Affinage

SPRY2

Protein sprouty homolog 2 · UniProt O43597

Length
315 aa
Mass
34.7 kDa
Annotated
2026-04-28
83 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPRY2 is an inducible intracellular antagonist of receptor tyrosine kinase (RTK) signaling that constrains the Ras/Raf/MEK/ERK cascade across diverse developmental and homeostatic contexts. Upon growth factor stimulation, SPRY2 is tyrosine-phosphorylated, translocates to the plasma membrane, and suppresses ERK activation by binding GRB2, scaffolding Raf-1, and interacting directly with oncogenic K-Ras to block effector access (PMID:10940627, PMID:15313890, PMID:20356462, PMID:41362608). SPRY2 abundance and activity are tightly regulated: c-Cbl–mediated ubiquitination targets it for proteasomal degradation upon EGF/FGF stimulation, PKD phosphorylation at Ser112 cooperates with the COP9 signalosome to promote its turnover, Tesk1 relocalizes it to endosomes abrogating GRB2 binding, and an intersectin-1/Shp2 axis dephosphorylates SPRY2 to relieve its inhibition of Cbl-dependent EGFR ubiquitylation and lysosomal trafficking (PMID:12593796, PMID:37045830, PMID:17974561, PMID:24216759). Beyond canonical RTK-ERK feedback, SPRY2 modulates EGFR/HER2 endosomal signaling in prostate cancer, stabilizes MET receptor in rhabdomyosarcoma, suppresses SRC-dependent LDHA phosphorylation and glycolysis in fibroblasts, maintains ER calcium homeostasis and insulin secretion in pancreatic β-cells, and is required for palatal closure during development (PMID:22649008, PMID:29445192, PMID:37507768, PMID:28246293, PMID:17693063).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 Medium

    Identifying SPRY2 as a GRB2-binding intracellular protein that inhibits FGF-driven proliferation established it as a candidate negative regulator of RTK signaling in human cells.

    Evidence Co-immunoprecipitation of SPRY2-GRB2, GFP fusion localization, and conditioned-medium proliferation assay in endothelial cells

    PMID:10940627

    Open questions at the time
    • Non-cell-autonomous inhibition mechanism not fully reconstituted
    • Direct 3′UTR or signaling node target not identified
    • No in vivo loss-of-function data
  2. 2003 High

    Demonstrating that c-Cbl ubiquitinates SPRY2 in an EGF-dependent manner and targets it for proteasomal degradation revealed the first post-translational mechanism limiting the duration of SPRY2 activity.

    Evidence Co-IP, ubiquitination assay, and proteasome inhibitor treatment in EGF/FGF-stimulated cells

    PMID:12593796

    Open questions at the time
    • Structural basis of Cbl-SPRY2 interaction unknown
    • Whether other E3 ligases contribute not tested
  3. 2004 High

    Showing that SPRY2 binds wild-type BRAF but not oncogenic V599E BRAF to inhibit ERK signaling pinpointed the Raf level of the cascade as a direct node of SPRY2 action and explained why mutant-BRAF tumors escape SPRY2 inhibition.

    Evidence Co-IP/binding assay with BRAF mutant panel and siRNA knockdown with ERK phosphorylation readout in melanocytes

    PMID:15313890

    Open questions at the time
    • SPRY2-BRAF binding interface not mapped
    • Whether SPRY2 affects BRAF dimerization not addressed
  4. 2007 High

    Two studies resolved distinct regulatory layers: Tesk1 relocalizes SPRY2 to endosomes to abrogate GRB2 binding and PP2A-mediated reactivation, while Spry2-knockout mice develop cleft palate from excess FGF-driven proliferation, confirming SPRY2 as an essential dosage-sensitive negative-feedback regulator of FGF signaling in vivo.

    Evidence Endogenous co-IP, kinase-dead mutant analysis, and neurite outgrowth assay (Tesk1); Spry2 KO and BAC-transgene rescue with proliferation and FGF-target gene analysis (palate)

    PMID:17693063 PMID:17974561

    Open questions at the time
    • Tesk1 interaction domain on SPRY2 not mapped
    • Downstream FGF target selectivity in palate not fully dissected
  5. 2010 Medium

    Multiple discoveries expanded the SPRY2 mechanism: SPRY2 scaffolds Raf-1 without directly regulating its kinase activity, a Spry2-cCbl-TSC2 complex links FGF-10 signaling to mTORC1 activation in fetal lung, and JMJD1A-dependent H3K9 demethylation at the SPRY2 promoter was identified as a transcriptional on-switch.

    Evidence Raf-1 phosphorylation-site mutant panel with Co-IP and kinase assay; Spry2-cCbl-TSC2 Co-IP and GTPase assay in lung explants; ChIP-on-chip for H3K9me2 at SPRY2 promoter with functional rescue

    PMID:20356462 PMID:20622121 PMID:20881000

    Open questions at the time
    • Raf-1 scaffolding model lacks structural detail
    • TSC2-SPRY2 interaction stoichiometry unclear
    • JMJD1A regulation confirmed only in nickel/hypoxia context
  6. 2011 Medium

    miR-21 was identified as a post-transcriptional repressor of SPRY2 in glioma and mesenchymal stem cells, revealing how the SPRY2 feedback loop can be hijacked to sustain ERK signaling in tumor and differentiation contexts.

    Evidence miR-21 overexpression/knockdown with SPRY2 protein quantification, invasion assay in glioma, and differentiation assay in MSCs

    PMID:21278789 PMID:23239100

    Open questions at the time
    • Direct 3′UTR luciferase validation not provided in these studies
    • Other miRNAs targeting SPRY2 not systematically evaluated
  7. 2011 High

    Conditional double knockout of Spry1/Spry2 in the lens demonstrated that FGF-induced Sprouty proteins restrain ERK to permit lens vesicle separation, establishing a non-redundant developmental requirement.

    Evidence Le-Cre conditional double KO with ERK phosphorylation and apoptosis assays

    PMID:21743007

    Open questions at the time
    • Individual contributions of Spry1 vs. Spry2 in this tissue not fully resolved
  8. 2012 High

    Two studies placed SPRY2 at the intersection of RTK trafficking and cancer: SPRY2 loss enhanced EGFR/HER2 endosomal signaling and PI3K/AKT-driven invasion in prostate cancer, while dominant-negative SPRY2Y55F accelerated AKT-driven hepatocarcinogenesis via MAPK and PKM2.

    Evidence siRNA/shRNA with receptor internalization and endosome fractionation (prostate); hydrodynamic gene delivery of Spry2Y55F in mouse liver with pharmacological rescue (liver)

    PMID:22617155 PMID:22649008

    Open questions at the time
    • Whether SPRY2 directly contacts endosomal machinery not shown
    • PKM2 regulation mechanism downstream of SPRY2 not dissected
  9. 2013 High

    Reconstitution of an ITSN1–Shp2–Cbl–SPRY2 complex showed that Shp2-mediated dephosphorylation of SPRY2 relieves its sequestration of Cbl, thereby promoting EGFR ubiquitylation and lysosomal degradation—mechanistically connecting SPRY2 phosphorylation status to receptor downregulation.

    Evidence Co-IP of quaternary complex, catalytic-dead Shp2 mutant, Spry2 ITSN1-binding site mutant, EGFR ubiquitylation assay

    PMID:24216759

    Open questions at the time
    • In vivo relevance of ITSN1-Shp2 axis not validated
    • Whether other phosphatases substitute in ITSN1-null cells unknown
  10. 2016 High

    Conditional knockout studies in tracheal basal cells and neural progenitors revealed that FGFR1-dependent post-translational modification of SPRY2 restrains stem-cell proliferation, and that homocysteine disrupts the Spry2/Dyrk1A/PP2A triad to alter SPRY2 phosphorylation and neural progenitor proliferation.

    Evidence Fgfr1 and Spry2 conditional KO in adult mouse trachea with BrdU assay; Spry2 promoter methylation, Dyrk1A/PP2A expression, and proliferation assays in neural progenitors

    PMID:27046834 PMID:27686255

    Open questions at the time
    • Identity of FGFR1-induced post-translational modification not determined
    • Dyrk1A phosphorylation site on SPRY2 not mapped
  11. 2017 High

    Discovery that SPRY2 is a PERK-dependent UPR target in β-cells, required for SERCA2 expression and ER calcium homeostasis, expanded its function beyond RTK-ERK feedback to organelle stress management and insulin secretion.

    Evidence Whole-genome RNAi screen, PERK pathway analysis, SERCA2/calcium measurements, conditional β-cell-specific Spry2 KO mouse

    PMID:28246293

    Open questions at the time
    • Mechanism by which SPRY2 maintains SERCA2 levels unknown
    • Whether SPRY2-ER calcium link exists outside β-cells not tested
  12. 2018 Medium

    SPRY2 was found to physically interact with and stabilize the MET receptor in rhabdomyosarcoma, demonstrating a context where SPRY2 sustains rather than inhibits RTK signaling.

    Evidence Co-IP and colocalization of SPRY2-MET, siRNA knockdown leading to MET degradation, ERK and differentiation assays

    PMID:29445192

    Open questions at the time
    • Mechanism of SPRY2-mediated MET stabilization not defined
    • Whether this is unique to rhabdomyosarcoma or generalizable unclear
  13. 2020 High

    In glioblastoma, NF-κB–driven autocrine FGFR signaling was shown to reactivate ERK, which induces SPRY2 transcription; paradoxically, SPRY2 itself promotes resistance to EGFR/MET inhibitors, revealing a context-dependent pro-survival role.

    Evidence Pharmacological epistasis (EGFR, MET, FGFR, NF-κB inhibitors), ERK-bioluminescent reporter, shRNA knockdown, xenograft model

    PMID:32160544

    Open questions at the time
    • Mechanism by which SPRY2 promotes drug resistance not defined at the molecular level
    • Generalizability across GBM subtypes not tested
  14. 2023 High

    Two studies uncovered novel regulatory inputs: PKD phosphorylates SPRY2 at Ser112 cooperating with the COP9 signalosome to promote proteasomal turnover, and SPRY2 suppresses SRC-mediated LDHA Y10 phosphorylation to inhibit glycolysis in fibroblasts.

    Evidence In vitro kinase assay, Ser112Ala mutagenesis, CSN3 co-IP and stability assay (PKD); co-IP of LDHA-SRC disrupted by SPRY2, LDHA activity assay, in vivo tumor/metastasis model (LDHA)

    PMID:37045830 PMID:37507768

    Open questions at the time
    • Whether PKD-Ser112 and c-Cbl ubiquitination are sequential or parallel degradation pathways unknown
    • SPRY2-SRC interaction interface not mapped
  15. 2024 Medium

    Paclitaxel was shown to sequester SPRY2 on tubulin, depleting it from the plasma membrane and thereby de-repressing Raf/ERK signaling—a drug-induced redistribution mechanism aggravating pulmonary fibrosis.

    Evidence Co-IP of SPRY2-tubulin, membrane fractionation, microtubule depolymerization rescue, in vivo fibrosis model

    PMID:37918858

    Open questions at the time
    • Tubulin-binding domain on SPRY2 not identified
    • Whether this mechanism applies to other microtubule-targeting agents not tested
  16. 2025 High

    Proximity proteomics and BRET studies established that SPRY2 is a direct K-Ras effector: the C-terminal fragment binds active K-Ras at the plasma membrane, homo/hetero-oligomerizes with SPRY4, and blocks Ras effector access, providing the first structural-level model of SPRY2 inhibition at the Ras node.

    Evidence TurboID proximity proteomics, BRET assay, interface mutagenesis, K-Ras membrane anchorage inhibitors, C2C12 differentiation assay

    PMID:41362608

    Open questions at the time
    • Full atomic-resolution structure of K-Ras–SPRY2 complex not yet available
    • Stoichiometry and dynamics of SPRY2 oligomers at the membrane not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of SPRY2 interactions with K-Ras/Raf/GRB2, how SPRY2 switches between tumor-suppressive and pro-survival roles in different cancer contexts, and the mechanism linking SPRY2 to ER calcium homeostasis and SERCA2 expression.
  • No atomic-resolution structure of any SPRY2 signaling complex
  • Molecular determinants of context-dependent pro-tumorigenic vs. tumor-suppressive function uncharacterized
  • SPRY2-SERCA2 regulatory mechanism undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0060090 molecular adaptor activity 3
Localization
GO:0005768 endosome 2 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 1
Partners
BRAFCBLGRB2ITSN1KRASMETRAF1TESK1

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 hSpry2 is ubiquitinated by the E3-ubiquitin ligase c-Cbl in an EGF-dependent manner; EGF stimulation induces tyrosine phosphorylation of hSpry2, which enhances its interaction with c-Cbl, targeting hSpry2 for degradation by the 26S proteasome. FGF-induced degradation of hSpry2 limits the duration of its inhibitory effect on ERK activation. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, in vitro binding Current biology : CB High 12593796
2004 SPRY2 acts as an inhibitor of ERK signaling in melanocytes and wild-type BRAF melanoma cells by directly binding wild-type BRAF but not the V599E or other exon 15 BRAF mutants; siRNA-mediated knockdown confirmed the ERK inhibitory function. siRNA knockdown, co-immunoprecipitation/binding assay, ERK phosphorylation assay Cancer research High 15313890
2000 Human SPRY2 protein binds the intracellular adaptor protein GRB2; a SPRY2/GFP fusion protein remains intracellular, and overexpression of SPRY2 leads to secretion of a soluble factor that inhibits FGF2- but not VEGF-stimulated endothelial cell proliferation, acting non-cell-autonomously. Co-immunoprecipitation (GRB2 binding), GFP fusion localization, conditioned medium proliferation assay Mechanisms of development Medium 10940627
2007 Tesk1 (testicular protein kinase 1) forms an endogenous complex with Spry2 in cell lines and mouse tissues, relocalizes Spry2 to vesicles/endosomes independently of its kinase activity, abrogates Spry2's interaction with Grb2, and interferes with Spry2 serine dephosphorylation by PP2A, thereby nullifying Spry2's inhibition of ERK phosphorylation and FGF/NGF-induced neurite outgrowth. Co-immunoprecipitation (endogenous), subcellular fractionation/localization, kinase-dead mutant analysis, siRNA knockdown, neurite outgrowth assay The Journal of biological chemistry High 17974561
2010 In fetal lung epithelial cells, FGF-10 stimulation induces formation of a complex between Spry2, the c-Cbl ubiquitin ligase, and the mTOR repressor TSC2, which abolishes GTPase activity directed against Rheb (the G-protein inducer of mTORC1), linking the FGF-10/FGFR2b/Spry2 pathway to mTORC1 activation and HIF-1α-driven vasculogenesis. Co-immunoprecipitation (Spry2-cCbl-TSC2 complex), GTPase activity assay, fetal lung explant culture, HIF-1α reporter assay American journal of physiology. Lung cellular and molecular physiology Medium 20622121
2010 Histone demethylase JMJD1A maintains active H3K9me2 demethylation at the Spry2 promoter; inhibition of JMJD1A by hypoxia or nickel increases H3K9me2 at the Spry2 promoter, represses Spry2 expression, and potentiates ERK phosphorylation and anchorage-independent growth. ChIP-on-chip (H3K9me2 at Spry2 promoter), Affymetrix GeneChip, forced Spry2 expression, ERK phosphorylation assay, anchorage-independent growth assay Carcinogenesis High 20881000
2012 SPRY2 loss in prostate cancer cells results in enhanced internalization of EGFR/HER2 via clathrin-mediated endocytosis and their sustained signalling at the early endosome; this involves p38 MAPK activation by PI3K to facilitate ErbB receptor endocytosis, creating a positive feedback loop driving PI3K/AKT-dependent proliferation and invasion in a PTEN-dependent manner. siRNA/shRNA knockdown, receptor internalization assay, endosome fractionation, pharmacological PI3K/p38 inhibition, in vitro invasion assay, in vivo xenograft EMBO molecular medicine High 22649008
2012 Inactivation of Spry2 (via dominant-negative Spry2Y55F) accelerates AKT-driven hepatocarcinogenesis in mice by activating MAPK and PKM2 pathways; concomitant suppression of MAPK and PKM2 strongly inhibited the growth induced by Spry2Y55F loss. Hydrodynamic gene delivery in vivo (mouse liver), dominant-negative Spry2Y55F overexpression, histological/biochemical assays, pharmacological pathway inhibition Journal of hepatology High 22617155
2013 Intersectin 1 (ITSN1) recruits the Shp2 tyrosine phosphatase to the Cbl-Spry2 complex, enhancing Spry2 dephosphorylation; this disrupts the inhibitory effect of phospho-Spry2 on Cbl and enhances Cbl-mediated EGFR ubiquitylation and lysosomal trafficking. A catalytically inactive Shp2 mutant reverses this effect. Co-immunoprecipitation, phospho-Spry2 western blot, EGFR ubiquitylation assay, catalytic mutant Shp2 expression, point mutation of Spry2 ITSN1-binding site Molecular and cellular biology High 24216759
2016 In adult mouse tracheal basal cells, SPRY2 is post-translationally modified in response to FGFR1 signaling, allowing SPRY2 to inhibit intracellular signaling downstream of other receptor tyrosine kinases and restrain basal cell proliferation; deletion of Fgfr1 or Spry2 each caused increased steady-state basal cell proliferation. Conditional knockout (Fgfr1 and Spry2) in adult mouse trachea, BrdU proliferation assay, phospho-protein analysis Developmental cell High 27046834
2017 Spry2 is a novel UPR target whose upregulation is PERK-dependent; Spry2 knockdown reduces Serca2 expression, lowers ER calcium levels, and induces the unfolded protein response in pancreatic β-cells. Spry2 deletion in the adult mouse β-cell causes hyperglycemia and hypoinsulinemia. Whole-genome RNAi screen, PERK pathway analysis, Serca2/calcium measurements, conditional β-cell-specific Spry2 knockout mouse, glucose/insulin measurements Diabetes High 28246293
2018 SPRY2 physically interacts with MET receptor in rhabdomyosarcoma cells, colocalizing with and binding MET; depletion of SPRY2 leads to MET receptor degradation, reducing migratory and clonogenic potential and inducing differentiation by downregulating ERK/MAPK signaling. Co-immunoprecipitation, co-localization (immunofluorescence), siRNA knockdown of SPRY2/MET, ERK phosphorylation assay, migration/invasion assay, differentiation assay Cell death & disease Medium 29445192
2020 In glioblastoma, NF-κB pathway activation drives autocrine FGFR signaling, which reactivates ERK; ERK controls SPRY2 transcription, and SPRY2 in turn promotes resistance to EGFR and MET inhibitors. Blocking FGFR prevents ERK reactivation and SPRY2 rebound, overcoming resistance. Pharmacological inhibition (EGFR, MET, FGFR, NF-κB inhibitors), ERK-bioluminescent reporter in vivo, shRNA knockdown, xenograft mouse model Cell reports High 32160544
2011 miR-21 post-transcriptionally downregulates Spry2 protein in glioma cells, disrupting the negative feedback circuit of Ras/MAPK signaling; upregulation of miR-21 is triggered by tumor microenvironmental factors (hyaluronan and growth factors) in PTEN-deficient glioma cells, and loss of Spry2 promotes invasion. miR-21 overexpression/knockdown, western blot for Spry2 protein vs. mRNA, invasion assay, correlation analysis in human tumor tissues Oncogene Medium 21278789
2013 miR-21 modulates ERK-MAPK signaling during mesenchymal stem cell differentiation by directly repressing SPRY2 expression, increasing the duration and magnitude of ERK-MAPK activity to promote adipogenesis and osteogenesis. miR-21 overexpression/knockdown in MSCs, western blot for SPRY2 and pERK, adipogenic/osteogenic differentiation assay Journal of cellular biochemistry Medium 23239100
2010 Spry2 interacts with Raf-1 but does not directly regulate Raf-1 kinase activity; Spry2 acts as a scaffolding protein facilitating interactions between Raf-1 and its regulators, as shown by lack of correlation between Raf-1 mutant activation state and Spry2 binding strength. FLAG-tagged Raf-1 phosphorylation site mutants, co-immunoprecipitation, immunofluorescence co-localization, kinase activity assay BMB reports Medium 20356462
2023 SPRY2 suppresses Y10 phosphorylation of LDHA and LDHA enzymatic activity in fibroblasts by interfering with the interaction between LDHA and the kinase SRC, thereby inhibiting glycolytic metabolism and cancer-associated fibroblast activation. Co-immunoprecipitation (LDHA-SRC interaction), LDHA kinase activity assay, SPRY2 knockdown in fibroblasts, in vivo tumor growth and metastasis assay Breast cancer research : BCR Medium 37507768
2023 Protein kinase D (PKD) phosphorylates Spry2 at serine 112 and interacts with the C-terminal half of Spry2 in vivo; phosphorylation at Ser112 promotes Spry2 degradation via the proteasome. The COP9/Signalosome (via CSN3) binds PKD and contributes to Spry2 instability; knockdown of PKD isoforms or CSN3 stabilizes Spry2. In vitro kinase assay (PKD phosphorylating Spry2), site-directed mutagenesis (Ser112Ala), Co-IP (PKD-Spry2 and CSN3-PKD), protein stability assay (cycloheximide chase), siRNA knockdown Oncogenesis High 37045830
2008 Cerebral ischemia/reperfusion induces Src-mediated upregulation of Spry2 in rat hippocampus in a NMDA receptor-dependent manner, contributing to suppression of the Ras/Raf/MEK/ERK cascade; NMDA receptor antagonist ketamine and Src inhibitor PP2 both blocked ischemia-induced Spry2 upregulation. Co-immunoprecipitation (Src-Spry2), western blot for Spry2 activity, pharmacological inhibition (ketamine, PP2), four-vessel occlusion ischemia model Brain injury Medium 18297599
2025 SPRY2 acts as a K-Ras effector: the SPRY2 C-terminal fragment (residues 161–315) binds oncogenic RasG12V more strongly than full-length SPRY2; both forms localize to the plasma membrane in a K-Ras activity-dependent manner. Mutations at the predicted K-Ras/SPRY2 interface disrupt the interaction. SPRY2 also homo- and hetero-oligomerizes with SPRY4. Active K-Ras is proposed to recruit SPRY2 dimers to the membrane where they block Ras effector access. TurboID proximity proteomics, BRET assay, Co-immunoprecipitation, K-Ras membrane anchorage inhibitors, interface mutagenesis, C2C12 differentiation assay iScience High 41362608
2024 Paclitaxel increases binding of Spry2 to tubulin, sequestering Spry2 away from the plasma membrane; reduced membrane Spry2 relieves its negative regulation of Raf/ERK signaling, upregulating p-c-Raf and p-ERK and aggravating pulmonary fibrosis. Microtubule depolymerizing agents abolish PTX's inhibition of Spry2 membrane distribution. Co-immunoprecipitation (Spry2-tubulin), immunofluorescence colocalization, plasma membrane fractionation, Spry2 knockdown in fibroblasts, microtubule depolymerization rescue, ERK/Raf phosphorylation assay, in vivo fibrosis model The Journal of pharmacology and experimental therapeutics Medium 37918858
2016 Homocysteine alters the Spry2/Dyrk1A/PP2A triad in neural progenitor cells: elevated Hcy causes Spry2 promoter demethylation and sustained upregulation of Spry2 mRNA/protein, while Dyrk1A (Spry2-activating kinase) levels decrease and PP2A (Spry2-inactivating phosphatase) levels increase, altering Spry2 phosphorylation status and inhibiting FGFR-ERK-cyclin E-dependent proliferation. Spry2 promoter methylation analysis, Dyrk1A/PP2A protein expression, Spry2 phosphorylation assay, neural progenitor proliferation assay, methyltransferase inhibitor treatment Biochimica et biophysica acta Medium 27686255
2007 Spry2-deficient mice develop cleft palate due to excessive cell proliferation and abnormal FGF-responsive transcription factor expression (Etv5, Msx1, Barx1) and disorganized Shh in the palate; Spry2 dosage is critical as hypomorphic BAC transgenic rescue shows intermediate phenotypes, establishing Spry2 as a negative regulator of FGF signaling in palate development. Spry2 knockout mouse, Spry2-BAC transgene rescue, in situ hybridization, immunohistochemistry, cell proliferation assay Mechanisms of development High 17693063
2011 Spry1 and Spry2 function downstream of FGF signaling in the lens (FGF is necessary and sufficient for their induction) and, via negative modulation of ERK, allow lens vesicle separation from the overlying ectoderm. Combined loss causes persistent keratolenticular stalks with inhibited apoptosis of stalk cells and concomitant ERK activation. Conditional double knockout (Le-Cre), in situ hybridization, immunohistochemistry, ERK phosphorylation assay, apoptosis assay Investigative ophthalmology & visual science High 21743007

Source papers

Stage 0 corpus · 83 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 miR-21 modulates the ERK-MAPK signaling pathway by regulating SPRY2 expression during human mesenchymal stem cell differentiation. Journal of cellular biochemistry 139 23239100
2011 Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene 139 21278789
2003 hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl. Current biology : CB 117 12593796
2005 Epigenetic inactivation of the human sprouty2 (hSPRY2) homologue in prostate cancer. Oncogene 110 15735753
2004 SPRY2 is an inhibitor of the ras/extracellular signal-regulated kinase pathway in melanocytes and melanoma cells with wild-type BRAF but not with the V599E mutant. Cancer research 98 15313890
2018 miR-21 promotes EGF-induced pancreatic cancer cell proliferation by targeting Spry2. Cell death & disease 89 30464258
2018 miR-330-5p targets SPRY2 to promote hepatocellular carcinoma progression via MAPK/ERK signaling. Oncogenesis 73 30464168
2007 A dosage-dependent role for Spry2 in growth and patterning during palate development. Mechanisms of development 73 17693063
2006 Concomitant down-regulation of SPRY1 and SPRY2 in prostate carcinoma. Endocrine-related cancer 70 16954433
2010 Hypoxia and nickel inhibit histone demethylase JMJD1A and repress Spry2 expression in human bronchial epithelial BEAS-2B cells. Carcinogenesis 68 20881000
2002 Cloning of the mouse Sef gene and comparative analysis of its expression with Fgf8 and Spry2 during embryogenesis. Mechanisms of development 58 11960706
2018 MiR-592 Promotes Gastric Cancer Proliferation, Migration, and Invasion Through the PI3K/AKT and MAPK/ERK Signaling Pathways by Targeting Spry2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 56 29949784
2014 Crystal structures of wild type and disease mutant forms of the ryanodine receptor SPRY2 domain. Nature communications 54 25370123
2018 Long non-coding RNA GAS5 inhibits ovarian cancer cell proliferation via the control of microRNA-21 and SPRY2 expression. Experimental and therapeutic medicine 48 29896229
2009 Fibroblast growth factors and epidermal growth factor cooperate with oocyte-derived members of the TGFbeta superfamily to regulate Spry2 mRNA levels in mouse cumulus cells. Biology of reproduction 42 19553596
2020 ASIC1a regulates miR-350/SPRY2 by N6 -methyladenosine to promote liver fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 40 32949431
2019 Knockdown of FOXO3a induces epithelial-mesenchymal transition and promotes metastasis of pancreatic ductal adenocarcinoma by activation of the β-catenin/TCF4 pathway through SPRY2. Journal of experimental & clinical cancer research : CR 40 30691517
2012 Inactivation of Spry2 accelerates AKT-driven hepatocarcinogenesis via activation of MAPK and PKM2 pathways. Journal of hepatology 38 22617155
2012 SPRY2 loss enhances ErbB trafficking and PI3K/AKT signalling to drive human and mouse prostate carcinogenesis. EMBO molecular medicine 38 22649008
2011 Spry1 and Spry2 are necessary for lens vesicle separation and corneal differentiation. Investigative ophthalmology & visual science 37 21743007
2009 Revitalization of a diastemal tooth primordium in Spry2 null mice results from increased proliferation and decreased apoptosis. Journal of experimental zoology. Part B, Molecular and developmental evolution 37 19127536
2019 The Role of the miR-21/SPRY2 Axis in Modulating Proangiogenic Factors, Epithelial Phenotypes, and Wound Healing in Corneal Epithelial Cells. Investigative ophthalmology & visual science 33 31529118
2012 Spry1 and spry2 are essential for development of the temporomandibular joint. Journal of dental research 32 22328578
2007 Tesk1 interacts with Spry2 to abrogate its inhibition of ERK phosphorylation downstream of receptor tyrosine kinase signaling. The Journal of biological chemistry 32 17974561
2020 Glioblastoma Cell Resistance to EGFR and MET Inhibition Can Be Overcome via Blockade of FGFR-SPRY2 Bypass Signaling. Cell reports 31 32160544
2010 Control of HIF-1{alpha} and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock. American journal of physiology. Lung cellular and molecular physiology 31 20622121
2011 Genetic variants at CDC123/CAMK1D and SPRY2 are associated with susceptibility to type 2 diabetes in the Japanese population. Diabetologia 27 21909839
2017 MiR-21 enhanced glioma cells resistance to carmustine via decreasing Spry2 expression. European review for medical and pharmacological sciences 26 29228450
2016 An FGFR1-SPRY2 Signaling Axis Limits Basal Cell Proliferation in the Steady-State Airway Epithelium. Developmental cell 24 27046834
2013 Coordinated activity of Spry1 and Spry2 is required for normal development of the external genitalia. Developmental biology 24 24361260
2008 Epigenetic inactivation of the ERK inhibitor Spry2 in B-cell diffuse lymphomas. Oncogene 24 18427547
2021 m(6)A demethylase ALKBH5 inhibits cell proliferation and the metastasis of colorectal cancer by regulating the FOXO3/miR-21/SPRY2 axis. American journal of translational research 22 34786052
2018 Dyrk1A promotes the proliferation, migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis via down-regulating Spry2 and activating the ERK MAPK pathway. Tissue & cell 22 30503061
2015 MicroRNA-27b inhibits Spry2 expression and promotes cell invasion in glioma U251 cells. Oncology letters 22 25663918
2023 Hsa-miR-22-3p inhibits liver cancer cell EMT and cell migration/ invasion by indirectly regulating SPRY2. PloS one 21 36749775
2018 SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma. Cell death & disease 21 29445192
2016 Altered regulation of the Spry2/Dyrk1A/PP2A triad by homocysteine impairs neural progenitor cell proliferation. Biochimica et biophysica acta 21 27686255
2013 Spry1 and Spry2 are necessary for eyelid closure. Developmental biology 20 24055172
2022 MeCP2 inhibits ischemic neuronal injury by enhancing methylation of the FOXO3a promoter to repress the SPRY2-ZEB1 axis. Experimental & molecular medicine 18 35915222
2000 Human SPRY2 inhibits FGF2 signalling by a secreted factor. Mechanisms of development 18 10940627
2018 microRNA-23a promotes cell growth and metastasis in gastric cancer via targeting SPRY2-mediated ERK signaling. Oncology letters 17 29805579
2013 Receptor tyrosine kinase ubiquitylation involves the dynamic regulation of Cbl-Spry2 by intersectin 1 and the Shp2 tyrosine phosphatase. Molecular and cellular biology 16 24216759
2020 Crystal Structure of the Ryanodine Receptor SPRY2 Domain from the Diamondback Moth Provides Insights into the Development of Novel Insecticides. Journal of agricultural and food chemistry 15 31951399
2016 Anacardic acid inhibits gelatinases through the regulation of Spry2, MMP-14, EMMPRIN and RECK. Experimental cell research 15 27737732
2011 The elusive role of the SPRY2 domain in RyR1. Channels (Austin, Tex.) 14 21239886
2021 Exosomal miR-27 negatively regulates ROS production and promotes granulosa cells apoptosis by targeting SPRY2 in OHSS. Journal of cellular and molecular medicine 13 33638619
2011 3D Mapping of the SPRY2 domain of ryanodine receptor 1 by single-particle cryo-EM. PloS one 13 21998699
2017 A Whole-Genome RNA Interference Screen Reveals a Role for Spry2 in Insulin Transcription and the Unfolded Protein Response. Diabetes 12 28246293
2015 Mutation of Spry2 induces proliferation and differentiation of osteoblasts but inhibits proliferation of gingival epithelial cells. Journal of cellular biochemistry 12 25399781
2015 A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy. European journal of human genetics : EJHG 12 25782674
2015 Induction of Resistance to BRAF Inhibitor Is Associated with the Inability of Spry2 to Inhibit BRAF-V600E Activity in BRAF Mutant Cells. Biomolecules & therapeutics 12 26157547
2009 Search for pathogenetic variants of the SPRY2 gene in intestinal innervation defects. Internal medicine journal 12 19545245
2023 Loss of SPRY2 contributes to cancer-associated fibroblasts activation and promotes breast cancer development. Breast cancer research : BCR 10 37507768
2021 SNHG12 regulates biological behaviors of ox-LDL-induced HA-VSMCs through upregulation of SPRY2 and NUB1. Atherosclerosis 10 34847450
2023 TRAF7-targeted HOXA5 acts as a tumor suppressor in prostate cancer progression and stemness via transcriptionally activating SPRY2 and regulating MEK/ERK signaling. Cell death discovery 9 37845209
2021 MicroRNA-124 facilitates lens epithelial cell apoptosis by inhibiting SPRY2 and MMP-2. Molecular medicine reports 8 33760112
2020 Overexpression of Cancer Upregulated Gene 2 (CUG2) Decreases Spry2 Through c-Cbl, Leading to Activation of EGFR and β-Catenin Signaling. Cancer management and research 8 33116878
2015 Intraarticular gene transfer of SPRY2 suppresses adjuvant-induced arthritis in rats. Applied microbiology and biotechnology 8 25935347
2010 Spry2 does not directly modulate Raf-1 kinase activity in v-Ha-ras-transformed NIH 3T3 fibroblasts. BMB reports 8 20356462
2024 The ceRNA Mechanism of lncRNA MEG3/miR-21-5p/SPRY2 in Cell Proliferation and Apoptosis in Bladder Cancer. Critical reviews in eukaryotic gene expression 7 37824392
2010 Spry2 expression correlates with BRAF mutation in thyroid cancer. Surgery 7 21134562
2009 The enhancement of Raf-1 kinase activity by knockdown of Spry2 is associated with high sensitivity to paclitaxel in v-Ha-ras-transformed NIH 3T3 fibroblasts. Molecular and cellular biochemistry 7 19588231
2023 Crocin suppresses breast cancer cell proliferation by down-regulating tumor promoter miR-122-5p and up-regulating tumor suppressors FOXP2 and SPRY2. Environmental toxicology 6 36988377
2019 Haplotype and Haplotype-Environment Interaction Analysis Revealed Roles of SPRY2 for NSCL/P among Chinese Populations. International journal of environmental research and public health 6 30769929
2019 CRISPR-Cas9-mediated knockout of SPRY2 in human hepatocytes leads to increased glucose uptake and lipid droplet accumulation. BMC endocrine disorders 6 31664995
2008 Spry2-mediated inhibition of the Ras/ERK pathway through interaction with Src kinase following cerebral ischemia. Brain injury 6 18297599
2021 Epigenetic DNA Modifications Upregulate SPRY2 in Human Colorectal Cancers. Cells 5 34685612
2018 A potential clinical significance of DAB2IP and SPRY2 transcript variants in prostate cancer. Pathology, research and practice 4 30301636
2025 Poricoic Acid A attenuated TGF-β1-induced epithelial-mesenchymal transition in renal tubular epithelial cells through SPRY2/ERK signaling pathway. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 3 40915975
2014 Placental sprouty 2 (SPRY2): relation to placental growth and maternal metabolic status. Neonatology 3 24969401
2024 Paclitaxel Aggravating Radiation-Induced Pulmonary Fibrosis Is Associated with the Down-Regulation of the Negative Regulatory Function of Spry2. The Journal of pharmacology and experimental therapeutics 2 37918858
2024 LncRNA SLNCR1 facilitates angiogenesis and tumor growth in melanoma via DNMT1-mediated epigenetically silencing SPRY2. Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI) 2 39297702
2022 Transcription Factor FOXO3a Overexpression Inhibits the Progression of Neuroblastoma by Regulating the miR-21/SPRY2/ERK Axis. World neurosurgery 2 35405317
2019 MicroRNA-330-5p promotes the development of osteosarcoma by regulating SPRY2. European review for medical and pharmacological sciences 2 31696462
2015 Spry2 regulates signalling dynamics and terminal bud branching behaviour during lung development. Genetics research 2 25825238
2023 PKD phosphorylation and COP9/Signalosome modulate intracellular Spry2 protein stability. Oncogenesis 1 37045830
2021 microRNA-23a promotes cell growth and metastasis in gastric cancer via targeting SPRY2-mediated ERK signaling. Oncology letters 1 34457054
2026 A Novel lncRNA MSTRG.16386.1 as ceRNA Promotes Kidney Injury Induced by Deep Hypothermic Circulatory Arrest via Mediating miR-466b-5p/Spry2 Axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41480712
2025 Functional Variant Discovery Identifies a Novel Genetic Link Between SPRY2, Wood Smoke, and Asthma. American journal of respiratory cell and molecular biology 0 41021275
2025 Investigating SPRY2 Single-Nucleotide Polymorphisms in the Etiology of Nonsyndromic Orofacial Cleft in the Chinese Han Population. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 0 41212736
2025 Proteomics- and BRET- screens identify SPRY2 as a Ras effector that impacts its membrane organization. iScience 0 41362608
2017 [Establishment of a human bladder cancer cell line stably co-expressing hSPRY2 and luciferase genes and its subcutaneous tumor xenograft model in nude mice]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 28274312
2014 [Over-expression of human SPRY2 promotes the proliferation and survival of HEK293T cells]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 0 24796743