Affinage

SPRY4

Protein sprouty homolog 4 · UniProt Q9C004

Length
299 aa
Mass
32.5 kDa
Annotated
2026-04-28
97 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPRY4 is a negative feedback regulator of receptor tyrosine kinase (RTK) signaling that suppresses RAS-dependent ERK/MAPK and, in certain contexts, PI3K/AKT pathway activation to control cell proliferation, differentiation, migration, and stem cell self-renewal. Induced transcriptionally by FGF, GDNF, and other growth factors, SPRY4 inhibits ERK1/2 phosphorylation downstream of FGFR, EGFR, and KIT, and also directly binds KIT to inhibit its activation and PTPRB to enhance its phosphatase activity against TIE2, thereby suppressing angiogenic PI3K/AKT signaling (PMID:37222910, PMID:40660390, PMID:37552049, PMID:24811094). SPRY4 transcription is itself regulated by the MEF2D/HDAC4 repressor complex and by LSD1-mediated H3K4me2 demethylation at its promoter, while its mRNA is destabilized by KSRP and targeted by miR-411-5p and miR-1293, enabling multilayered control of its expression in cancer and development (PMID:34339801, PMID:33230474, PMID:28275056, PMID:26291313). Loss-of-function mutations in SPRY4 have been identified in congenital hypogonadotropic hypogonadism patients, and Spry4-null mice show defects in spermatogonial stem cell maintenance, oocyte redox homeostasis, and ovarian function, establishing SPRY4 as essential for reproductive biology (PMID:23643382, PMID:41852347, PMID:39348320).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 Low

    The question of how SPRY4 transcription is linked to developmental signaling was addressed by identifying conserved TCF/LEF binding sites in the SPRY4 promoter, placing it as a potential WNT-responsive gene.

    Evidence Comparative genomics across mammalian SPRY4 orthologs identified double TCF/LEF-binding elements

    PMID:16465403

    Open questions at the time
    • Computational prediction without experimental validation of TCF/LEF binding or transcriptional activation
    • No ChIP or reporter assay confirmation
    • No functional consequence of WNT-mediated SPRY4 induction tested
  2. 2013 Medium

    Two key advances established SPRY4's physiological significance: its genetic association with congenital hypogonadotropic hypogonadism placed it in the FGF8-FGFR1 signaling axis controlling GnRH neuron development, while its opposing role to SPRY1 in vascular smooth muscle cells revealed that SPRY4 suppresses both ERK and Akt to inhibit differentiation.

    Evidence Sequencing of 386 CHH patients with in vitro functional assays for mutations; siRNA knockdown with ChIP and Western blot in human VSMCs

    PMID:23554919 PMID:23643382

    Open questions at the time
    • CHH mutations not shown to be fully causative (oligogenic model)
    • VSMC findings from a single lab without independent replication
    • Molecular mechanism of SPRY4 dual ERK/Akt inhibition in VSMCs not resolved
  3. 2014 Medium

    Direct functional evidence confirmed that SPRY4 inhibits FGF2-stimulated ERK1/2 signaling and cell proliferation, while Spry4 knockout mice revealed an unexpected role in modulating inflammatory responses after spinal cord injury.

    Evidence Luciferase reporter and Western blot in endometrial cancer cells; Spry4−/− mice with SCI histology and cytokine measurements

    PMID:24811094 PMID:25541251

    Open questions at the time
    • Endometrial cancer study used overexpression only without KD validation
    • SCI phenotype mechanism (which RTK pathway) not dissected
    • No direct biochemical mechanism of ERK inhibition identified
  4. 2015 Medium

    Multiple studies revealed that SPRY4 expression is tightly regulated post-transcriptionally and by microRNAs, and that endogenous SPRY4 suppresses cancer stem cell properties: KSRP destabilizes SPRY4 mRNA in NSCLC, miR-411-5p directly targets SPRY4 to relieve p38MAPK inhibition in rhabdomyosarcoma, and SPRY4 knockdown expands the CD133+CD44+ stem cell population in breast cancer.

    Evidence siRNA knockdown of KSRP with mRNA stability assays; luciferase reporter validation of miR-411-5p targeting SPRY4 3′UTR; lentiviral shRNA with flow cytometry and limiting dilution xenograft

    PMID:26291313 PMID:26973433 PMID:28275056

    Open questions at the time
    • Post-transcriptional regulation by KSRP not confirmed across cell types
    • p38MAPK regulation by SPRY4 contrasts with canonical ERK-centered models — specificity unclear
    • Cancer stem cell findings from a single triple-negative breast cancer line
  5. 2017 Medium

    Genetic epistasis between Spry4 and Irf6 in mouse embryos demonstrated that SPRY4-mediated RTK/FGF feedback regulation cooperates with IRF6 in periderm differentiation, with compound mutants showing synergistic oral epithelial adhesion defects.

    Evidence Double mutant cross (Irf6+/− × TgKRT14::Spry4) with quantitative adhesion scoring and GRHL3 immunofluorescence

    PMID:28732181

    Open questions at the time
    • Only Spry4 gain-of-function tested; Spry4 loss-of-function epistasis with Irf6 not examined
    • Downstream target of SPRY4 in periderm not identified beyond GRHL3 mislocalization
    • Single developmental context
  6. 2018 High

    Direct protein-protein interaction between SPRY4 and KIT was demonstrated, showing that SPRY4 inhibits KIT expression and activation in GISTs and enhances imatinib sensitivity for primary but not secondary KIT mutants, while miR-411 was confirmed to target SPRY4 mRNA to activate EGFR/AKT signaling in NSCLC.

    Evidence Co-immunoprecipitation of SPRY4-KIT, Ba/F3 and GIST-T1 cell assays, KITV558A/WT mouse model; luciferase reporter for miR-411/SPRY4 with phenotypic rescue in NSCLC cells and xenografts

    PMID:30390072 PMID:37222910

    Open questions at the time
    • SPRY4-KIT binding domain not mapped
    • Whether SPRY4 binds other RTKs besides KIT via the same mechanism is unknown
    • miR-411 studies do not address SPRY4-independent miR-411 targets
  7. 2019 Medium

    SPRY4's role in stem cell differentiation was extended to osteogenesis and tooth development: SPRY4 knockdown in adipose-derived stem cells enhanced osteogenic differentiation via ERK1/2, while transgenic Spry4 overexpression in dental epithelium disrupted cusp morphology and enamel mineralization, and SPRY4 promoted osteogenesis in AIS mesenchymal stem cells downstream of melatonin signaling.

    Evidence siRNA KD with in vivo bone formation models; K14-Spry4 transgenic mice with microCT; gain/loss-of-function in AIS MSCs

    PMID:30982407 PMID:31485553 PMID:31645544

    Open questions at the time
    • Opposing effects of SPRY4 on osteogenesis in different MSC sources (enhances in AIS MSCs, inhibits in hASCs) not reconciled
    • Melatonin-SPRY4 axis mechanism not fully delineated
    • Tooth phenotype not linked to specific downstream targets
  8. 2021 High

    Transcriptional and epigenetic control of SPRY4 was mechanistically resolved: MEF2D/HDAC4 directly binds and represses the SPRY4 promoter to drive sorafenib resistance in hepatocellular carcinoma, while LINC00675 redirects LSD1 to demethylate H3K4me2 at the SPRY4 promoter in gastric cancer, and SPRY4 was placed upstream of EZH2 in colorectal cancer signaling.

    Evidence ChIP for MEF2D/HDAC4 at SPRY4 promoter with HDAC4 inhibitor rescue in vivo; RIP/ChIP for LINC00675-LSD1-H3K4me2 axis; EZH2 inhibitor rescue of SPRY4-silenced CRC cells with xenograft

    PMID:33230474 PMID:33879635 PMID:34339801

    Open questions at the time
    • Whether MEF2D/HDAC4 and LSD1-mediated mechanisms operate in the same tissues is untested
    • EZH2 as downstream effector of SPRY4 lacks direct biochemical evidence of connection
    • Chromatin regulation of SPRY4 in non-cancer contexts unexplored
  9. 2023 High

    Single-cell signaling analysis in spermatogonial stem cells established that SPRY4 is an ERK-specific negative feedback regulator induced by GDNF/FGF2 that maintains stem cell identity by preventing premature differentiation, while a miR-1293/SPRY4/ERK1/2 axis was shown to control tumor-associated angiogenesis.

    Evidence Single-cell ERK analysis in Spry4 KO SSC cultures, Spry4 reporter mouse; miR-1293 KD with SPRY4 siRNA rescue and HUVEC tube formation

    PMID:37552049 PMID:38972427

    Open questions at the time
    • Whether SPRY4 controls SSC self-renewal versus differentiation balance cell-autonomously versus via niche signals not resolved
    • miR-1293/SPRY4 axis tested only in lung adenocarcinoma context
  10. 2024 High

    SPRY4's direct interaction partners were expanded and reproductive functions solidified: exosomal SPRY4 binds PTPRB to enhance its phosphatase activity against TIE2 and suppress angiogenic PI3K/AKT signaling, a SPRY4 coding variant disrupts oocyte redox homeostasis and mitochondrial function with partial rescue by Nrf1, and a familial thyroid cancer variant activates MAPK/ERK signaling.

    Evidence Co-IP/mass spectrometry for SPRY4-PTPRB with in vivo SONFH rat model; Spry4−/− mice with oocyte ROS/mitochondrial assays and Nrf1 cRNA rescue; phosphokinase array for SPRY4 Thr234Met variant in thyroid cancer cells

    PMID:33906393 PMID:39348320 PMID:40660390

    Open questions at the time
    • SPRY4-PTPRB binding interface not mapped
    • Whether Nrf1-mediated rescue of oocyte defects reflects a direct SPRY4-Nrf1 regulatory axis or parallel pathway is unclear
    • Thyroid cancer variant functional effect tested in a single cell line
  11. 2025 High

    Germline-specific Spry4 conditional knockout confirmed that SPRY4 provides an ERK-specific checkpoint essential for spermatogonial stem cell recovery after injury, with MEK1/2 inhibitor rescue demonstrating pathway specificity over mTOR.

    Evidence Conditional Spry4 G-KO with busulfan injury, PD0325901 rescue versus rapamycin control, fertility assays

    PMID:41852347

    Open questions at the time
    • Downstream ERK substrates mediating SSC recovery not identified
    • Whether SPRY4's checkpoint function operates in female germline stem cells is untested
    • Long-term fertility restoration after MEK inhibitor withdrawal not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of SPRY4's interactions with KIT, PTPRB, and other RTKs, the molecular mechanism by which SPRY4 inhibits RAS-ERK signaling (direct RAS binding versus adaptor sequestration versus other), and how SPRY4 oligomerization with other Sprouty family members modulates its activity remain unresolved.
  • No crystal structure or cryo-EM structure of SPRY4 or its complexes
  • Whether SPRY4 directly binds RAS (as suggested for SPRY2) has not been demonstrated
  • Tissue-specific and context-dependent switching between tumor suppressor and oncogenic functions lacks a unifying mechanistic model

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7
Localization
GO:0005829 cytosol 3 GO:0005576 extracellular region 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4
Partners
HDAC4KITKSRPMEF2DPTPRBSPRY2

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 SPRY4 protein acts as a negative modulator of the FGF8-FGFR1 signaling pathway; loss-of-function mutations in SPRY4 were identified in congenital hypogonadotropic hypogonadism (CHH) patients, placing SPRY4 in the FGF synexpression group that regulates GnRH neuron development. Most FGF17 and IL17RD mutations (the top-ranked candidates) altered protein function in vitro. Sequencing of 386 CHH individuals, functional in vitro assays for candidate mutations, bioinformatics interactome analysis (IBAS) American journal of human genetics Medium 23643382
2006 SPRY4 gene is a transcriptional target of the WNT/β-catenin signaling pathway; conserved double TCF/LEF-binding sites were identified in the 5′-promoter region of SPRY4 orthologs across mammals, establishing SPRY4 as an evolutionarily conserved negative feedback inhibitor of FGF/RTK signaling downstream of WNT activation in progenitor cells. Bioinformatics/comparative genomics identification of TCF/LEF binding sites; humint (literature integration) International journal of molecular medicine Low 16465403
2013 Spry1 and Spry4 have opposing roles in human aortic vascular smooth muscle cell (VSMC) phenotype: Spry1 maintains the differentiated contractile state by sustaining Akt activation and myocardin expression via FoxO3a, while Spry4 suppresses VSMC differentiation marker expression by antagonizing both MAPK/ERK and Akt signaling. ChIP assays showed FoxO3a represses myocardin promoter activity, and Spry1/Spry4 modulate myocardin mRNA levels through this pathway. siRNA knockdown, ChIP assays, Western blotting for pathway components, phenotypic marker quantification in human VSMCs in vitro PloS one Medium 23554919
2014 SPRY4 inhibits FGF2-induced ERK1/2 signaling in endometrial adenocarcinoma (Ishikawa) cells; plasmid-driven SPRY4 expression blocked FGF2-induced ERK1/2 activity as measured by luciferase reporter and Western blot, and significantly reduced cell proliferation including 17β-estradiol-induced proliferation. Luciferase reporter assay, Western blot, colony formation and cell counting assays in Ishikawa cells Gynecological endocrinology Medium 24811094
2015 MT1-MMP negatively regulates SPRY4 transcription in melanoma cells through an MMP2/RAC1 axis; MT1-MMP knockdown increases SPRY4 mRNA and protein, and SPRY4 modulates MT1-MMP-dependent cell migration such that SPRY4 knockdown rescues impaired migration caused by MT1-MMP knockdown. Microarray gene expression, shRNA knockdown of MT1-MMP, qRT-PCR, Western blot, migration assays in melanoma cells Oncotarget Medium 26392417
2015 KSRP (K-homology splicing regulatory protein), an AU-rich element-binding protein, promotes post-transcriptional destabilization of SPRY4 transcripts in non-small cell lung cancer cells; silencing KSRP decreased cell proliferation, reversed anchorage-independent growth, and reduced migration/invasion in a SPRY4-dependent manner. siRNA knockdown of KSRP, qRT-PCR measurement of SPRY4 transcript stability, functional assays (proliferation, migration, anchorage-independent growth) The Journal of biological chemistry Medium 28275056
2015 SPRY4 knockdown in human MDA-MB-231 breast cancer cells increased cell proliferation and migration, elevated β3-integrin expression and CD133+CD44+ stem cell subpopulation, enhanced mammosphere formation, reduced paclitaxel sensitivity, and increased tumor initiation potency in vivo, identifying endogenous SPRY4 as a suppressor of cancer stem cell properties. Lentiviral shRNA knockdown, flow cytometry, mammosphere assay, limiting dilution xenograft, Western blotting Cancer cell international Medium 26973433
2015 SPRY4 acts as a negative regulator of PKCα-mediated activation of MAPK, especially p38MAPK phosphorylation; miR-411-5p directly targets SPRY4, and SPRY4 siRNA or miR-411-5p overexpression both activate p38MAPK phosphorylation, promoting apoptosis and myogenic differentiation in rhabdomyosarcoma (RMS) cells. This establishes a TGF-β1/miR-411-5p/SPRY4/p38MAPK autoregulatory loop governing proliferation vs. differentiation. Luciferase reporter system, siRNA knockdown of SPRY4, miRNA overexpression, Western blot for p38MAPK phosphorylation, miRNA microarray, in vivo tumorigenicity assay Cell death & disease High 26291313
2017 IRF6 and SPRY4 signaling interact genetically in periderm development; crossing Irf6+/- mice with TgKRT14::Spry4 transgenic mice (which express Spry4 in the basal epithelial layer to reduce FGF/RTK signaling) produced a non-additive increase in oral epithelial adhesion severity, and the double mutant embryos showed abnormal GRHL3 expression at adhesion sites, placing SPRY4/RTK signaling and IRF6 in the same periderm differentiation pathway. Genetic epistasis (double mutant cross), quantitative oral adhesion assay, immunofluorescence for GRHL3 and K6 in mouse embryos Journal of dental research Medium 28732181
2018 SPRY4 binds directly to wild-type KIT and primary KIT mutants in gastrointestinal stromal tumors (GISTs), inhibiting KIT expression and activation and thereby decreasing cell survival and proliferation. SPRY4 also enhances the inhibitory effect of imatinib on primary KIT mutants but does not affect secondary drug-resistant KIT mutants, suggesting primary and secondary KIT mutants signal through different downstream cascades. Inhibition of SPRY4 in KITV558A/WT mice increased GIST tumorigenesis in vivo. Co-immunoprecipitation (protein binding), Western blot (KIT expression/activation), Ba/F3 and GIST-T1 cell assays, germline KITV558A/WT mouse model, imatinib sensitivity assays Gastric cancer High 37222910
2019 SPRY4 overexpression inhibited trophoblast (HTR8/SVneo) proliferation and promoted apoptosis in vitro; mechanistically, IFN-γ-induced STAT1 expression and activation (via PI3K/AKT pathway) were identified as downstream effectors of SPRY4 in regulating trophoblast proliferation and apoptosis, and IFN-γ upregulated SPRY4 expression. Both STAT1 and phospho-STAT1 were elevated in RM patient trophoblasts and positively correlated with SPRY4. siRNA knockdown and lentiviral overexpression of SPRY4, gene expression microarray, Western blot for STAT1/pSTAT1/pAKT, proliferation and apoptosis assays in HTR8/SVneo cells American journal of reproductive immunology Medium 32196809
2019 SPRY4 knockdown in AIS (adolescent idiopathic scoliosis) bone marrow-derived MSCs impaired osteogenic differentiation, while SPRY4 overexpression in AIS MSCs enhanced it. SPRY4 contributes to osteogenic differentiation and melatonin response via MEK-ERK1/2-dependent signaling; melatonin upregulated SPRY4 and promoted osteogenesis, while SPRY4 ablation abolished these melatonin effects. siRNA knockdown, lentiviral overexpression, Western blot, qRT-PCR, osteogenic differentiation assays, melatonin treatment Cell death & disease Medium 31645544
2019 SPRY4 knockdown in human adipose-derived stem cells (hASCs) significantly enhanced osteogenic differentiation (ALP 2.3-fold, OPN 3.5-fold increase; increased calcium deposition) via induction of ERK1/2 phosphorylation, and promoted bone formation in ectopic and calvarial defect mouse models in vivo. siRNA knockdown (transient), Western blot, qRT-PCR, Alizarin red staining, microCT, histological analysis of ectopic and calvarial defect models Tissue engineering. Part A Medium 30982407
2021 SPRY4 suppresses ERK signaling downstream of RAS; SPRY4 overexpression suppressed proliferation and invasion of colorectal cancer cells, and the increased proliferation/invasion from SPRY4 silencing was reversed by EZH2 inhibition, placing SPRY4 upstream of EZH2 in CRC. SPRY4 overexpression also inhibited tumorigenesis in nude mice. SPRY4 overexpression/silencing plasmids, CCK-8, colony formation, EdU, wound healing, Transwell assays, flow cytometry, EZH2 inhibitor rescue, xenograft Aging Medium 33879635
2021 MEF2D in complex with HDAC4 directly binds to the SPRY4 promoter and suppresses SPRY4 transcription, which relieves SPRY4-mediated inhibition of the MAPK/ERK signaling pathway and contributes to sorafenib resistance in hepatocellular carcinoma. HDAC4 inhibition restored SPRY4 expression and ERK inhibition, sensitizing tumor cells to sorafenib in vivo. ChIP assays (MEF2D/HDAC4 binding to SPRY4 promoter), Western blot, HDAC4 inhibitor treatment, mouse liver tumor model with sorafenib Cancer letters High 34339801
2021 SPRY4 overexpression in chondrocytes prevents hypertrophy, reduces senescence, ROS production, and ECM protease expression via regulation of the MAPK signaling pathway; SPRY4 knockdown in healthy chondrocytes caused all these pathological features. SPRY4 is downregulated in degenerated human cartilage and OA-model rat tissue. siRNA knockdown and lentiviral overexpression of SPRY4, histological analysis, Western blot, fluorescent ROS assay, DMM rat model NPJ Regenerative medicine Medium 34535669
2021 LINC00675 competes with LSD1 binding and enhances the interaction of LSD1 with H3K4me2, reducing H3K4me2 enrichment at the SPRY4 promoter and suppressing SPRY4 transcription, thereby acting as a suppressor of gastric cancer cell proliferation and migration. RIP assay confirmed LINC00675-LSD1 interaction; ChIP assay verified reduced H3K4me2 at SPRY4 promoter. RIP, coIP, ChIP, RNA-sequencing, in vitro and in vivo functional assays Molecular therapy. Nucleic acids Medium 33230474
2022 SPRY4 promotes adipogenic differentiation of human adipose-derived MSCs (hAMSCs) via activation of the MEK-ERK1/2 pathway; gain- and loss-of-function experiments demonstrated SPRY4 positively correlates with and causally promotes adipogenesis both in vitro and in vivo. Gain/loss-of-function (siRNA and overexpression), Western blot, qPCR, adipogenic differentiation assays in vitro, in vivo fat pad model Adipocyte Medium 36082406
2023 SPRY4 acts as an ERK-dependent negative feedback regulator of growth factor (GDNF and FGF2) signaling in mouse spermatogonial stem cells (SSCs); Spry4 mRNA is robustly induced by GDNF/FGF2, and Spry4 ablation dysregulates ERK MAPK downstream of RAS. Loss of Spry4 shifts SSC fate toward early differentiation with loss of stem cell activity, and a Spry4 reporter line showed strong Spry4 promoter activity demarcates the adult SSC population in vivo. Single-cell quantitative ERK MAPK signaling analysis, Spry4 KO cultures, Spry4 reporter mouse line, in vivo spermatogonial stem cell assays, qRT-PCR Biology of reproduction High 37552049
2024 A SPRY4 variant (c.157C>T, p.Arg53Trp) reduces SPRY4 protein levels in HEK293T cells and disrupts the redox system and mitochondrial function in mouse oocytes; Spry4-/- mice exhibit ovarian oxidative stress and decreased ovarian function. These phenotypes could be partially reversed by exogenous Nrf1 cRNA, identifying a role for SPRY4 in maintaining oocyte redox homeostasis and early embryonic developmental potential. Whole-exome sequencing, Sanger sequencing, Western blot (protein level in HEK293T), cRNA injection in mouse oocytes, RNA sequencing, fluorescence/absorbance assays, ELISA, Spry4 KO mouse histology Human reproduction High 39348320
2024 A SPRY4 variant (c.701C>T, p.Thr234Met) identified in familial nonmedullary thyroid cancer increases cell viability and colony formation; phosphokinase array and Western blot showed these effects are mediated through MAPK/ERK pathway activation, and cells with this variant showed higher responsiveness to a MEK inhibitor. Whole-exome sequencing, Sanger sequencing, in vitro cell viability/colony formation assays, phosphokinase array, Western blot, MEK inhibitor treatment Thyroid Medium 33906393
2024 SPRY4 knockdown in PCOS mice normalized the estrous cycle, reduced serum androgens and LH/FSH ratio, alleviated ovarian oxidative stress, and restored steroidogenic enzyme expression by reducing ERK1/2 phosphorylation. ERK2 agonist (tBHQ) reversed the effects of SPRY4 knockdown, establishing that SPRY4 modulates oxidative stress and steroidogenesis via ERK1/2 phosphorylation in granulosa cells. Lentiviral SPRY4 knockdown in DHEA-induced PCOS mice, ERK2 agonist rescue, ELISA, Western blot, ROS/MDA/SOD assays, granulosa cell isolation Steroids Medium 39313103
2024 Exosomal SPRY4 from adipogenic BMSCs impairs angiogenesis by directly interacting with PTPRB (receptor-type tyrosine phosphatase B), enhancing its phosphatase activity, thereby inhibiting TIE2 receptor autophosphorylation and downstream PI3K/AKT signaling. In vivo, SPRY4 overexpression exacerbated impaired bone mass and microvascular density in SONFH rat model; pharmacological modulation of PTPRB and PI3K reversed these effects. Co-immunoprecipitation, mass spectrometry, exosome co-culture, tube formation assay, Western blot, RNA-seq, in vivo SONFH rat model, HE staining, IHC Stem cell research & therapy High 40660390
2025 Germline-specific Spry4 deletion (Spry4 G-KO) in adult mice causes hyper-activation of MAPK/ERK in undifferentiated spermatogonia, reducing genome integrity after busulfan injury, unleashing excessive early spermatogenesis, and ultimately impairing SSC regeneration and fertility restoration. MEK1/2 inhibitor (PD0325901), but not rapamycin, rescued spermatogonial proliferation in Spry4 G-KO testes post-injury, confirming that SPRY4 controls an ERK-specific checkpoint for SSC recovery. Germline-specific Spry4 KO (conditional), busulfan injury model, MEK inhibitor (PD0325901) rescue, rapamycin comparison, Western blot, qRT-PCR for Id1/Cxcl12, fertility assays Biology of reproduction High 41852347
2014 Spry4 knockout mice (spry4-/-) showed reduced inflammatory responses after spinal cord injury (SCI), including decreased TNFα secretion and reduced macrophage/neutrophil invasion into the lesion site, as well as attenuated astrocytic gliosis and increased neuronal survival, establishing that SPRY4-mediated suppression of FGF signaling limits pro-regenerative responses after SCI. Spry4-/- mouse model, histological analysis, cytokine measurements (TNFα), immunostaining for macrophage/neutrophil markers and GFAP, neuronal survival counting post-SCI Neuroscience Medium 25541251
2019 Overexpression of the FGF negative feedback regulator Sprouty4 in the dental epithelium (K14-Spry4 transgenic mice) caused defects in cusp morphology, enamel irregularities, and delayed signaling center formation in the mouse molar, demonstrating that FGF signaling through SPRY4 feedback regulation controls tooth shape and enamel mineralization. Transgenic mouse overexpression (K14-Spry4), histological analysis, microCT, developmental staging of tooth morphogenesis JBMR plus Medium 31485553
2018 SPRY4 mRNA directly confirmed as a target of miR-411-5p and miR-411-3p; miR-411 overexpression decreased SPRY4 expression and induced EGFR/AKT signaling activation and EMT in NSCLC, while SPRY4 knockdown phenocopied miR-411 overexpression, and SPRY4 restoration reversed the oncogenic effects. Luciferase reporter assay (direct target confirmation), Western blot, NSCLC cell proliferation/migration/apoptosis assays, in vivo tumor growth model Oncogene High 30390072
2018 SPRY4 knockdown in TGCT cell lines (833K and NT2-D1) resulted in decreased cell growth, migration, and invasion, and a significant reduction in Akt phosphorylation, indicating SPRY4 acts as an oncogene in TGCTs through activation of the PI3K/Akt signaling pathway. siRNA-mediated knockdown, Western blot for pAkt, cell growth, migration, and invasion assays in two TGCT cell lines Scientific reports Medium 29410498
2023 miR-1293 knockdown attenuates lung adenocarcinoma-induced angiogenesis by de-repressing Spry4, which inhibits ERK1/2 phosphorylation and nuclear translocation, reducing VEGF-A and bFGF secretion. siRNA-mediated Spry4 perturbation abolished the ERK1/2 inhibition caused by miR-1293 knockdown, confirming the miR-1293/Spry4/ERK1/2 axis. miRNA knockdown, siRNA rescue, Western blot for pERK1/2 and nuclear/cytoplasm distribution, HUVEC tube formation, in vivo angiogenesis markers Biochemical pharmacology Medium 38972427
2025 SPRY2 and SPRY4 form homo- or hetero-oligomers; SPRY2 acts as a novel effector of K-Ras at the plasma membrane, and SPRY4 participates in these oligomeric complexes. Co-immunoprecipitation and BRET assays showed SPRY2-KRas interaction; relevance to SPRY4 is through its hetero-oligomerization with SPRY2. TurboID proximity proteomics, BRET assays, Co-immunoprecipitation, membrane anchorage inhibitors, interface mutagenesis bioRxiv (preprint)preprint Low bio_10.1101_2025.06.13.659437

Source papers

Stage 0 corpus · 97 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion. Cancer research 403 21558391
2017 H3K27 acetylation activated-long non-coding RNA CCAT1 affects cell proliferation and migration by regulating SPRY4 and HOXB13 expression in esophageal squamous cell carcinoma. Nucleic acids research 274 27956498
2014 EZH2-mediated epigenetic suppression of long noncoding RNA SPRY4-IT1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition. Cell death & disease 214 24967960
2016 LncRNA SPRY4-IT1 sponges miR-101-3p to promote proliferation and metastasis of bladder cancer cells through up-regulating EZH2. Cancer letters 209 27998761
2013 Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. American journal of human genetics 200 23643382
2015 The long noncoding RNA SPRY4-IT1 increases the proliferation of human breast cancer cells by upregulating ZNF703 expression. Molecular cancer 140 25742952
2014 The functional characterization of long noncoding RNA SPRY4-IT1 in human melanoma cells. Oncotarget 137 25344859
2018 SP1-induced upregulation of lncRNA SPRY4-IT1 exerts oncogenic properties by scaffolding EZH2/LSD1/DNMT1 and sponging miR-101-3p in cholangiocarcinoma. Journal of experimental & clinical cancer research : CR 128 29642935
2015 Decreased long noncoding RNA SPRY4-IT1 contributing to gastric cancer cell metastasis partly via affecting epithelial-mesenchymal transition. Journal of translational medicine 88 26238992
2013 Upregulation of long noncoding RNA SPRY4-IT1 modulates proliferation, migration, apoptosis, and network formation in trophoblast cells HTR-8SV/neo. PloS one 81 24223182
2016 Overexpression of the long non-coding RNA SPRY4-IT1 promotes tumor cell proliferation and invasion by activating EZH2 in hepatocellular carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 72 27899259
2018 Oncogenic microRNA-411 promotes lung carcinogenesis by directly targeting suppressor genes SPRY4 and TXNIP. Oncogene 71 30390072
2016 The Lnc RNA SPRY4-IT1 Modulates Trophoblast Cell Invasion and Migration by Affecting the Epithelial-Mesenchymal Transition. Scientific reports 66 27853262
2015 Knockdown of long noncoding RNA SPRY4-IT1 suppresses glioma cell proliferation, metastasis and epithelial-mesenchymal transition. International journal of clinical and experimental pathology 60 26464658
2016 Potential diagnostic value of lncRNA SPRY4-IT1 in hepatocellular carcinoma. Oncology reports 54 27278245
2006 FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells. International journal of molecular medicine 54 16465403
2019 LncRNA SPRY4-IT1 regulates breast cancer cell stemness through competitively binding miR-6882-3p with TCF7L2. Journal of cellular and molecular medicine 50 31736268
2019 lncRNA SPRY4-IT1 Regulates Cell Proliferation and Migration by Sponging miR-101-3p and Regulating AMPK Expression in Gastric Cancer. Molecular therapy. Nucleic acids 48 31330497
2018 Knockdown of SPRY4 and SPRY4-IT1 inhibits cell growth and phosphorylation of Akt in human testicular germ cell tumours. Scientific reports 45 29410498
2016 Long noncoding RNA SPRY4-IT1 promotes malignant development of colorectal cancer by targeting epithelial-mesenchymal transition. OncoTargets and therapy 44 27621655
2011 Associations between variants in KITLG, SPRY4, BAK1, and DMRT1 and pediatric germ cell tumors. Genes, chromosomes & cancer 44 22072546
2019 Long non-coding RNA SPRY4-IT1 promotes epithelial-mesenchymal transition of cervical cancer by regulating the miR-101-3p/ZEB1 axis. Bioscience reports 42 31092700
2013 Spry1 and Spry4 differentially regulate human aortic smooth muscle cell phenotype via Akt/FoxO/myocardin signaling. PloS one 42 23554919
2016 Clinical significance of long noncoding RNA SPRY4-IT1 in melanoma patients. FEBS open bio 38 27239436
2017 SPRY4-IT1: A novel oncogenic long non-coding RNA in human cancers. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 36 28651500
2017 Long non-coding RNA SPRY4-IT1 promotes proliferation and invasion by acting as a ceRNA of miR-101-3p in colorectal cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 36 28720069
2016 Long noncoding RNA SPRY4-IT1 promotes esophageal squamous cell carcinoma cell proliferation, invasion, and epithelial-mesenchymal transition. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 34 26883252
2015 Autoregulatory loop between TGF-β1/miR-411-5p/SPRY4 and MAPK pathway in rhabdomyosarcoma modulates proliferation and differentiation. Cell death & disease 34 26291313
2017 Long non-coding RNA SPRY4-IT1 pormotes colorectal cancer metastasis by regulate epithelial-mesenchymal transition. Oncotarget 33 27391336
2016 Upregulation of long noncoding RNA SPRY4-IT1 promotes metastasis of esophageal squamous cell carcinoma via induction of epithelial-mesenchymal transition. Cell biology and toxicology 31 27250657
2021 NF-κB-activated SPRY4-IT1 promotes cancer cell metastasis by downregulating TCEB1 mRNA via Staufen1-mediated mRNA decay. Oncogene 28 34163032
2020 Long noncoding RNA SPRY4-IT1 promotes proliferation and metastasis of hepatocellular carcinoma via mediating TNF signaling pathway. Journal of cellular physiology 28 31943198
2020 SPRY4 regulates trophoblast proliferation and apoptosis via regulating IFN-γ-induced STAT1 expression and activation in recurrent miscarriage. American journal of reproductive immunology (New York, N.Y. : 1989) 28 32196809
2017 Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group. Genes, chromosomes & cancer 28 28295819
2020 Deregulation of long noncoding RNAs ANCR, TINCR, HOTTIP and SPRY4-IT1 in plasma of systemic sclerosis patients: SPRY4-IT1 as a novel biomarker of scleroderma and its subtypes. Cytokine 26 32442909
2018 The long non-coding RNA SPRY4-IT1: An emerging player in tumorigenesis and osteosarcoma. Cell proliferation 26 29484753
2017 IRF6 and SPRY4 Signaling Interact in Periderm Development. Journal of dental research 24 28732181
2018 Long non-coding RNA SPRY4-IT1 promotes cell proliferation and invasion by regulation of Cdc20 in pancreatic cancer cells. PloS one 23 29489909
2018 MicroRNA‑181 serves an oncogenic role in breast cancer via the inhibition of SPRY4. Molecular medicine reports 23 30365052
2017 K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer. The Journal of biological chemistry 23 28275056
2016 Suppression of Spry4 enhances cancer stem cell properties of human MDA-MB-231 breast carcinoma cells. Cancer cell international 23 26973433
2013 Investigation of six testicular germ cell tumor susceptibility genes suggests a parent-of-origin effect in SPRY4. Human molecular genetics 23 23640991
2019 SPRY4 is responsible for pathogenesis of adolescent idiopathic scoliosis by contributing to osteogenic differentiation and melatonin response of bone marrow-derived mesenchymal stem cells. Cell death & disease 22 31645544
2017 Up-regulation of long non-coding RNA SPRY4-IT1 promotes tumor cell migration and invasion in lung adenocarcinoma. Oncotarget 22 28881629
2020 Long Non-Coding RNA SPRY4-IT1 Reverses Cisplatin Resistance by Downregulating MPZL-1 via Suppressing EMT in NSCLC. OncoTargets and therapy 20 32308413
2017 Decreased long non-coding RNA SPRY4-IT1 contributes to ovarian cancer cell metastasis partly via affecting epithelial-mesenchymal transition. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 20 28691641
2017 Effects of long noncoding RNA SPRY4-IT1-mediated EZH2 on the invasion and migration of lung adenocarcinoma. Journal of cellular biochemistry 20 28796375
2021 Coupling HDAC4 with transcriptional factor MEF2D abrogates SPRY4-mediated suppression of ERK activation and elicits hepatocellular carcinoma drug resistance. Cancer letters 19 34339801
2019 LncRNA SPRY4‑IT1 promotes progression of osteosarcoma by regulating ZEB1 and ZEB2 expression through sponging of miR‑101 activity. International journal of oncology 18 31746422
2019 Interference from LncRNA SPRY4-IT1 restrains the proliferation, migration, and invasion of melanoma cells through inactivating MAPK pathway by up-regulating miR-22-3p. International journal of clinical and experimental pathology 18 31933852
2016 Effects of long non-coding RNA SPRY4-IT1 on osteosarcoma cell biological behavior. American journal of translational research 17 28078006
2017 Long non-coding RNA SPRY4-IT1 promotes gallbladder carcinoma progression. Oncotarget 16 27902971
2016 SPRY4 Intronic Transcript 1 Promotes Epithelial-Mesenchymal Transition Through Association with Snail1 in Osteosarcoma. DNA and cell biology 16 26982001
2015 MT1-MMP dependent repression of the tumor suppressor SPRY4 contributes to MT1-MMP driven melanoma cell motility. Oncotarget 15 26392417
2022 LncRNA SPRY4-IT1 facilitates cell proliferation and angiogenesis of glioma via the miR-101-3p/EZH2/VEGFA signaling axis. Cancer medicine 14 36479622
2020 LINC00675 Suppresses Cell Proliferation and Migration via Downregulating the H3K4me2 Level at the SPRY4 Promoter in Gastric Cancer. Molecular therapy. Nucleic acids 14 33230474
2019 Suppression of SPRY4 Promotes Osteogenic Differentiation and Bone Formation of Mesenchymal Stem Cell. Tissue engineering. Part A 14 30982407
2022 A Review on the Role of SPRY4-IT1 in the Carcinogenesis. Frontiers in oncology 13 35096580
2021 SPRY4 suppresses proliferation and induces apoptosis of colorectal cancer cells by repressing oncogene EZH2. Aging 13 33879635
2021 Identification of SPRY4 as a Novel Candidate Susceptibility Gene for Familial Nonmedullary Thyroid Cancer. Thyroid : official journal of the American Thyroid Association 13 33906393
2021 SPRY4 acts as an indicator of osteoarthritis severity and regulates chondrocyte hypertrophy and ECM protease expression. NPJ Regenerative medicine 13 34535669
2015 Upregulated long noncoding RNA SPRY4-IT1 contributes to increased cell viability by activating zinc finger 703 expression in esophageal squamous cell carcinoma. Indian journal of cancer 13 27453415
2020 SPRY4-IT1 promotes survival of colorectal cancer cells through regulating PDK1-mediated glycolysis. Animal cells and systems 12 33029299
2014 Decreased anti-regenerative effects after spinal cord injury in spry4-/- mice. Neuroscience 12 25541251
2024 Role of SPRY4 in health and disease. Frontiers in oncology 11 38686189
2019 A Rare SPRY4 Gene Mutation Is Associated With Anosmia and Adult-Onset Isolated Hypogonadotropic Hypogonadism. Frontiers in endocrinology 11 31781046
2018 Long non-coding RNA SPRY4-IT1 promotes the proliferation and invasion of U251 cells through upregulation of SKA2. Oncology letters 11 29467908
2018 The N-terminal polypeptide derived from vMIP-II exerts its anti-tumor activity in human breast cancer by regulating lncRNA SPRY4-IT1. Bioscience reports 11 30104400
2023 PDK1-stabilized LncRNA SPRY4-IT1 promotes breast cancer progression via activating NF-κB signaling pathway. Molecular carcinogenesis 8 37042573
2017 [Effect of long noncoding RNA SPRY4-IT1 on proliferation and metastasis of medulloblastoma]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 8 29926610
2014 SPRY4-mediated ERK1/2 signaling inhibition abolishes 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 8 24811094
2020 Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism. Journal of medical genetics 7 32389901
2019 Clinical significance of SPRY4-IT1 in efficacy and survival prediction in breast cancer patients undergoing neoadjuvant chemotherapy. Histology and histopathology 7 31638266
2025 Dissecting the role of SPRY4-IT1 and TUG1 in modulating miR-425/TGF-β/ Smad signaling in mediating renal fibrosis and inflammation in lupus nephritis: Novel biomarkers and therapeutic targets. International immunopharmacology 6 40561829
2023 SPRY4 inhibits and sensitizes the primary KIT mutants in gastrointestinal stromal tumors (GISTs) to imatinib. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 6 37222910
2023 SPRY4-dependent ERK negative feedback demarcates functional adult stem cells in the male mouse germline†. Biology of reproduction 6 37552049
2021 Long Noncoding RNA SPRY4-IT1 Modulates Ketamine-Induced Neurotoxicity in Human Embryonic Stem Cell-Derived Neurons through EZH2. Developmental neuroscience 6 33827085
2023 LncRNA SPRY4‑IT1 is upregulated and promotes the proliferation of prostate cancer cells under hypoxia in vitro. Oncology letters 5 36909367
2022 SPRY4 promotes adipogenic differentiation of human mesenchymal stem cells through the MEK-ERK1/2 signaling pathway. Adipocyte 5 36082406
2019 Downregulation of FGF Signaling by Spry4 Overexpression Leads to Shape Impairment, Enamel Irregularities, and Delayed Signaling Center Formation in the Mouse Molar. JBMR plus 5 31485553
2021 Long non-coding RNA SPRY4-IT1 as a promising indicator for three field lymph-node dissection of thoracic esophageal carcinoma. Journal of cardiothoracic surgery 4 33757566
2024 Knockdown of miR-1293 attenuates lung adenocarcinoma angiogenesis via Spry4 upregulation-mediated ERK1/2 signaling inhibition. Biochemical pharmacology 3 38972427
2022 Long non-coding RNA SPRY4-IT1 promotes proliferation and metastasis in nasopharyngeal carcinoma cell. PeerJ 3 35378932
2015 [Effect of Long Non-coding RNA SPRY4-IT1 on Invasion and Migration of A549 Cells]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 3 26302345
2025 Exosomal SPRY4 from adipogenic BMSCs impairs angiogenesis via the PTPRB/TIE2/PI3K axis in Steroid-induced osteonecrosis of the femoral head. Stem cell research & therapy 2 40660390
2024 SPRY4 regulates ERK1/2 phosphorylation to affect oxidative stress and steroidogenesis in polycystic ovary syndrome. Steroids 2 39313103
2023 Long noncoding RNA SPRY4-IT1 acts as a miR-101-5p sponge to promote gastrointestinal stromal tumor progression by inhibiting ZEB1. American journal of translational research 2 36915750
2023 SPRY4 as a Potential Mediator of the Anti-Tumoral Role of Macrophages in Anaplastic Thyroid Cancer Cells. Cancers 2 37686663
2023 LncRNA SPRY4-IT1 regulates 16HBE cell malignant transformation induced by particulate matter through DUSP6-ERK1/2-Chk1 signaling pathway. Chemosphere 2 37797900
2025 CircPFKP orchestrates a novel competing endogenous RNA network to regulate SPRY4/p38-MAPK signaling and modulate papillary thyroid carcinoma aggressiveness. International journal of biological macromolecules 1 41075905
2024 A heterozygous SPRY4 variant identified in female infertility characterized by reduced oocyte potential and early embryonic arrest. Human reproduction (Oxford, England) 1 39348320
2016 [Polymorphisms of KITLG, SPRY4, and BAK1 genes in patients with testicular germ cell tumors and individuals with infertility associated with AZFc deletion of the Y chromosome]. Molekuliarnaia biologiia 1 28064312
2026 Restoration of Spermatogenesis is Dependent on Activation of a SPRY4-ERK Checkpoint Following Germline Stem Cell Damage. Biology of reproduction 0 41852347
2025 Restoration of Spermatogenesis is Dependent on Activation of a SPRY4-ERK Checkpoint Following Germline Stem Cell Damage. bioRxiv : the preprint server for biology 0 41279276
2024 Retraction Notice to: lncRNA SPRY4-IT1 Regulates Cell Proliferation and Migration by Sponging miR-101-3p and Regulating AMPK Expression in Gastric Cancer. Molecular therapy. Nucleic acids 0 38784177
2022 [Retracted] MicroRNA‑181 serves an oncogenic role in breast cancer via the inhibition of SPRY4. Molecular medicine reports 0 35266013
2017 Erratum to: Suppression of Spry4 enhances cancer stem cell properties of human MDA-MB-231 breast carcinoma cells. Cancer cell international 0 28507453