Affinage

SPRED1

Sprouty-related, EVH1 domain-containing protein 1 · UniProt Q7Z699

Length
444 aa
Mass
50.5 kDa
Annotated
2026-06-10
79 papers in source corpus 29 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

SPRED1 is a negative regulator of RAS-MAPK/ERK signaling that limits proliferation, self-renewal, and ERK-driven responses across hematopoietic, neural, immune, and ocular cell types (PMID:15465815, PMID:15630138, PMID:19118178, PMID:29706577). Its central mechanism is a scaffolding one: the N-terminal EVH1 domain, which adopts a pleckstrin-homology fold (PMID:15710406), directly engages the noncatalytic GAPex region of the neurofibromin (NF1) GTPase-activating domain, thereby recruiting neurofibromin to membrane-anchored active KRAS without altering neurofibromin's intrinsic GAP catalysis (PMID:26635368, PMID:27313208, PMID:32697994). Structural and biophysical analyses show this EVH1-GRD interface simultaneously accommodates KRAS, explains why SPRED1 binds neurofibromin but not other RasGAPs, and rationalizes Legius syndrome mutations that abolish binding and ERK suppression (PMID:31401120, PMID:32697994). SPRED1 activity is controlled by post-translational and membrane-targeting inputs: the C-terminal SPR domain requires palmitoylation for plasma-membrane localization (PMID:39510187), oncogenic EGFR disrupts the neurofibromin complex by phosphorylating Ser105 (PMID:32697994), and SHP2 dephosphorylates Tyr-420 to attenuate SPRED1's inhibitory function (PMID:21531714). Beyond RAS regulation, SPRED1 inhibits the kinases TESK1 and DYRK1A through its cysteine-rich domain, linking it to cytoskeletal dynamics and substrate phosphorylation (PMID:18216281, PMID:20736167). Germline loss-of-function mutations in SPRED1 cause Legius syndrome through constitutive RAS-MAPK hyperactivation (PMID:17704776), and somatic SPRED1 loss reactivates MAPK signaling to drive melanoma progression and resistance to KIT and BRAF inhibitors (PMID:30385465, PMID:33306107).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2004 High

    Established SPRED1 as a cell-intrinsic negative regulator of growth-factor-induced ERK activation, defining its core biological function.

    Evidence Reciprocal gain/loss-of-function with dominant-negative and knockout hematopoietic cells, ERK and proliferation assays

    PMID:15465815

    Open questions at the time
    • Molecular target within the RAS-ERK cascade not yet identified
    • No structural basis for inhibition
  2. 2005 High

    Extended SPRED1's ERK-suppressing role to allergic airway inflammation and tied its activity to membrane microdomains via caveolin-1.

    Evidence Spred1-knockout mouse allergen model; subcellular fractionation and co-IP with Cav-1 plus ERK assays

    PMID:15630138 PMID:16115197

    Open questions at the time
    • Direct molecular partner mediating ERK inhibition still unknown
    • Cav-1 interaction is single-lab, mechanism of cooperative suppression unresolved
  3. 2005 High

    Resolved the EVH1 domain fold, revealing a pleckstrin-homology architecture and a peptide-binding groove distinct from other EVH1 domains.

    Evidence 1.15 Å X-ray crystal structure of Xenopus Spred1 EVH1

    PMID:15710406

    Open questions at the time
    • Binding partner of the EVH1 groove not yet identified
    • Structure from Xenopus ortholog, not human
  4. 2007 High

    Identified SPRED1 loss-of-function as the cause of Legius syndrome, establishing it as a tumor suppressor acting through a two-hit mechanism on RAS-MAPK signaling.

    Evidence Germline and somatic mutation analysis in patient melanocytes

    PMID:17704776

    Open questions at the time
    • Biochemical mechanism linking mutations to RAS hyperactivation not yet defined
  5. 2008 Medium

    Connected SPRED1 to cytoskeletal regulation by showing it inhibits TESK1 to promote dynamic F-actin, broadening its role beyond ERK.

    Evidence Yeast two-hybrid, co-IP, kinase assays in CHO cells

    PMID:18216281

    Open questions at the time
    • Physiological relevance of cytoskeletal role in vivo unclear
    • Single-lab; MARKK/TAO1 binding has no functional consequence
  6. 2008 High

    Demonstrated that SPRED1 restrains Ras/ERK in the brain to maintain synaptic plasticity and learning, linking the gene to cognitive function.

    Evidence Spred1-knockout mice, behavioral testing, LTP/LTD electrophysiology, pERK western blot

    PMID:19118178

    Open questions at the time
    • Cell-type and circuit specificity of ERK dysregulation not dissected
  7. 2010 High

    Showed SPRED1 dampens neural stem/progenitor proliferation and is required for cortical organization, and that it inhibits DYRK1A via its CRD.

    Evidence In vivo/in vitro shRNA knockdown, imaging, vesicle fractionation; co-IP and kinase substrate assays for DYRK1A

    PMID:20047999 PMID:20736167

    Open questions at the time
    • Vesicular localization function not mechanistically explained
    • DYRK1A inhibition is Medium-confidence, single lab
  8. 2011 High

    Defined upstream regulation of SPRED1 by SHP2-mediated dephosphorylation and by miR-126, and identified an FGFRL1 membrane interaction, showing SPRED1 activity is tunable.

    Evidence In vitro dephosphorylation and mutagenesis (SHP2); conditional knockout and miRNA overexpression (miR-126); yeast two-hybrid and co-localization (FGFRL1)

    PMID:21531714 PMID:21616146 PMID:21668589

    Open questions at the time
    • Functional consequence of FGFRL1 retention unclear
    • How phosphorylation at Tyr residues couples to neurofibromin recruitment not yet established
  9. 2016 High

    Defined the EVH1–neurofibromin GRD interface and established that SPRED1 acts as a membrane-targeting scaffold for neurofibromin rather than a direct GAP modulator.

    Evidence Yeast two-hybrid, reciprocal co-IP, mutagenesis, ERK assays, and biochemical reconstitution of binding and GAP activity

    PMID:26635368 PMID:27313208

    Open questions at the time
    • Structure of the ternary SPRED1-neurofibromin-RAS complex not yet solved
    • Membrane delivery dynamics not directly visualized
  10. 2016 Medium

    Revealed isoform-selective regulation through B-Raf and galectin-1 binding, with SPRED1 perturbing KRAS but not HRAS membrane organization.

    Evidence Co-IP, super-resolution and FRET nanoclustering assays, mutagenesis

    PMID:27503857

    Open questions at the time
    • Single-lab; mechanism of isoform selectivity at the membrane unresolved
    • Relationship to neurofibromin scaffolding pathway unclear
  11. 2019 High

    Quantified how a Legius mutation cripples neurofibromin binding without unfolding EVH1, pinpointing affinity loss as the disease mechanism.

    Evidence NMR mapping, binding affinity and protein stability measurements of the T102R EVH1 mutant

    PMID:31401120

    Open questions at the time
    • Single mutation analyzed
    • Cellular and organismal consequences not measured in this study
  12. 2020 High

    Provided the structural basis for SPRED1's RasGAP specificity and revealed EGFR-driven Ser105 phosphorylation as a means to disrupt the complex.

    Evidence X-ray structure of NF1 GRD–SPRED1 EVH1–KRAS, phosphorylation mapping, mutagenesis, ERK assays

    PMID:32697994

    Open questions at the time
    • Stoichiometry and kinetics of complex assembly at the membrane not defined
    • Generality of Ser105 phosphorylation across RTKs unknown
  13. 2020 Medium

    Showed SPRED1 (with SPRED2) is required for lens morphogenesis by restraining ERK1/2, extending its developmental role to the eye.

    Evidence Spred1/2 double-knockout mice, ERK western blot, histology

    PMID:31923414

    Open questions at the time
    • Redundancy with SPRED2 not separated for SPRED1 alone
    • Single-lab
  14. 2018 High

    Established somatic SPRED1 loss as a melanoma tumor-suppressor event and as a driver of KIT-inhibitor resistance through MAPK reactivation.

    Evidence Human tumor sequencing, tissue-specific zebrafish CRISPR, MAPK and drug-resistance assays

    PMID:30385465

    Open questions at the time
    • Mechanism of resistance downstream of MAPK reactivation not fully resolved
  15. 2018 High

    Defined SPRED1 as a restraint on hematopoietic stem cell self-renewal whose loss, under metabolic stress, produces myeloproliferative disease.

    Evidence Spred1 conditional knockout mice, HSC functional and ERK assays, high-fat diet model

    PMID:29706577

    Open questions at the time
    • Contribution of ROCK versus ERK arms not quantitatively separated
  16. 2021 High

    Showed SPRED1 loss drives MAPK-targeted-therapy resistance in melanoma and promotes CML transformation via miR-126/ERK/Bcl-2 signaling, and that NF2/Merlin can join the neurofibromin-SPRED1 axis.

    Evidence Human cell lines, zebrafish models, patient sample (BRAFi resistance); conditional KO and pathway dissection (CML); co-IP and GAP assays (Merlin)

    PMID:33306107 PMID:33331896 PMID:34564700

    Open questions at the time
    • Merlin trimeric complex is Medium-confidence, single lab
    • Whether miR-126 and Bcl-2 axis generalizes beyond CML unclear
  17. 2021 Medium

    Linked SPRED1 loss to social behavior and immune (ILC2) phenotypes mediated by RAS-MAPK, with pharmacological MEK inhibition reversing behavioral effects.

    Evidence Spred1-knockout mice, behavioral testing with MEK-inhibitor rescue; ILC2 assays with GATA3 stability analysis

    PMID:26116510 PMID:34311771

    Open questions at the time
    • Single-lab phenotypes
    • Direct molecular link between SPRED1 and GATA3 stability not established
  18. 2024 High

    Showed that SPR-domain mutations impairing palmitoylation cause SPRED1 mislocalization and toxic cytoplasmic aggregates, defining a neurodegenerative mechanism distinct from simple RAS hyperactivation.

    Evidence Mutagenesis, knock-in mice, palmitoylation and localization assays, ataxia testing, spermidine rescue; EZH2 transcriptional suppression by luciferase and xenograft

    PMID:36629984 PMID:39510187

    Open questions at the time
    • EZH2 regulation is Medium-confidence, single lab
    • Link between aggregate toxicity and Purkinje loss mechanism incompletely defined
  19. 2026 Medium

    Revealed RAS-MAPK-independent cooperation between NF1 and SPRED1/2, including suppression of RRAS/RRAS2 and a RAS-independent gene signature, broadening SPRED1's functional scope.

    Evidence CRISPR knockout in isogenic RASless MEFs, transcriptomics, signaling assays, NF1 patient Schwann cells

    PMID:42201959

    Open questions at the time
    • Mechanism of RRAS/RRAS2 suppression undefined
    • Single-lab; RAS-independent signature not functionally validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SPRED1 integrates its many regulatory inputs (palmitoylation, Tyr/Ser phosphorylation, miRNA, EZH2) to dynamically control neurofibromin delivery at the membrane, and the molecular basis of its RAS-independent functions, remain unresolved.
  • No integrated model of membrane-targeting kinetics in vivo
  • RAS-independent NF1-SPRED1 mechanism uncharacterized
  • Interplay between scaffolding and kinase-inhibitory (DYRK1A/TESK1) functions unknown

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
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3
Partners
BRAFCAV1DYRK1AKRASLGALS1NF1SHP2TESK1
Complex memberships
SPRED1–neurofibromin(NF1)–KRAS ternary complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype (Legius syndrome). SPRED1 acts as a negative regulator of the RAS→RAF interaction and MAPK signaling pathway. Biallelic SPRED1 inactivation (germline + somatic mutation) was required to generate café-au-lait spots, establishing a tumor-suppressor two-hit mechanism. Germline mutation identification, somatic mutation analysis of melanocytes from café-au-lait spots Nature genetics High 17704776
2004 SPRED1 negatively regulates IL-3-induced ERK/MAP kinase activation and cell proliferation in hematopoietic cells. Forced expression of wild-type SPRED1 reduced proliferation and ERK activation in response to both SCF and IL-3; a dominant-negative form (DeltaC-Spred) augmented both. SPRED1-deficient mast cells showed augmented ERK activation and proliferation in response to IL-3. Retroviral gene transfer, loss-of-function (Spred1 knockout cells), dominant-negative overexpression, proliferation assays, ERK phosphorylation assays The Journal of biological chemistry High 15465815
2005 SPRED1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness by suppressing IL-5-dependent ERK activation and cell proliferation in eosinophils, without affecting T helper cell differentiation. Spred1-deficient mice, allergen challenge model, biochemical ERK activation assays, cell proliferation assays The Journal of experimental medicine High 15630138
2005 SPRED1 localizes in lipid raft/caveola membrane fractions and interacts with caveolin-1 (Cav-1). Co-localization with Cav-1 enhances ERK inhibition beyond either protein alone; forced Cav-1 expression in hematopoietic cells suppressed SCF/IL-3-induced ERK activation, and additional Spred-1 expression further suppressed it. Subcellular fractionation, co-immunoprecipitation, overexpression in hematopoietic cells, ERK activation assays Genes to cells Medium 16115197
2005 Crystal structure of the Xenopus tropicalis Spred1 EVH1 domain solved to 1.15 Å resolution. The EVH1 domain adopts a pleckstrin-homology fold; a narrowed peptide-binding groove and structural flexibility at one end suggest Spred1 binds peptides less proline-rich than other EVH1 domains, likely via an induced-fit mechanism. X-ray crystallography FEBS letters High 15710406
2008 SPRED1 is a binding partner of both MARKK/TAO1 and TESK1 kinases, linking microtubule and actin cytoskeleton regulation. SPRED1-MARKK binding does not affect MARKK activity or microtubule stability. SPRED1-TESK1 binding inhibits TESK1, which normally phosphorylates cofilin to stabilize F-actin stress fibers; thus SPRED1 promotes dynamic F-actin through TESK1 inhibition. Yeast two-hybrid, co-immunoprecipitation, kinase activity assays, CHO cell overexpression Molecular biology of the cell Medium 18216281
2008 Spred1 deficiency in mice causes defects in hippocampus-dependent learning, short- and long-term synaptic plasticity (including LTP/LTD imbalance in CA1), and increased ERK phosphorylation after LTP induction, demonstrating that SPRED1 limits Ras/ERK hyperactivation to maintain normal cognitive function and synaptic plasticity. Spred1 knockout mice, Morris water maze, T-maze, electrophysiology (LTP/LTD recordings), western blot for pERK The Journal of neuroscience High 19118178
2010 SPRED1 is highly enriched in CNS germinal zones and functions to dampen neural stem cell (NSC) self-renewal and progenitor proliferation cell-autonomously. SPRED1 localizes within distinct vesicles in cortical progenitor cells. Knockdown in vivo in embryonic mouse forebrain disrupts apical ventricular zone organization, impairs radial glia alignment, and causes periventricular heterotopia due to impaired late neuronal migration. shRNA knockdown in vivo and in vitro, overexpression, immunofluorescence/live imaging, subcellular fractionation/vesicle localization, cortical progenitor proliferation assays Genes & development High 20047999
2010 SPRED1 and SPRED2 directly interact with the novel kinase DYRK1A via their cysteine-rich domain (CRD), which binds the kinase domain of DYRK1A. SPRED1/2 inhibit DYRK1A-mediated phosphorylation of substrates Tau and STAT3 by competing for the substrate binding site on DYRK1A. Co-immunoprecipitation (endogenous and overexpressed), direct binding assays, kinase substrate phosphorylation assays, domain mapping The Journal of biological chemistry Medium 20736167
2011 SPRED1 is a substrate of the tyrosine phosphatase SHP2. SPRED proteins (but not Sprouty2) bind to the tyrosine phosphatase domain of SHP2. Overexpressed SHP2 dephosphorylates SPRED1. Two tyrosine residues on SPRED1, when phosphorylated, are required for Ras/ERK inhibition; Tyr-420 is a specific dephosphorylation target of SHP2, indicating that SHP2 attenuates the inhibitory activity of SPRED1. Co-immunoprecipitation, in vitro dephosphorylation assay, site-directed mutagenesis, ERK activation assays The Journal of biological chemistry High 21531714
2011 SPRED1 interacts with FGFRL1 via the C-terminal SPR domain of SPRED1 and the histidine-rich domain of FGFRL1. This interaction was verified by coprecipitation and co-distribution at the plasma membrane; SPRED1 increased the retention time of FGFRL1 at the plasma membrane. Yeast two-hybrid, coprecipitation, co-localization by immunofluorescence in COS1 and HEK293 cells Cellular signalling Medium 21616146
2011 miR-126 positively regulates mast cell proliferation and FcεRI-mediated cytokine production by suppressing SPRED1 expression. Overexpression of miR-126 suppressed SPRED1 and enhanced ERK activity. Hematopoietic-specific Spred1 conditional knockout mice showed increased mast cell numbers and hyperactivation, establishing SPRED1 as the functional target of miR-126 in this context. miR-126 overexpression, conditional Spred1 knockout mice, SPRED1 western blot, ERK assays, cytokine production assays Genes to cells High 21668589
2015 The SPRED1 EVH1 domain interacts with the N-terminal 16 aa and C-terminal 20 aa of the GTPase-activating protein-related domain (GRD) of neurofibromin (NF1), forming two crossing α-helix coils outside the GAP catalytic domain. These regions are dispensable for GAP activity and are absent from p120GAP. Pathogenic missense mutations in the EVH1 domain of SPRED1 (Legius syndrome) and in the GRD (NF1 patients) reduce binding affinity and disrupt ERK suppression, showing SPRED1 inhibits Ras-ERK by recruiting neurofibromin to Ras via EVH1-GRD interaction. Yeast two-hybrid, co-immunoprecipitation in HEK293 cells, ERK activation assays, mutational analysis The Journal of biological chemistry High 26635368
2016 The SPRED1 EVH1 domain binds specifically to the noncatalytic GAPex subdomain of the neurofibromin GRD. This binding is compatible with simultaneous Ras binding and does not interfere with neurofibromin's GAP activity, establishing that SPRED1 functions as a membrane-targeting scaffold for neurofibromin rather than a direct modulator of its catalytic activity. Biochemical binding assays, mutational analysis, GAP activity assays Proceedings of the National Academy of Sciences of the United States of America High 27313208
2016 SPRED1 interaction with B-Raf and galectin-1 (Gal-1) facilitates SPRED1 translocation to the plasma membrane upon growth factor stimulation or pharmacological/Gal-1-mediated Raf dimer induction. At the plasma membrane, SPRED1 selectively perturbs membrane organization and ERK signaling of K-ras4B but not H-ras, and blocks positive effects of Gal-1 on H-ras nanoclusters. Two Legius syndrome mutations show diminished binding to both Gal-1 and B-Raf. Co-immunoprecipitation, super-resolution microscopy, FRET-based nanoclustering assays, mutational analysis, plasma membrane fractionation Molecular and cellular biology Medium 27503857
2018 SPRED1 functions as a tumor suppressor in mucosal melanoma, particularly in the context of KIT mutations. SPRED1 knockdown in zebrafish caused MAPK activation, increased cell proliferation, and conferred resistance to KIT tyrosine kinase inhibitors, establishing SPRED1 loss as a driver of KIT-mutant melanoma through MAPK pathway activation. Human tumor sequencing (43 mucosal melanomas), tissue-specific CRISPR in zebrafish, MAPK activation assays, cell proliferation assays, drug resistance assays Science High 30385465
2018 SPRED1 negatively regulates hematopoietic stem cell (HSC) self-renewal and fitness under steady-state conditions, in part through Rho kinase (ROCK) activity. Under high-fat diet conditions, Spred1 deficiency leads to ERK hyperactivation and aberrant HSC self-renewal, causing functional HSC failure and myeloproliferative neoplasm-like disease. Spred1 conditional knockout mice, HSC functional assays, ERK activation assays, high-fat diet model Cell stem cell High 29706577
2019 A pathogenic Legius syndrome missense mutation in the EVH1 domain of SPRED1 (T102R) weakens the interaction with neurofibromin by approximately 3 orders of magnitude without perturbing the overall EVH1 protein fold. NMR spectroscopy was used to map the neurofibromin GRD binding site on the mutant Spred1 EVH1 domain. Binding affinity measurements, NMR spectroscopy, protein stability assays Journal of molecular biology High 31401120
2020 Crystal/cryo structure of the neurofibromin GAP-related domain complexed with the SPRED1 EVH1 domain and KRAS reveals how SPRED1 membrane-targeting of neurofibromin allows simultaneous interaction with activated KRAS. Oncogenic EGFR(L858R) signaling leads to phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. Analysis of the interface rationalizes Legius syndrome mutations and explains why SPRED1 binds neurofibromin but no other RasGAPs. Crystal structure (X-ray), biochemical binding assays, phosphorylation mapping, mutagenesis, cell-based ERK signaling assays Cell reports High 32697994
2020 Spred1 and Spred2 double-deficiency in lens results in elevated ERK1/2 phosphorylation, irregular lens epithelial and fiber cell activity, and impaired lens and eye development, demonstrating that Spred1 negatively regulates ERK1/2 activity to maintain normal lens morphogenesis. Spred1/2 double-knockout mice, ERK phosphorylation western blot, histological analysis of lens development Experimental eye research Medium 31923414
2021 SPRED1 loss in human melanoma cell lines and primary zebrafish melanoma confers resistance to BRAFV600E inhibition by reactivating MAPK activity. Biallelic SPRED1 deletion was observed in a patient whose melanoma acquired resistance to MAPK-targeted therapy. SPRED1 inactivation in human cell lines, in vivo zebrafish melanoma model, MAPK pathway activation assays, drug resistance assays The Journal of experimental medicine High 33306107
2021 Spred1 deficiency in CML promotes transformation from chronic phase to accelerated/blast crisis CML. Spred1 knockout (in HSCs or endothelial cells) increased miR-126 in leukemic stem cells (LSKs), causing LSC expansion through MAPK/ERK hyperactivation, augmented Bcl-2 expression and stability, and enhanced Bcl-2-dependent oxidative phosphorylation. Conditional knockout mouse models, leukemia transformation assays, miR-126 quantification, pERK assays, Bcl-2 expression/stability assays Leukemia Medium 34564700
2021 Spred1-deficient mice exhibit increased social dominance and impaired nesting behavior mediated by RAS-MAPK hyperactivation. Acute MEK inhibitor (PD325901) treatment in adulthood reversed the enhanced social dominance phenotype, demonstrating that Ras-MAPK dysregulation mediates social behavior phenotypes downstream of SPRED1 loss. Spred1 knockout mice, automated tube test, ultrasonic vocalization recording, nesting behavior, MEK inhibitor pharmacological rescue Molecular autism Medium 34311771
2022 Molecular dynamics simulation and Markov state model analysis of the KRAS-NF1-SPRED1 ternary complex suggest that SPRED1 loading allosterically enhances KRAS-NF1 binding at a site distal from the SPRED1-NF1 interface, but that this allosteric effect also hinders conformational transformation of the NF1 catalytic center required for RAS GTP hydrolysis. Allosteric pathways were identified by difference contact network analysis. Gaussian accelerated molecular dynamics simulations, Markov state model analysis, contact network analysis Journal of molecular biology Low 35872068
2015 SPRED1 negatively regulates proliferation, apoptosis, and cytokine secretion of group 2 innate lymphoid cells (ILC2s) through the Ras-ERK pathway. Spred1 deficiency enhanced IL-33-induced ILC2 proliferation and cytokine production; MEK inhibitor suppressed these. Spred1 deficiency resulted in stabilization of GATA3, a key transcription factor for ILC2 function. Spred1 knockout mice, ILC2 proliferation and cytokine assays, MEK inhibitor treatment, GATA3 protein stability assays Journal of immunology Medium 26116510
2024 Missense mutations in the C-terminal SPR (Sprouty-related) domain of SPRED1 (e.g., C368S, M369L, V408E, P415A, P415L, P422R) identified in Legius syndrome patients impair palmitoylation of SPRED1, causing loss of plasma membrane localization and formation of cytoplasmic granular aggregates. In knock-in mice, P415A and P415V mutations (but not a C-terminal deletion M417Afs*4) formed granular aggregates and led to Purkinje cell loss and cerebellar ataxia with age. Autophagy inducer spermidine rescued ataxia and Purkinje cell loss in Spred1P415A mice, suggesting aggregate toxicity as a potential neurodegenerative mechanism. Site-directed mutagenesis, knock-in mice, palmitoylation assay, live cell imaging/localization, histological analysis, behavioral (ataxia) testing, spermidine treatment rescue The Journal of biological chemistry High 39510187
2024 EZH2 epigenetically suppresses SPRED1 transcriptional activity and expression; the EZH2 inhibitor Tazemetostat reverses this suppression. Overexpression of SPRED1 inhibits lung adenocarcinoma cell proliferation, migration, and invasion in vitro and retards tumor growth in vivo, while EZH2 elevation rescues these effects. Dual-luciferase reporter assay, EZH2 inhibitor treatment, overexpression gain-of-function, in vivo xenograft Human cell Medium 36629984
2021 Merlin (NF2 protein) can interact with both neurofibromin and SPRED1, forming a trimeric complex. Merlin directly binds the Ras-binding domain (RBD) and kinase domain (KiD) of Raf1, functioning as a 'selective Ras barrier' that blocks Ras binding to Raf1 without increasing neurofibromin's GAP activity. Co-immunoprecipitation, direct binding assays, RAS-GAP activity assays, Schwann cell models Human molecular genetics Medium 33331896
2026 NF1 and SPRED1/2 cooperate through RAS-MAPK-independent functions. CRISPR-Cas9 ablation of NF1 or SPRED1/2 in 'RASless' MEFs showed that SPRED1/2 loss phenocopies NF1 loss and their cooperation modulates MAPK-AKT signaling. Additionally, NF1 or SPRED1/2 loss suppressed the RAS family GTPases RRAS and RRAS2 independently of RAS or AKT pathway activation. A RAS-independent, NF1-SPRED1/2-dependent gene signature was identified. CRISPR-Cas9 knockout in isogenic RASless MEFs, transcriptome microarray, signaling pathway assays, Schwann cell models from NF1 patients Proceedings of the National Academy of Sciences of the United States of America Medium 42201959

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Endothelial microparticle-mediated transfer of MicroRNA-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles. Circulation 380 24014835
2007 Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature genetics 319 17704776
2012 Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1. Journal of molecular and cellular cardiology 209 22525256
2018 Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma. Science (New York, N.Y.) 114 30385465
2005 Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. The Journal of experimental medicine 96 15630138
2008 Spred1 is required for synaptic plasticity and hippocampus-dependent learning. The Journal of neuroscience : the official journal of the Society for Neuroscience 80 19118178
2012 Review and update of SPRED1 mutations causing Legius syndrome. Human mutation 78 22753041
2004 Spred-1 negatively regulates interleukin-3-mediated ERK/mitogen-activated protein (MAP) kinase activation in hematopoietic cells. The Journal of biological chemistry 78 15465815
2009 SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype. Journal of medical genetics 75 19366998
2018 Estrogen-induced miR-196a elevation promotes tumor growth and metastasis via targeting SPRED1 in breast cancer. Molecular cancer 72 29685157
2010 Spred1, a negative regulator of Ras-MAPK-ERK, is enriched in CNS germinal zones, dampens NSC proliferation, and maintains ventricular zone structure. Genes & development 69 20047999
2009 SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype. Journal of medical genetics 66 19443465
2020 Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR. Cell reports 54 32697994
2008 Spred1 and TESK1--two new interaction partners of the kinase MARKK/TAO1 that link the microtubule and actin cytoskeleton. Molecular biology of the cell 54 18216281
2011 miR126 positively regulates mast cell proliferation and cytokine production through suppressing Spred1. Genes to cells : devoted to molecular & cellular mechanisms 52 21668589
2015 Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1. The Journal of biological chemistry 51 26635368
2016 The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation. Proceedings of the National Academy of Sciences of the United States of America 50 27313208
2014 MicroRNAs 206 and 21 cooperate to promote RAS-extracellular signal-regulated kinase signaling by suppressing the translation of RASA1 and SPRED1. Molecular and cellular biology 49 25202123
2014 SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia. Oncogene 45 24469042
2013 Legius syndrome, an Update. Molecular pathology of mutations in SPRED1. The Keio journal of medicine 45 24334617
2005 The Sprouty-related protein, Spred-1, localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1. Genes to cells : devoted to molecular & cellular mechanisms 39 16115197
2018 Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress. Cell stem cell 29 29706577
2010 SPRED 1 mutations in a neurofibromatosis clinic. Journal of child neurology 29 20179001
2009 TGF-beta modulates the functionality of tumor-infiltrating CD8+ T cells through effects on TCR signaling and Spred1 expression. Cancer immunology, immunotherapy : CII 28 19319531
2015 Spred1, a Suppressor of the Ras-ERK Pathway, Negatively Regulates Expansion and Function of Group 2 Innate Lymphoid Cells. Journal of immunology (Baltimore, Md. : 1950) 27 26116510
2011 Sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein (SPRED1), a tyrosine-protein phosphatase non-receptor type 11 (SHP2) substrate in the Ras/extracellular signal-regulated kinase (ERK) pathway. The Journal of biological chemistry 27 21531714
2022 Mechanistic Insights into the Long-range Allosteric Regulation of KRAS Via Neurofibromatosis Type 1 (NF1) Scaffold Upon SPRED1 Loading. Journal of molecular biology 26 35872068
2023 Astragaloside IV promotes exosome secretion of endothelial progenitor cells to regulate PI3KR2/SPRED1 signaling and inhibit pyroptosis of diabetic endothelial cells. Cytotherapy 24 37747393
2021 SPRED1 deletion confers resistance to MAPK inhibition in melanoma. The Journal of experimental medicine 24 33306107
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
2017 miR182 activates the Ras-MEK-ERK pathway in human oral cavity squamous cell carcinoma by suppressing RASA1 and SPRED1. OncoTargets and therapy 22 28223824
2016 Inhibition of microRNA-126 promotes the expression of Spred1 to inhibit angiogenesis in hepatocellular carcinoma after transcatheter arterial chemoembolization: in vivo study. OncoTargets and therapy 22 27499630
2016 SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling. Molecular and cellular biology 22 27503857
2023 IFN-γ enhances the therapeutic efficacy of MSCs-derived exosome via miR-126-3p in diabetic wound healing by targeting SPRED1. Journal of diabetes 21 37646268
2018 Icariside II ameliorates endothelial dysfunction by regulating the MAPK pathway via miR-126/SPRED1 in diabetic human cavernous endothelial cells. Drug design, development and therapy 20 29942117
2021 miR-126-3p contributes to sorafenib resistance in hepatocellular carcinoma via downregulating SPRED1. Annals of translational medicine 19 33553331
2011 Interaction of the receptor FGFRL1 with the negative regulator Spred1. Cellular signalling 18 21616146
2005 1.15 A crystal structure of the X. tropicalis Spred1 EVH1 domain suggests a fourth distinct peptide-binding mechanism within the EVH1 family. FEBS letters 17 15710406
2012 Association of Piebaldism, multiple café-au-lait macules, and intertriginous freckling: clinical evidence of a common pathway between KIT and sprouty-related, ena/vasodilator-stimulated phosphoprotein homology-1 domain containing protein 1 (SPRED1). Pediatric dermatology 16 23016555
2020 Constitutional mismatch repair deficiency is the diagnosis in 0.41% of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1. Genetics in medicine : official journal of the American College of Medical Genetics 15 32773772
2011 Identification of SPRED1 deletions using RT-PCR, multiplex ligation-dependent probe amplification and quantitative PCR. American journal of medical genetics. Part A 14 21548021
2024 Hypoxic Bone Marrow Stromal Cells Secrete miR-140-5p and miR-28-3p That Target SPRED1 to Confer Drug Resistance in Multiple Myeloma. Cancer research 13 37756570
2021 MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders. Molecular autism 13 34311771
2020 Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients. Genes 13 32575496
2020 Micro RNA-126 promoting angiogenesis in diabetic heart by VEGF/Spred-1/Raf-1 pathway: effects of high-intensity interval training. Journal of diabetes and metabolic disorders 13 33520826
2021 Spred1 deficit promotes treatment resistance and transformation of chronic phase CML. Leukemia 11 34564700
2020 Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1. Molecular genetics & genomic medicine 11 32107864
2020 Moyamoya syndrome in a child with Legius syndrome: Introducing a cerebral vasculopathy to the SPRED1 phenotype? American journal of medical genetics. Part A 11 33078527
2018 MiR-126 enhances VEGF expression in induced pluripotent stem cell-derived retinal neural stem cells by targeting spred-1. International journal of clinical and experimental pathology 10 31938197
2021 Up-regulated miR-204-5p promoted the migration, invasion, and angiogenesis of endothelial progenitor cells to enhance the thrombolysis of rats with deep venous thrombosis by targeting SPRED1. Experimental cell research 9 34942190
2011 The SPRED1 Variants Repository for Legius Syndrome. G3 (Bethesda, Md.) 9 22384355
2023 SPOCK2 and SPRED1 function downstream of EZH2 to impede the malignant progression of lung adenocarcinoma in vitro and in vivo. Human cell 8 36629984
2023 Long noncoding RNA LOC646029 functions as a ceRNA to suppress ovarian cancer progression through the miR-627-3p/SPRED1 axis. Frontiers of medicine 8 37434064
2021 Merlin cooperates with neurofibromin and Spred1 to suppress the Ras-Erk pathway. Human molecular genetics 8 33331896
2019 A Pilot Study of Aberrant CpG Island Hypermethylation of SPRED1 in Acute Myeloloid Leukemia. International journal of medical sciences 8 30745814
2020 The negative regulatory Spred1 and Spred2 proteins are required for lens and eye morphogenesis. Experimental eye research 7 31923414
2024 Novel causative variants in Legius syndrome: SPRED1 Genotype spectrum expansion. American journal of medical genetics. Part A 6 39031930
2020 Role of SPRED1 in keratinocyte proliferation in psoriasis. The Journal of dermatology 6 32396270
2019 Pathogenic Mutations Associated with Legius Syndrome Modify the Spred1 Surface and Are Involved in Direct Binding to the Ras Inactivator Neurofibromin. Journal of molecular biology 6 31401120
2013 A cost savings approach to SPRED1 mutational analysis in individuals at risk for neurofibromatosis type 1. American journal of medical genetics. Part A 6 23401230
2024 Legius syndrome mutations in the Ras-regulator SPRED1 abolish its membrane localization and potentially cause neurodegeneration. The Journal of biological chemistry 5 39510187
2017 NMR resonance assignments of the EVH1 domain of neurofibromin's recruitment factor Spred1. Biomolecular NMR assignments 5 28831766
2011 Sprouty2 and Spred1-2 proteins inhibit the activation of the ERK pathway elicited by cyclopentenone prostanoids. PloS one 5 21364986
2024 Conditional Ablation of Spred1 and Spred2 in the Eye Lens Negatively Impacts Its Development and Growth. Cells 4 38391903
2021 Impaired instrumental learning in Spred1-/- mice, a model for a rare RASopathy. Genes, brain, and behavior 4 33624414
2020 A Study on the Expression of SPRED1 and PBRM1 (Baf180) and their Clinical Significances in Patients with Gastric Cancer. Clinical laboratory 4 33073945
2025 miR-486-3p Suppresses Osteosarcoma Proliferation and Migration by Targeting the SPRED1-MAPK/ERK Pathway. Biochemical genetics 3 40358892
2023 Circ_TEX2 Functions as a Tumor Suppressor in Hepatoma via miR-96-5p/SPRED1 Axis. Molecular biotechnology 3 36745282
2022 Methylation of SPRED1: A New Target in Acute Myeloid Leukemia. Frontiers in oncology 3 35359401
2015 Legius Syndrome: two novel mutations in the SPRED1 gene. Human genome variation 2 27081556
2025 The role of SPRED1 mutation in melanoma. European journal of medical research 1 41094606
2017 The first Slovak Legius syndrome patient carrying the SPRED1 gene mutation. General physiology and biophysics 1 28150585
2013 [Relationship between Spred1 and acute myeloid leukemia]. Zhongguo shi yan xue ye xue za zhi 1 23998617
2009 Expanding the phenotype of a neurofibromatosis type 1-like syndrome: a patient with a SPRED1 mutation and orbital manifestations. Ophthalmic plastic and reconstructive surgery 1 19966658
2026 NF1 and SPRED1/2 cooperate through RAS-MAPK-independent functions. Proceedings of the National Academy of Sciences of the United States of America 0 42201959
2025 Enhancing the sensitivity of lung adenocarcinoma to immune therapeutic agents through SPRED1. Translational lung cancer research 0 40948827
2025 TTC36-Mediated Tumor Suppression via YBX3/SPRED1 Axis Paradoxically Reduces Sorafenib Sensitivity in Hepatocellular Carcinoma. International journal of biological sciences 0 41208883
2024 [Clinical and genetic analysis of three children with Legius syndrome due to variants of SPRED1 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 39097276
2018 [Regulation of hematopoietic stem cell homeostasis by Spred1]. [Rinsho ketsueki] The Japanese journal of clinical hematology 0 30531141

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