Affinage

SPRED1

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

Length
444 aa
Mass
50.5 kDa
Annotated
2026-04-28
78 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPRED1 is a membrane-associated negative regulator of the RAS-MAPK/ERK signaling pathway that controls cell proliferation, differentiation, and synaptic plasticity across diverse tissues including hematopoietic, neural, and immune compartments. SPRED1 suppresses RAS signaling primarily by recruiting neurofibromin (NF1) to the plasma membrane via its N-terminal EVH1 domain binding the noncatalytic GAPex subdomain of neurofibromin's GRD, forming a ternary complex with KRAS that enables RAS-GAP activity without directly modulating it (PMID:26635368, PMID:27313208, PMID:32697994); its C-terminal SPR domain mediates palmitoylation-dependent membrane anchoring, and mutations disrupting palmitoylation cause cytoplasmic aggregation and cerebellar neurodegeneration in mice (PMID:39510187). Regulatory inputs include SHP2-mediated dephosphorylation of SPRED1 Tyr-420, which attenuates its inhibitory function (PMID:21531714), and oncogenic EGFR-driven phosphorylation of Ser-105, which disrupts the SPRED1–neurofibromin complex (PMID:32697994). Germline loss-of-function mutations in SPRED1 cause Legius syndrome (a neurofibromatosis 1-like disorder with café-au-lait macules requiring biallelic inactivation in melanocytes), and SPRED1 loss acts as a tumor suppressor mechanism whose disruption confers resistance to BRAF and KIT inhibitors in melanoma (PMID:17704776, PMID:30385465, PMID:33306107).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2004 High

    Establishing that SPRED1 is a functional negative regulator of ERK/MAPK signaling in hematopoietic cells answered whether this Sprouty-related protein has pathway-suppressive activity in a physiological context beyond overexpression systems.

    Evidence Dominant-negative SPRED1, wild-type retroviral expression, and Spred1-deficient bone marrow mast cells with ERK and proliferation assays

    PMID:15465815

    Open questions at the time
    • Mechanism of ERK suppression not defined—direct target unknown
    • Relevance beyond hematopoietic lineage not tested
  2. 2005 High

    Knockout mouse studies extended SPRED1's inhibitory role to in vivo immune (eosinophilic airway inflammation) and structural (lipid raft/caveola localization with Caveolin-1) contexts, establishing tissue-breadth and membrane compartmentalization of its function.

    Evidence Spred1-/- mice in allergen challenge; subcellular fractionation and Cav-1 co-IP in hematopoietic cells

    PMID:15630138 PMID:16115197

    Open questions at the time
    • Caveolin-1 interaction shown in single lab without reciprocal validation
    • Whether raft localization is essential for SPRED1 function not tested genetically
  3. 2005 High

    Determination of the EVH1 domain crystal structure revealed a PH-fold with an atypically narrow peptide groove, predicting that SPRED1 recognizes non-canonical (less proline-rich) ligands distinct from classical EVH1 targets.

    Evidence X-ray crystallography of Xenopus tropicalis Spred1 EVH1 at 1.15 Å resolution

    PMID:15710406

    Open questions at the time
    • Cognate binding peptide/partner not identified from the structure alone
    • Mammalian EVH1 structure not yet determined
  4. 2007 High

    Identification of germline SPRED1 loss-of-function mutations as the cause of Legius syndrome, with biallelic inactivation in melanocyte café-au-lait spots, established SPRED1 as a bona fide RASopathy gene and implicated two-hit tumor-suppressor-like behavior.

    Evidence Patient mutation screening plus somatic LOH analysis in melanocytes

    PMID:17704776

    Open questions at the time
    • Molecular mechanism linking SPRED1 loss to melanocyte phenotype not resolved
    • Genotype–phenotype correlations across mutation types not defined
  5. 2008 Medium

    Discovery of SPRED1 interaction with TESK1 and MARKK/TAO1 revealed a non-MAPK function—inhibition of TESK1-mediated cofilin phosphorylation to regulate actin dynamics—broadening SPRED1's role beyond RAS-ERK to cytoskeletal regulation.

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

    PMID:18216281

    Open questions at the time
    • Physiological relevance of SPRED1–TESK1 axis not confirmed in vivo
    • Whether this interaction is independent of MAPK suppression is unclear
  6. 2008 High

    Spred1-/- mice exhibited hippocampal learning deficits and LTP/LTD imbalance with increased ERK phosphorylation, demonstrating that SPRED1 constrains RAS-ERK in neurons to regulate synaptic plasticity—paralleling cognitive features of RASopathies.

    Evidence Behavioral testing (Morris water maze, T-maze), electrophysiology, and ERK assays in Spred1-/- mice

    PMID:19118178

    Open questions at the time
    • Cell-type specificity within the hippocampus not dissected
    • Whether neurofibromin recruitment underlies the neuronal phenotype not tested
  7. 2010 High

    Spred1 was shown to govern neural stem cell self-renewal and cortical progenitor migration; knockdown caused periventricular heterotopia, linking SPRED1 to neurodevelopmental architecture and Legius syndrome brain phenotypes.

    Evidence In utero electroporation knockdown/overexpression, EdU assays, live imaging, and Spred1-/- mice

    PMID:20047999

    Open questions at the time
    • Downstream ERK targets mediating migration defects not identified
    • Vesicular localization in progenitors not functionally characterized
  8. 2011 High

    Identification of SHP2-mediated dephosphorylation of SPRED1 Tyr-420 as a mechanism that attenuates SPRED1's inhibitory activity established a direct phosphatase-based regulatory switch controlling SPRED1 function, explaining how SHP2 (a positive RAS-ERK regulator) counteracts SPRED1.

    Evidence Co-IP, in vitro dephosphorylation, site-directed mutagenesis, and ERK activation assays

    PMID:21531714

    Open questions at the time
    • Kinase that phosphorylates Tyr-420 not identified
    • In vivo significance of Tyr-420 phosphorylation not confirmed in animal models
  9. 2015 High

    Mapping of the SPRED1 EVH1–neurofibromin GRD interaction to the noncatalytic GAPex subdomain, with Legius and NF1 disease mutations disrupting binding, unified the molecular basis of Legius syndrome and NF1 into a shared SPRED1–NF1 complex disruption model.

    Evidence Yeast two-hybrid, co-IP, domain truncations, disease mutation mutagenesis, and ERK suppression assays

    PMID:26635368

    Open questions at the time
    • Whether SPRED1 binding modifies NF1 conformation was not resolved
    • Quantitative affinity of disease mutants not fully determined
  10. 2016 High

    Biochemical demonstration that the SPRED1–NF1 complex binds RAS simultaneously without altering GAP catalytic activity confirmed SPRED1 as a membrane-targeting adaptor rather than an allosteric GAP modulator, clarifying its mechanistic role.

    Evidence Reconstituted binding and GAP activity assays with purified components

    PMID:27313208

    Open questions at the time
    • Whether membrane lipid context affects GAP efficiency of the complex not tested
    • Role of the SPR domain in the ternary complex not addressed
  11. 2018 High

    SPRED1 was established as a melanoma tumor suppressor: loss conferred MAPK reactivation and resistance to KIT inhibitors, linking Legius syndrome biology to cancer vulnerability.

    Evidence CRISPR zebrafish melanoma model and human mucosal melanoma sequencing with MAPK assays

    PMID:30385465

    Open questions at the time
    • Whether SPRED1 loss cooperates with specific oncogenic drivers beyond KIT not fully explored
    • Mechanism by which SPRED1 loss causes drug resistance (neurofibromin-dependent or not) not dissected
  12. 2018 High

    Spred1 was found essential for hematopoietic stem cell homeostasis partly through ROCK activity; under metabolic stress (high-fat diet), its loss caused ERK hyperactivation, HSC failure, and myeloproliferative disease, revealing a context-dependent tumor-suppressor function in hematopoiesis.

    Evidence Spred1 KO mice, HSC transplantation, ROCK inhibitor treatment, and dietary stress models

    PMID:29706577

    Open questions at the time
    • How SPRED1 connects to ROCK signaling mechanistically is not defined
    • Compensatory role of SPRED2 complicates interpretation of single-KO steady-state phenotypes
  13. 2020 High

    A crystal structure of the ternary NF1-GRD–SPRED1-EVH1–KRAS complex revealed the structural basis for membrane targeting, and discovery that oncogenic EGFR phosphorylates SPRED1 Ser-105 to disrupt the complex provided a mechanism for EGFR-driven MAPK reactivation.

    Evidence X-ray crystallography, binding assays, mutagenesis, and phosphorylation analysis in EGFR-mutant cells

    PMID:32697994

    Open questions at the time
    • Kinase(s) other than EGFR that target Ser-105 not identified
    • In vivo consequences of Ser-105 phosphorylation not tested in animal models
  14. 2021 High

    SPRED1 deletion was shown to confer resistance to BRAFV600E inhibitors in melanoma by reactivating MAPK, extending its tumor-suppressor role to the most common targeted therapy in melanoma and nominating SPRED1 status as a resistance biomarker.

    Evidence SPRED1 KO human melanoma cell lines and zebrafish in vivo melanoma models treated with BRAF inhibitors

    PMID:33306107

    Open questions at the time
    • Whether SPRED1 re-expression can re-sensitize resistant tumors not tested
    • Interaction with RAF dimerization-based resistance mechanisms not explored
  15. 2024 High

    SPR domain missense mutations were shown to abolish palmitoylation and membrane localization, causing cytoplasmic aggregation and Purkinje cell degeneration (cerebellar ataxia) in knock-in mice—rescued by the autophagy inducer spermidine—revealing a gain-of-toxic-function mechanism for certain SPRED1 mutations distinct from simple loss-of-function.

    Evidence Palmitoylation assays, live imaging, knock-in mouse models, behavioral/cerebellar phenotyping, and spermidine rescue

    PMID:39510187

    Open questions at the time
    • Whether aggregate toxicity operates through autophagy impairment or proteasomal overload not distinguished
    • Relevance of this mechanism to human Legius syndrome patients with SPR domain mutations not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the structural basis of full-length SPRED1 autoinhibition and activation, the identity of the kinase phosphorylating Tyr-420, the in vivo relevance of SPRED1 interactions with DYRK1A and TESK1, and whether SPRED1 status predicts clinical response to MAPK-pathway inhibitors in cancer.
  • No full-length SPRED1 structure or autoinhibition model exists
  • Kinase for Tyr-420 phosphorylation unknown
  • Clinical utility of SPRED1 as a drug-resistance biomarker not validated in patients

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
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2
Partners
CAV1DYRK1AFGFRL1KRASNF1NF2SHP2TESK1
Complex memberships
SPRED1-merlin-neurofibromin complexSPRED1-neurofibromin-KRAS ternary complex

Evidence

Reading pass · 27 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) by impairing negative regulation of RAS→RAF interaction and MAPK signaling; melanocytes from café-au-lait spots showed biallelic SPRED1 inactivation (germline + somatic mutation), indicating complete loss is required for the phenotype. Germline mutation identification + somatic mutation analysis in melanocytes (LOH/second-hit analysis) Nature genetics High 17704776
2004 SPRED1 negatively regulates IL-3- and SCF-induced ERK/MAP kinase activation and cell proliferation in hematopoietic cells; a dominant-negative SPRED1 (ΔC-Spred) augmented IL-3-induced ERK activation, and Spred-1-deficient bone marrow mast cells showed augmented ERK activation in response to IL-3. Retroviral gene transfer of wild-type and dominant-negative SPRED1 into hematopoietic cell lines; Spred1-deficient bone marrow mast cells; ERK activation assays; colony formation assays The Journal of biological chemistry High 15465815
2005 Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness by suppressing IL-5-dependent cell proliferation and ERK activation in eosinophils. Spred-1-deficient mice; allergen challenge model; biochemical ERK activation assays; cell proliferation assays The Journal of experimental medicine High 15630138
2005 Spred-1 localizes to lipid raft/caveola membrane fractions and physically interacts with caveolin-1 (Cav-1), collaborating with Cav-1 to inhibit SCF- and IL-3-induced ERK activation and cell proliferation. Subcellular fractionation (lipid raft isolation); co-immunoprecipitation; forced expression of Cav-1 and Spred-1 in hematopoietic cells; proliferation and ERK activation assays Genes to cells Medium 16115197
2005 Crystal structure of the Xenopus tropicalis Spred1 EVH1 domain (1.15 Å resolution) reveals a pleckstrin-homology fold with a narrowed peptide-binding groove, suggesting a distinct peptide-binding mechanism compared to other EVH1 domains, likely binding less proline-rich peptides. X-ray crystallography at 1.15 Å resolution FEBS letters High 15710406
2008 SPRED1 physically interacts with MARKK/TAO1 kinase (no effect on MARKK activity) and with TESK1 kinase; Spred1 binding to TESK1 inhibits TESK1, thereby preventing TESK1-mediated phosphorylation of cofilin and making F-actin stress fibers dynamic. This three-way Spred1/MARKK/TESK1 interaction links regulation of both microtubule and F-actin cytoskeleton. Yeast two-hybrid; co-immunoprecipitation; kinase activity assays; overexpression in CHO cells with cytoskeletal readouts Molecular biology of the cell Medium 18216281
2008 Spred1 deficiency in mice causes defects in hippocampus-dependent learning and memory, short- and long-term synaptic plasticity (including LTP/LTD imbalance in CA1), and increased ERK phosphorylation after LTP induction, demonstrating that Spred1 suppresses the Ras/ERK pathway in neurons to regulate synaptic plasticity. Spred1-/- mice; Morris water maze; T-maze; electrophysiological recordings (LTP/LTD); biochemical ERK phosphorylation assays The Journal of neuroscience High 19118178
2010 Spred1 is highly enriched in CNS germinal zones; knockdown increases neural stem cell self-renewal and progenitor proliferation cell-autonomously, while overexpression causes premature differentiation. In vivo knockdown disrupts apical ventricular zone integrity, impairs late neuronal migration, and causes periventricular heterotopia. Spred1 localizes within distinct vesicles in cortical progenitors. In utero electroporation knockdown/overexpression; EdU proliferation assays; live imaging; subcellular localization (vesicle fractionation/immunofluorescence); Spred1-/- mice Genes & development High 20047999
2010 SPRED1 and SPRED2 directly interact with DYRK1A kinase via their CRD domain binding to the kinase domain of DYRK1A, and this interaction competitively inhibits DYRK1A-mediated phosphorylation of its substrates Tau and STAT3. Yeast two-hybrid; endogenous co-immunoprecipitation; in vitro kinase activity assays; domain mapping (CRD required) The Journal of biological chemistry Medium 20736167
2011 SPRED1 is a substrate of the tyrosine phosphatase SHP2: SPRED1 binds to the catalytic (phosphatase) domain of SHP2 (unlike Sprouty2 which binds the C-terminal tail), SHP2 dephosphorylates SPRED1, and two tyrosine residues on SPRED1 (including Tyr-420) are required when phosphorylated to inhibit Ras/ERK activation. SHP2-mediated dephosphorylation of Tyr-420 attenuates SPRED1's inhibitory action. Co-immunoprecipitation; in vitro dephosphorylation assays; site-directed mutagenesis of SPRED1 tyrosines; ERK activation assays The Journal of biological chemistry High 21531714
2011 FGFRL1 interacts with SPRED1 via the SPR (Sprouty) domain of SPRED1 binding to the C-terminal histidine-rich domain of FGFRL1; this interaction was verified by co-precipitation and co-distribution at the plasma membrane. Spred1 increases the retention time of FGFRL1 at the plasma membrane. Yeast two-hybrid; co-precipitation; co-localization at cell membrane in COS1 and HEK293 cells; truncation experiments Cellular signalling Medium 21616146
2011 miR-126 positively regulates mast cell proliferation and cytokine production by suppressing Spred1 expression; Spred1 overexpression or deficiency inversely regulated ERK activity and FcεRI-mediated cytokine production. Hematopoietic cell-specific Spred1 conditional KO mice showed increased mast cell numbers and heightened activation. miR-126 overexpression; Spred1 conditional knockout mice; ERK activity assays; cytokine production assays Genes to cells High 21668589
2015 The SPRED1 EVH1 domain interacts with the N-terminal 16 and C-terminal 20 amino acids of the GAP-related domain (GRD) of neurofibromin (two crossing α-helix coils outside the GAP catalytic site, not present in p120GAP). Pathogenic missense mutations in the EVH1 domain of SPRED1 (Legius syndrome) and in these GRD regions (NF1) reduce binding affinity. EVH1 domain mutations that disrupt GRD binding also abolish SPRED1's ERK suppression activity. Yeast two-hybrid; co-immunoprecipitation in HEK293 cells; domain mapping with truncations; mutagenesis; ERK suppression assays The Journal of biological chemistry High 26635368
2016 The EVH1 domain of SPRED1 binds to the noncatalytic GAPex subdomain of neurofibromin's GRD; this binding is compatible with simultaneous Ras binding and does not interfere with neurofibromin's GAP activity, supporting a targeting/recruitment function rather than GAP modulation. Biochemical binding assays; domain mapping; GAP activity assays in the presence and absence of Spred1 PNAS High 27313208
2016 SPRED1 is translocated to the plasma membrane upon growth factor stimulation or pharmacological/galectin-1-mediated induction of B/C-Raf dimers; this translocation involves SPRED1 interaction with B-Raf and, via its N terminus, with galectin-1 (Gal-1). On the plasma membrane, SPRED1 perturbs membrane organization and ERK signaling specifically of active K-ras4B but not H-ras. Legius syndrome mutations show diminished binding to both Gal-1 and B-Raf. Live-cell imaging; FRET/FLIM nanoscale membrane analysis; co-immunoprecipitation; pharmacological treatments; mutagenesis Molecular and cellular biology Medium 27503857
2018 SPRED1 functions as a tumor suppressor in 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. CRISPR-based tissue-specific zebrafish melanoma model; human mucosal melanoma sequencing; MAPK activation assays; drug resistance assays Science High 30385465
2018 Spred1 safeguards hematopoietic stem cell (HSC) homeostasis partly through Rho kinase (ROCK) activity under steady-state conditions. Under high-fat diet, Spred1 deficiency causes ERK hyperactivation and aberrant HSC self-renewal, leading to functional HSC failure, anemia, and myeloproliferative disease; compensatory upregulation of Spred2 prevents leukemogenesis in steady-state Spred1 KO. Spred1 knockout mice; HSC transplantation assays; ERK phosphorylation assays; ROCK inhibitor treatment; gut microbiota manipulation Cell stem cell High 29706577
2019 A pathogenic Legius syndrome missense mutation (T102R) in the EVH1 domain of Spred1 weakens interaction with neurofibromin by ~1000-fold without perturbing the protein fold; NMR spectroscopy identified the binding site of NF1-GAP on the mutant Spred1(EVH1) variant. NMR spectroscopy; binding affinity measurements; mutagenesis; protein folding analysis Journal of molecular biology High 31401120
2020 Crystal/cryo structure of the neurofibromin GRD complexed with SPRED1 EVH1 domain and KRAS reveals how SPRED1 membrane-targets neurofibromin to allow simultaneous interaction with activated KRAS. Oncogenic EGFR(L858R) signaling leads to phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. X-ray crystallography (structure of neurofibromin GRD-SPRED1 EVH1-KRAS ternary complex); biochemical binding assays; mutagenesis; cell-based phosphorylation assays Cell reports High 32697994
2021 SPRED1 deletion confers resistance to BRAFV600E inhibition in melanoma by reactivating MAPK activity; this was demonstrated in human melanoma cell lines and primary zebrafish melanoma models in vivo. SPRED1 KO in human melanoma cell lines; zebrafish melanoma in vivo model; MAPK activity assays; BRAF inhibitor treatment The Journal of experimental medicine High 33306107
2021 Merlin interacts with both neurofibromin and Spred1 in a complex via merlin-binding sites on both proteins; as a third component, merlin blocks Ras binding to Raf1 (acting as a 'selective Ras barrier') without increasing neurofibromin's GAP activity. Merlin-deficient Schwann cells require Ras-ERK pathway for proliferation. Co-immunoprecipitation; binding domain analysis; Ras-GAP activity assays; cell proliferation assays in merlin-deficient Schwann cells Human molecular genetics Medium 33331896
2021 Spred1 deficiency in CML promotes disease transformation from chronic phase to accelerated/blast crisis CML by expanding leukemic stem cells (LSCs) through hyperactivation of MAPK/ERK, increased miR-126 in LSKs, augmented Bcl-2 expression and stability, and enhanced Bcl-2-dependent oxidative phosphorylation supporting LSC survival. Spred1 KO in CML mouse models (global, HSC-specific, endothelial cell-specific); ERK phosphorylation; miR-126 quantification; Bcl-2 assays; oxidative phosphorylation measurements Leukemia Medium 34564700
2022 Molecular dynamics simulations and Markov state model analysis revealed that SPRED1 loading allosterically enhances KRAS-NF1 (neurofibromin) binding but hinders conformational transformation of the NF1 catalytic center required for RAS GTP hydrolysis; allosteric signal transduction pathways upon SPRED1 binding were mapped through difference contact network analysis. Gaussian accelerated molecular dynamics simulations; Markov state model analysis; contact network analysis Journal of molecular biology Low 35872068
2024 Missense mutations in the SPR (Sprouty-related) C-terminal domain of SPRED1 (e.g., C368S, M369L, V408E, P415A, P415L, P422R) cause loss of palmitoylation, loss of plasma membrane localization, and formation of cytoplasmic granular aggregates. Knock-in mice with P415A and P415V (but not M417Afs*4 which lacks the C-terminal region) developed cerebellar ataxia and Purkinje cell loss, which was rescued by the autophagy inducer spermidine. Mutagenesis of palmitoylation sites; subcellular localization (live imaging/immunofluorescence); knock-in mouse generation; behavioral/cerebellar phenotype analysis; spermidine treatment The Journal of biological chemistry High 39510187
2015 Spred1 negatively regulates the expansion and function of group 2 innate lymphoid cells (ILC2s) through suppression of the Ras-ERK pathway; Spred1 deficiency leads to faster ILC2 proliferation, higher cytokine (IL-5, IL-13) production in response to IL-33, and stabilization of GATA3. A MEK inhibitor suppressed ILC2 proliferation and cytokine production. Spred1-/- mice; in vivo papain challenge; in vitro ILC2 stimulation; MEK inhibitor treatment; GATA3 protein stability assays Journal of immunology Medium 26116510
2020 Combined loss of Spred1 and Spred2 in mouse lens leads to increased ERK1/2 phosphorylation, irregular lens epithelial and fiber cell activity, and impaired lens and eye development, demonstrating that these proteins negatively regulate ERK1/2 to control lens cell proliferation and differentiation. Spred1/Spred2 double-KO mice; ERK phosphorylation assays; histological analysis of lens development Experimental eye research Medium 31923414
2009 TGF-β upregulates SPRED1 expression in CD8+ tumor-infiltrating lymphocytes, and elevated SPRED1 correlates with reduced TCR-mediated ITK and ERK kinase activation, contributing to T cell hyporesponsiveness in the tumor microenvironment. Gene expression analysis; TGF-β inhibitor treatment; ITK and ERK activation assays in TILs vs. splenic CD8+ T cells Cancer immunology, immunotherapy Low 19319531

Source papers

Stage 0 corpus · 78 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 373 24014835
2007 Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature genetics 318 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 208 22525256
2018 Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma. Science (New York, N.Y.) 113 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 74 19366998
2018 Estrogen-induced miR-196a elevation promotes tumor growth and metastasis via targeting SPRED1 in breast cancer. Molecular cancer 71 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 44 24469042
2013 Legius syndrome, an Update. Molecular pathology of mutations in SPRED1. The Keio journal of medicine 44 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 28 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
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
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) 26 26116510
2021 SPRED1 deletion confers resistance to MAPK inhibition in melanoma. The Journal of experimental medicine 24 33306107
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
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 22 20736167
2023 Astragaloside IV promotes exosome secretion of endothelial progenitor cells to regulate PI3KR2/SPRED1 signaling and inhibit pyroptosis of diabetic endothelial cells. Cytotherapy 21 37747393
2017 miR182 activates the Ras-MEK-ERK pathway in human oral cavity squamous cell carcinoma by suppressing RASA1 and SPRED1. OncoTargets and therapy 21 28223824
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
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 18 37646268
2021 miR-126-3p contributes to sorafenib resistance in hepatocellular carcinoma via downregulating SPRED1. Annals of translational medicine 18 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
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 Spred1 deficit promotes treatment resistance and transformation of chronic phase CML. Leukemia 9 34564700
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
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 Legius syndrome mutations in the Ras-regulator SPRED1 abolish its membrane localization and potentially cause neurodegeneration. The Journal of biological chemistry 4 39510187
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
2024 Conditional Ablation of Spred1 and Spred2 in the Eye Lens Negatively Impacts Its Development and Growth. Cells 3 38391903
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
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
2025 Enhancing the sensitivity of lung adenocarcinoma to immune therapeutic agents through SPRED1. Translational lung cancer research 0 40948827
2025 The role of SPRED1 mutation in melanoma. European journal of medical research 0 41094606
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