Affinage

SPRED2

Sprouty-related, EVH1 domain-containing protein 2 · UniProt Q7Z698

Length
418 aa
Mass
47.6 kDa
Annotated
2026-06-10
59 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPRED2 is a membrane-associated negative regulator of the RAS/RAF/ERK-MAPK pathway that restrains growth-factor signaling across many tissues and developmental contexts (PMID:15946934, PMID:34626534). It attenuates receptor signaling by routing activated receptors for degradation: its EVH1 domain binds the late endosomal adaptor NBR1 to redirect activated FGF receptors to the lysosomal pathway (PMID:19822672), while tyrosines Y303/Y343/Y353 in its SPR domain mediate EGF-induced binding to the p85 subunit of PI3K, increasing Ras association with SPRED2 and reinforcing Ras/ERK inhibition (PMID:22305891). SPRED2 protein levels are set by Cbl/Cbl-b-mediated ubiquitination triggered by phosphorylation at Y228/Y231, coupling its abundance to receptor activation (PMID:17094949). Beyond Ras, SPRED2 directly engages additional kinases—inhibiting DYRK1A substrate phosphorylation through its cysteine-rich domain (PMID:20736167) and binding the N-terminal kinase domain of RSK2 via residues 123–201 (critical F145) to limit RSK substrate phosphorylation (PMID:37149146). Through LIR motifs in its SPR domain SPRED2 binds LC3 and associates with p62/SQSTM1 and NBR1 to promote autophagosome maturation and autophagic flux (PMID:27028858, PMID:30771306). Loss of SPRED2 produces ERK hyperactivation with phenotypes including dwarfism via unrestrained FGFR3 signaling in chondrocytes (PMID:15946934), OCD-like grooming through amygdalar TrkB/ERK signaling (PMID:28070119), cardiomyocyte hypertrophy and arrhythmia with impaired autophagy (PMID:30771306), and exaggerated inflammatory responses (PMID:25275324); in cancer, SPRED2 acts as a tumor suppressor that restrains proliferation, EMT, and stemness (PMID:21703232, PMID:36902429). Biallelic loss-of-function variants in SPRED2 cause a recessive Noonan syndrome-like RASopathy, with patient variants destabilizing the protein and failing to dampen EGF-induced RAF1/MEK/ERK activation (PMID:34626534).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 High

    Established SPRED2 as a functional negative regulator of the MAPK pathway with a defined cellular consequence, moving it from sequence to physiology.

    Evidence Spred-2 overexpression and knockout in AGM hematopoiesis explant cultures and mice

    PMID:14981116

    Open questions at the time
    • Molecular mechanism of MAPK inhibition not resolved
    • No defined direct binding partners at this stage
  2. 2005 High

    Linked SPRED2 to a specific developmental signaling axis by showing it restrains FGFR3/MAPK in chondrocytes to control bone growth.

    Evidence Gene-trap knockout mouse with ERK phosphorylation assays in primary chondrocytes and skeletal phenotyping

    PMID:15946934

    Open questions at the time
    • Direct molecular interaction with FGFR machinery not demonstrated
    • Does not address receptor trafficking mechanism
  3. 2006 High

    Defined how SPRED2 abundance is controlled, showing tyrosine-phosphorylation-dependent Cbl/Cbl-b ubiquitination drives its proteasomal degradation.

    Evidence Ubiquitination assays, Y228/Y231 mutagenesis, Cbl/Cbl-b RNAi, MG-132 treatment

    PMID:17094949

    Open questions at the time
    • Kinase responsible for Y228/Y231 phosphorylation not identified
    • Functional consequence of degradation on downstream signaling not quantified here
  4. 2009 High

    Provided a degradation-based mechanism for signal attenuation, showing the EVH1 domain binds NBR1 to route activated FGF receptors to lysosomes.

    Evidence Reciprocal Co-IP, colocalization, NBR1 depletion, receptor trafficking assays

    PMID:19822672

    Open questions at the time
    • Generality to receptors beyond FGFR not established
    • Structural basis of EVH1–NBR1 binding unknown
  5. 2010 High

    Expanded SPRED2's targets beyond Ras by showing its CRD directly inhibits DYRK1A kinase activity via substrate competition.

    Evidence Endogenous Co-IP, domain-mapping pulldowns, in vitro kinase assays with substrate competition

    PMID:20736167

    Open questions at the time
    • Cellular contexts where DYRK1A inhibition is physiologically relevant not defined
    • Relationship to ERK regulation unclear
  6. 2010 Medium

    Demonstrated SPRED2 selectively blocks the ERK branch of TGF-β1 signaling, controlling EMT and migration without affecting Smad activation.

    Evidence Stable overexpression/knockdown, reporter assays, ERK vs Smad phosphorylation, migration and EMT marker analysis in keratinocytes

    PMID:19908229

    Open questions at the time
    • Mechanism of ERK-branch selectivity within TGF-β signaling not resolved
    • Limited to a single transformed cell context
  7. 2012 High

    Identified phosphotyrosine-dependent recruitment of p85/PI3K and EGFR to the SPR domain as a mechanism that tunes Ras inhibition and SPRED2 stability.

    Evidence Y303/Y343/Y353 mutagenesis, Co-IP, proliferation and neurite outgrowth assays, ubiquitination assays

    PMID:22305891

    Open questions at the time
    • Kinase phosphorylating the SPR tyrosines not identified
    • Quantitative contribution of p85 binding versus EGFR dissociation not separated
  8. 2016 High

    Connected SPRED2 to autophagy directly, showing SPR-domain LIR motifs bind LC3 and p62 to drive autophagosome maturation.

    Evidence Co-IP, GFP-LC3 puncta colocalization, LIR motif and SPR-deletion mutagenesis, ATG5/LC3/p62 silencing

    PMID:27028858

    Open questions at the time
    • Whether autophagy role is independent of ERK inhibition not fully separated
    • In vivo relevance not yet shown in this study
  9. 2019 High

    Extended the autophagy role to cardiac and metabolic physiology, showing SPRED2 complexes with p62/NBR1/Cathepsin D and that ERK-driven autophagy failure underlies cardiac pathology.

    Evidence SPRED2 KO cardiac phenotyping and macrophage assays, endogenous Co-IP, LC3 ratios, in vivo selumetinib and U0126 rescue

    PMID:30723473 PMID:30771306

    Open questions at the time
    • Direct versus ERK-mediated contributions to autophagy in vivo not fully dissected
    • Tissue-specific partner stoichiometry unknown
  10. 2021 High

    Established SPRED2 as a Mendelian disease gene, showing biallelic loss-of-function variants cause recessive Noonan-like RASopathy via destabilization and failed MAPK suppression.

    Evidence Patient variant overexpression with EGF time-course signaling, primary fibroblasts, zebrafish morpholino knockdown with rescue

    PMID:34626534

    Open questions at the time
    • Genotype–phenotype correlations across the variant spectrum incomplete
    • Tissue-specific disease mechanisms not resolved
  11. 2023 High

    Provided structural definition of a SPRED2 kinase interaction, showing residues 123–201 (F145) bind specifically to the RSK2 N-terminal kinase domain to limit RSK substrate phosphorylation.

    Evidence AP-MS, X-ray crystallography, F145A mutagenesis, Co-IP, knockdown with YB1/CREB phosphorylation and localization readouts

    PMID:37149146

    Open questions at the time
    • Selectivity for RSK2 over RSK1/RSK3 mechanism beyond the interface not fully explained
    • Physiological output of RSK regulation in vivo undefined
  12. 2025 Medium

    Defined how SPRED2 reaches its site of action, showing neurofibromin forms a complex with SPRED2 and drives its plasma membrane translocation for RAF/ERK inhibition.

    Evidence Co-IP, overexpression/knockdown functional assays, IHC of NF1-negative breast cancers

    PMID:41155378

    Open questions at the time
    • Structural basis of the NF1–SPRED2 membrane-targeting complex not defined
    • Single-lab Co-IP without orthogonal interaction validation
  13. 2026 Medium

    Identified a transcriptional axis for SPRED2 tumor suppression, showing a SPRED2–p53 complex activates miR-506 to suppress KLF4 and limit HCC stemness.

    Evidence Co-IP, ChIP-qPCR, overexpression/knockdown, 3D sphere assays, RT-qPCR/Western blotting

    PMID:41560328

    Open questions at the time
    • How a cytoplasmic MAPK regulator engages nuclear p53 not mechanistically explained
    • Generality beyond HCC not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SPRED2's multiple direct activities (NBR1/lysosomal targeting, LC3-autophagy, DYRK1A/RSK2 inhibition, p53/transcriptional roles) are integrated and prioritized within a single cell remains unresolved.
  • No unified model of how SPRED2 partitions between membrane Ras inhibition, autophagy scaffolding, and nuclear functions
  • Upstream kinases setting SPRED2 phospho-state across contexts not fully mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005829 cytosol 2 GO:0005768 endosome 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 3 R-HSA-168256 Immune System 2 R-HSA-1643685 Disease 1
Partners
CBLDYRK1AMAP1LC3NBR1NF1PIK3R1RSK2SQSTM1

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 SPRED2 interacts directly with the late endosomal protein NBR1 via its EVH1 domain, and this interaction is required for SPRED2-mediated attenuation of FGF signaling by redirecting activated FGF receptors to the lysosomal degradation pathway. Co-immunoprecipitation, colocalization, loss-of-function (NBR1 depletion), receptor trafficking assays The Journal of cell biology High 19822672
2010 SPRED2 directly interacts with the kinase domain of DYRK1A via the cysteine-rich domain (CRD) of SPRED2, and this interaction inhibits DYRK1A-mediated phosphorylation of its substrates Tau and STAT3 by competing for the substrate-binding site on DYRK1A. Co-immunoprecipitation (endogenous), domain-mapping pulldowns, in vitro kinase assays with substrate competition The Journal of biological chemistry High 20736167
2012 Tyrosines Y303, Y343, and Y353 within the SPR domain of SPRED2 are critical for EGF-induced binding to the p85 subunit of PI3K; this p85 interaction enhances SPRED2-mediated inhibition of Ras/ERK by increasing Ras binding to SPRED2 and decreasing SPRED2 ubiquitination. SPRED2 also constitutively associates with EGFR via its SPR domain and dissociates upon EGF stimulation; mutation of these tyrosines enhances EGFR binding. Site-directed mutagenesis, Co-immunoprecipitation, cell proliferation assays, neurite outgrowth assays, ubiquitination assays The international journal of biochemistry & cell biology High 22305891
2006 SPRED2 is ubiquitinated in an EGF/pervanadate-stimulated manner; tyrosines Y228 and/or Y231 in the Kit-binding domain are required for SPRED2 ubiquitination. The E3 ubiquitin ligases Cbl and Cbl-b mediate SPRED2 ubiquitination, requiring the Cbl SH2 domain; this ubiquitination reduces SPRED2 steady-state levels via proteasomal degradation. Ubiquitination assays, site-directed mutagenesis, RNAi depletion of Cbl/Cbl-b, co-immunoprecipitation, proteasome inhibitor (MG-132) treatment Biochemical and biophysical research communications High 17094949
2023 SPRED2 specifically interacts with the N-terminal kinase domain of RSK2 (but not SPRED1 or SPRED3) via SPRED2 residues 123–201, with F145 being critical for the interaction as determined by X-ray crystallography. This SPRED2–RSK2 complex formation is regulated by MAPK signaling, and SPRED2 knockdown increases RSK substrate phosphorylation (YB1, CREB) and alters phospho-RSK subcellular localization. Affinity purification mass spectrometry, X-ray crystallography, site-directed mutagenesis (F145A), Co-immunoprecipitation, knockdown with substrate phosphorylation and localization readouts The Journal of biological chemistry High 37149146
2004 Spred-2 functions as a negative regulator of the MAP kinase pathway in AGM hematopoiesis; overexpression of Spred-2 reduced CD45+ hematopoietic cell production in AGM culture, and Spred-2-null mice showed elevated CD45+ cell production and enhanced hematopoietic colony formation from VE-cadherin+ cells. Gain-of-function (overexpression) in AGM explant culture, Spred-2 knockout mouse analysis, colony-forming assays The Journal of experimental medicine High 14981116
2005 Loss of Spred-2 in mice causes dwarfism similar to achondroplasia; Spred-2-deficient chondrocytes show earlier and augmented ERK phosphorylation in response to FGF stimulation, indicating that Spred-2 normally restrains the FGFR3/MAPK pathway to control bone growth via chondrocyte differentiation. Gene-trap knockout mouse, ERK phosphorylation assays in primary chondrocytes, skeletal measurements, histology The Journal of biological chemistry High 15946934
2011 SPRED2 deficiency leads to upregulated ERK/MAPK signaling in the hypothalamus, increasing ERK phosphorylation and Ets-dependent CRH promoter activity. Overexpressed SPRED2 suppresses CRH production in hypothalamic cells, linking SPRED2 to negative regulation of the hypothalamic–pituitary–adrenal (HPA) axis. SPRED2 KO mouse phenotyping, CRH promoter reporter assays in hypothalamic cells, Western blotting of ERK phosphorylation, hormone measurements The Journal of biological chemistry High 21199868
2016 SPRED2 promotes autophagosome maturation and autophagy-dependent cell death in cancer cells via direct interaction with LC3 through LIR motifs in its SPR domain; mutations of LIR motifs or deletion of the SPR domain impair autophagosome maturation and cell death. SPRED2 also interacts and colocalizes with p62/SQSTM1 through its SPR domain. Co-immunoprecipitation, colocalization (GFP-LC3 puncta), LIR motif mutagenesis, SPR domain deletion, gene silencing (ATG5, LC3, p62), lysosomal inhibitor treatment Oncotarget High 27028858
2019 SPRED2 deficiency causes impaired autophagy, cardiomyocyte hypertrophy, cardiac fibrosis, and life-threatening arrhythmias via ERK hyperactivation; SPRED2 physically interacts with p62/SQSTM1, NBR1, and Cathepsin D in wild-type hearts, indicating a role in autophagolysosome formation. MEK inhibition with selumetinib restores autophagic flux in vivo. SPRED2 KO mouse cardiac phenotyping, Co-immunoprecipitation, LC3-II/LC3-I ratio, Atg protein expression, MEK inhibitor treatment in vivo Journal of molecular and cellular cardiology High 30771306
2017 SPRED2 deficiency in mice causes OCD-like excessive grooming mediated by upregulated TrkB/ERK-MAPK signaling in the amygdala, with increased activity of TrkB, Ras, and ERK. Electrophysiology reveals altered thalamo-amygdala synaptic transmission. MEK inhibition with selumetinib reduces OCD-like behavior in SPRED2 KO mice. SPRED2 KO mouse behavioral analysis, electrophysiology, Western blotting of pathway components, MEK inhibitor treatment in vivo, fluoxetine treatment Molecular psychiatry High 28070119
2021 SPRED2 loss-of-function variants (p.Arg63*, p.Leu100Pro, p.Leu381Hisfs*95) cause a recessive Noonan syndrome-like RASopathy; all variants impair protein stability and fail to negatively modulate EGF-induced RAF1, MEK, and ERK phosphorylation. Primary fibroblasts with these variants show increased and prolonged MAPK cascade activation in response to EGF. Morpholino knockdown of spred2a/b in zebrafish causes convergence/extension defects rescued by wild-type SPRED2 but not by the frameshift variant. Variant overexpression in cells, EGF stimulation/time-course signaling assays (RAF1/MEK/ERK phosphorylation), primary fibroblast experiments, zebrafish morpholino knockdown with rescue experiments American journal of human genetics High 34626534
2010 Spred2 inhibits TGF-β1-induced ERK1/2 activation (but not Smad2 activation), blocking TGF-β1-induced uPA expression, EMT (E-cadherin disruption, actin reorganization, vimentin upregulation), and cell migration in transformed keratinocytes. Knockdown of Spred2 enhances TGF-β1-induced ERK activation. Stable overexpression and knockdown, luciferase reporter assay, Western blotting (ERK/Smad phosphorylation), cell migration assays, EMT marker analysis International journal of cancer Medium 19908229
2010 Adenovirus-mediated Spred2 overexpression in CML cells inhibits constitutive and SCF-stimulated sphingosine kinase-1 (SPHK1) expression, Mcl-1 expression, and the Ras-ERK cascade, promoting apoptosis. Imatinib induces endogenous Spred2 expression in CML cells, and Spred2 silencing partially protects K562 cells from imatinib-induced apoptosis. Adenoviral overexpression, stable RNAi knockdown, imatinib treatment, apoptosis assays, Western blotting Biochemical and biophysical research communications Medium 20153728
2014 Spred-2 negatively regulates LPS-induced acute lung inflammation by inhibiting the ERK-MAPK pathway; Spred-2 KO mice show augmented ERK activation, increased cytokines/chemokines (TNF-α, CXCL2, CCL2), and enhanced leukocyte infiltration. MEK inhibitor U0126 reduces the augmented inflammation in Spred-2 KO mice. Spred-2 KO mouse model, siRNA knockdown and overexpression in macrophage/lung epithelial cell lines, MEK inhibitor treatment, cytokine ELISA, ERK phosphorylation assays PloS one Medium 25275324
2011 Adenoviral Spred2 overexpression in hepatocellular carcinoma (HCC) cells reduces ERK activation, inhibits proliferation and migration, activates caspase-3-mediated apoptosis, and reduces Mcl-1 expression; Spred2 knockdown markedly enhances tumor growth in vivo. Adenoviral overexpression, RNAi knockdown, tumor xenograft in vivo, caspase-3 activation assay, Western blotting Biochemical and biophysical research communications Medium 21703232
2022 SPRED2 knockdown in ERα-positive breast cancer cells increases ERK1/2 activation, enhances ERα transcriptional activity, increases proliferation, and causes tamoxifen resistance. Combined treatment with ERK1/2 inhibitor ulixertinib and 4-OHT overcomes this resistance. siRNA knockdown, cell proliferation assays, ERK phosphorylation assays, ERα transcriptional reporter, pharmacological inhibitor combination treatment Cancers Medium 35205702
2025 Neurofibromin (NF1 gene product) forms a protein complex with SPRED2 and facilitates its translocation to the plasma membrane; NF or SPRED2 downregulation in breast cancer cells enhances RAF/ERK activation, cell proliferation, migration and invasion, while overexpression has opposite effects. Membrane localization of SPRED2 is absent in NF1-negative breast cancers. Co-immunoprecipitation, overexpression and knockdown, cell functional assays, immunohistochemistry of clinical samples, database analysis International journal of molecular sciences Medium 41155378
2024 SPRED2 overexpression in HCC cells increases autophagosomes/autophagic vacuoles, decreases p62, and increases LC3-II via reduction of ERK activation and downstream mTORC1-mediated signaling; SPRED2 deficiency shows the opposite pattern. SPRED2-deficient mice show impaired hepatic autophagy with lipid droplet accumulation during starvation. Overexpression and KO in HCC cell lines, LC3-II/p62/TOM20 Western blotting, electron microscopy of autophagic vacuoles, SPRED2 KO mouse starvation model, mTORC1 signaling assays International journal of molecular sciences Medium 38892460
2026 SPRED2 forms a protein complex with p53 and cooperatively upregulates miR-506 gene transcription by binding to its promoter region; increased miR-506-3p then downregulates KLF4 mRNA, suppressing HCC cell stemness. SPRED2-KO HCC cells show elevated KLF4, Nanog, and c-Myc expression in an ERK-dependent manner. Co-immunoprecipitation, ChIP-qPCR, overexpression/knockdown, Western blotting, RT-qPCR, 3D sphere formation assays Cancer biology & medicine Medium 41560328
2020 SPRED2 knockout in HCC cells promotes EMT (elongated morphology, cadherin switching) and cancer stem cell features (sphere/colony formation, elevated CD44/CD90/stemness markers, cisplatin resistance) via ERK1/2 pathway activation; endogenous SPRED2 expression is lower in CD44+CD90+ stem-like populations and in 3D culture conditions. CRISPR/gene-KO, overexpression, knockdown, EMT marker analysis, sphere/colony formation, flow cytometry for stem cell markers, drug resistance assays International journal of molecular sciences Medium 36902429
2019 Spred2 in macrophages negatively regulates high-fat diet-induced ERK activation; Spred2 KO bone marrow-derived macrophages produce higher TNFα and MCP-1 upon palmitate stimulation and show enhanced ERK activation, which is reversed by MEK inhibitor U0126, linking Spred2 to adipose tissue inflammation and metabolic dysregulation. Spred2 KO mouse model, bone marrow-derived macrophage stimulation assays, MEK inhibitor treatment, ELISA, ERK phosphorylation assays Frontiers in immunology Medium 30723473
2024 SPRED2 interacts with RSK kinases through a DDVF-like short linear motif (SLiM) at the same interface used by pathogen-derived proteins, as confirmed by co-immunoprecipitation experiments; this interaction is consistent with the previously crystallographically documented SPRED2–RSK2 interface. AlphaFold docking prediction, co-immunoprecipitation bioRxivpreprint Low bio_10.1101_2024.08.08.607128

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Upregulated METTL3 promotes metastasis of colorectal Cancer via miR-1246/SPRED2/MAPK signaling pathway. Journal of experimental & clinical cancer research : CR 316 31492150
2017 OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency. Molecular psychiatry 67 28070119
2004 Spred-2 suppresses aorta-gonad-mesonephros hematopoiesis by inhibiting MAP kinase activation. The Journal of experimental medicine 62 14981116
2021 SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype. American journal of human genetics 55 34626534
2005 Gene disruption of Spred-2 causes dwarfism. The Journal of biological chemistry 49 15946934
2009 Spred2 interaction with the late endosomal protein NBR1 down-regulates fibroblast growth factor receptor signaling. The Journal of cell biology 44 19822672
2014 Spred-2 deficiency exacerbates lipopolysaccharide-induced acute lung inflammation in mice. PloS one 34 25275324
2019 Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice. Frontiers in immunology 32 30723473
2016 Tumor suppressor Spred2 interaction with LC3 promotes autophagosome maturation and induces autophagy-dependent cell death. Oncotarget 32 27028858
2012 Evidence for downregulation of the negative regulator SPRED2 in clinical prostate cancer. British journal of cancer 29 23169297
2020 miR-19 Promotes Cell Proliferation, Invasion, Migration, and EMT by Inhibiting SPRED2-mediated Autophagy in Osteosarcoma Cells. Cell transplantation 28 33023313
2019 SPRED2 deficiency elicits cardiac arrhythmias and premature death via impaired autophagy. Journal of molecular and cellular cardiology 26 30771306
2022 Hyperactivation of MAPK Induces Tamoxifen Resistance in SPRED2-Deficient ERα-Positive Breast Cancer. Cancers 23 35205702
2010 Direct association of Sprouty-related protein with an EVH1 domain (SPRED) 1 or SPRED2 with DYRK1A modifies substrate/kinase interactions. The Journal of biological chemistry 23 20736167
2011 Regulation of human hepatocellular carcinoma cells by Spred2 and correlative studies on its mechanism. Biochemical and biophysical research communications 22 21703232
2020 Spred2 inhibits epithelial‑mesenchymal transition of colorectal cancer cells by impairing ERK signaling. Oncology reports 18 32319644
2018 Spred2 Deficiency Exacerbates D-Galactosamine/Lipopolysaccharide -induced Acute Liver Injury in Mice via Increased Production of TNFα. Scientific reports 18 29317674
2017 Spred2-deficiecy Protects Mice from Polymicrobial Septic Peritonitis by Enhancing Inflammation and Bacterial Clearance. Scientific reports 17 28993690
2016 A Novel Role of Spred2 in the Colonic Epithelial Cell Homeostasis and Inflammation. Scientific reports 17 27869219
2018 SPRED2 deficiency may lead to lung ischemia-reperfusion injury via ERK1/2 signaling pathway activation. Surgery today 16 30022248
2005 Tissue-specific Spred-2 promoter activity characterized by a gene trap approach. Gene expression patterns : GEP 16 16378760
2020 Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin. Scientific reports 15 33020583
2021 Resveratrol improves Gly-LDL-induced vascular endothelial cell apoptosis, inflammatory factor secretion and oxidative stress by regulating miR-142-3p and regulating SPRED2-mediated autophagy. Aging 14 33621197
2011 Identification of SPRED2 (sprouty-related protein with EVH1 domain 2) as a negative regulator of the hypothalamic-pituitary-adrenal axis. The Journal of biological chemistry 14 21199868
2010 Spred2 inhibits TGF-beta1-induced urokinase type plasminogen activator expression, cell motility and epithelial mesenchymal transition. International journal of cancer 14 19908229
2010 Spred2 expression during mouse development. Developmental dynamics : an official publication of the American Association of Anatomists 14 20882678
2024 Mesenchymal stem cells-derived exosomes carrying microRNA-30b confer protection against pulmonary fibrosis by downregulating Runx1 via Spred2. Molecular genetics and genomics : MGG 13 38478174
2021 Spred2 controls the severity of Concanavalin A-induced liver damage by limiting interferon-gamma production by CD4+ and CD8+ T cells. Journal of advanced research 13 35003795
2010 Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells. Biochemical and biophysical research communications 13 20153728
2012 Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice. Clinical immunology (Orlando, Fla.) 12 22868447
2022 Sprouty-related proteins with EVH1 domain (SPRED2) prevents high-glucose induced endothelial-mesenchymal transition and endothelial injury by suppressing MAPK activation. Bioengineered 11 35707829
2021 miR-140-3p regulates the osteogenic differentiation ability of bone marrow mesenchymal stem cells by targeting spred2-mediated autophagy. Molecular and cellular biochemistry 11 34406574
2020 Cav 1.3 damages the osteogenic differentiation in osteoporotic rats by negatively regulating Spred 2-mediated autophagy-induced cell senescence. Journal of cellular and molecular medicine 11 33124763
2016 Spred-2 expression is associated with neural repair of injured adult zebrafish brain. Journal of chemical neuroanatomy 11 27427471
2023 SPRED2: A Novel Regulator of Epithelial-Mesenchymal Transition and Stemness in Hepatocellular Carcinoma Cells. International journal of molecular sciences 10 36902429
2023 SPRED2 promotes autophagy and attenuates inflammatory response in IL-1β induced osteoarthritis chondrocytes via regulating the p38 MAPK signaling pathway. Tissue & cell 10 37058811
2023 The ribosomal S6 kinase 2 (RSK2)-SPRED2 complex regulates the phosphorylation of RSK substrates and MAPK signaling. The Journal of biological chemistry 10 37149146
2006 Spred-2 steady-state levels are regulated by phosphorylation and Cbl-mediated ubiquitination. Biochemical and biophysical research communications 10 17094949
2024 SPRED2 Is a Novel Regulator of Autophagy in Hepatocellular Carcinoma Cells and Normal Hepatocytes. International journal of molecular sciences 9 38892460
2012 Tyrosines 303/343/353 within the Sprouty-related domain of Spred2 are essential for its interaction with p85 and inhibitory effect on Ras/ERK activation. The international journal of biochemistry & cell biology 9 22305891
2023 microRNA-141-3p mediates epithelial cell proliferation, apoptosis, and epithelial-mesenchymal transition and alleviates pulmonary fibrosis in mice via Spred2. Histology and histopathology 8 36704943
2020 LncRNA TUG1 reverses LPS-induced cell apoptosis and inflammation of macrophage via targeting MiR-221-3p/SPRED2 axis. Bioscience, biotechnology, and biochemistry 8 32841583
2021 Expression of Spred2 in the urothelial tumorigenesis of the urinary bladder. PloS one 7 34818323
2020 The negative regulatory Spred1 and Spred2 proteins are required for lens and eye morphogenesis. Experimental eye research 7 31923414
2023 Enhancer variants on chromosome 2p14 regulating SPRED2 and ACTR2 act as a signal amplifier to protect against rheumatoid arthritis. American journal of human genetics 6 36924774
2022 MiR-218 promotes oxidative stress and inflammatory response by inhibiting SPRED2-mediated autophagy in HG-induced HK-2 cells. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 6 35506187
2021 Genotype- and Age-Dependent Differences in Ultrasound Vocalizations of SPRED2 Mutant Mice Revealed by Machine Deep Learning. Brain sciences 6 34679429
2015 Spred2 modulates the erythroid differentiation induced by imatinib in chronic myeloid leukemia cells. PloS one 5 25688862
2024 Conditional Ablation of Spred1 and Spred2 in the Eye Lens Negatively Impacts Its Development and Growth. Cells 4 38391903
2019 Negative impact of recipient SPRED2 deficiency on transplanted lung in a mouse model. Transplant immunology 4 31446154
2024 Expression of SPRED2 in the lung adenocarcinoma. Pathology, research and practice 2 39580880
2023 A Novel Homozygous Loss-of-Function Variant in SPRED2 Causes Autosomal Recessive Noonan-like Syndrome. Genes 2 38254922
2022 Strong Association of Polymorphism in SPRED2 Gene with Disease Susceptibility and Clinical Characteristics of Rheumatoid Arthritis in the Iranian Population. Avicenna journal of medical biotechnology 2 35633988
2021 Thrombin aggravates hypoxia/reoxygenation injury of astrocytes by activating the autophagy pathway mediated by SPRED2. Experimental and therapeutic medicine 1 34504561
2021 MicroRNA-218 aggravates H2O2-induced damage in PC12 cells via spred2-mediated autophagy. Experimental and therapeutic medicine 1 34659498
2026 SPRED2 suppresses the stemness of hepatocellular carcinoma through the p53/miR-506-3p/KLF4 pathway. Cancer biology & medicine 0 41560328
2025 Molecular Dynamics Simulations of the SPRED2Leu100Pro EVH-1 Domain Complexed with the GAP-Related Domain of Neurofibromin. International journal of molecular sciences 0 40362579
2025 Neurofibromin Encoded by the Neurofibromatosis Type 1 (NF1) Gene Promotes the Membrane Translocation of SPRED2, Thereby Inhibiting the ERK Pathway in Breast Cancer Cells. International journal of molecular sciences 0 41155378
2025 SPRED2 controls the severity of cisplatin-induced acute kidney injury by inhibiting ERK activation and TNFα production in mice. Biochimica et biophysica acta. Molecular cell research 0 41330472

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