Affinage

RASGRP1

RAS guanyl-releasing protein 1 · UniProt O95267

Length
797 aa
Mass
90.4 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RASGRP1 is a diacylglycerol (DAG)- and calcium-regulated guanine nucleotide exchange factor (GEF) for Ras family GTPases that couples receptor-generated lipid second messengers to Ras-ERK/MAPK signaling, with essential roles in lymphocyte development, immune effector function, and neuronal signaling. Membrane recruitment is governed by cooperative engagement of its C1 domain with DAG, a plasma membrane-targeting (PT) domain that senses PI3K-generated phosphoinositides, and EF-hand–mediated conformational changes; autoinhibition involves an interdomain linker occluding the Ras-binding site and a dimerization interface masking the membrane-interaction surface, both relieved by Ca²⁺ and membrane localization (PMID:9582122, PMID:23908768, PMID:21285350, PMID:17567957). In T and B cells, RASGRP1 is the dominant Ras GEF downstream of antigen receptor–activated PLCγ, and it primes SOS-mediated positive feedback amplification of Ras-GTP; loss of RASGRP1 blocks thymocyte positive selection, impairs NK cell cytotoxicity, abolishes mast cell degranulation, and causes human immunodeficiency (PMID:11017103, PMID:17283063, PMID:27776107, PMID:17190838). Beyond classical Ras, RASGRP1 acts as a GEF for Rheb to activate mTOR signaling in striatal neurons, where it is a causal mediator of L-DOPA–induced dyskinesia (PMID:32426479).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Identification of RASGRP1 as a DAG-responsive Ras GEF resolved how lipid second messengers directly activate Ras independently of receptor tyrosine kinase–SOS pathways, establishing a new signaling paradigm.

    Evidence cDNA characterization, domain deletion mutagenesis, cellular fractionation, Ras-ERK assays, and fibroblast transformation assays

    PMID:9582122 PMID:9819387

    Open questions at the time
    • Endogenous substrates beyond H-Ras not yet defined
    • Regulation by calcium through EF hands not yet mechanistically resolved
  2. 2000 High

    Genetic knockout and antibody-inhibition studies established that RASGRP1 is the essential Ras GEF linking TCR/PLCγ1–generated DAG to Ras-ERK activation in thymocytes, explaining the long-standing gap between TCR engagement and Ras activation.

    Evidence RasGRP1-null mice with thymocyte phenotyping; inhibitory antibodies and PLCγ1 inhibitors in Jurkat T cells; high-affinity C1 domain binding measured by radioligand assay

    PMID:10779365 PMID:10807788 PMID:11017103

    Open questions at the time
    • Whether RASGRP1 and SOS cooperate or compete in physiological TCR signaling unknown
    • Compartment-specific Ras activation not yet explored
  3. 2003 High

    Discovery that RASGRP1 activates Ras specifically at the Golgi apparatus (and not plasma membrane) after TCR stimulation revealed that Ras signaling is compartmentalized, with Ca²⁺ positively regulating Golgi-Ras and negatively regulating plasma membrane-Ras.

    Evidence Live-cell imaging of RASGRP1 translocation, compartment-specific Ras activation assays, Ca²⁺ manipulation in Jurkat T cells; systematic GEF comparison across compartments

    PMID:12782630 PMID:12845332

    Open questions at the time
    • How DAG and Ca²⁺ signals are spatially segregated between Golgi and plasma membrane not fully resolved
    • Functional consequences of Golgi-specific vs. plasma membrane Ras signaling on downstream gene expression unclear
  4. 2004 High

    RASGRP1 was shown to promote BCR-induced apoptosis in immature B cells through NF-κB/Bcl-xL downregulation independently of ERK, revealing a pro-apoptotic function relevant to B cell tolerance.

    Evidence Overexpression and dominant-negative mutant of RasGRP1, NF-κB reporter assays, Bcl-xL immunoblot, apoptosis assays in WEHI-231 B cells

    PMID:14970203

    Open questions at the time
    • The Ras-independent mechanism by which RASGRP1 suppresses NF-κB not identified
    • Physiological relevance to in vivo B cell selection not tested
  5. 2005 High

    Phosphorylation of Thr184 by novel PKCs was identified as a key regulatory input, and DAG-PKC-RASGRP1 was placed as a pathway parallel to SOS, resolving how two distinct GEF arms cooperate downstream of TCR.

    Evidence RasGRP1-deficient Jurkat clone, RNAi, domain mutagenesis, phosphorylation mapping, ERK activation assays

    PMID:15899849

    Open questions at the time
    • Structural basis for PKC-mediated Thr184 phosphorylation effect unknown
    • Whether Thr184 phosphorylation is required in vivo not tested
  6. 2007 High

    The discovery that RASGRP1-generated Ras-GTP primes the allosteric site of SOS established a positive-feedback amplification loop, explaining why RASGRP1 dominates over SOS in lymphocyte Ras activation and providing a mechanistic basis for digital/analog Ras signaling responses.

    Evidence SOS allosteric mutants, RasGTP measurement, RasV12C40 rescue in T and B cell lines

    PMID:17283063

    Open questions at the time
    • Quantitative parameters of the feedback loop (thresholds, kinetics) not measured in primary cells
    • Whether this loop operates identically in B versus T cells unknown
  7. 2007 High

    Systematic domain dissection in B cells identified the PT domain as essential for plasma membrane targeting and the SuPT domain as an intramolecular brake, establishing that RASGRP1 membrane recruitment requires cooperative relief of autoinhibition by DAG and the PT/EF-hand modules.

    Evidence Domain deletion/mutation analysis, live-cell imaging of RASGRP1 translocation after BCR ligation in B cell lines; Vav1 KO epistasis defining upstream pathway

    PMID:14764585 PMID:17567957

    Open questions at the time
    • Structural basis of SuPT-mediated inhibition not resolved at atomic level
    • Whether SuPT regulation differs between T and B cells not tested
  8. 2007 High

    Beyond immune cells, RASGRP1 was found to mediate phorbol ester– and PTH-induced suppression of the renal sodium-chloride cotransporter NCC via H-Ras-ERK signaling, expanding RASGRP1 function to epithelial ion transport regulation.

    Evidence RasGRP1 siRNA, thiazide-sensitive ²²Na⁺ uptake, H-Ras and ERK assays, PKC inhibitor controls in mDCT cells

    PMID:18077438 PMID:20392800 PMID:22005268

    Open questions at the time
    • Whether RASGRP1 regulation of NCC is physiologically relevant in vivo not demonstrated
    • Mechanism connecting ERK activation to NCC ubiquitination not fully defined
  9. 2011 High

    PI3K-generated phosphoinositides were identified as direct ligands of the RASGRP1 PT domain, establishing a novel PI3K-RAS signaling cross-talk mechanism that cooperates with DAG sensing for membrane targeting.

    Evidence Phospholipid vesicle binding assay, PI3K inhibition, point mutagenesis of basic/hydrophobic cluster, subcellular localization in B cells

    PMID:21285350

    Open questions at the time
    • Which specific phosphoinositide species are preferred in vivo not determined
    • Whether PI3K-PT interaction is regulated by Ca²⁺ or phosphorylation unknown
  10. 2011 High

    A Ca²⁺-driven, PKCδ-dependent pathway through RASGRP1 was shown to activate proapoptotic ERK signaling during B cell development, distinguishing Ca²⁺-triggered from DAG-triggered RASGRP1 activation modes and linking RASGRP1 to B cell negative selection.

    Evidence PKCδ knockout mice, STIM1 overexpression, Ca²⁺ flux manipulation, ERK assays in developing B cells

    PMID:21441934

    Open questions at the time
    • How Ca²⁺ and PKCδ mechanistically converge on RASGRP1 at the molecular level unclear
    • Whether this pathway operates in human B cell development not tested
  11. 2013 High

    The crystal structure of autoinhibited RASGRP1 revealed the atomic mechanism of autoinhibition: an interdomain linker blocks the Ras-binding site and dimerization buries the membrane-interaction surface; Ca²⁺ binding induces conformational changes incompatible with this inactive assembly, providing a structural framework for activation.

    Evidence X-ray crystallography, NMR spectroscopy, functional domain mutagenesis

    PMID:23908768

    Open questions at the time
    • Structure of the fully active, membrane-bound RASGRP1-Ras complex not determined
    • How DAG binding cooperates structurally with Ca²⁺-induced conformational change not visualized
  12. 2015 High

    In intestinal epithelial cells, RASGRP1 was found to oppose SOS1-driven proliferative Ras-ERK signaling, functioning as a negative feedback regulator downstream of EGFR — a role opposite to its activating function in lymphocytes — with genetic depletion exacerbating tumorigenesis in KRas and Apc mutant mice.

    Evidence RasGRP1 knockout mice crossed with KRas and Apc mutant mice, Ras-ERK signaling and proliferation assays in intestinal crypts

    PMID:26005835

    Open questions at the time
    • Molecular basis for how RASGRP1 generates negative feedback (competition with SOS, substrate selectivity?) not defined
    • Whether this tumor-suppressive role extends to other epithelia unknown
  13. 2016 High

    Human RASGRP1 deficiency was identified as a cause of combined immunodeficiency, with impaired T cell, B cell, and NK cell function including defective ERK phosphorylation and granule convergence; DYNLL1 was identified as a physical interactor linking RASGRP1 to cytoskeletal dynamics and RhoA activation.

    Evidence Homozygosity mapping, exome sequencing, wild-type rescue, interaction proteomics, RhoA activation and NK cytotoxicity assays

    PMID:27776107

    Open questions at the time
    • Full spectrum of clinical phenotype across patients not established
    • Mechanism by which RASGRP1-DYNLL1 interaction regulates granule convergence not resolved
  14. 2017 High

    His212 was identified as a pH sensor controlling the balance between autoinhibited and active conformations, providing a structural mechanism for environmental pH regulation of RASGRP1 signaling.

    Evidence SNP variant analysis, crystal structure comparison with active RasGRP4:H-Ras complex, plasma membrane recruitment and signaling assays with His212 mutants

    PMID:28952923

    Open questions at the time
    • Physiological contexts where pH fluctuations regulate RASGRP1 not identified
    • Whether pH sensing cooperates with Ca²⁺ and DAG inputs not tested
  15. 2019 High

    RUNX1/CBFB was established as a direct transcriptional regulator of RASGRP1 through an intronic enhancer harboring autoimmunity-associated SNPs, connecting genetic risk for SLE to RASGRP1 expression levels in T cells.

    Evidence CRISPR-Cas9 enhancer disruption, EMSA, ChIP-qPCR, mass spectrometry identifying hnRNP-K, luciferase reporters in Jurkat and primary T cells; mouse models with graded Rasgrp1 expression

    PMID:31164884 PMID:33065764

    Open questions at the time
    • Whether additional transcription factors beyond RUNX1 and hnRNP-K regulate this enhancer unknown
    • Causal link from SNP to SLE pathogenesis through RASGRP1 dosage not demonstrated in patients
  16. 2020 High

    RASGRP1 was shown to function as a GEF for Rheb (in addition to Ras), activating mTOR signaling in striatal neurons and causally driving L-DOPA–induced dyskinesia, extending RASGRP1 substrate range beyond classical Ras GTPases.

    Evidence RasGRP1 knockout mice and macaque PD models, L-DOPA dyskinesia scoring, ERK and mTOR signaling assays, mass spectrometry

    PMID:32426479

    Open questions at the time
    • Biochemical GEF activity toward Rheb not reconstituted in vitro with purified proteins
    • Whether Rheb is a physiological substrate in immune cells not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of active membrane-bound RASGRP1 in complex with Ras, the quantitative integration of DAG/Ca²⁺/PI3K/pH inputs into a unified activation model, the molecular basis for context-dependent tumor-suppressive versus oncogenic roles, and whether Rheb GEF activity is a general or tissue-specific function.
  • No structure of full-length active RASGRP1 on membranes
  • Quantitative signaling model integrating all regulatory inputs absent
  • Rheb GEF activity not biochemically reconstituted in vitro

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0008289 lipid binding 3
Localization
GO:0005886 plasma membrane 4 GO:0005794 Golgi apparatus 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-168256 Immune System 5 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 2
Partners
DYNLL1HSP90RHESSKAP55SOS1ZAP70

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RasGRP1 was characterized as a guanine nucleotide exchange factor (GEF) for Ras with a catalytic domain, an atypical pair of EF hands that bind calcium, and a diacylglycerol (DAG)-binding C1 domain. DAG/phorbol ester binding recruits RasGRP1 to the membrane fraction, and deletion of the DAG-binding domain abolished sustained Ras-ERK signaling and membrane partitioning. cDNA characterization, domain deletion mutagenesis, cellular fractionation, Ras-ERK signaling assays, fibroblast transformation assay Science High 9582122
1998 The C1 domain of RasGRP1 (or membrane-localizing prenylation signal replacing it) is required for transforming activity and MAP kinase activation; a point mutation in the catalytic domain preventing Ras interaction abolishes transformation; the C1 domain mediates translocation to cell membranes in response to phorbol ester or serum stimulation. Point mutagenesis, domain deletion, NIH 3T3 transformation assay, MAP kinase activation assay, membrane translocation imaging Molecular and cellular biology High 9819387
2000 RasGRP1 links T cell receptor (TCR) signaling to Ras activation downstream of PLCγ1 and DAG. Antibodies against RasGRP1 inhibited Ras-guanyl nucleotide exchange activity in membranes from TCR-stimulated Jurkat cells; a PLCγ1 inhibitor reduced Ras activation; overexpression of RasGRP1 enhanced TCR-Ras-ERK signaling and IL-2 secretion. Inhibitory antibody experiments, PLCγ1 inhibitor treatment, overexpression in T cells, Ras activation assays, IL-2 secretion assay Blood High 10807788
2000 RasGRP1 is essential for thymocyte differentiation: RasGRP1-null mice have normal immature thymocyte numbers but a marked deficiency of mature single-positive thymocytes, and mutant thymocytes completely lack Ras signaling and proliferation in response to DAG analogs or TCR stimulation. RasGRP1 knockout mouse model, thymocyte phenotyping (flow cytometry), Ras signaling and proliferation assays Nature immunology High 11017103
2000 RasGRP1's C1 domain binds phorbol esters and DAG with high affinity (Kd ~0.58 nM for [3H]PDBu), similar to PKC; calcium does not affect phorbol ester binding; acidic phospholipid requirements differ from PKC. Radioligand binding assay ([3H]PDBu), competition binding with phorbol ester analogs and bryostatin 1 Molecular pharmacology High 10779365
2003 In response to Src-dependent activation of PLCγ1, RasGRP1 translocates to the Golgi apparatus where it activates Ras. Ca2+ positively regulates Ras on the Golgi through RasGRP1 while negatively regulating Ras on the plasma membrane via CAPRI. Ras activation after TCR stimulation in Jurkat cells (rich in RasGRP1) is limited to the Golgi. Live-cell imaging of RasGRP1 translocation, Ras activation assays at specific compartments, Src inhibition, Ca2+ manipulation, Jurkat T cell TCR stimulation Nature High 12845332
2003 Members of the RasGRP family (including RasGRP1) are the only Ras activators that localize to the Golgi and can induce GTP loading of Ras at the Golgi; Ras activation at the plasma membrane can be achieved by most Ras activators but Golgi-specific Ras activation requires RasGRPs. Subcellular distribution assays, compartment-specific Ras activation assays in cells expressing various GEFs The Journal of biological chemistry High 12782630
2002 DGKα (diacylglycerol kinase alpha) acts as a negative modulator of RasGRP1 signaling by metabolizing DAG; expression of catalytically inactive DGKα leads to sustained DAG accumulation, sustained RasGRP1 membrane translocation, and sustained MAPK activation downstream of TCR. Expression of kinase-dead DGKα, DAG measurement, RasGRP1 membrane translocation assay, MAPK activation assay in T cells FASEB journal High 11919165
2004 The C1 domains of RasGRP1 and PKCθ show specific localization within T cells and distinct responses to pharmacological stimulation and TCR triggering, reflecting their binding to different DAG pools at distinct subcellular locations (plasma membrane vs. internal membranes); overexpression of C1 domains can attenuate DAG-dependent Ras activation signals from specific compartments. Live-cell imaging of GFP-tagged C1 domains in Jurkat T cells, pharmacological stimulation, TCR triggering, Ras activation assays Molecular biology of the cell High 15064353
2005 RasGRP1 is required for optimal antigen receptor-triggered Ras-ERK activation in T cells via its DAG-binding domain; phosphorylation of threonine 184 in RasGRP1 (driven by novel PKC kinases) correlates with ERK activation; active PKCθ requires RasGRP1 sufficiency to trigger downstream events, defining a DAG-PKC-RasGRP1-Ras-ERK pathway distinct from SOS-mediated activation. RasGRP1-deficient Jurkat T-cell clone, RNAi knockdown, domain mutagenesis (DAG-binding domain), phosphorylation analysis, ERK activation assays, genetic epistasis Molecular and cellular biology High 15899849
2007 RasGRP1 orchestrates Ras signaling in lymphocytes in two ways: (i) by directly activating Ras, and (ii) by facilitating priming of SOS with Ras-GTP that binds SOS's allosteric pocket, creating a positive RasGTP-SOS feedback loop that functions as a rheostat. Without RasGRP1, initiation of this SOS feedback loop is impaired, explaining RasGRP1 dominance over SOS. T- and B-cell line genetic manipulation, SOS allosteric mutants, RasGTP measurement, active Ras-like molecule (RasV12C40) rescue experiment Molecular and cellular biology High 17283063
2007 Vav1 transduces TCR signals to Ras-ERK by controlling membrane recruitment of RasGRP1 (via PLCγ1 activation) and recruitment of Sos1/2 to LAT; Vav1 is required for TCR-induced LAT phosphorylation, which is a key upstream event for PLCγ1 activation and subsequent RasGRP1 membrane recruitment. Genetic KO of Vav1, epistasis analysis, membrane recruitment assays, LAT phosphorylation analysis in double-positive thymocytes The Journal of biological chemistry High 14764585
2007 RasGRP1 regulation by B cell antigen receptor (BCR) requires cooperativity between three domains: the C1 domain (binds DAG from BCR-coupled PLCγ2), the Plasma membrane Targeter (PT) domain (sufficient and essential for plasma membrane targeting), and the Suppressor of PT (SuPT) domain (attenuates PT activity, preventing constitutive plasma membrane localization). DAG binding by C1 counteracts SuPT, enabling translocation. Domain deletion and mutation analysis, BCR ligation, live-cell imaging of RasGRP1 translocation, subcellular fractionation in B cell lines Molecular biology of the cell High 17567957
2009 The EF1 hand of RasGRP1 is required for receptor-induced translocation to the plasma membrane in B cell lines by counteracting the SuPT domain; EF1-mediated translocation does not involve antigen receptor-induced Ca2+ flux but is regulated by alternative splicing. The Ras-binding site in the catalytic GEF domain is required for both PT-mediated plasma membrane targeting and C1-mediated endomembrane localization, suggesting positive feedback between the GEF domain and membrane-binding domains. EF1 mutagenesis, alternative splicing analysis, Ca2+ chelation, subcellular localization assays in B cell lines, GEF domain mutagenesis Biochimica et biophysica acta High 19168098
2011 Phosphoinositide 3-kinase (PI3K) signaling generates phosphoinositides that are directly detected by a basic/hydrophobic cluster within the plasma membrane-targeting domain of RasGRP1, providing a novel mechanism for plasma membrane targeting that cooperates with DAG detection by the C1 domain; this couples PI3K and RAS signaling. Phospholipid vesicle binding assay, PI3K inhibition, BCR ligation, point mutagenesis of basic/hydrophobic cluster, subcellular localization assays The Journal of biological chemistry High 21285350
2011 A Ca2+-driven, PKCδ- and RasGRP1-dependent pathway activates ERK in a proapoptotic manner during B cell development; this pathway is biochemically distinct from DAG-driven ERK activation and depends on STIM1 concentration controlling Ca2+ entry magnitude. PKCδ knockout mice, genetic epistasis, Ca2+ flux manipulation, STIM1 overexpression, ERK activation assays in B cells Nature immunology High 21441934
2013 Crystal structure of an autoinhibited fragment of RasGRP1 revealed that the Ras-binding site is blocked by an interdomain linker and the membrane-interaction surface is hidden within a dimerization interface stabilized by the C-terminal oligomerization domain. NMR data showed Ca2+ binding to the regulatory module generates conformational changes incompatible with the inactive assembly, establishing a structural basis for activation by Ca2+ and membrane-localization signals. X-ray crystallography, NMR spectroscopy, functional domain mutagenesis eLife High 23908768
2016 Human RASGRP1 deficiency causes immunodeficiency with impaired ERK phosphorylation in T and B cells (rescued by wild-type RASGRP1 expression), defective proliferation, activation and motility; NK cell cytotoxicity was impaired due to defective granule convergence and actin accumulation. Interaction proteomics identified dynein light chain DYNLL1 as a RASGRP1-interacting protein linking it to cytoskeletal dynamics; RASGRP1-deficient cells showed decreased RhoA GTPase activation. Homozygosity mapping, exome sequencing, RASGRP1 rescue by wild-type expression, interaction proteomics, RhoA activation assay, NK cell cytotoxicity assay, live-cell imaging Nature immunology High 27776107
2017 His 212 in RasGRP1 acts as a pH sensor that alters signaling activity and plasma membrane recruitment by modulating the balance between inactive and active conformations; structural comparison of autoinhibited RasGRP1 with active RasGRP4:H-Ras and RasGRP2:Rap1b complexes revealed that the transition from inactive to active involves rearrangement of an inter-domain linker at His 212, which displaces inhibitory inter-domain interactions. SNP variant analysis, RasGRP1 crystal structure comparison, plasma membrane recruitment assays, signaling activity assays with His212 mutants eLife High 28952923
2007 SKAP55 co-immunoprecipitates with RasGRP1 via its C-terminus in a tyrosine phosphorylation-enhanced manner; SKAP55 modulates TCR signaling to Ras-ERK-AP1 by binding RasGRP1, and loss of this binding abolishes SKAP55-mediated inhibition of ERK and ELK activation. Co-immunoprecipitation, RNAi knockdown, overexpression, reporter gene assays in primary human T cells and Jurkat cells Molecular immunology Medium 17658605
2011 SDF-1 (CXCL12) stimulation induces formation of a molecular signaling complex containing RasGRP1, Gαi2, and ZAP-70, causing RasGRP1 to localize to the plasma membrane (activating K-Ras) and Golgi (activating N-Ras); SDF-1-dependent RasGRP1 localization does not require its DAG-binding domain (unlike antigen receptor stimulation) but requires TCR expression, Gi proteins, and ZAP-70. RasGRP1 knockdown (RNAi), co-immunoprecipitation, subcellular localization assays, compartment-specific Ras activation assays, Gi inhibition (pertussis toxin), ZAP-70 inhibition in human T cells Journal of immunology High 21856938
2007 RasGRP1 stimulation by phorbol ester (TPA) regulates the sodium-chloride cotransporter (NCC) surface expression through a PKC-independent, RasGRP1-ERK pathway: gene silencing of RasGRP1 prevented PE-mediated suppression of NCC activity, H-Ras activation, and ERK1/2 activation. RasGRP1 gene silencing (siRNA), thiazide-sensitive 22Na+ uptake assay, biotinylation assay, PKC inhibitors, MAPK inhibitors, H-Ras activation assay in mDCT cells Proceedings of the National Academy of Sciences High 18077438
2010 RasGRP1 stimulation enhances ubiquitination and dynamin-dependent endocytosis of NCC; MEK1/2 inhibitors and RasGRP1 gene silencing blocked NCC ubiquitination, and inhibition of ubiquitination prevented PE-mediated decrease in NCC surface expression and activity. Biotinylation/internalization assays, dominant-negative dynamin construct, NCC immunoprecipitation/ubiquitin immunoblotting, RasGRP1 siRNA, radiotracer uptake assay American journal of physiology. Renal physiology High 20392800
2010 The transcription factor Gfi1 promotes RasGRP1 expression and RasGRP1 is required for G-CSF-induced Ras/MEK/ERK signaling and neutrophil differentiation; Gfi1-null myeloid cells have reduced RasGRP1 protein and are selectively defective at G-CSF-induced ERK1/2 activation; expression of RasGRP1 in Gfi1-deficient cells rescues ERK activation and neutrophil maturation. Gfi1 knockout mice, RasGRP1 mRNA/protein quantification, Gfi1 transduction in myeloid cells, G-CSF stimulation assays, RasGRP1 re-expression rescue experiment Blood High 20203268
2006 RasGRP1 plays an essential role in FcεRI-mediated PI3K activation in mast cells; RasGRP1-deficient mice failed to mount anaphylactic reactions; RasGRP1-/- mast cells had reduced degranulation, cytokine production, PI3K/Akt activation, and impaired granule translocation, microtubule formation, and RhoA activation; constitutively active N-Ras rescued degranulation and Akt activation. RasGRP1 knockout mice, passive systemic anaphylaxis assay, mast cell degranulation assay, PI3K/Akt activation assays, rescue with constitutively active N-Ras, RhoA activation assay The Journal of experimental medicine High 17190838
2009 In B cells, DAG analogue-stimulated RasGRP-Ras-Raf-MEK-ERK signaling leads to phosphorylation of proapoptotic BH3-only protein Bim by ERK; in vitro, Bim is phosphorylated by ERK on sites associated with increased apoptotic activity. Apoptosis in Toledo B-NHL cells can be suppressed by Bim downregulation or Bcl-2 overexpression. Biochemical signaling assays, in vitro ERK kinase assay with Bim substrate, Bim siRNA, Bcl-2 overexpression, Bak-Bax complex assay, mitochondrial membrane permeability assay Experimental hematology High 19100522
2012 The unique C-terminal tail domain (~200 residues) of RasGRP1 is required for its membrane trafficking in response to TCR stimulation; tail-deleted RasGRP1 cannot traffic to the cell membrane following stimulation and cannot activate ERK; knock-in mice lacking the tail domain show aberrant thymic selection and CD4+ T cell expansion with autoantibody production. Knock-in mouse with tail domain deletion, thymocyte phenotyping, ERK activation assays, membrane localization assays after TCR stimulation PloS one High 22719950
2016 HDAC inhibitors cause acetylation of HSP90, releasing and degrading the HSP90 client proteins RASGRP1 and CRAF, leading to downregulation of MAPK pathway signaling and upregulation of pro-apoptotic BIM; RASGRP1 siRNA mimics HDAC inhibitor pro-apoptotic effects; RASGRP1 is identified as a novel HSP90 client protein. HSP90 co-immunoprecipitation, RASGRP1 siRNA, constitutively active MEK1 overexpression, BIM siRNA, in vitro and in vivo lymphoma cell assays Leukemia High 27890930
2015 RasGRP1 and SOS1 lie downstream of EGFR but act in functional opposition in intestinal epithelial cells; RasGRP1 creates a negative feedback loop limiting proliferative EGFR-SOS1-Ras signals; genetic Rasgrp1 depletion in mice with KRas activating mutation or Apc mutation exacerbates Ras-ERK signaling and cell proliferation. RasGRP1 knockout mice, KRas and Apc mutant mouse crosses, Ras-ERK signaling assays, cell proliferation assays in intestinal crypts Nature cell biology High 26005835
2015 Overexpression of RasGRP1 in T-ALL results in constitutively high GTP-loading rate of Ras (increased flux through RasGTP/GDP cycle) rather than static RasGTP accumulation as in KRAS(G12D); IL-2/7/9 stimulation activates Erk and Akt downstream of Ras in RasGRP1-overexpressing T-ALL relying on baseline DAG levels (not acute PLCγ activation), and IL-2/7/9 likely decrease RasGAP activity. Three distinct Ras GTP/GDP cycle assays, PLCγ inhibition, IL-2/7/9 stimulation assays, comparison with KRAS(G12D) T-ALL cells Oncogene High 26549032
2016 RasGRP1 promotes amphetamine-induced motor behavior through interaction with Rhes in the striatum; RasGRP1 stabilizes Rhes and increases its synaptic accumulation; depletion of RasGRP1 attenuates the enhanced locomotor response to amphetamine in partially Rhes-deficient mice; RasGRP1 affects the composition of the amphetamine-induced Rhes interactome. RasGRP1/Rhes knockout mouse crosses, locomotor behavior assay, proteomic analysis of striatal lysates (Rhesactome), synaptic fractionation Science signaling High 27902448
2020 RasGRP1 is a causal factor in L-DOPA-induced dyskinesia (LID); L-DOPA rapidly up-regulates RasGRP1 in striatum of mouse and macaque PD models; RasGRP1 knockout dramatically diminishes LID without interfering with L-DOPA therapeutic effects; RasGRP1 acts as a GEF for Rheb (activator of mTOR) in addition to Ras, promoting L-DOPA-induced ERK and mTOR signaling in striatum. RasGRP1 knockout mice, macaque PD model, L-DOPA-induced dyskinesia scoring, ERK and mTOR signaling assays, high-resolution tandem mass spectrometry for downstream targets Science advances High 32426479
2018 SRSF1 directly binds exon 11 of RASGRP1 mRNA (via oligonucleotide-protein pulldown assay) and controls its alternative splicing; silencing SRSF1 in human T cells increases alternatively spliced (exon 11-skipping) RasGRP1 isoforms and decreases RasGRP1 protein; SRSF1 overexpression in SLE T cells recovers RasGRP1 expression, which in turn induces DNMT1/IL-2 expression. Oligonucleotide-protein pulldown assay, SRSF1 siRNA, SRSF1 overexpression, qPCR and Western blot for RasGRP1 isoforms in human T cells Arthritis & rheumatology High 29905030
2012 In LAT-Y136F mutant mice where PLCγ1 binding to LAT is lost, RasGRP1 (not Sos1 or Sos2) is the major Ras GEF responsible for ERK activation and the lymphoproliferative phenotype, operating through a PLCγ1-independent pathway requiring Lck/Fyn, PKCθ, and RasGRP1 downstream of a Zap70-independent LAT pathway. Genetic analysis in LAT-Y136F mice, crosses with RasGRP1 KO, Sos1/Sos2 KO mice; kinase inhibitor experiments; ERK activation assays Journal of immunology High 23209318
2019 The transcription factor RUNX1 (with CBFB) directly regulates RASGRP1 transcription through an intronic enhancer; CRISPR-Cas9 disruption of this enhancer reduces RasGRP1 expression and RUNX1/CBFB binding; hnRNP-K binds to the SLE risk allele of rs11631591 in this enhancer in an allele-dependent manner and modulates RASGRP1 expression in T cells. CRISPR-Cas9 enhancer disruption, EMSA, mass spectrometry, ChIP-qPCR, luciferase reporter assays, hnRNP-K inhibition in Jurkat and primary T cells Frontiers in immunology High 31164884
2020 RUNX1 transcriptionally regulates RASGRP1; diminished Rasgrp1 expression causes defective T lymphocyte selection and inflammatory disease whose severity inversely correlates with Rasgrp1 levels; H3K27 acetylation profiling identified a RASGRP1 enhancer harboring autoimmunity-associated SNPs with RUNX1/CBFB binding. Mouse models with graded Rasgrp1 expression, H3K27 acetylation ChIP, RUNX1 expression analysis in patient T cells, CRISPR disruption European journal of immunology High 33065764
2004 RasGRP1 elevates apoptosis of immature B cells (WEHI-231) upon BCR ligation through down-regulation of NF-κB and Bcl-xL in a manner independent of ERK1/2; a dominant negative RasGRP1 mutant suppresses BCR-induced apoptosis. RasGRP1 overexpression, dominant negative RasGRP1 mutant, BCR ligation, NF-κB reporter, Bcl-xL immunoblot, apoptosis assay, NF-κB inhibition The Journal of biological chemistry High 14970203
2011 PTH suppresses NCC function via a PLC/RasGRP1/ERK pathway: PLC inhibition prevented PTH effect; gene silencing of RasGRP1 prevented PTH-mediated NCC activity suppression, H-Ras activation, and ERK1/2 activation; PKC and PKA inhibitors had no effect, establishing a PKC-independent pathway. RasGRP1 gene silencing, PTH stimulation, PLC inhibitor, PKC/PKA inhibitors, MAPK inhibitor, 22Na+ uptake assay, H-Ras and ERK activation assays Translational research High 22005268

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. Science (New York, N.Y.) 565 9582122
2003 Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature 355 12845332
2000 RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nature immunology 349 11017103
2000 RasGRP links T-cell receptor signaling to Ras. Blood 287 10807788
1998 Regulation of RasGRP via a phorbol ester-responsive C1 domain. Molecular and cellular biology 195 9819387
2005 A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells. Molecular and cellular biology 163 15899849
2012 A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. Diabetes 152 22961080
2007 Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes. Molecular and cellular biology 145 17283063
2002 RasGRP1 transduces low-grade TCR signals which are critical for T cell development, homeostasis, and differentiation. Immunity 129 12433368
2004 Diacylglycerol-dependent binding recruits PKCtheta and RasGRP1 C1 domains to specific subcellular localizations in living T lymphocytes. Molecular biology of the cell 117 15064353
2005 RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling. Journal of immunology (Baltimore, Md. : 1950) 111 16301621
2003 Exchange factors of the RasGRP family mediate Ras activation in the Golgi. The Journal of biological chemistry 110 12782630
2016 RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nature immunology 109 27776107
2000 The guanine nucleotide exchange factor RasGRP is a high -affinity target for diacylglycerol and phorbol esters. Molecular pharmacology 102 10779365
2011 STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nature immunology 101 21441934
2011 Regulation and Function of the RasGRP Family of Ras Activators in Blood Cells. Genes & cancer 94 21779502
2004 Vav1 transduces T cell receptor signals to the activation of the Ras/ERK pathway via LAT, Sos, and RasGRP1. The Journal of biological chemistry 80 14764585
2002 Expression of a catalytically inactive form of diacylglycerol kinase alpha induces sustained signaling through RasGRP. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 65 11919165
2013 Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1. eLife 64 23908768
2018 Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility. EMBO molecular medicine 63 29282224
2015 RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth. Nature cell biology 62 26005835
2006 An essential role for RasGRP1 in mast cell function and IgE-mediated allergic response. The Journal of experimental medicine 55 17190838
2003 Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1. Immunity 51 12932358
2009 Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy. Proceedings of the National Academy of Sciences of the United States of America 49 19171906
2005 A novel diacylglycerol-lactone shows marked selectivity in vitro among C1 domains of protein kinase C (PKC) isoforms alpha and delta as well as selectivity for RasGRP compared with PKCalpha. The Journal of biological chemistry 48 15923197
2017 RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease. The Journal of allergy and clinical immunology 46 29155103
2017 Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1. Clinical immunology (Orlando, Fla.) 45 28822832
2013 Dysregulated RasGRP1 responds to cytokine receptor input in T cell leukemogenesis. Science signaling 45 23532335
2013 RasGRP Ras guanine nucleotide exchange factors in cancer. Frontiers in biology 45 24744772
2013 Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios⁺ T cells and autoantibodies. eLife 43 24336796
2011 Critical roles of RasGRP1 for invariant NKT cell development. Journal of immunology (Baltimore, Md. : 1950) 43 21957144
2018 Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma. Journal of clinical immunology 42 30030704
2010 The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1. Blood 42 20203268
2010 RasGRP1 stimulation enhances ubiquitination and endocytosis of the sodium-chloride cotransporter. American journal of physiology. Renal physiology 41 20392800
2008 Preferential development of CD4 and CD8 T regulatory cells in RasGRP1-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 40 18424717
2015 RasGRP1 overexpression in T-ALL increases basal nucleotide exchange on Ras rendering the Ras/PI3K/Akt pathway responsive to protumorigenic cytokines. Oncogene 39 26549032
2009 Association of RASGRP1 with type 1 diabetes is revealed by combined follow-up of two genome-wide studies. Journal of medical genetics 39 19465406
2017 A Histidine pH sensor regulates activation of the Ras-specific guanine nucleotide exchange factor RasGRP1. eLife 38 28952923
2003 RasGRP1 represents a novel non-protein kinase C phorbol ester signaling pathway in mouse epidermal keratinocytes. The Journal of biological chemistry 38 14532295
2009 A proapoptotic signaling pathway involving RasGRP, Erk, and Bim in B cells. Experimental hematology 36 19100522
2003 Diacylglycerols containing Omega 3 and Omega 6 fatty acids bind to RasGRP and modulate MAP kinase activation. The Journal of biological chemistry 36 14583629
2007 Phorbol ester stimulation of RasGRP1 regulates the sodium-chloride cotransporter by a PKC-independent pathway. Proceedings of the National Academy of Sciences of the United States of America 35 18077438
2009 RasGRP1 is required for human NK cell function. Journal of immunology (Baltimore, Md. : 1950) 34 19933860
2007 Transgenic overexpression of RasGRP1 in mouse epidermis results in spontaneous tumors of the skin. Cancer research 34 17210708
2005 Deregulated expression of RasGRP1 initiates thymic lymphomagenesis independently of T-cell receptors. Oncogene 33 15829980
2011 A RasGRP, C. elegans RGEF-1b, couples external stimuli to behavior by activating LET-60 (Ras) in sensory neurons. Neuron 32 21482356
2020 Nurr1 performs its anti-inflammatory function by regulating RasGRP1 expression in neuro-inflammation. Scientific reports 31 32612143
2001 Iridals are a novel class of ligands for phorbol ester receptors with modest selectivity for the RasGRP receptor subfamily. Journal of medicinal chemistry 31 11689073
2016 Histone deacetylase inhibitors interrupt HSP90•RASGRP1 and HSP90•CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells. Leukemia 29 27890930
2018 Sp1-regulated transcription of RasGRP1 promotes hepatocellular carcinoma (HCC) proliferation. Liver international : official journal of the International Association for the Study of the Liver 28 29655291
2016 RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network ("Rhesactome") in the striatum. Science signaling 28 27902448
2007 Chronic immunodeficiency in mice lacking RasGRP1 results in CD4 T cell immune activation and exhaustion. Journal of immunology (Baltimore, Md. : 1950) 28 17675473
2001 Guanine nucleotide exchange factors CalDAG-GEFI and CalDAG-GEFII are colocalized in striatal projection neurons. The Journal of comparative neurology 28 11503142
2017 Thymic progenitors of TCRαβ+ CD8αα intestinal intraepithelial lymphocytes require RasGRP1 for development. The Journal of experimental medicine 27 28652304
2020 RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson's disease. Science advances 26 32426479
2011 Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis. Leukemia 26 22116551
2020 BRD2 induces drug resistance through activation of the RasGRP1/Ras/ERK signaling pathway in adult T-cell lymphoblastic lymphoma. Cancer communications (London, England) 25 32459053
2018 Decreased Expression of Serine/Arginine-Rich Splicing Factor 1 in T Cells From Patients With Active Systemic Lupus Erythematosus Accounts for Reduced Expression of RasGRP1 and DNA Methyltransferase 1. Arthritis & rheumatology (Hoboken, N.J.) 25 29905030
2003 Transgenic expression of RasGRP1 induces the maturation of double-negative thymocytes and enhances the production of CD8 single-positive thymocytes. Journal of immunology (Baltimore, Md. : 1950) 24 12538669
2012 Differential requirement of RasGRP1 for γδ T cell development and activation. Journal of immunology (Baltimore, Md. : 1950) 23 22623331
2007 SKAP55 modulates T cell antigen receptor-induced activation of the Ras-Erk-AP1 pathway by binding RasGRP1. Molecular immunology 23 17658605
2004 RasGRP1 sensitizes an immature B cell line to antigen receptor-induced apoptosis. The Journal of biological chemistry 23 14970203
2022 RasGRP1 promotes the acute inflammatory response and restricts inflammation-associated cancer cell growth. Nature communications 22 36385095
2019 RasGRP1 is a potential biomarker to stratify anti-EGFR therapy response in colorectal cancer. JCI insight 22 31237864
2012 Regulation of RasGRP1 function in T cell development and activation by its unique tail domain. PloS one 22 22719950
2004 Synthetic bryostatin analogues activate the RasGRP1 signaling pathway. Journal of medicinal chemistry 22 15588099
2007 Regulation of RasGRP1 by B cell antigen receptor requires cooperativity between three domains controlling translocation to the plasma membrane. Molecular biology of the cell 21 17567957
2007 RasGRP1 overexpression in the epidermis of transgenic mice contributes to tumor progression during multistage skin carcinogenesis. Cancer research 21 17974959
2011 Constitutive abnormal expression of RasGRP-1 isoforms and low expression of PARP-1 in patients with systemic lupus erythematosus. Lupus 20 21976405
2009 RasGRP1 regulates antigen-induced developmental programming by naive CD8 T cells. Journal of immunology (Baltimore, Md. : 1950) 20 20007535
2002 Structural basis of RasGRP binding to high-affinity PKC ligands. Journal of medicinal chemistry 20 11831896
2009 Membrane localization of RasGRP1 is controlled by an EF-hand, and by the GEF domain. Biochimica et biophysica acta 19 19168098
2009 RasGRP1 transgenic mice develop cutaneous squamous cell carcinomas in response to skin wounding: potential role of granulocyte colony-stimulating factor. The American journal of pathology 19 19497993
2016 Novel identified associations of RGS1 and RASGRP1 variants in IgA Nephropathy. Scientific reports 18 27804980
2015 Dysregulation of RasGRP1 in rheumatoid arthritis and modulation of RasGRP3 as a biomarker of TNFα inhibitors. Arthritis research & therapy 18 26714738
2014 Targeted deletion of RasGRP1 impairs skin tumorigenesis. Carcinogenesis 18 24464785
2011 Phosphoinositide 3-kinase regulates plasma membrane targeting of the Ras-specific exchange factor RasGRP1. The Journal of biological chemistry 18 21285350
2006 RasGRP1 transmits prodifferentiation TCR signaling that is crucial for CD4 T cell development. Journal of immunology (Baltimore, Md. : 1950) 18 16849453
2020 Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity. European journal of immunology 17 33065764
2019 Mechanistic Characterization of RASGRP1 Variants Identifies an hnRNP-K-Regulated Transcriptional Enhancer Contributing to SLE Susceptibility. Frontiers in immunology 17 31164884
2020 Novel tumour suppressor roles for GZMA and RASGRP1 in Theileria annulata-transformed macrophages and human B lymphoma cells. Cellular microbiology 16 32830401
2011 G alpha i2 and ZAP-70 mediate RasGRP1 membrane localization and activation of SDF-1-induced T cell functions. Journal of immunology (Baltimore, Md. : 1950) 16 21856938
2006 Differential effects of bryostatin 1 and 12-O-tetradecanoylphorbol-13-acetate on the regulation and activation of RasGRP1 in mouse epidermal keratinocytes. Molecular cancer therapeutics 16 16546974
2019 High-throughput transcriptome analysis reveals that the loss of Pten activates a novel NKX6-1/RASGRP1 regulatory module to rescue microphthalmia caused by Fgfr2-deficient lenses. Human genetics 15 31691004
2016 RasGRP1 Is an Essential Signaling Molecule for Development of B1a Cells with Autoantigen Receptors. Journal of immunology (Baltimore, Md. : 1950) 15 26851222
2014 Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP. Bioorganic & medicinal chemistry 15 24794745
2013 Multiple checkpoint breach of B cell tolerance in Rasgrp1-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 15 23997211
2012 A phospholipase C-γ1-independent, RasGRP1-ERK-dependent pathway drives lymphoproliferative disease in linker for activation of T cells-Y136F mutant mice. Journal of immunology (Baltimore, Md. : 1950) 15 23209318
2011 Parathyroid hormone (PTH) regulates the sodium chloride cotransporter via Ras guanyl releasing protein 1 (Ras-GRP1) and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway. Translational research : the journal of laboratory and clinical medicine 15 22005268
2008 Adaptor SKAP-55 binds p21 activating exchange factor RasGRP1 and negatively regulates the p21-ERK pathway in T-cells. PloS one 15 18320039
2024 Targeting macrophagic RasGRP1 with catechin hydrate ameliorates sepsis-induced multiorgan dysfunction. Phytomedicine : international journal of phytotherapy and phytopharmacology 14 38759314
2000 Distribution of ras guanyl releasing protein (RasGRP) mRNA in the adult rat central nervous system. Journal of neurocytology 14 11279364
2013 RasGRP1, but not RasGRP3, is required for efficient thymic β-selection and ERK activation downstream of CXCR4. PloS one 13 23308188
2016 RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors. Journal of immunology (Baltimore, Md. : 1950) 12 27465532
2010 RasGRP1 is essential for ras activation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate in epidermal keratinocytes. The Journal of biological chemistry 12 20308057
2019 RasGRP1 is a target for VEGF to induce angiogenesis and involved in the endothelial-protective effects of metformin under high glucose in HUVECs. IUBMB life 11 31120617
2021 Nras Q61R/+ and Kras-/- cooperate to downregulate Rasgrp1 and promote lympho-myeloid leukemia in early T-cell precursors. Blood 10 33512434
2017 Exploring the influence of indololactone structure on selectivity for binding to the C1 domains of PKCα, PKCε, and RasGRP. Bioorganic & medicinal chemistry 10 28392275
2016 Autoantibody-Mediated Pulmonary Alveolar Proteinosis in Rasgrp1-Deficient Mice. Journal of immunology (Baltimore, Md. : 1950) 9 27279372
1999 RasGRP, a Ras activator: mouse and human cDNA sequences and chromosomal positions. Mammalian genome : official journal of the International Mammalian Genome Society 9 10087292