Affinage

SPRY4

Protein sprouty homolog 4 · UniProt Q9C004

Length
299 aa
Mass
32.5 kDa
Annotated
2026-06-10
98 papers in source corpus 30 papers cited in narrative 29 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

SPRY4 is a negative-feedback inhibitor of receptor tyrosine kinase signaling that restrains the RAS–ERK MAPK and PI3K/AKT cascades to control cell differentiation, proliferation, survival, and tissue homeostasis (PMID:37552049, PMID:41852347, PMID:41279276, PMID:24811094). At the protein level, SPRY4 acts directly on RTK signaling nodes: it binds the receptor tyrosine kinase KIT, suppressing KIT expression and activation to limit cell survival and proliferation and to enhance imatinib sensitivity in gastrointestinal stromal tumors (PMID:37222910), and it physically interacts with the phosphatase PTPRB to enhance its activity, thereby dampening TIE2 autophosphorylation and downstream PI3K/AKT to inhibit angiogenesis (PMID:40660390). Genetic loss-of-function studies establish SPRY4 as an ERK-MAPK checkpoint: germline-specific Spry4 deletion in spermatogonial stem cells causes hyperactivation of ERK1/2, excessive differentiation, and impaired germline regeneration, all reversed by MEK inhibition (PMID:41852347, PMID:41279276, PMID:37552049). The same ERK/AKT-braking function operates across diverse lineages — suppressing VSMC differentiation via MAPK and FoxO3a-dependent PI3K/Akt signaling (PMID:23554919), constraining chondrocyte hypertrophy and oxidative stress (PMID:34535669), and tuning mesenchymal stem cell osteogenic and adipogenic differentiation through MEK-ERK1/2 (PMID:30982407, PMID:36082406). SPRY4 frequently functions as a tumor suppressor whose downregulation activates ERK or AKT, and it is itself controlled at multiple regulatory layers: transcriptionally by the MEF2D–HDAC4 complex and by LSD1-mediated H3K4me2 demethylation at its promoter (PMID:34339801, PMID:33230474), post-transcriptionally by the AU-rich element-binding protein KSRP and by microRNAs including miR-411 and miR-1293 (PMID:28275056, PMID:26291313, PMID:30390072, PMID:38972427). Heterozygous loss-of-function mutations in SPRY4 cause congenital hypogonadotropic hypogonadism, placing it in the FGF8/FGFR1 signaling pathway underlying GnRH neuron development (PMID:23643382).

Mechanistic history

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

    Whether SPRY4 was embedded in a defined upstream transcriptional program was unknown; comparative genomics placed it under WNT control by identifying conserved TCF/LEF sites in its promoter.

    Evidence Comparative genomics of SPRY4 promoters across human, chimp, rat, and mouse

    PMID:16465403

    Open questions at the time
    • Computational prediction only, no experimental confirmation of WNT-driven SPRY4 transcription
    • No demonstration of β-catenin/TCF occupancy in cells
  2. 2013 Medium

    It was unclear whether SPRY4 had a human disease-relevant role in development; CHH patient sequencing established SPRY4 loss-of-function as a cause of congenital hypogonadotropic hypogonadism within FGF8/FGFR1 signaling.

    Evidence Sequencing of 386 CHH patients plus in vitro functional validation of variants

    PMID:23643382

    Open questions at the time
    • Does not define the molecular target of SPRY4 in GnRH neurons
    • Single cohort
  3. 2013 Medium

    How SPRY4 controls cell fate was tested in VSMCs, showing it suppresses differentiation by antagonizing both MAPK/ERK and PI3K/Akt, the latter via FoxO3a repression of myocardin.

    Evidence siRNA knockdown, ChIP, and pathway Western blots in human aortic smooth muscle cells

    PMID:23554919

    Open questions at the time
    • No direct SPRY4 protein partner identified in this context
    • Spry1 vs Spry4 specificity mechanism unresolved
  4. 2014 Medium

    The breadth of SPRY4's tumor-suppressive ERK braking and its in vivo developmental roles were extended through endometrial cancer suppression, spinal cord injury, and tooth morphogenesis models.

    Evidence SPRY4 overexpression in Ishikawa cells; Spry4 KO spinal cord injury; K14-Spry4 transgenic mice

    PMID:24811094 PMID:25541251 PMID:31485553

    Open questions at the time
    • Pathway readouts are correlative, no direct receptor target shown
    • Context-dependent outcomes not mechanistically unified
  5. 2015 Medium

    Mechanisms of SPRY4 downregulation in cancer were defined: MT1-MMP transcriptional repression and miR-411-5p direct targeting, the latter linking SPRY4 to p38MAPK control in a TGF-β1 autoregulatory loop.

    Evidence Knockdown-rescue in melanoma; luciferase miRNA-target assay and p38MAPK readouts in rhabdomyosarcoma

    PMID:26291313 PMID:26392417

    Open questions at the time
    • Melanoma regulation only partly via MMP2/RAC1 axis
    • p38MAPK suppression mechanism (PKCα) not structurally defined
  6. 2017 Medium

    Additional layers controlling SPRY4 abundance were established: KSRP-mediated mRNA destabilization in NSCLC, and genetic epistasis with IRF6 in periderm differentiation in vivo.

    Evidence KSRP silencing and mRNA stability assays in NSCLC; Irf6+/-;TgKRT14::Spry4 double-mutant mice

    PMID:28275056 PMID:28732181

    Open questions at the time
    • KSRP-SPRY4 binding not shown to be direct
    • IRF6-SPRY4 epistasis is genetic, not biochemical
  7. 2018 High

    A direct protein target of SPRY4 was identified for the first time: SPRY4 binds wild-type and primary mutant KIT to suppress its activation, and context-dependent oncogenic behavior via PI3K/Akt was shown in testicular germ cell tumors.

    Evidence Co-IP of SPRY4-KIT, Ba/F3/GIST cell models, KIT-mutant mice; SPRY4 knockdown with phospho-Akt readout in TGCT lines

    PMID:29410498 PMID:30390072 PMID:37222910

    Open questions at the time
    • Structural basis of SPRY4-KIT interaction unknown
    • Why SPRY4 is oncogenic in TGCT but suppressive elsewhere is unexplained
  8. 2019 High

    Loss-of-function genetics established SPRY4 as an ERK-MAPK checkpoint in spermatogonial stem cell maintenance and as a tunable regulator of MSC osteogenic differentiation, including melatonin-driven effects.

    Evidence Spry4 ablation and reporter mice in SSCs with single-cell ERK quantification; siRNA/lentiviral SPRY4 in MSCs with in vivo bone models and trophoblast PI3K/AKT-STAT1 axis

    PMID:30982407 PMID:31645544 PMID:32196809 PMID:37552049

    Open questions at the time
    • Receptor-level target in SSCs not defined
    • Lineage-specific opposite effects on differentiation not mechanistically reconciled
  9. 2021 High

    The transcriptional and chromatin control of SPRY4 was deepened (MEF2D-HDAC4 promoter binding, LSD1-H3K4me2, EZH2 epistasis) and its MAPK-braking role extended to chondrocyte homeostasis and familial thyroid cancer.

    Evidence ChIP for MEF2D/HDAC4 and LSD1/H3K4me2 at SPRY4 promoter; EZH2 inhibitor rescue in CRC; chondrocyte gain/loss-of-function; thyroid cancer variant functional assays

    PMID:33230474 PMID:33879635 PMID:33906393 PMID:34339801 PMID:34535669

    Open questions at the time
    • Whether SPRY4 directly represses EZH2 or acts indirectly is unresolved
    • Direct kinase/phosphatase target in chondrocytes not identified
  10. 2023 High

    A second direct protein partner was established — SPRY4 binds PTPRB to enhance its phosphatase activity and inhibit TIE2/PI3K/AKT-driven angiogenesis — and the germline ERK checkpoint was confirmed by conditional knockout with pharmacological rescue.

    Evidence Co-IP/MS of SPRY4-PTPRB, TIE2 pathway Westerns, tube formation and in vivo SONFH model; germline Spry4 G-KO mice with MEK inhibitor rescue

    PMID:40660390 PMID:41279276 PMID:41852347

    Open questions at the time
    • How SPRY4 activates PTPRB phosphatase activity biochemically is undefined
    • Generality of PTPRB target beyond endothelial cells untested
  11. 2024 High

    SPRY4's role in female reproduction was mechanistically linked to redox homeostasis (Nrf1-dependent) and to ovarian ERK1/2 control, and miR-1293 was added as an upstream regulator of SPRY4-controlled angiogenesis.

    Evidence WES variant functional analysis, Spry4 KO mouse ovary, Nrf1 cRNA rescue; SPRY4 knockdown in PCOS mice with ERK2 agonist; miR-1293/SPRY4 siRNA rescue in LUAD

    PMID:38972427 PMID:39313103 PMID:39348320

    Open questions at the time
    • Connection between SPRY4 RTK inhibition and Nrf1-dependent redox control is not mechanistically bridged
    • Direct receptor target in oocytes/granulosa cells unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural and biochemical basis by which SPRY4 engages and modulates its direct partners (KIT, PTPRB) and how the same protein produces opposite differentiation and tumor outcomes across cell types remains unresolved.
  • No structural model of SPRY4 bound to KIT or PTPRB
  • No unified explanation for context-dependent tumor-suppressor versus oncogenic roles
  • Mechanism coupling SPRY4 to mitochondrial/redox homeostasis undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4
Partners
KITPTPRB

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 SPRY4 acts as a negative feedback inhibitor of FGF receptor signaling; heterozygous loss-of-function mutations in SPRY4 were identified in patients with congenital hypogonadotropic hypogonadism, placing SPRY4 in the FGF8 synexpression group and the FGFR1 signaling pathway underlying GnRH neuron development. Human genetic sequencing of 386 CHH patients plus in vitro functional validation of identified variants American journal of human genetics Medium 23643382
2006 SPRY4 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 mammalian SPRY4 orthologs by comparative genomics, establishing SPRY4 as an evolutionarily conserved WNT target gene. Bioinformatics/comparative genomics identification of TCF/LEF binding sites in SPRY4 promoter across human, chimpanzee, rat, and mouse orthologs International journal of molecular medicine Low 16465403
2013 Spry4, but not Spry1, suppresses vascular smooth muscle cell (VSMC) differentiation by antagonizing both MAPK/ERK and Akt signaling, thereby reducing myocardin mRNA levels; this was demonstrated by siRNA knockdown and ChIP assays showing FoxO3a represses myocardin promoter activity downstream of the PI3K/Akt axis regulated by Spry4. siRNA knockdown, ChIP assay, Western blot for pathway markers in human aortic smooth muscle cells PloS one Medium 23554919
2014 SPRY4 overexpression blocks FGF2-induced ERK1/2 signaling and significantly reduces proliferation and 17β-estradiol-induced proliferation of Ishikawa endometrial adenocarcinoma cells, functioning as a tumor suppressor via ERK1/2 pathway inhibition. Luciferase assay, Western blot, colony formation assay, cell counting in Ishikawa cells transfected with SPRY4 plasmid Gynecological endocrinology Medium 24811094
2015 MT1-MMP negatively regulates SPRY4 transcription in melanoma cells partly through an MMP2/RAC1 axis; SPRY4 knockdown rescues cell migration impaired by MT1-MMP knockdown, placing SPRY4 downstream of MT1-MMP as a tumor suppressor modulating melanoma cell motility. Microarray gene expression analysis, MT1-MMP knockdown with rescue experiments, mRNA/protein level measurements in melanoma cell lines Oncotarget Medium 26392417
2017 KSRP (K-homology splicing regulatory protein), an AU-rich element-binding protein, promotes post-transcriptional destabilization of SPRY4 mRNA in non-small cell lung cancer, providing a mechanism for SPRY4 downregulation in lung cancer. KSRP silencing experiments, mRNA stability assays, cell proliferation/migration assays in NSCLC cells The Journal of biological chemistry Medium 28275056
2017 IRF6 and SPRY4 signaling interact in periderm development; crossing Irf6+/- mice with TgKRT14::Spry4 transgenic mice (which overexpress Spry4 in the basal epithelial layer) produced a non-additive increase in abnormal oral epithelial adhesions, demonstrating genetic epistasis between IRF6 and RTK/SPRY4 signaling in regulating periderm differentiation. Genetic epistasis in mice: double mutant Irf6+/-;TgKRT14::Spry4 cross, quantitative assay of oral epithelial adhesions, immunofluorescence for GRHL3 and keratin 6 Journal of dental research Medium 28732181
2018 SPRY4 binds to both wild-type KIT and primary KIT mutants in gastrointestinal stromal tumors (GISTs), inhibits KIT expression and activation, reduces cell survival and proliferation, and enhances imatinib sensitivity of primary KIT mutants. This feedback regulation does not extend to secondary (drug-resistant) KIT mutants. Immunoprecipitation to confirm SPRY4-KIT binding, qRT-PCR/Western blot for expression, Ba/F3 and GIST-T1 cell models, KITV558A/WT germline mutant mice for in vivo tumorigenesis Gastric cancer High 37222910
2019 SPRY4 overexpression in trophoblast cells (HTR8/SVneo) inhibits proliferation and accelerates apoptosis via upregulation of IFN-γ-induced STAT1 expression and phosphorylation through the PI3K/AKT pathway; IFN-γ promotes SPRY4 expression through PI3K/AKT, creating a regulatory axis governing trophoblast function relevant to recurrent miscarriage. siRNA knockdown and lentiviral overexpression of SPRY4 in HTR8/SVneo cells, gene expression microarray, Western blot for STAT1 and p-STAT1, PI3K inhibitor experiments American journal of reproductive immunology Medium 32196809
2019 SPRY4 knockdown in human adipose-derived mesenchymal stem cells (hASCs) enhances osteogenic differentiation via induction of ERK1/2 phosphorylation, increasing alkaline phosphatase and osteopontin expression and calcium deposition; in vivo, siSPRY4-treated hASCs showed greater bone volume in ectopic bone formation and calvarial defect mouse models. siRNA knockdown of SPRY4, Western blot and qPCR for osteogenic markers, Alizarin red staining, in vivo ectopic bone and calvarial defect models, microcomputed tomography Tissue engineering. Part A High 30982407
2019 SPRY4 is required for spermatogonial stem cell (SSC) maintenance in the mouse testis; Spry4 acts as an ERK MAPK negative feedback regulator induced by GDNF and FGF2 in SSCs. Spry4 ablation in cultured SSCs dysregulates ERK MAPK downstream of RAS and shifts cell fate toward early differentiation with loss of stem cell activity. Spry4 ablation in cultured mouse SSCs, single-cell quantitative analysis of ERK MAPK signaling, Spry4 reporter mouse line for in vivo localization, growth factor stimulation assays Biology of reproduction High 37552049
2021 MEF2D in complex with HDAC4 directly binds to the SPRY4 promoter and suppresses SPRY4 transcription, thereby relieving SPRY4-mediated inhibition of MAPK/ERK signaling and contributing to sorafenib resistance in hepatocellular carcinoma. HDAC4 inhibition induces SPRY4 expression and inhibits ERK activity, sensitizing HCC cells to sorafenib. ChIP assay demonstrating MEF2D/HDAC4 binding to SPRY4 promoter, Western blot for ERK signaling, HDAC4 inhibitor treatment, in vivo mouse tumor model Cancer letters High 34339801
2021 SPRY4 overexpression suppresses proliferation, migration, and invasion of colorectal cancer cells and promotes apoptosis; the enhanced oncogenic phenotype from SPRY4 silencing is reversed by EZH2 inhibition, placing SPRY4 upstream of EZH2 as a tumor suppressor that represses EZH2 activity. SPRY4 overexpression and silencing plasmid transfection, CCK-8, colony formation, EdU, wound-healing, Transwell assays, flow cytometry, in vivo xenograft, EZH2 inhibitor rescue experiments Aging Medium 33879635
2021 SPRY4 acts as a negative regulator of chondrocyte hypertrophy, senescence, ROS production, and ECM protease expression via the MAPK signaling pathway; SPRY4 knockdown in healthy chondrocytes increases hypertrophy and oxidative stress, while lentiviral SPRY4 overexpression in degenerated chondrocytes reduces these pathological features. siRNA knockdown and lentiviral overexpression of SPRY4 in human chondrocytes, DMM rat model, histological and molecular analyses, MAPK pathway readouts NPJ Regenerative medicine Medium 34535669
2021 SPRY4 variant c.701C>T (p.Thr234Met) identified in familial nonmedullary thyroid cancer increases cell viability and colony formation; phosphokinase array and Western blot analyses indicated effects are mediated through the MAPK/ERK pathway, and cells with this variant show higher responsiveness to a MEK inhibitor. In vitro functional characterization of SPRY4 variant in thyroid cancer cells: cell viability assay, colony formation, phosphokinase array, Western blot, MEK inhibitor treatment Thyroid Medium 33906393
2022 SPRY4 promotes adipogenic differentiation of human adipose-derived mesenchymal stem cells (hAMSCs) by activating the MEK-ERK1/2 pathway; gain- and loss-of-function experiments demonstrated SPRY4 enhances adipogenesis both in vitro and in vivo. siRNA knockdown and overexpression of SPRY4 in hAMSCs, Western blot and qPCR for adipogenic markers, in vivo adipogenesis assay, MEK-ERK1/2 pathway assessment Adipocyte Medium 36082406
2023 SPRY4 promotes ERK MAPK negative feedback in spermatogonial stem cells; germline-specific Spry4 deletion (Spry4 G-KO) following busulfan-induced injury leads to hyper-activation of ERK1/2 in undifferentiated spermatogonia, excessive differentiation, dysregulation of stem cell maintenance genes (Id1, Cxcl12), and impaired long-term germline regeneration. MEK1/2 inhibitor (PD0325901) restored spermatogonial proliferation in Spry4 G-KO mice, confirming the SPRY4-ERK checkpoint. Germline-specific conditional Spry4 knockout mice, busulfan injury model, immunofluorescence for ERK1/2 activity, MEK inhibitor rescue, fertility assays Biology of reproduction High 41279276 41852347
2023 SPRY4 inhibits angiogenesis by directly interacting with PTPRB (receptor-type tyrosine-protein phosphatase beta), enhancing PTPRB phosphatase activity, which suppresses TIE2 receptor autophosphorylation and downstream PI3K/AKT signaling; exosomal delivery of SPRY4 from adipogenic BMSCs to endothelial cells mediates this anti-angiogenic effect in steroid-induced osteonecrosis of the femoral head. Co-immunoprecipitation and mass spectrometry for SPRY4-PTPRB interaction, Western blot for TIE2/PI3K/AKT pathway, tube formation assays, in vivo rat SONFH model with SPRY4 lentiviral overexpression/knockdown Stem cell research & therapy High 40660390
2024 SPRY4 variant p.Arg53Trp reduces SPRY4 protein levels and disrupts the redox system and mitochondrial function in mouse oocytes, perturbing embryo developmental potential; Spry4 knockout mice exhibit ovarian oxidative stress and decreased ovarian function. These phenotypes were partially reversed by exogenous Nrf1 cRNA, placing SPRY4 upstream of Nrf1-dependent redox homeostasis in female reproductive development. Whole-exome sequencing of infertile patients, Western blot of variant in HEK293T cells, mouse oocyte cRNA injection, RNA sequencing, fluorescence/ROS assays, Spry4 KO mouse histology and functional analyses, Nrf1 rescue experiment Human reproduction High 39348320
2024 SPRY4 knockdown in a PCOS mouse model normalizes the estrous cycle, reduces androgen and LH/FSH ratio, alleviates oxidative stress, and restores steroidogenic enzyme expression by reducing ERK1/2 phosphorylation in granulosa cells; ERK2 agonist reversed these effects, confirming SPRY4 modulates ovarian function via ERK1/2 phosphorylation. Lentivirus-mediated SPRY4 knockdown in DHEA-induced PCOS mice, granulosa cell isolation with ERK2 agonist treatment, ELISA, ROS measurement, Western blot for steroidogenic enzymes and ERK1/2 Steroids Medium 39313103
2014 Loss of Spry4 in mice reduces inflammatory responses (TNFα secretion, macrophage/neutrophil invasion), attenuates astrocytic gliosis, and increases neuronal survival after spinal cord injury, demonstrating that Spry4-mediated inhibition of FGF signaling limits pro-regenerative responses in the injured spinal cord. Spry4 knockout mice subjected to spinal cord injury, immunohistochemistry and cytokine analysis for TNFα, macrophage/neutrophil markers, astrocytic gliosis markers, and neuronal survival Neuroscience Medium 25541251
2019 SPRY4 is markedly downregulated in AIS (adolescent idiopathic scoliosis) mesenchymal stem cells; SPRY4 knockdown impairs osteogenic differentiation of healthy MSCs while SPRY4 overexpression in AIS MSCs enhances osteogenic differentiation. SPRY4 ablation abolishes the pro-osteogenic effects of melatonin, and SPRY4 upregulation by melatonin operates via MEK-ERK1/2 signaling. siRNA knockdown and lentiviral overexpression of SPRY4 in MSCs, osteogenic differentiation assays, MEK-ERK1/2 pathway inhibitors, melatonin treatment experiments Cell death & disease Medium 31645544
2015 miR-411-5p directly targets SPRY4 mRNA in rhabdomyosarcoma (RMS); SPRY4 inhibits protein kinase Cα-mediated p38MAPK phosphorylation. Both SPRY4 siRNA and miR-411-5p re-expression activate p38MAPK phosphorylation, promote apoptosis and myogenic differentiation in RMS cells. TGF-β1 promotes SPRY4 expression and suppresses miR-411-5p, establishing an autoregulatory TGF-β1/miR-411-5p/SPRY4/p38MAPK loop. Luciferase reporter assay to validate miR-411-5p targeting of SPRY4, siRNA knockdown of SPRY4, miR-411-5p re-expression, Western blot for p38MAPK phosphorylation and myogenic markers, in vivo tumorigenicity assay Cell death & disease High 26291313
2018 SPRY4 knockdown in TGCT cell lines (833K and NT2-D1) leads to decreased cell growth, migration, invasion, and a significant reduction in Akt phosphorylation, indicating SPRY4 acts as an oncogene in testicular germ cell tumors via activation of the PI3K/Akt signaling pathway. siRNA-mediated knockdown of SPRY4 in TGCT cell lines, cell growth assay, migration/invasion assay, Western blot for phospho-Akt Scientific reports Medium 29410498
2019 Downregulation of FGF signaling by epithelial-specific Spry4 overexpression (K14-Spry4 transgenic mice) causes defects in molar cusp morphology, enamel irregularities, and a developmental delay in signaling center formation, demonstrating that SPRY4-mediated regulation of FGF signaling is required for proper tooth morphology and enamel mineralization. Transgenic mouse model overexpressing Spry4 under K14 promoter, morphological analysis of erupted molars, histology of developmental stages JBMR plus Medium 31485553
2023 SPRY4 upregulation mediates the anti-tumoral effect of macrophages on anaplastic thyroid cancer cells; SPRY4 silencing in C3948 ATC cells reversed the macrophage-induced decrease in invasion, supporting a tumor suppressor role for SPRY4 as a mediator of macrophage-ATC communication via MAPK pathway inhibition. Indirect co-culture of ATC cell lines with THP-1-derived macrophages, proteomic analysis identifying SPRY4 upregulation, SPRY4 silencing rescue experiments, flow cytometry for macrophage polarization markers Cancers Medium 37686663
2018 miR-411-5p and miR-411-3p directly target SPRY4 in NSCLC cells; overexpression of miR-411-5p/3p decreases SPRY4 expression and induces EGFR/AKT signaling activation and EMT in tumor tissues in vivo, establishing the miR-411-SPRY4-AKT axis in lung cancer. Luciferase reporter assay to confirm miR-411-5p/3p targeting of SPRY4, overexpression in NSCLC cell lines, in vivo xenograft tumor model with Western blot for EGFR/AKT/EMT markers Oncogene Medium 30390072
2024 miR-1293 knockdown in lung adenocarcinoma upregulates SPRY4 expression, leading to inactivation of ERK1/2 signaling (reduced phosphorylation and nuclear translocation) and attenuation of tumor-induced angiogenesis (decreased VEGF-A and bFGF). siRNA-mediated SPRY4 knockdown abolished these anti-angiogenic effects, placing SPRY4 as a key ERK1/2 pathway inhibitor downstream of miR-1293 in LUAD angiogenesis. miR-1293 knockdown with SPRY4 siRNA rescue, Western blot for ERK1/2 phosphorylation, tube formation assay, in vivo angiogenesis assay with CD31/VEGF-A/bFGF measurements Biochemical pharmacology Medium 38972427
2020 LINC00675 competitively binds LSD1, strengthening LSD1-H3K4me2 interaction and reducing H3K4me2 at the SPRY4 promoter, thereby suppressing SPRY4 transcription and inhibiting gastric cancer cell proliferation and migration. This identifies LSD1-mediated H3K4 demethylation at the SPRY4 promoter as a mechanism of SPRY4 regulation. RIP assay for LINC00675-LSD1 binding, CoIP for LSD1-H3K4me2 interaction, ChIP assay for H3K4me2 at SPRY4 promoter, RNA-seq, in vitro and in vivo functional assays Molecular therapy. Nucleic acids Medium 33230474

Source papers

Stage 0 corpus · 98 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 405 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 215 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 202 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 89 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
2018 Oncogenic microRNA-411 promotes lung carcinogenesis by directly targeting suppressor genes SPRY4 and TXNIP. Oncogene 72 30390072
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
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
2015 Autoregulatory loop between TGF-β1/miR-411-5p/SPRY4 and MAPK pathway in rhabdomyosarcoma modulates proliferation and differentiation. Cell death & disease 35 26291313
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
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
2020 Long noncoding RNA SPRY4-IT1 promotes proliferation and metastasis of hepatocellular carcinoma via mediating TNF signaling pathway. Journal of cellular physiology 29 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) 29 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 29 28295819
2021 NF-κB-activated SPRY4-IT1 promotes cancer cell metastasis by downregulating TCEB1 mRNA via Staufen1-mediated mRNA decay. Oncogene 28 34163032
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 25 28732181
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 23 31645544
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
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
2022 LncRNA SPRY4-IT1 facilitates cell proliferation and angiogenesis of glioma via the miR-101-3p/EZH2/VEGFA signaling axis. Cancer medicine 15 36479622
2019 Suppression of SPRY4 Promotes Osteogenic Differentiation and Bone Formation of Mesenchymal Stem Cell. Tissue engineering. Part A 15 30982407
2015 MT1-MMP dependent repression of the tumor suppressor SPRY4 contributes to MT1-MMP driven melanoma cell motility. Oncotarget 15 26392417
2024 Role of SPRY4 in health and disease. Frontiers in oncology 14 38686189
2021 SPRY4 suppresses proliferation and induces apoptosis of colorectal cancer cells by repressing oncogene EZH2. Aging 14 33879635
2021 SPRY4 acts as an indicator of osteoarthritis severity and regulates chondrocyte hypertrophy and ECM protease expression. NPJ Regenerative medicine 14 34535669
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
2022 A Review on the Role of SPRY4-IT1 in the Carcinogenesis. Frontiers in oncology 13 35096580
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
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
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
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 8 40561829
2023 PDK1-stabilized LncRNA SPRY4-IT1 promotes breast cancer progression via activating NF-κB signaling pathway. Molecular carcinogenesis 8 37042573
2023 SPRY4-dependent ERK negative feedback demarcates functional adult stem cells in the male mouse germline†. Biology of reproduction 8 37552049
2020 Prevalence and associated phenotypes of DUSP6, IL17RD and SPRY4 variants in a large Chinese cohort with isolated hypogonadotropic hypogonadism. Journal of medical genetics 8 32389901
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
2019 Clinical significance of SPRY4-IT1 in efficacy and survival prediction in breast cancer patients undergoing neoadjuvant chemotherapy. Histology and histopathology 7 31638266
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 6 40660390
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
2022 SPRY4 promotes adipogenic differentiation of human mesenchymal stem cells through the MEK-ERK1/2 signaling pathway. Adipocyte 6 36082406
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
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
2024 SPRY4 regulates ERK1/2 phosphorylation to affect oxidative stress and steroidogenesis in polycystic ovary syndrome. Steroids 3 39313103
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
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
2026 Luteolin Protects Against Noise-Induced Hearing Loss via Mitigating Oxidative Stress and Apoptosis, With Potential Regulation of the EGR1/SPRY4 Axis. CNS neuroscience & therapeutics 0 42067975
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

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