184S	0.999
13:80337156:A:T	C184S	0.999
13:80337173:C:G	C178S	0.999
13:80337174:A:G	C178R	0.999
13:80337174:A:T	C178S	0.999
13:80336828:C:G	C293S	0.998
13:80336829:A:G	C293R	0.998
13:80336829:A:T	C293S	0.998
13:80336833:G:C	C291W	0.998
13:80336834:C:T	C291Y	0.998
13:80336837:C:T	G290D	0.998
13:80336843:C:A	R288M	0.998
13:80336883:A:G	C275R	0.998
13:80336904:A:G	C268R	0.998
13:80336984:G:T	P241Q	0.998
13:80337024:G:C	H228D	0.998
13:80337141:A:G	C189R	0.998
13:80337149:C:G	C186S	0.998
13:80337150:A:G	C186R	0.998
13:80337150:A:T	C186S	0.998
13:80337156:A:G	C184R	0.998

dbSNP variants (sampled 300 via entrez): RS1000211033 (13:80342077 T>C), RS1000327283 (13:80342381 T>C,G), RS1000656787 (13:80340393 C>T), RS1000937830 (13:80340130 C>T), RS1001652646 (13:80335831 T>C), RS1002909679 (13:80340475 C>T), RS1003337580 (13:80341020 C>A,G,T), RS1004003940 (13:80335948 C>CAA), RS1004272703 (13:80336318 T>C), RS1004500245 (13:80341434 G>A,C,T), RS1004785089 (13:80339586 C>T), RS1004838880 (13:80339885 C>A), RS1005331231 (13:80336289 T>C), RS1005455287 (13:80342737 C>T), RS1006835741 (13:80336712 A>G,T)

Disease associations

OMIM: gene MIM:602466 | disease phenotypes: MIM:616818

GenCC curated gene-disease

Disease	Classification	Inheritance
IgA nephropathy, susceptibility to, 3	Limited	Autosomal dominant
Tourette syndrome	Limited	Unknown

Mondo (2): IgA nephropathy, susceptibility to, 3 (MONDO:0014786), Tourette syndrome (MONDO:0007661)

Orphanet (0):

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000093	Proteinuria
HP:0000790	Hematuria
HP:0000794	IgA deposition in the glomerulus
HP:0000822	Hypertension
HP:0003676	Progressive
HP:0003774	Stage 5 chronic kidney disease
HP:0011462	Young adult onset
HP:0012574	Mesangial hypercellularity

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST000547_6	Orofacial clefts	3.000000e-07
GCST000796_2	Type 2 diabetes	6.000000e-09
GCST001128_2	Adiposity	7.000000e-08
GCST001526_17	Fasting blood insulin (BMI interaction)	2.000000e-06
GCST001628_30	Orofacial clefts	3.000000e-10
GCST001628_4	Orofacial clefts	9.000000e-11
GCST002352_21	Type 2 diabetes	6.000000e-06
GCST002432_4	Response to inhaled corticosteroid treatment in asthma (change in FEV1)	3.000000e-06
GCST002647_103	Height	1.000000e-08
GCST002711_9	Sleep duration	4.000000e-07
GCST003400_6	Type 2 diabetes	3.000000e-06
GCST003435_14	Body fat percentage	4.000000e-07
GCST003435_24	Body fat percentage	9.000000e-09
GCST003435_35	Body fat percentage	2.000000e-07
GCST003435_47	Body fat percentage	7.000000e-09
GCST004068_81	Venous thromboembolism adjusted for sickle cell variant rs77121243-T	1.000000e-06
GCST004136_15	Methadone dose in opioid dependence	1.000000e-06
GCST004166_22	Nonsyndromic cleft lip with cleft palate	2.000000e-09
GCST004894_120	Type 2 diabetes	1.000000e-15
GCST004894_16	Type 2 diabetes	8.000000e-12
GCST005047_25	Type 2 diabetes	1.000000e-08
GCST005414_3	Type 2 diabetes	1.000000e-07
GCST006435_1	Thrombocytopenia in coronary artery bypass surgery	8.000000e-06
GCST006627_5	Diastolic blood pressure	5.000000e-11
GCST006858_3	Leisure-time exercise behaviour (age-stratified)	4.000000e-06
GCST006867_124	Type 2 diabetes	3.000000e-23
GCST007324_99	Adventurousness	8.000000e-09
GCST007325_219	General risk tolerance (MTAG)	3.000000e-09
GCST007847_19	Type 2 diabetes	2.000000e-19
GCST007923_3	Medication use (drugs used in diabetes)	1.000000e-15

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0003959	cleft lip
EFO:0004340	body mass index
EFO:0005921	FEV change measurement
EFO:0007800	body fat percentage
EFO:0007907	methadone dose measurement
EFO:0006336	diastolic blood pressure
EFO:0000483	exercise
EFO:0008579	risk-taking behaviour
EFO:0009924	Drugs used in diabetes use measurement
EFO:0010557	lactose tolerance test
EFO:0004467	insulin measurement
EFO:0005213	central corneal thickness

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	6
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	4
Asbestos, Crocidolite	increases expression, increases methylation, affects expression	3
bisphenol A	affects expression, decreases expression	2
sodium arsenite	decreases expression	2
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, increases expression	2
(+)-JQ1 compound	decreases expression, increases expression, affects cotreatment	2
Acetaminophen	increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Hydrogen Peroxide	affects expression, decreases expression	2
Tretinoin	affects expression, decreases expression	2
Tunicamycin	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
3,19-(2-bromobenzylidene)andrographolide	decreases response to substance, decreases expression	1
FR900359	decreases phosphorylation	1
methylmercuric chloride	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	decreases expression	1
arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	decreases expression, decreases reaction, increases expression	1
zinc chromate	increases abundance, increases expression	1
potassium chromate(VI)	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
rutecarpine	increases expression	1
crocin	increases expression	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
diallyl trisulfide	increases expression	1
beta-methylcholine	affects expression	1

Cellosaurus cell lines

5 cell lines: 3 embryonic stem cell, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A6Q9	SEES3-1V human SPRY2, clone1	Embryonic stem cell	Male
CVCL_A6R0	SEES3-1V human SPRY2, clone2	Embryonic stem cell	Male
CVCL_A6R1	SEES3-1V human SPRY2, clone3	Embryonic stem cell	Male
CVCL_XG21	MSU-1.1-S41	Transformed cell line	Male
CVCL_XG22	MSU-1.1-S62	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	PHASE4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	PHASE4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	PHASE4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	PHASE4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	PHASE4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	PHASE4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT00004376	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine for Tourette Syndrome and Attention Deficit Hyperactivity Disorder
NCT00206323	PHASE3	COMPLETED	A Randomized, Placebo-controlled, Tourette Syndrome Study.
NCT00206336	PHASE3	COMPLETED	An Open-label Study to Determine the Efficacy and Safety of Topiramate in the Treatment of Tourette Syndrome.
NCT00478842	PHASE3	COMPLETED	Pallidal Stimulation and Gilles de la Tourette Syndrome
NCT00681863	PHASE3	TERMINATED	Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome
NCT01501695	PHASE3	COMPLETED	Phase III Study of 5LGr to Treat Tic Disorder
NCT03087201	PHASE3	COMPLETED	CANNAbinoids in the Treatment of TICS (CANNA-TICS)
NCT03487783	PHASE3	COMPLETED	Aripiprazole Oral Solution in the Treatment of Children and Adolescents With Tourette’s Syndrome
NCT03567291	PHASE3	TERMINATED	Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents
NCT03571256	PHASE3	COMPLETED	A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)
NCT06021522	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-term Safety of Ecopipam Tablets in Children, Adolescents and Adults With Tourette’s Disorder
NCT00004393	PHASE2	COMPLETED	Phase II Double Blind Placebo Controlled Trial of Risperidone in Tourette Syndrome
NCT00004652	PHASE2	COMPLETED	Phase II Pilot Controlled Study of Short Vs Longer Term Pimozide (Orap) Therapy in Tourette Syndrome
NCT00231985	PHASE2	COMPLETED	Effectiveness of Behavior Therapy and Psychosocial Therapy for the Treatment of Tourette Syndrome and Chronic Tic Disorder
NCT00311909	PHASE2	COMPLETED	Thalamic Deep Brain Stimulation for Tourette Syndrome
NCT00529308	PHASE2	COMPLETED	Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette’s Syndrome
NCT00558467	PHASE2	COMPLETED	Pramipexole Pilot Phase II Study in Children and Adolescents With Tourette Disorder According to DSM-IV Criteria
NCT01043549	PHASE2	TERMINATED	Repetitive Transcranial Magnetic Stimulation of the Posterior Parietal Cortex in Patients Suffering From Gilles de la Tourette Syndrome
NCT01133353	PHASE2	WITHDRAWN	A Study of the Effectiveness and Safety of Tetrabenazine MR in Pediatric Subjects With Tourette’s Syndrome
NCT01475383	PHASE2	WITHDRAWN	Study Evaluating The Safety And Efficacy Of PF-03654746 In Adult Subjects With Tourette’s Syndrome
NCT01647269	PHASE2	COMPLETED	A Trial of Bilateral Deep Brain Stimulation to the Globus Pallidus Internum in Tourette Syndrome
NCT01904773	PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetic, and Efficacy Study of AZD5213 in Adolescents With Tourette’s Disorder
NCT02102698	PHASE2	COMPLETED	Ecopipam Treatment of Tourette’s Syndrome in Subjects 7-17 Years
NCT02217007	PHASE2	WITHDRAWN	A Trial Evaluating the Efficacy, Safety, and Pharmacokinetics of SNC-102 in Subjects With Tourette Syndrome
NCT02247206	PHASE2	COMPLETED	VoIP Delivered Behavior Therapy for Tourette Syndrome
NCT02581865	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome
NCT02619084	PHASE2	COMPLETED	Subthalamic Stimulation in Tourette’s Syndrome
NCT02679079	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Children and Adolescents With Tourette Syndrome
NCT02879578	PHASE2	COMPLETED	Safety and Tolerability Study of NBI-98854 for the Treatment of Subjects With Tourette Syndrome
NCT03066193	PHASE2	COMPLETED	Efficacy of a Therapeutic Combination of Dronabinol and PEA for Tourette Syndrome
NCT03247244	PHASE2	TERMINATED	Safety and Efficacy of Cannabis in Tourette Syndrome
NCT03325010	PHASE2	COMPLETED	Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome
NCT03444038	PHASE2	COMPLETED	Open-Label Safety and Tolerability Study of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome