Affinage

RASGRF1

Ras-specific guanine nucleotide-releasing factor 1 · UniProt Q13972

Length
1273 aa
Mass
145.2 kDa
Annotated
2026-06-10
86 papers in source corpus 32 papers cited in narrative 30 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RASGRF1 is a calcium/calmodulin-regulated guanine nucleotide exchange factor that couples cell-surface receptors to small-GTPase signaling, acting on H-Ras through its Cdc25 domain and on Rac1 through its DH domain, with coordinated engagement of both activities required for its full morphological effects in neurons (PMID:7684828, PMID:16481401). In the nervous system it is a dedicated effector of NR2B-containing NMDA receptors, binding the NR2B subunit (not NR2A or NR1) to drive NMDAR-dependent ERK activation and to route signaling toward the Rac/p38 MAPK cascade that promotes hippocampal LTD, dendritogenesis, and superoxide production via NOX2 (PMID:14622581, PMID:16467520, PMID:20107120, PMID:31245854). Its catalytic output is gated by PKA-dependent phosphorylation at Ser916/898 (human Ser927), a regulatory node engaged downstream of muscarinic, Gs-coupled 5-HT7, and other receptors that is required for maximal GEF activity and Ras-dependent neurite outgrowth (PMID:10601308, PMID:12538592, PMID:15853814). RASGRF1 integrates dopamine D1 and glutamate signals in striatal medium spiny neurons to activate Ras-ERK, controlling cocaine-induced behavioral plasticity and L-DOPA-induced dyskinesia (PMID:19446794, PMID:21115823). Beyond neurons it links the Dectin-1/Syk/CARD9 module to H-Ras/ERK for antifungal cytokine responses (PMID:25267792, PMID:26521038), is required for IGF-I-dependent beta-cell proliferation and survival signaling (PMID:12805218), and supports Ras/ERK and AKT signaling driving tumorigenesis, including oncogenic RASGRF1 fusions that elevate GTP-RAS and confer RAF-MEK-ERK inhibitor sensitivity (PMID:22752028, PMID:36098964, PMID:35247929, PMID:32312893). The locus is subject to paternal imprinting controlled by a CTCF-dependent, methylation-sensitive differentially methylated domain whose paternal methylation is established by a 3' direct repeat and the piRNA pathway (PMID:16314537, PMID:11753386, PMID:21566194).

Mechanistic history

Synthesis pass · year-by-year structured walk · 29 steps
  1. 1993 High

    Established that the human gene encodes a functional Ras-specific guanine nucleotide-releasing factor, defining its core biochemical activity.

    Evidence In vitro GEF assay with recombinant protein, yeast complementation of cdc25/RAS2 mutants, and mammalian Ras-responsive reporter

    PMID:7684828

    Open questions at the time
    • Did not address regulation by calcium/calmodulin or receptors
    • No cellular context or upstream activator identified
  2. 1999 High

    Identified PKA phosphorylation at Ser916 as a regulatory input linking cAMP signaling to RASGRF1 GEF activity, answering how receptor signals tune its catalysis.

    Evidence Site-directed mutagenesis, in vivo phosphorylation mapping, in vitro PKA kinase assay, and GEF activity readout downstream of muscarinic receptors

    PMID:10601308

    Open questions at the time
    • PKA phosphorylation alone insufficient for activation; additional inputs unresolved
    • Structural basis of phospho-activation unknown
  3. 1999 Medium

    Showed RASGRF1 directly and specifically binds activated TrkA and is a TrkA substrate, providing a receptor tyrosine kinase entry point distinct from GPCRs.

    Evidence Yeast two-hybrid and in vitro kinase assay with TrkB/TrkC specificity comparisons

    PMID:10691301

    Open questions at the time
    • Single-lab, no cellular functional consequence established
    • Tyr phosphosites on RASGRF1 not mapped
  4. 2002 Medium

    Defined how RASGRF1 biases output toward p38 by binding the IB2/JIP2 scaffold that assembles the MLK3-MKK3-p38 cassette.

    Evidence Co-immunoprecipitation and kinase activation assays in overexpression systems

    PMID:12024021

    Open questions at the time
    • Single lab, largely overexpression-based
    • Endogenous scaffold complex stoichiometry unresolved
  5. 2003 High

    Identified the direct, subunit-specific NR2B–RASGRF1 interaction as the molecular link coupling NR2B-NMDARs to ERK.

    Evidence Reciprocal Co-IP in vivo and in vitro plus interaction-disrupting peptides in living neurons with ERK readout

    PMID:14622581

    Open questions at the time
    • Binding interface on NR2B not mapped at residue level
    • How Ca2+ entry triggers complex remodeling unresolved
  6. 2003 High

    Extended PKA regulation to function, showing Ser916/898 phosphorylation is required for Ras-dependent neurite outgrowth and occurs on endogenous brain RASGRF1.

    Evidence Phospho-specific antibody, 32P labeling in brain slices, mutagenesis, and neurite outgrowth assays

    PMID:12538592

    Open questions at the time
    • Upstream kinase activation in vivo context partial
    • Quantitative contribution of each site unresolved
  7. 2003 High

    Established a peripheral, non-neuronal role: RASGRF1 is required for IGF-I-driven Akt/Erk activation and beta-cell proliferation.

    Evidence Knockout mice, isolated islet IGF-I stimulation immunoblots, glucose tolerance, and histology

    PMID:12805218

    Open questions at the time
    • Direct GEF coupling to the IGF-I receptor not demonstrated
    • Mechanism of IGF-I-dependent recruitment unknown
  8. 2005 High

    Resolved imprinting control: the DMD acts as a methylation-sensitive CTCF enhancer blocker dictating monoallelic expression.

    Evidence CTCF binding assays, in vitro and in vivo enhancer-blocking, and methylation analysis

    PMID:16314537

    Open questions at the time
    • Tissue-specific enhancer targets not enumerated
    • Connection of imprinting to physiological RASGRF1 dosage incomplete
  9. 2005 Medium

    Showed Gs-coupled 5-HT7 receptors drive PKA phosphorylation of human RASGRF1 (Ser927) and that the Ca2+/calmodulin IQ domain is required for full ERK output.

    Evidence Phosphorylation and IQ-deletion mutant analysis with ERK immunoblot and Ca2+ measurement

    PMID:15853814

    Open questions at the time
    • Single lab
    • Interplay between Ca2+/CaM and PKA inputs not quantitatively dissected
  10. 2006 High

    Genetically separated RASGRF1 from RASGRF2, assigning RASGRF1 to the NR2B–Rac–p38 LTD axis and RASGRF2 to the NR2A–ERK LTP axis.

    Evidence Ras-GRF1 and Ras-GRF2 knockout mice with electrophysiology and NMDAR-subtype pharmacology

    PMID:16467520

    Open questions at the time
    • Molecular basis of effector selectivity not fully defined
    • Developmental timing dependence only partially characterized
  11. 2006 High

    Defined the dual-GEF architecture, showing distinct Cdc25 (H-Ras) and DH (Rac1) domains must act in concert, with H-Ras·GTP binding coupling to Rac via PI3K/Akt.

    Evidence Truncation mutants, bacterial-lysate pulldowns, HEK293 Co-IP, dominant-negative Rac1/RhoA, and morphological analysis

    PMID:16481401

    Open questions at the time
    • Structural coupling between domains unresolved
    • How upstream signals choose H-Ras vs Rac output unclear
  12. 2006 Medium

    Identified SCLIP as a DH-domain binding partner that selectively dampens the Rac/p38 arm without affecting Ras/ERK, providing an effector-arm-specific brake.

    Evidence Yeast two-hybrid, Co-IP, pathway-specific activity assays, and neurite outgrowth in PC12 cells

    PMID:17135267

    Open questions at the time
    • Single lab
    • In vivo relevance of SCLIP regulation not tested
  13. 2007 Medium

    Showed RASGRF1 abundance is controlled post-translationally, with Filamin A driving its ubiquitylation and destabilization to limit H-Ras/ERK and MMP-9 in melanoma.

    Evidence Ubiquitylation assay, MMP-9 reporter, dominant-negative and ectopic RASGRF1, and kinase assays

    PMID:17389601

    Open questions at the time
    • E3 ligase mediating ubiquitylation not identified
    • Single lab
  14. 2009 High

    Placed RASGRF1 as the integrator of dopamine D1 and glutamate signals driving striatal ERK and cocaine-related behaviors.

    Evidence Knockout and overexpressing mice, striatal cultures/slices, pERK assays, and behavioral tests

    PMID:19446794

    Open questions at the time
    • Molecular coupling of D1/cAMP to RASGRF1 in MSNs only partly defined
    • Circuit specificity not fully resolved
  15. 2010 High

    Demonstrated therapeutic relevance: striatal dominant-negative RASGRF1 reverses L-DOPA-induced dyskinesia in primates, establishing causal requirement of RASGRF1-Ras-ERK signaling.

    Evidence Knockout mice plus lentiviral dominant-negative RASGRF1 in a non-human primate model with AIMs scoring

    PMID:21115823

    Open questions at the time
    • Downstream ERK targets mediating dyskinesia not identified
    • Long-term consequences of striatal RASGRF1 inhibition unknown
  16. 2010 Medium

    Showed the NR2B–RASGRF1 interaction is required for NR2B-driven dendritic branch formation, linking the complex to neuronal morphogenesis.

    Evidence Interaction-disrupting mutants, NR2-null neurons reconstituted with NR2A/NR2B, dendritic morphology, and electrophysiology

    PMID:20107120

    Open questions at the time
    • Single lab
    • Downstream effector arm for dendritogenesis not specified here
  17. 2011 High

    Revealed the mechanism establishing paternal DMD methylation: piRNAs targeting a retrotransposon within a DMD-spanning noncoding RNA, with the direct repeat acting as its promoter.

    Evidence Mili/Miwi2 knockout mice, bisulfite sequencing, and RNA analysis

    PMID:21566194

    Open questions at the time
    • How piRNA-guided complexes recruit de novo methyltransferases at this locus not fully detailed
    • Generality across tissues not addressed
  18. 2001 High

    Identified the 3' direct repeat as the germ-line element required to establish paternal DMD methylation and imprinted expression.

    Evidence Targeted repeat deletion in mice, bisulfite methylation, and allele-specific expression analysis

    PMID:11753386

    Open questions at the time
    • Mechanism by which the repeat directs methylation only later resolved
    • Trans-acting factors not identified at this stage
  19. 2012 Medium

    Showed transcriptional control of Rasgrf1 by Zac1/Plagl1 in beta cells, linking its dosage to insulin secretion and MAPK/PI3K signaling.

    Evidence Overexpression and rescue in beta cells, pathway and insulin secretion assays, and diabetic transplantation model

    PMID:22547676

    Open questions at the time
    • Direct vs indirect repression mechanism partly defined
    • Single lab
  20. 2012 Medium

    Established RASGRF1 as required for Ras/ERK and AKT signaling downstream of pro-metastatic ligands and for rhabdomyosarcoma tumor growth.

    Evidence shRNA knockdown, MAPK/AKT phosphorylation, chemotaxis, and xenograft tumor assays

    PMID:22752028

    Open questions at the time
    • Receptor coupling mechanism to RASGRF1 not defined
    • Single lab
  21. 2014 High

    Identified the CARD9–RASGRF1 complex linking Dectin-1/Syk to H-Ras/ERK in antifungal innate immunity.

    Evidence Co-IP, phosphorylation assays, CARD9 KO cells, ERK readout, and an in vivo infection model

    PMID:25267792

    Open questions at the time
    • Syk phosphosites on RASGRF1 not mapped
    • How phosphorylation enables CARD9/H-Ras recruitment unresolved
  22. 2014 Medium

    Demonstrated a cell-autonomous role for RASGRF1 in adult hippocampal neurogenesis, promoting dendritic arborization and survival of young neurons.

    Evidence Knockout mice, BrdU labeling, and retroviral shRNA in new neurons with morphology analysis

    PMID:24174283

    Open questions at the time
    • Upstream activators in new neurons not defined
    • Age-dependence mechanism unresolved
  23. 2015 Medium

    Confirmed disease relevance of the CARD9-RASGRF1 axis: a CARD9 Y91H mutation selectively impairs RASGRF1 binding, ERK/NF-κB activation, and GM-CSF responses.

    Evidence Co-IP and signaling/cytokine assays in patient-derived monocytes with CARD9 mutant analysis

    PMID:26521038

    Open questions at the time
    • Single lab
    • Structural basis of selective RASGRF1 binding loss not defined
  24. 2015 Medium

    Placed RASGRF1 downstream of VLDLR in CaMKII-dependent dendritic spinogenesis.

    Evidence Co-IP, shRNA knockdown, and spine morphology in hippocampal cultures

    PMID:25644714

    Open questions at the time
    • Single lab; epistasis-based positioning
    • Directness of VLDLR-RASGRF1 coupling unclear
  25. 2018 Medium

    Expanded substrate range, showing RASGRF1 acts as a GEF for R-Ras in BDNF-induced axonal growth, with PKA Ser916/898 phosphorylation required.

    Evidence RNAi, overexpression, R-Ras pulldown, axonal morphology, and phosphorylation assays

    PMID:30582008

    Open questions at the time
    • Single lab
    • Direct R-Ras GEF kinetics not measured
  26. 2018 Medium

    Showed receptor competition controls RASGRF1 targeting: TrkB/BDNF recruits RASGRF1 away from NR2B toward TrkB, biasing toward ERK and away from LTD.

    Evidence Competitive Co-IP, phosphorylation, and neurite outgrowth assays

    PMID:30547417

    Open questions at the time
    • Single lab
    • In vivo significance of the switch not tested
  27. 2019 Medium

    Defined an effector branch downstream of the NR2B–RASGRF1 complex, showing it drives NOX2-dependent superoxide required for dendritogenesis.

    Evidence DHE superoxide detection, interaction-disrupting peptide, and dendritic branching analysis

    PMID:31245854

    Open questions at the time
    • Single lab
    • Mechanism coupling RASGRF1 to NOX2 not defined
  28. 2022 High

    Established RASGRF1 as a chromatin-regulated, oncogenic driver: MLL/H3K4me3 controls its expression, it is required for active GTP-Kras, and RASGRF1 fusions transform cells with RAF-MEK-ERK inhibitor sensitivity.

    Evidence GEMMs, ChIP-seq, CRISPR-edited cells, Ras-GTP pulldown, transformation and xenograft assays, MEK inhibitor treatment (multiple labs)

    PMID:32312893 PMID:35247929 PMID:36098964

    Open questions at the time
    • Whether fusion proteins retain calcium/PKA regulation unresolved
    • Structural basis of fusion-driven GEF activation undefined
  29. 2025 Medium

    Showed RASGRF1 functions as a mechanosensitive activator, transducing matrix stiffness into Ras-GTP, AKT-FOXO3a-Bim survival signaling in lung fibroblasts.

    Evidence RNAi, AKT/ERK inhibitors, Ras-GTP pulldown, FOXO3a/Bim immunoblots, and fibroblast survival assays on variable-stiffness hydrogels

    PMID:39793891

    Open questions at the time
    • Single lab
    • Mechanosensing mechanism upstream of RASGRF1 not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RASGRF1 integrates its Ca2+/calmodulin, PKA, and tyrosine-kinase inputs at the structural level to select between H-Ras, R-Ras, and Rac1 outputs in a given cell type remains unresolved.
  • No structural model of full-length regulated RASGRF1
  • Quantitative rules governing effector selection unknown
  • Whether oncogenic fusions bypass normal regulatory inputs untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2
Partners
CARD9FLNAGRIN2BH-RASNTRK1NTRK2RAC1VLDLR

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 RasGRF1 directly interacts with the NR2B subunit (but not NR2A or NR1) of NMDA receptors in vivo and in vitro; specific disruption of this interaction in living neurons abrogates NMDAR-dependent ERK activation, establishing RasGRF1 as the Ca2+/calmodulin-dependent regulator linking NR2B-containing NMDARs to the ERK kinase pathway. Co-immunoprecipitation (in vivo and in vitro), disruption peptides in living neurons, ERK activation assays Neuron High 14622581
2006 Ras-GRF1 mediates signaling from NR2B-containing NMDARs to the Rac effector p38 MAP kinase to promote long-term depression (LTD) in the CA1 hippocampus of postpubescent mice, while Ras-GRF2 (not Ras-GRF1) mediates signaling from NR2A-containing NMDARs to ERK1/2 to promote LTP. Genetic knockout mice (Ras-GRF1 KO, Ras-GRF2 KO), electrophysiology (LTP/LTD), pharmacological receptor subtype blockade (ifenprodil, NVP-AAM077) The Journal of neuroscience High 16467520
2002 The N-terminal region of Ras-GRF1 (containing PH domain, coiled-coil, and adjacent sequences) binds to the scaffold protein IB2/JIP2, which scaffolds the p38 MAP kinase cascade (MLK3-MKK3-p38); Ras-GRF1 binding to IB2/JIP2 selectively potentiates p38 activation but not JNK activation and increases assembly of the p38 signaling cassette. Co-immunoprecipitation, overexpression in cells, kinase activation assays Molecular and cellular biology Medium 12024021
2014 CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras: Dectin-1 engagement initiates Syk-dependent phosphorylation of Ras-GRF1, and phosphorylated Ras-GRF1 recruits and activates H-Ras through forming a complex with CARD9, leading to downstream ERK activation and antifungal cytokine production. Co-immunoprecipitation, phosphorylation assays, CARD9 KO cells, ERK activation assays, in vivo infection model The Journal of experimental medicine High 25267792
1999 Phosphorylation of Ras-GRF1 at Ser916 is a major in vivo phosphorylation site required for full activation of its guanine nucleotide exchange activity by muscarinic receptors; Ser916 is a substrate for protein kinase A both in vivo and in vitro, establishing a link between the cAMP and Ras signaling systems, though PKA phosphorylation alone is not sufficient to activate RasGRF1. Site-directed mutagenesis, in vivo phosphorylation mapping, in vitro kinase assay, GEF activity assay The Journal of biological chemistry High 10601308
2003 Phosphorylation of Ras-GRF1 at Ser916/898 is required for maximal Ras-dependent neurite outgrowth in PC12 cells and is increased by protein kinase A activation in brain slices; a phospho-specific antibody confirmed regulated phosphorylation of endogenous Ras-GRF1 in rat forebrain, including in the dendritic tree of prefrontal cortex neurons. Phospho-specific antibody, confocal immunofluorescence, 32P incorporation in brain slices, mutagenesis, neurite outgrowth assays The Journal of biological chemistry High 12538592
2006 Ras-GRF1 has separate GEF activities for H-Ras (through its Cdc25 domain) and Rac1 (through its DH domain); coordinated activation of both is required for full morphological effects in neurons. The Rac GEF-containing truncation (GRFdeltaC) binds H-Ras·GTP directly, coupling H-Ras activation to Rac-dependent cell expansion via PI3K/Akt. Truncation mutant expression, pulldown assays from bacterial lysates, co-immunoprecipitation from HEK293 cells, dominant-negative Rac1/RhoA, pharmacological inhibitors (wortmannin), morphological analysis Molecular biology of the cell High 16481401
2007 Filamin A (FLNa) down-regulates Ras-GRF1 protein stability through destabilization and ubiquitylation of Ras-GRF1, thereby suppressing constitutive H-Ras/MAPK-ERK activation and reducing MMP-9 transcription in melanoma cells; ectopic Ras-GRF1 restores ERK activation and MMP-9 elevation, while a catalytically inactive dominant-negative Ras-GRF1 reduces MMP-9 expression. Ubiquitylation assay, MMP-9 promoter-luciferase reporter, dominant-negative Ras-GRF1, ectopic expression, in vitro kinase assay The Journal of biological chemistry Medium 17389601
2003 Ras-GRF1 is expressed in pancreatic islets; GRF1-deficient mice exhibit impaired beta-cell proliferation and reduced neogenesis, and isolated islets from GRF1 knockouts fail to activate Akt and Erk downstream of IGF-I treatment, demonstrating that Ras-GRF1 is required for IGF-I signaling in beta cells. Knockout mice, isolated islet IGF-I stimulation, immunoblot for Akt/Erk activation, glucose tolerance tests, histology The EMBO journal High 12805218
1993 Human H-GRF55/RASGRF1 encodes a Ras-specific guanine nucleotide-releasing factor that functions in vitro to promote GDP release from Ras; expression in yeast reverses cdc25.5 and RAS2 Ala-22 mutations, and in CHO cells transactivates a Ras-responsive reporter element. In vitro GEF assay with recombinant GST-fusion protein, yeast complementation, mammalian cell reporter assay Oncogene High 7684828
2005 The differentially methylated domain (DMD) at the Rasgrf1 locus functions as an enhancer blocker that binds CTCF in a methylation-sensitive manner; CTCF binds the unmethylated maternal allele to silence expression, while repeat-mediated methylation on the paternal allele prevents CTCF binding and allows expression. CTCF binding assays, in vitro enhancer-blocking assay, in vivo imprinting analysis with extra-enhancer transgene, methylation analysis Molecular and cellular biology High 16314537
2001 A direct repeat sequence immediately 3' of the differentially methylated domain (DMD) at Rasgrf1 is required for establishing paternal allele-specific DNA methylation in the male germ line; loss of the repeat abolishes DMD methylation and imprinted expression, establishing the repeat-DMD binary switch as the imprinting control region. Targeted deletion of repeat sequence in mice, bisulfite methylation analysis, allele-specific expression analysis Nature genetics High 11753386
2011 piRNA pathway components are required for de novo methylation of the Rasgrf1 DMD in the paternal germ line; piRNAs generated from a separate locus target a retrotransposon sequence within a noncoding RNA spanning the DMD, and the direct repeat acts as a promoter for this RNA, directing sequence-specific methylation. piRNA pathway mutant mice (Mili, Miwi2 knockouts), bisulfite sequencing, RNA analysis Science High 21566194
2009 Ras-GRF1 is required for ERK1/2 activation by glutamate or dopamine D1 receptor agonists in striatal medium spiny neurons of the direct pathway; Ras-GRF1 integrates glutamate and dopamine signals to activate ERK and drive long-term behavioral responses to cocaine including locomotor sensitization and conditioned place preference. Ras-GRF1 KO and overexpressing transgenic mice, striatal primary cultures, organotypic slices, immunoblot/immunofluorescence for pERK, behavioral assays Biological psychiatry High 19446794
2010 Dominant-negative forms of Ras-GRF1 delivered by lentiviral vectors into the striatum cause dramatic reversion of L-DOPA-induced dyskinesia in a non-human primate model, demonstrating that Ras-GRF1-dependent Ras-ERK signaling in the striatum is mechanistically required for dyskinesia expression. Ras-GRF1 KO mice, lentiviral dominant-negative Ras-GRF1 in primate model, behavioral scoring (AIMs scale) PNAS High 21115823
2006 The microtubule-destabilizing factor SCLIP binds the Dbl-homology (DH) domain of RasGRF1 (identified by yeast two-hybrid) and selectively inhibits RasGRF1-mediated activation of the Rac/p38 MAPK pathway without affecting the Ras/ERK pathway; SCLIP co-expression counteracts RasGRF1-induced neurite outgrowth in PC12 cells. Yeast two-hybrid, co-immunoprecipitation, Rac/p38 and Ras/ERK activity assays, neurite outgrowth assay The Journal of biological chemistry Medium 17135267
2005 Gs-coupled serotonin 5-HT7 receptor stimulation induces protein kinase A-dependent phosphorylation of endogenous human Ras-GRF1 at Ser927 (equivalent to mouse Ser916), and deletion of the Ca2+/calmodulin-binding IQ domain (residues 1-225) reduces both basal and serotonin-stimulated ERK1/2 phosphorylation, indicating the IQ domain is required for full Ras-GRF1 activity downstream of Gs-coupled receptors. Phosphorylation assay, deletion mutant expression, ERK1/2 phosphorylation immunoblot, intracellular Ca2+ measurement The FEBS journal Medium 15853814
1999 RasGRF1 directly interacts with the intracellular domain of the activated TrkA receptor tyrosine kinase in a kinase-activity-dependent manner (yeast two-hybrid and in vitro), and RasGRF1 is directly phosphorylated by TrkA; the interaction is highly specific for TrkA over TrkB and TrkC and is independent of the major TrkA phosphotyrosine sites Tyr499 and Tyr794. Yeast two-hybrid, in vitro kinase assay, specificity comparisons with TrkB/TrkC Journal of molecular neuroscience Medium 10691301
2012 The transcription factor Zac1/Plagl1 directly represses Rasgrf1 expression in pancreatic beta cells; doubling Zac1 expression reduces Rasgrf1 levels, impairs stimulus-induced MAPK and PI3K pathway activation, and reduces insulin secretion, and normalizing Rasgrf1 expression reverses this phenotype. Transfection/overexpression in beta cells, rescue by Rasgrf1 normalization, MAPK/PI3K pathway assays, insulin secretion assay, diabetic mouse transplantation model Molecular and cellular biology Medium 22547676
2010 Disruption of the NR2B-RasGRF1 interaction dramatically impairs dendritic branch formation in ventral spinal cord neurons and hippocampal neurons, establishing that the NR2B-RasGRF1 association is required for NR2B-driven dendritogenesis. NR2B interaction-disrupting mutants, NR2-null neurons with exogenous NR2A or NR2B introduction, dendritic morphology analysis, electrophysiology Journal of neurophysiology Medium 20107120
2015 CARD9 p.Y91H mutation specifically impairs the ability of CARD9 to complex with RASGRF1 (while BCL10/MALT1 association is intact), leading to impaired activation of ERK and NF-κB in monocytes and a defective GM-CSF response, establishing the CARD9/RASGRF1/ERK/GM-CSF axis as critical for antifungal immunity. Immunoprecipitation (CARD9-RASGRF1 complex), signaling assays (pERK, NF-κB) in patient-derived cells, CARD9 mutant analysis The Journal of allergy and clinical immunology Medium 26521038
2012 RasGRF1 is required for activation of the Ras/ERK and AKT pathways downstream of pro-metastatic factors (SDF-1, HGF/SF, IGF-2, insulin) in alveolar rhabdomyosarcoma cells; shRNA knockdown of RasGRF1 abolishes ligand-induced MAPK/AKT phosphorylation and eliminates chemotactic responses, and RasGRF1-depleted cells form significantly smaller tumors in vivo. shRNA knockdown, MAPK/AKT phosphorylation assays, chemotaxis assay, xenograft tumor model International journal of oncology Medium 22752028
2019 The NR2B-NMDAR/RasGRF1/NOX2 pathway promotes superoxide production required for dendritogenesis; disrupting the NR2B-RasGRF1 interaction reduces superoxide levels (measured with DHE) and inhibits dendritic branching in hippocampal neurons, placing RasGRF1 as a required intermediary between NR2B-NMDARs and NOX2-dependent reactive oxygen species generation. Dihydroethidium (DHE) fluorescence for superoxide detection, NR2B-RasGRF1 interaction-disrupting peptide, dendritic branching analysis in primary hippocampal neurons Journal of cellular physiology Medium 31245854
2014 GRF1 is expressed in newly born hippocampal neurons and promotes late stages of adult neurogenesis (dendritic arborization and survival of 2-3 week-old new neurons) in an age-dependent manner; retroviral shRNA knockdown specifically in new neurons phenocopies the reduced neurogenesis of global GRF1 knockout. Knockout mice, BrdU labeling, retroviral shRNA in new neurons, dendritic morphology analysis Hippocampus Medium 24174283
2018 BDNF induces R-Ras activation through RasGRF1 acting as a GEF for R-Ras; RNAi knockdown and overexpression experiments show RasGRF1 is required for BDNF-induced R-Ras activation and axonal growth, and PKA-dependent phosphorylation of RasGRF1 at Ser916/898 is required for full GEF activity in this pathway. RNA interference, overexpression, R-Ras activation assay (pulldown), axonal morphology analysis, phosphorylation assay Biochemistry and biophysics reports Medium 30582008
2018 TrkB activation by BDNF uncouples RasGRF1 from NR2B and recruits it to TrkB; NMDA stimulation recruits RasGRF1 to NR2B, but co-stimulation with BDNF shifts RasGRF1 association to TrkB, and TrkB stimulates tyrosine phosphorylation of RasGRF1, promoting ERK activation and neurite outgrowth while reducing NR2B-LTD signaling. Co-immunoprecipitation (competitive association NR2B vs TrkB), neurite outgrowth assay, phosphorylation assay Journal of molecular neuroscience Medium 30547417
2022 MLL deficiency decreases H3K4me3 at the Rasgrf1 locus, suppressing Rasgrf1 expression; Rasgrf1 is essential for the GTP-bound active state of Kras and activation of Kras downstream pathways; RASGRF1 fusions (TMEM87A-RASGRF1, OCLN-RASGRF1, SLC4A4-RASGRF1, IQGAP1-RASGRF1) increase cellular GTP-RAS levels, induce cellular transformation, and promote in vivo tumorigenesis, with sensitivity to RAF-MEK-ERK pathway inhibition. Genetically engineered mouse models, ChIP-seq (H3K4me3), CRISPR-Cas9 edited cell lines, Ras-GTP pulldown, transformation assays, xenograft models, MEK inhibitor treatment Cancer research / Clinical cancer research High 32312893 35247929 36098964
2015 VLDLR interacts with RasGRF1 (co-immunoprecipitation), and knockdown of RasGRF1 blocks VLDLR-induced increases in dendritic spine number in hippocampal neurons; VLDLR cannot rescue spine deficits caused by loss of CaMKIIα or CaMKIIβ, placing RasGRF1 downstream of VLDLR and requiring CaMKII for the VLDLR-RasGRF1 spinogenesis pathway. Co-immunoprecipitation, shRNA knockdown, dendritic spine morphology analysis in primary hippocampal cultures Biochimica et biophysica acta Medium 25644714
2008 The N-terminal PHCCIQ region of RasGRF1 interacts with ribosomal proteins, cytoskeletal proteins, and proteins involved in vesicular trafficking from mouse brain extracts; the PHCCIQ domain exhibits RNA-binding properties, associating with poly(A)-containing RNA and ribosomal protein S6. Affinity purification with chitin-binding domain fusion, mass spectrometry, co-immunoprecipitation, poly(A)-Sepharose binding Journal of molecular neuroscience Low 18607774
2025 Matrix stiffness activates RasGRF1, leading to increased Ras-GTP levels and downstream activation of both AKT and ERK pathways; RasGRF1-dependent AKT activation leads to FOXO3a phosphorylation/inactivation and Bim degradation, promoting lung fibroblast survival on stiff substrates; RNAi depletion of FOXO3a or Bim recapitulates the survival phenotype. RNAi knockdown of RasGRF1, pharmacological AKT/ERK inhibitors, Ras-GTP pulldown assay, FOXO3a/Bim western blot, fibroblast survival assay on hydrogels of varying stiffness The Journal of biological chemistry Medium 39793891

Source papers

Stage 0 corpus · 86 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron 372 14622581
2011 Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus. Science (New York, N.Y.) 303 21566194
2002 Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade. Molecular and cellular biology 163 12024021
2006 Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the induction of long-term potentiation and long-term depression. The Journal of neuroscience : the official journal of the Society for Neuroscience 150 16467520
2010 Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia. Proceedings of the National Academy of Sciences of the United States of America 132 21115823
2001 Regulation of DNA methylation of Rasgrf1. Nature genetics 131 11753386
2014 CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity. The Journal of experimental medicine 119 25267792
2001 Hippocampus-dependent learning and memory is impaired in mice lacking the Ras-guanine-nucleotide releasing factor 1 (Ras-GRF1). Neuropharmacology 117 11640934
2008 Antagonism between DNA and H3K27 methylation at the imprinted Rasgrf1 locus. PLoS genetics 97 18670629
2009 Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) controls activation of extracellular signal-regulated kinase (ERK) signaling in the striatum and long-term behavioral responses to cocaine. Biological psychiatry 85 19446794
2005 Rasgrf1 imprinting is regulated by a CTCF-dependent methylation-sensitive enhancer blocker. Molecular and cellular biology 83 16314537
2012 The effect of preconception paternal alcohol exposure on epigenetic remodeling of the h19 and rasgrf1 imprinting control regions in mouse offspring. Frontiers in genetics 77 22371710
2015 Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians. The Journal of allergy and clinical immunology 70 26521038
2003 Ras-GRF1 signaling is required for normal beta-cell development and glucose homeostasis. The EMBO journal 68 12805218
2010 Differential roles of NMDA Receptor Subtypes NR2A and NR2B in dendritic branch development and requirement of RasGRF1. Journal of neurophysiology 66 20107120
2014 Derangement of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and extracellular signal-regulated kinase (ERK) dependent striatal plasticity in L-DOPA-induced dyskinesia. Biological psychiatry 60 24844602
2011 RasGrf1 deficiency delays aging in mice. Aging 50 21422498
2007 Filamin A-mediated down-regulation of the exchange factor Ras-GRF1 correlates with decreased matrix metalloproteinase-9 expression in human melanoma cells. The Journal of biological chemistry 49 17389601
1999 A direct repeat sequence at the Rasgrf1 locus and imprinted expression. Genomics 44 9933566
1993 Identification of a human guanine nucleotide-releasing factor (H-GRF55) specific for Ras proteins. Oncogene 44 7684828
2009 RasGRF1 disruption causes retinal photoreception defects and associated transcriptomic alterations. Journal of neurochemistry 38 19457086
1999 Activity-dependent interaction of the intracellular domain of rat trkA with intermediate filament proteins, the beta-6 proteasomal subunit, Ras-GRF1, and the p162 subunit of eIF3. Journal of molecular neuroscience : MN 38 10691301
2003 Phosphorylation of the Ras-GRF1 exchange factor at Ser916/898 reveals activation of Ras signaling in the cerebral cortex. The Journal of biological chemistry 34 12538592
2012 Aberrant methylation of RASGRF1 is associated with an epigenetic field defect and increased risk of gastric cancer. Cancer prevention research (Philadelphia, Pa.) 33 22961779
2008 Transcriptomic and proteomic analyses of mouse cerebellum reveals alterations in RasGRF1 expression following in vivo chronic treatment with delta 9-tetrahydrocannabinol. Journal of molecular neuroscience : MN 31 18584336
2011 Mice Lacking Ras-GRF1 Show Contextual Fear Conditioning but not Spatial Memory Impairments: Convergent Evidence from Two Independently Generated Mouse Mutant Lines. Frontiers in behavioral neuroscience 30 22164138
2009 Imprint switch mutations at Rasgrf1 support conflict hypothesis of imprinting and define a growth control mechanism upstream of IGF1. Mammalian genome : official journal of the International Mammalian Genome Society 30 19513790
2005 Endogenous expression and protein kinase A-dependent phosphorylation of the guanine nucleotide exchange factor Ras-GRF1 in human embryonic kidney 293 cells. The FEBS journal 30 15853814
2002 Structural characterization of Rasgrf1 and a novel linked imprinted locus. Gene 29 12095702
2003 Two ENU-induced mutations in Rasgrf1 and early mouse growth retardation. Mammalian genome : official journal of the International Mammalian Genome Society 28 12925882
2012 Transient neonatal diabetes mellitus gene Zac1 impairs insulin secretion in mice through Rasgrf1. Molecular and cellular biology 26 22547676
2011 RasGrf1: genomic imprinting, VSELs, and aging. Aging 26 21765200
2006 The Ras-GRF1 exchange factor coordinates activation of H-Ras and Rac1 to control neuronal morphology. Molecular biology of the cell 26 16481401
1999 Phosphorylation of serine 916 of Ras-GRF1 contributes to the activation of exchange factor activity by muscarinic receptors. The Journal of biological chemistry 26 10601308
2006 Timing and sequence requirements defined for embryonic maintenance of imprinted DNA methylation at Rasgrf1. Molecular and cellular biology 24 17030618
2012 RasGRF1 regulates proliferation and metastatic behavior of human alveolar rhabdomyosarcomas. International journal of oncology 22 22752028
2020 Identification of a RAS-activating TMEM87A-RASGRF1 Fusion in an Exceptional Responder to Sunitinib with Non-Small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 20 32312893
2015 Very low density lipoprotein receptor regulates dendritic spine formation in a RasGRF1/CaMKII dependent manner. Biochimica et biophysica acta 20 25644714
2015 miR-137 acts as a tumor suppressor in astrocytoma by targeting RASGRF1. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 20 26440052
2009 The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue. Arthritis research & therapy 20 19678938
2018 Deletion of RasGRF1 Attenuated Interstitial Fibrosis in Streptozotocin-Induced Diabetic Cardiomyopathy in Mice through Affecting Inflammation and Oxidative Stress. International journal of molecular sciences 19 30308936
2016 A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Increases Dendritic Spine Density via RasGRF1/ERK Pathway. Journal of Alzheimer's disease : JAD 17 26890742
2015 Differential involvement of Ras-GRF1 and Ras-GRF2 in L-DOPA-induced dyskinesia. Annals of clinical and translational neurology 17 26125041
2014 Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory. Frontiers in human neuroscience 17 24808846
2011 Novel RasGRF1-derived Tat-fused peptides inhibiting Ras-dependent proliferation and migration in mouse and human cancer cells. Biotechnology advances 17 21620943
2009 Differential methylation persists at the mouse Rasgrf1 DMR in tissues displaying monoallelic and biallelic expression. Epigenetics 17 19502804
2022 Loss of MLL Induces Epigenetic Dysregulation of Rasgrf1 to Attenuate Kras-Driven Lung Tumorigenesis. Cancer research 16 36098964
2006 SCLIP, a microtubule-destabilizing factor, interacts with RasGRF1 and inhibits its ability to promote Rac activation and neurite outgrowth. The Journal of biological chemistry 16 17135267
2022 RASGRF1 Fusions Activate Oncogenic RAS Signaling and Confer Sensitivity to MEK Inhibition. Clinical cancer research : an official journal of the American Association for Cancer Research 14 35247929
2014 Age-dependent role for Ras-GRF1 in the late stages of adult neurogenesis in the dentate gyrus. Hippocampus 14 24174283
2013 Evaluating the association between pathological myopia and SNPs in RASGRF1. ACTC1 and GJD2 genes at chromosome 15q14 and 15q25 in a Chinese population. Ophthalmic genetics 14 23834555
2012 Decreased expression of Ras-GRF1 in the brain tissue of the intractable epilepsy patients and experimental rats. Brain research 14 23200899
2011 Imprinted Rasgrf1 expression in neonatal mice affects olfactory learning and memory. Genes, brain, and behavior 14 21251221
2025 IGF2BP3-mediated m6A modification of RASGRF1 promoting joint injury in rheumatoid arthritis. Bone research 13 40355406
2022 RASGRF1-rearranged Cutaneous Melanocytic Neoplasms With Spitzoid Cytomorphology: A Clinicopathologic and Genetic Study of 3 Cases. The American journal of surgical pathology 13 34799483
2018 RASGRF1 Hypermethylation, a Putative Biomarker of Colorectal Cancer. Annals of clinical and laboratory science 13 29530990
2015 Polymorphism in the RASGRF1 gene with high myopia: A meta-analysis. Molecular vision 13 26644762
2019 The Inhibition of RasGRF2, But Not RasGRF1, Alters Cocaine Reward in Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 12 31182637
2017 Association of RASgrf1 methylation with epileptic seizures. Oncotarget 12 28611277
2012 Ras guanine nucleotide releasing factor 1 (RasGrf1) enhancement of Trk receptor-mediated neurite outgrowth requires activation of both H-Ras and Rac. Journal of molecular neuroscience : MN 12 22744634
2014 Transcriptional profiling reveals functional links between RasGrf1 and Pttg1 in pancreatic beta cells. BMC genomics 11 25421944
2010 A non-coding RNA within the Rasgrf1 locus in mouse is imprinted and regulated by its homologous chromosome in trans. PloS one 11 21072176
2020 RasGRF1 participates in the protective effect of tanshinone IIA on depressive like behaviors of a chronic unpredictable mild stress induced mouse model. Gene 10 32473965
2019 Superoxide generation via the NR2B-NMDAR/RasGRF1/NOX2 pathway promotes dendritogenesis. Journal of cellular physiology 10 31245854
2018 Heritability of myopia and its relation with GDJ2 and RASGRF1 genes in Lithuania. BMC ophthalmology 10 29793445
2018 Spatial learning and long-term memory impairments in RasGrf1 KO, Pttg1 KO, and double KO mice. Brain and behavior 10 30259712
2018 RasGRF1 mediates brain-derived neurotrophic factor-induced axonal growth in primary cultured cortical neurons. Biochemistry and biophysics reports 10 30582008
2015 Hexa (ethylene glycol) derivative of benzothiazole aniline promotes dendritic spine formation through the RasGRF1-Ras dependent pathway. Biochimica et biophysica acta 9 26675527
2014 Amplification of B cell receptor-Erk signaling by Rasgrf-1 overexpression in chronic lymphocytic leukemia. Leukemia & lymphoma 8 24597981
2001 An expressed GNRP-like gene shares a bi-directional promoter with SF3A2 (SAP62) immediately upstream of AMH. Gene 8 11602354
2020 Benzothiazole amphiphiles promote RasGRF1-associated dendritic spine formation in human stem cell-derived neurons. FEBS open bio 7 31943943
2012 No Evidence for a Parent-of-Origin Specific Differentially Methylated Region Linked to RASGRF1. Frontiers in genetics 7 22470404
2010 Paternal genome effects on aging: evidence for a role of Rasgrf1 in longevity determination? Mechanisms of ageing and development 7 21182853
2018 TrkB Regulates N-Methyl-D-Aspartate Receptor Signaling by Uncoupling and Recruiting the Brain-Specific Guanine Nucleotide Exchange Factor, RasGrf1. Journal of molecular neuroscience : MN 6 30547417
2022 Median Nerve Stimulation Attenuates Traumatic Brain Injury-Induced Comatose State by Regulating the Orexin-A/RasGRF1 Signaling Pathway. World neurosurgery 5 36064116
2016 Rasgrf1 mRNA expression in myopic eyes of guinea pigs. Clinical & experimental optometry 5 27723119
2025 ECM stiffness regulates lung fibroblast survival through RasGRF1-dependent signaling. The Journal of biological chemistry 4 39793891
2018 RASgrf1, a Potential Methylatic Mediator of Anti-epileptogenesis? Neurochemical research 4 30242550
2025 FTO-mediated the destabilization of RASGRF1 mRNA impedes thyroid cancer progression and suppresses macrophage M2 polarization. Cell biology and toxicology 3 40760370
2023 Upregulation of RasGRF1 ameliorates spatial cognitive dysfunction in mice after chronic cerebral hypoperfusion. Aging 3 37053022
2021 A Rational Design of α-Helix-Shaped Peptides Employing the Hydrogen-Bond Surrogate Approach: A Modulation Strategy for Ras-RasGRF1 Interaction in Neuropsychiatric Disorders. Pharmaceuticals (Basel, Switzerland) 3 34832880
2013 Expression and genomic imprinting of the porcine Rasgrf1 gene. Gene 3 24342659
2008 Identification of novel RasGRF1 interacting partners by large-scale proteomic analysis. Journal of molecular neuroscience : MN 3 18607774
2025 LINC02418 suppresses endometrial cancer progression via regulating miR-494-3p/RASGRF1 axis. Journal of molecular histology 2 39841298
2023 Correlation between High Myopia Susceptibility and Polymorphisms of RASGRF1 Gene among College Students in Zhejiang. Journal of environmental and public health 2 36864897
2023 Retracted: Correlation between High Myopia Susceptibility and Polymorphisms of RASGRF1 Gene among College Students in Zhejiang. Journal of environmental and public health 0 38125881

Missed literature

Know a paper Affinage missed for RASGRF1? Flag it for the maintainers and the community.

No submissions yet.