Affinage

SPRY2

Protein sprouty homolog 2 · UniProt O43597

Length
315 aa
Mass
34.7 kDa
Annotated
2026-06-10
83 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPRY2 is an inducible intracellular antagonist of receptor tyrosine kinase (RTK)/Ras/ERK signaling that is itself induced and post-translationally tuned by the very growth-factor pathways it restrains (PMID:10940627, PMID:27046834). Upon EGF or FGF stimulation SPRY2 becomes tyrosine-phosphorylated, which both potentiates its inhibitory function and triggers its turnover: tyrosine-phosphorylated SPRY2 recruits the E3 ligase c-Cbl for ubiquitination and 26S proteasomal degradation, limiting the duration of ERK suppression (PMID:12593796). This degradation is layered with additional inputs — ITSN1 recruits the Shp2 phosphatase to dephosphorylate SPRY2 within the Cbl-SPRY2 complex (relieving SPRY2's restraint of Cbl-mediated EGFR ubiquitylation) (PMID:24216759), and protein kinase D phosphorylates SPRY2 at Ser112 to drive its degradation in a COP9/signalosome (CSN3)-dependent manner (PMID:37045830). SPRY2 acts within the ERK module as a scaffold and effector rather than a direct kinase modulator: it binds wild-type BRAF (but not the V599E mutant), engages Raf-1 as a scaffold without altering its intrinsic kinase activity, and binds oncogenic K-Ras through its C-terminal region while oligomerizing with SPRY4 at the plasma membrane (PMID:15313890, PMID:20356462, PMID:41362608). Beyond ERK, SPRY2 stabilizes the MET receptor (PMID:29445192) and exerts metabolic control by interfering with the LDHA-SRC interaction to suppress glycolysis (PMID:37507768), and in pancreatic β-cells it is a PERK/UPR target gene that maintains Serca2 expression and ER calcium homeostasis, with its deletion causing hyperglycemia and hypoinsulinemia (PMID:28246293). Across epithelial and stromal tissues SPRY2 functions as a tumor-suppressive brake whose loss sustains RTK/PI3K-AKT and MEK/ERK signaling to drive proliferation, invasion, EMT, and therapy resistance (PMID:22649008, PMID:30691517, PMID:32160544).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 Medium

    Established that SPRY2 functions as an intracellular regulator rather than a secreted inhibitor, anchoring the field's view of its site of action.

    Evidence Conditioned-medium transfer, SPRY2-GFP localization, and GRB2 pulldown in A375 cells

    PMID:10940627

    Open questions at the time
    • Identity of the secreted FGF2-inhibitory factor not defined
    • Mechanism linking intracellular SPRY2 to secretion unresolved
  2. 2003 High

    Answered how SPRY2 inhibition is terminated, showing growth-factor-induced tyrosine phosphorylation drives c-Cbl-mediated ubiquitination and proteasomal degradation as a built-in timer on ERK suppression.

    Evidence Reciprocal Co-IP, ubiquitination assay, and proteasome-inhibitor rescue with EGF/FGF stimulation

    PMID:12593796

    Open questions at the time
    • Specific tyrosine residues and kinases involved not mapped here
    • Quantitative contribution of degradation versus dephosphorylation to inhibition timing unresolved
  3. 2004 Medium

    Defined a node-specific target by showing SPRY2 directly binds wild-type BRAF but not oncogenic V599E, explaining why SPRY2 inhibition is bypassed in BRAF-mutant cells.

    Evidence siRNA knockdown, BRAF-SPRY2 pulldown, and ERK phosphorylation assays in melanoma cells

    PMID:15313890

    Open questions at the time
    • Structural basis of preferential wild-type BRAF binding not resolved
    • Single-lab finding without reciprocal validation
  4. 2007 High

    Identified a sequestration mechanism whereby Tesk1 relocalizes SPRY2 to endosomes, separating it from Grb2 and blocking its ERK inhibition independently of the Cbl degradation arm.

    Evidence Endogenous reciprocal Co-IP, localization imaging, ERK and neurite outgrowth assays in PC12 cells

    PMID:17974561

    Open questions at the time
    • Whether Tesk1-mediated sequestration is physiologically regulated by growth factors unclear
    • Relationship between endosomal pool and degradation not quantified
  5. 2010 Medium

    Refined the ERK-module mechanism, demonstrating SPRY2 acts as a scaffold for Raf-1 and its regulators rather than directly modulating Raf-1 kinase activity, while parallel work linked SPRY2 to mTORC1 via a Cbl-TSC2 complex.

    Evidence Co-IP of Raf-1 mutants with kinase assays; Co-IP of Spry2-Cbl-TSC2 with GTPase and mTORC1 assays

    PMID:20356462 PMID:20622121

    Open questions at the time
    • Direct effectors SPRY2 scaffolds onto Raf-1 not enumerated
    • mTORC1/TSC2 link established in a single tissue context
  6. 2010 High

    Showed SPRY2 expression is epigenetically controlled, with JMJD1A demethylase activity at the promoter setting SPRY2 levels and downstream ERK-driven transformation.

    Evidence ChIP for H3K9me2, JMJD1A manipulation, ERK and anchorage-independent growth assays in bronchial cells

    PMID:20881000

    Open questions at the time
    • Whether hypoxic SPRY2 repression operates in other tissues unknown
  7. 2012 High

    Demonstrated SPRY2's tumor-suppressive role by showing its loss reroutes ErbB receptor trafficking to sustain PI3K/AKT signaling and drive prostate cancer proliferation and invasion.

    Evidence SPRY2 KD/OE, receptor internalization and PI3K/AKT assays, in vitro and in vivo prostate models

    PMID:22649008

    Open questions at the time
    • Direct molecular link between SPRY2 and the endocytic machinery not defined
  8. 2012 High

    Linked SPRY2 inactivation to metabolic reprogramming, showing dominant-negative Spry2Y55F accelerates AKT-driven hepatocarcinogenesis through MAPK and PKM2 pathways.

    Evidence Hydrodynamic delivery of AKT and Spry2Y55F in mouse liver with pathway-inhibitor rescue

    PMID:22617155

    Open questions at the time
    • Mechanism connecting SPRY2 status to PKM2 activity unresolved
  9. 2013 High

    Resolved the phosphatase arm of SPRY2 regulation, showing ITSN1 recruits Shp2 to dephosphorylate SPRY2 within the Cbl complex, releasing SPRY2's brake on Cbl-mediated EGFR ubiquitylation.

    Evidence Reciprocal Co-IP, ITSN1-binding-site mutagenesis, catalytically inactive Shp2, EGFR ubiquitylation assay

    PMID:24216759

    Open questions at the time
    • How ITSN1/Shp2 recruitment is temporally coordinated with c-Cbl degradation unclear
  10. 2016 High

    Placed SPRY2 in vivo downstream of FGFR1, showing FGFR1-driven post-translational activation of SPRY2 enforces tracheal basal cell quiescence by cross-inhibiting other RTKs.

    Evidence Conditional Fgfr1/Spry2 deletion with proliferation epistasis in adult mouse trachea

    PMID:27046834

    Open questions at the time
    • Nature of the activating post-translational modification not chemically defined
  11. 2016 Medium

    Identified Dyrk1A as a SPRY2 kinase and connected SPRY2 regulation to pathological proliferation and to homocysteine-driven phosphatase/kinase balance affecting SPRY2 stability and FGF-ERK signaling.

    Evidence Dyrk1A KD with Spry2/p-ERK readouts in synoviocytes; Dyrk1A/PP2A activity and promoter-methylation analysis in neural progenitors

    PMID:27686255 PMID:30503061

    Open questions at the time
    • Exact serine residues phosphorylated by Dyrk1A not mapped in these studies
    • Functional integration of Dyrk1A and PP2A on SPRY2 not reconstituted
  12. 2017 High

    Revealed a non-ERK, organelle-homeostasis role, identifying SPRY2 as a PERK/UPR target gene that maintains Serca2-dependent ER calcium in β-cells, with deletion causing hyperglycemia and hypoinsulinemia.

    Evidence Genome-wide RNAi screen, PERK-dependence assay, Serca2/ER-calcium/UPR readouts, conditional β-cell knockout mouse

    PMID:28246293

    Open questions at the time
    • Molecular mechanism linking SPRY2 to Serca2 expression unknown
    • Whether ER-calcium role is independent of ERK regulation unclear
  13. 2018 High

    Uncovered a positive-regulatory function on an RTK, showing SPRY2 binds and stabilizes the MET receptor such that its loss phenocopies MET depletion in rhabdomyosarcoma.

    Evidence Reciprocal Co-IP, colocalization, parallel SPRY2/MET knockdown with migration, clonogenic and differentiation readouts

    PMID:29445192

    Open questions at the time
    • How SPRY2 protects MET from degradation mechanistically undefined
  14. 2019 Medium

    Connected SPRY2 to transcription-factor-controlled stability and to Wnt/EMT, showing FOXO3a stabilizes SPRY2 while SPRY2 loss stabilizes β-catenin to drive EMT and metastasis in pancreatic cancer.

    Evidence FOXO3a/SPRY2 KD, protein-stability and β-catenin assays, EMT markers, xenograft

    PMID:30691517

    Open questions at the time
    • Mechanism by which SPRY2 restrains β-catenin stability not defined
    • Single-lab epistasis
  15. 2019 Medium

    Reported an ERK/AKT-independent metabolic function, with SPRY2 knockout increasing glucose uptake and lipid droplet accumulation in hepatocytes without detectable kinase phosphorylation changes.

    Evidence CRISPR KO/OE with glucose-uptake, lipid-droplet, phosphoprotein panel and RNA-seq

    PMID:31664995

    Open questions at the time
    • Effector mediating the metabolic phenotype unidentified
    • Incomplete rescue on overexpression unexplained
  16. 2020 High

    Defined feedback and post-transcriptional control of SPRY2, showing an autocrine FGFR-NF-κB-ERK loop drives SPRY2 to confer RTK-inhibitor resistance, while miR-350 (m6A-regulated) directly represses SPRY2 in fibrosis.

    Evidence In vivo ERK reporter with FGFR/NF-κB inhibitors in glioblastoma; dual-luciferase and m6A assays in hepatic stellate cells

    PMID:32160544 PMID:32949431

    Open questions at the time
    • Whether the feedback loop and miRNA control intersect not addressed
    • Context specificity of SPRY2-mediated resistance across RTK inhibitors incomplete
  17. 2023 High

    Completed a major degradation mechanism by identifying PKD as the Ser112 kinase whose phosphorylation, with CSN3, drives SPRY2 turnover.

    Evidence In vitro kinase assay, Ser112Ala mutagenesis, PKD isoform KD/inhibition, CSN3 KD with stability readouts

    PMID:37045830

    Open questions at the time
    • How Ser112 phosphorylation interfaces with the c-Cbl/Shp2 tyrosine-phosphorylation circuit unresolved
  18. 2023 Medium

    Extended SPRY2's reach into stromal metabolism and transcriptional control, showing SPRY2 disrupts the LDHA-SRC interaction to suppress glycolysis in CAFs, and that HOXA5 transcriptionally activates SPRY2 to restrain prostate cancer stemness.

    Evidence SPRY2-LDHA-SRC Co-IP and LDHA activity assay; ChIP of HOXA5 at SPRY2 promoter with TRAF7 ubiquitin assay and epistasis rescue

    PMID:37507768 PMID:37845209

    Open questions at the time
    • Structural basis of SPRY2 interference with LDHA-SRC undefined
    • Both findings single-lab
  19. 2024 Medium

    Identified microtubule sequestration as an additional off-switch, showing paclitaxel-enhanced SPRY2-tubulin binding pulls SPRY2 from the membrane and de-represses Raf/ERK to worsen pulmonary fibrosis.

    Evidence Spry2-tubulin Co-IP and colocalization, depolymerizer reversal, in vivo irradiation+PTX model with ERK-inhibitor rescue

    PMID:37918858

    Open questions at the time
    • Whether tubulin sequestration occurs under physiological (non-paclitaxel) conditions unknown
  20. 2025 High

    Reframed SPRY2 as a direct K-Ras effector, mapping a C-terminal K-Ras-binding region, membrane recruitment dependent on K-Ras activity, and SPRY2-SPRY4 oligomerization coupled to differentiation control.

    Evidence TurboID, BRET, Co-IP, interface mutagenesis, K-Ras anchorage inhibitors, C2C12 differentiation assay

    PMID:41362608

    Open questions at the time
    • How K-Ras binding mechanistically blocks downstream effector access not structurally resolved
    • Interplay between K-Ras and BRAF/Raf-1 binding not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple, overlapping regulatory inputs on SPRY2 (Src/Cbl/Shp2 tyrosine cycle, Dyrk1A/PP2A and PKD/CSN3 serine control, Tesk1/tubulin sequestration) are integrated to set its activity and abundance in a given cellular context remains unresolved.
  • No unified model reconciling tyrosine- and serine-phosphorylation circuits
  • Structural basis for SPRY2's simultaneous engagement of K-Ras, BRAF, and Raf-1 undefined
  • Mechanism of the ERK-independent metabolic and ER-calcium roles unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 1
Partners
BRAFCBLGRB2ITSN1KRASMETPRKD1RAF1
Complex memberships
Cbl-SPRY2 complexSPRY2-SPRY4 oligomerSpry2-c-Cbl-TSC2 complex

Evidence

Reading pass · 25 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, leading to c-Cbl-mediated ubiquitination and degradation of hSpry2 by the 26S proteasome. FGF stimulation also induces hSpry2 degradation, which limits the duration of hSpry2 inhibition of ERK activation. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, in vitro and cell-based degradation assays Current biology : CB High 12593796
2004 SPRY2 directly binds wild-type BRAF but not the V599E or other exon 15 BRAF mutants, and acts as an inhibitor of ERK signaling in melanocytes and wild-type BRAF melanoma cells but not in cells with the V599E mutation. siRNA-mediated knockdown, co-immunoprecipitation/pulldown of BRAF-SPRY2 interaction, ERK phosphorylation assays Cancer research Medium 15313890
2007 Tesk1 (testicular protein kinase 1) interacts with endogenous Spry2, relocalizes Spry2 to vesicles/endosomes (preventing its translocation to membrane ruffles upon growth factor stimulation), and abrogates Spry2 inhibition of ERK phosphorylation. Tesk1 disrupts Spry2 interaction with Grb2 and interferes with Spry2 serine dephosphorylation by PP2A. Tesk1 does not affect Spry2 interaction with c-Cbl or Spry2 inhibition of Cbl-mediated EGFR ubiquitination. Co-immunoprecipitation of endogenous proteins, subcellular localization imaging, ERK phosphorylation assays, neurite outgrowth assay in PC12 cells, siRNA knockdown, kinase-dead mutants The Journal of biological chemistry High 17974561
2010 Spry2 forms a complex with c-Cbl ubiquitin ligase and the mTOR repressor TSC2, abolishing GTPase activity directed against Rheb (the G protein inducer of mTORC1), thereby linking FGF-10/FGFR2b/Spry2 signaling to mTORC1 activation and HIF-1α-driven vasculogenesis in fetal lung. Co-immunoprecipitation of Spry2, c-Cbl, and TSC2 complex; GTPase activity assay; mTORC1 activity assays in fetal lung epithelial cells American journal of physiology. Lung cellular and molecular physiology Medium 20622121
2010 Inhibition of histone demethylase JMJD1A by hypoxia or nickel increases H3K9me2 at the Spry2 promoter, repressing Spry2 expression in bronchial epithelial cells. Forced Spry2 expression decreased nickel-induced ERK phosphorylation and anchorage-independent growth. ChIP-on-chip, Affymetrix GeneChip, ChIP for H3K9me2, JMJD1A knockdown/overexpression, ERK phosphorylation assay, anchorage-independent growth assay Carcinogenesis High 20881000
2010 Spry2 does not directly modulate Raf-1 kinase activity; instead it acts as a scaffolding protein facilitating interactions between Raf-1 and its direct regulators. Association of Raf-1 with Spry2 does not correlate with Raf-1 activation state across phosphorylation-site mutants. Co-immunoprecipitation of FLAG-tagged Raf-1 point mutants with Spry2, immunofluorescence colocalization, Raf-1 kinase activity assay BMB reports Medium 20356462
2011 In the context of cerebral ischemia, reperfusion induces Src-Spry2 interaction, upregulating Spry2 activity and suppressing the Ras/Raf/MEK/ERK cascade. NMDA receptor antagonist (ketamine) and Src family kinase inhibitor (PP2) both block ischemia-induced Spry2 upregulation, indicating NMDA receptor- and Src kinase-dependent activation of Spry2. Co-immunoprecipitation of Src-Spry2 in rat hippocampus, immunoblotting for ERK pathway activation, pharmacological inhibitors (PP2, ketamine) in a four-vessel occlusion model Brain injury Medium 18297599
2012 Loss of SPRY2 in prostate cancer enhances internalization of EGFR/HER2 (ErbB receptors) via clathrin-mediated endocytosis driven by p38 MAPK activation by PI3K, resulting in sustained ErbB signaling at early endosomes and hyperactivation of PI3K/AKT signaling to drive proliferation and invasion. SPRY2 knockdown/overexpression, EGFR/HER2 internalization assay, PI3K/AKT signaling measurement, in vitro and in vivo prostate cancer models, PI3K inhibition EMBO molecular medicine High 22649008
2012 Inactivation of Spry2 (via dominant-negative Spry2Y55F) accelerates AKT-induced hepatocarcinogenesis by activating MAPK and PKM2 pathways. Concomitant suppression of MAPK and PKM2 strongly inhibited Spry2Y55F-driven growth in AKT-overexpressing hepatocellular carcinoma cells. Hydrodynamic gene delivery of AKT and Spry2Y55F in mouse liver, histological/biochemical assays, stable cell line transfection, MAPK and PKM2 pathway inhibition Journal of hepatology High 22617155
2013 ITSN1 (intersectin 1) recruits Shp2 tyrosine phosphatase to Spry2 within a Cbl-Spry2 complex, enhancing Spry2 dephosphorylation. Dephosphorylated Spry2 releases its inhibition on Cbl, enhancing Cbl-mediated EGFR ubiquitylation. A catalytically inactive Shp2 mutant reverses this effect. Disrupting the ITSN1-binding site on Spry2 decreases Shp2-Spry2 interaction and enhances Spry2 tyrosine phosphorylation. Co-immunoprecipitation, point mutagenesis of Spry2 Pro-rich ITSN1-binding site, dominant-negative Shp2, EGFR ubiquitylation assay Molecular and cellular biology High 24216759
2016 In adult mouse tracheal basal cells, SPRY2 is post-translationally modified (activated) in response to FGFR1 signaling. This allows SPRY2 to inhibit signaling downstream of other receptor tyrosine kinases and maintain basal cell quiescence. Deletion of either Fgfr1 or Spry2 in basal cells increases steady-state proliferation, placing SPRY2 downstream of FGFR1 in an in vivo quiescence mechanism. Conditional Cre-mediated deletion of Fgfr1 and Spry2 in adult mouse tracheal basal cells, proliferation assays, epistasis by double deletion Developmental cell High 27046834
2016 Spry2 is a substrate of Dyrk1A kinase; Dyrk1A knockdown increases Spry2 expression and suppresses ERK phosphorylation in TNF-α-treated fibroblast-like synoviocytes, placing Dyrk1A upstream of Spry2 in the ERK MAPK pathway regulation of synoviocyte proliferation, migration and invasion. Dyrk1A siRNA knockdown, Western blot for Spry2 and p-ERK, proliferation/migration/invasion assays (CCK-8, EdU, transwell) Tissue & cell Medium 30503061
2016 Homocysteine alters the expression/activity of Dyrk1A (Spry2 kinase) and PP2A (Spry2 phosphatase) in neural progenitor cells, changing Spry2 phosphorylation pattern, activity and stability, leading to impaired FGF receptor-ERK-cyclin E signaling and reduced proliferation. Hcy also demethylates the Spry2 promoter, upregulating Spry2 mRNA and protein. Promoter methylation analysis, Spry2 mRNA/protein quantification, Dyrk1A and PP2A activity measurements, neural progenitor proliferation assay Biochimica et biophysica acta Medium 27686255
2017 Spry2 is a novel UPR (unfolded protein response) target gene in pancreatic β-cells; its upregulation is dependent on the PERK kinase arm of the UPR. Knockdown of Spry2 reduces Serca2 expression, lowers ER calcium levels, and induces the UPR. Conditional deletion of Spry2 in adult mouse β-cells causes hyperglycemia and hypoinsulinemia. Whole-genome RNAi screen for insulin promoter regulators, PERK-dependent UPR induction assay, Spry2 KD with Serca2/ER calcium/UPR readout, conditional β-cell-specific Spry2 knockout mouse Diabetes High 28246293
2018 SPRY2 is a novel interactor of the MET receptor tyrosine kinase in rhabdomyosarcoma; SPRY2 colocalizes with and binds MET, and stabilizes MET protein. Depletion of SPRY2 leads to MET degradation, reducing ERK/MAPK pathway activation, migratory and clonogenic potential, and inducing differentiation—phenotypes identical to MET depletion. Co-immunoprecipitation and colocalization of SPRY2 and MET, siRNA knockdown of SPRY2 and MET, migration, clonogenic, and differentiation assays, ERK/MAPK phosphorylation measurement Cell death & disease High 29445192
2019 FOXO3a transcription factor promotes SPRY2 protein stability; knockdown of FOXO3a decreases SPRY2 protein stability. Loss of SPRY2 enhances β-catenin protein stability and activates the β-catenin/TCF4 pathway to induce EMT and promote metastasis in pancreatic ductal adenocarcinoma. Silencing SPRY2 reverses the suppressive effects of FOXO3a overexpression on EMT. siRNA knockdown of FOXO3a and SPRY2, protein stability assays, Western blot for β-catenin, EMT markers, migration/invasion assays, xenograft model Journal of experimental & clinical cancer research : CR Medium 30691517
2019 CRISPR-Cas9 knockout of SPRY2 in HepG2 hepatocytes causes significantly increased glucose uptake and lipid droplet accumulation, with upregulation of PLA2G2A mRNA. These metabolic effects were attenuated (but not reversed) by SPRY2 overexpression, without detectable changes in Akt or MAPK kinase phosphorylation. CRISPR-Cas9 KO and SPRY2 overexpression, glucose uptake assay, lipid droplet assay, phosphoprotein panel, RNA sequencing BMC endocrine disorders Medium 31664995
2020 In glioblastoma, SPRY2 expression is controlled by an autocrine FGFR-NF-κB-ERK feedback loop. ERK reactivation (via NF-κB-driven autocrine FGFR signaling) drives SPRY2 transcription, and SPRY2 in turn promotes resistance to EGFR and MET inhibition. Blocking FGFR signaling or preventing ERK reactivation overcomes this resistance mechanism in vivo. EGFR/MET inhibitor treatment, FGFR inhibitor combination, ERK-dependent bioluminescent reporter in vivo, SPRY2 knockdown/overexpression, tumor xenograft model Cell reports High 32160544
2020 ASIC1a promotes miR-350 expression via METTL3-dependent m6A modification of pri-miR-350 (through METTL3 binding to DGCR8); mature miR-350 directly targets the 3'-UTR of SPRY2 (dual luciferase assay), repressing SPRY2 and activating PI3K/AKT and ERK pathways to promote liver fibrosis. Dual luciferase reporter assay (miR-350 binding to SPRY2 3'-UTR), m6A modification assay, METTL3-DGCR8 binding assay, ASIC1a knockdown, hepatic stellate cell activation assay FASEB journal Medium 32949431
2023 Protein kinase D (PKD) phosphorylates Spry2 at serine 112 in vitro and in vivo, and interacts with the C-terminal half of Spry2. Ser112 phosphorylation promotes Spry2 intracellular degradation; mutation of Ser112 to alanine decreases the rate of Spry2 degradation. Knockdown of all three PKD isoforms or blocking PKD kinase activity stabilizes Spry2 protein. The COP9/Signalosome component CSN3 (which binds PKD) also regulates Spry2 stability in a Ser112-dependent manner. In vitro kinase assay (PKD phosphorylates Spry2-Ser112), co-immunoprecipitation of PKD-Spry2, Ser112Ala mutagenesis with protein stability assay, PKD isoform siRNA knockdown, PKD inhibitor treatment, CSN3 knockdown Oncogenesis High 37045830
2023 SPRY2 suppresses Y10 phosphorylation of LDHA and inhibits LDHA enzymatic activity by interfering with the interaction between LDHA and SRC kinase in cancer-associated fibroblasts. SPRY2 knockdown in fibroblasts promotes CAF activation dependent on glycolytic metabolism and enhances breast cancer cell stemness. Co-immunoprecipitation of SPRY2, LDHA, and SRC; LDHA activity assay; SPRY2 knockdown in fibroblasts; in vivo tumor growth model Breast cancer research : BCR Medium 37507768
2023 HOXA5 directly binds the SPRY2 promoter, transcriptionally activating SPRY2 expression, which in turn suppresses MEK/ERK signaling to inhibit prostate cancer stemness and malignant behavior. TRAF7 E3 ubiquitin ligase promotes HOXA5 protein degradation via ubiquitination, thereby indirectly reducing SPRY2 levels. ChIP assay (HOXA5 binding to SPRY2 promoter), HOXA5 overexpression/knockdown with SPRY2 reporter, TRAF7 ubiquitin ligase assay, SPRY2 knockdown epistasis rescue experiment Cell death discovery Medium 37845209
2025 SPRY2 acts as a Ras effector: the C-terminal fragment of SPRY2 (residues 161-315) binds oncogenic K-RasG12V more strongly than full-length SPRY2. SPRY2 localizes to the plasma membrane in a K-Ras membrane-anchorage- and activity-dependent manner. Mutations at the predicted K-Ras/SPRY2 C-terminal interface disrupt the interaction. SPRY2 homo- and hetero-oligomerizes with SPRY4. Both full-length SPRY2 and its C-terminal fragment promote C2C12 muscle cell differentiation (requiring MAPK inhibition). 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 (shown by co-IP and immunofluorescence), sequestering Spry2 from the plasma membrane and attenuating its negative regulation of the Raf/ERK pathway, thereby aggravating radiation-induced pulmonary fibrosis. Microtubule-depolymerizing agents abolish this effect. Co-immunoprecipitation (Spry2-tubulin), immunofluorescence colocalization, Spry2 knockdown in fibroblasts (p-c-Raf/p-ERK readout), in vivo mouse thoracic irradiation + PTX model, ERK inhibitor rescue The Journal of pharmacology and experimental therapeutics Medium 37918858
2000 Overexpression of SPRY2 in A375 cells leads to secretion of a soluble factor that inhibits FGF2-stimulated (but not VEGF-stimulated) proliferation of endothelial cells. SPRY2 protein itself binds the intracellular adaptor GRB2 and, as a GFP fusion, remains intracellular, indicating SPRY2 acts intracellularly to regulate secretion of an FGF2 inhibitor rather than functioning as an extracellular inhibitor directly. Conditioned medium transfer assay, recombinant SPRY2 treatment, SPRY2-GFP fusion localization, GRB2 co-immunoprecipitation/pulldown Mechanisms of development Medium 10940627

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 90 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 57 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 43 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 42 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 41 30691517
2012 SPRY2 loss enhances ErbB trafficking and PI3K/AKT signalling to drive human and mouse prostate carcinogenesis. EMBO molecular medicine 39 22649008
2012 Inactivation of Spry2 accelerates AKT-driven hepatocarcinogenesis via activation of MAPK and PKM2 pathways. Journal of hepatology 38 22617155
2011 Spry1 and Spry2 are necessary for lens vesicle separation and corneal differentiation. Investigative ophthalmology & visual science 38 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
2007 Tesk1 interacts with Spry2 to abrogate its inhibition of ERK phosphorylation downstream of receptor tyrosine kinase signaling. The Journal of biological chemistry 33 17974561
2020 Glioblastoma Cell Resistance to EGFR and MET Inhibition Can Be Overcome via Blockade of FGFR-SPRY2 Bypass Signaling. Cell reports 32 32160544
2012 Spry1 and spry2 are essential for development of the temporomandibular joint. Journal of dental research 32 22328578
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 32 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
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 23 30503061
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 SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma. Cell death & disease 22 29445192
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
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 19 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
2021 SNHG12 regulates biological behaviors of ox-LDL-induced HA-VSMCs through upregulation of SPRY2 and NUB1. Atherosclerosis 11 34847450
2023 Loss of SPRY2 contributes to cancer-associated fibroblasts activation and promotes breast cancer development. Breast cancer research : BCR 10 37507768
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
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 4 40915975
2018 A potential clinical significance of DAB2IP and SPRY2 transcript variants in prostate cancer. Pathology, research and practice 4 30301636
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 3 37918858
2014 Placental sprouty 2 (SPRY2): relation to placental growth and maternal metabolic status. Neonatology 3 24969401
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 Functional Variant Discovery Identifies a Novel Genetic Link between SPRY2, Wood Smoke, and Asthma. American journal of respiratory cell and molecular biology 0 41021275
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 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

Missed literature

Know a paper Affinage missed for SPRY2? Flag it for the maintainers and the community.

No submissions yet.