Affinage

RASGRP2

RAS guanyl-releasing protein 2 · UniProt Q7LDG7

Length
609 aa
Mass
69.2 kDa
Annotated
2026-04-28
61 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RASGRP2 (CalDAG-GEFI) is a calcium- and diacylglycerol-regulated guanine nucleotide exchange factor that activates Rap1 (and, in specific contexts, R-Ras and LRRK2) to drive inside-out integrin activation in platelets, neutrophils, and T cells, and to modulate neuronal signaling in striatal circuits. Calcium binding to its EF hands releases autoinhibition at the Cdc25–EF-hand linker interface, enabling catalytic exchange on Rap1B; its atypical C1 domain binds PIP2/PIP3 rather than DAG to control membrane targeting, while N-terminal acylation and F-actin association direct spatially restricted Rap1 activation (PMID:29622678, PMID:31758832, PMID:14988412, PMID:10918068). PKA-mediated phosphorylation at Ser116/Ser117 and Ser586/Ser587 inhibits CalDAG-GEFI GEF activity, providing a cAMP-dependent brake on platelet activation, and DARPP-32/PP1 regulates dephosphorylation of these sites in striatal neurons (PMID:23600630, PMID:36351540). Loss-of-function mutations in RASGRP2 cause leukocyte adhesion deficiency type III (LAD-III) by abolishing Rap1-dependent β1, β2, and β3 integrin activation in hematopoietic cells (PMID:17576779, PMID:24958846, PMID:27235135).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 High

    Establishing RasGRP2 as a plasma-membrane-targeted, acylated GEF with selectivity for Rap1 and N-/Ki-Ras, regulated by DAG and calcium, answered the basic question of substrate specificity and subcellular targeting for this exchange factor.

    Evidence Cloning, in vivo GEF assays, subcellular localization, and lipid analog treatment in NIH3T3 cells

    PMID:10918068

    Open questions at the time
    • Initial report suggested GEF activity toward N-Ras stimulated by DAG, later refined to Rap1 as physiological substrate
    • Mechanism of calcium inhibition versus activation not resolved
  2. 2001 High

    Demonstrating that CalDAG-GEFI forms a signaling complex with Rap1 and B-Raf downstream of muscarinic receptors established it as a node linking calcium/DAG signals to the MAPK cascade.

    Evidence Co-immunoprecipitation, antisense knockdown, and B-Raf activation assay in PC12D cells

    PMID:11292831

    Open questions at the time
    • Whether CalDAG-GEFI–B-Raf complex formation is direct or scaffolded
    • Relevance of this pathway outside neuroendocrine cells
  3. 2002 High

    Showing that CalDAG-GEFI enhances Rap1b activation and fibrinogen binding to αIIbβ3 in megakaryocytes first linked this GEF to inside-out integrin signaling in the platelet lineage.

    Evidence Retroviral overexpression in ES-derived megakaryocytes, Rap1 activation assay, fibrinogen binding flow cytometry

    PMID:12239348

    Open questions at the time
    • Overexpression system — endogenous requirement not yet shown
  4. 2004 High

    Genetic ablation of CalDAG-GEFI in mice proved it is essential for Rap1-dependent platelet aggregation and thrombus formation in vivo, and revealed that F-actin dynamics govern its spatial localization to membrane ruffles for regionalized Rap1 activation.

    Evidence KO mouse with platelet aggregation, in vivo thrombosis models; F-actin co-sedimentation, fluorescence microscopy, and Rac1 mutant analysis

    PMID:14988412 PMID:15334074

    Open questions at the time
    • Relative contributions of acylation versus F-actin binding to membrane targeting in primary platelets
    • Whether actin-dependent localization is required for thrombus formation
  5. 2007 High

    Extending the KO phenotype to neutrophils and identifying human LAD-III patients with RASGRP2 splice mutations established CalDAG-GEFI as the master regulator of Rap1-driven β1/β2/β3 integrin activation across hematopoietic lineages and as a disease gene for LAD-III.

    Evidence KO mouse neutrophil adhesion/migration assays, intravital microscopy; human patient genetics with Rap1 activation and integrin function assays

    PMID:17492052 PMID:17576779

    Open questions at the time
    • Whether residual integrin activation in patients/KO mice is CalDAG-GEFI-independent or represents hypomorphic alleles
    • Relative contribution of CalDAG-GEFI versus other Rap-GEFs in lymphocytes
  6. 2007 High

    Selective requirement of CalDAG-GEFI for LFA-1 but not VLA-4 activation in human T cells revealed integrin-specific control downstream of the same GEF, refining the model of inside-out signaling.

    Evidence siRNA knockdown in primary human CD3+ T cells, adhesion assays to ICAM-1 and VCAM-1

    PMID:17702895

    Open questions at the time
    • Mechanism by which CalDAG-GEFI/Rap1 discriminates between LFA-1 and VLA-4
    • Whether this selectivity operates in other leukocyte subsets
  7. 2008 High

    Dissecting the temporal hierarchy of platelet Rap1 activation revealed CalDAG-GEFI mediates the rapid, reversible first wave while PKC/P2Y12 sustains a second wave, clarifying why CalDAG-GEFI loss alone does not fully abolish aggregation.

    Evidence CalDAG-GEFI KO platelets with PKC inhibitor, P2Y12 pharmacology, aggregation and Rap1 assays

    PMID:18544684

    Open questions at the time
    • Identity of the GEF(s) mediating the PKC/P2Y12-dependent second wave
  8. 2009 High

    Identifying CalDAG-GEFI as the primary calcium sensor in platelets that triggers not only integrin activation but also ERK-dependent TxA2 generation revealed a feedforward loop amplifying platelet activation.

    Evidence KO mice with TxA2 measurement, ERK activation, granule secretion assays

    PMID:19628710

    Open questions at the time
    • Whether CalDAG-GEFI directly activates ERK or requires intermediate effectors
  9. 2011 High

    Placing CalDAG-GEFI/p38 MAPK between PLCγ2 and Rap1a downstream of E-selectin engagement explained how selectin signals trigger integrin-dependent slow rolling, extending CalDAG-GEFI function from platelet biology to neutrophil recruitment.

    Evidence Rasgrp2−/− mice, dominant-negative Tat-fusion mutants, intravital microscopy, peritonitis model

    PMID:21480213

    Open questions at the time
    • Whether p38 acts upstream or in parallel to CalDAG-GEFI in this context
  10. 2013 High

    Identification and functional validation of PKA phosphorylation sites Ser116/Ser117 and Ser586/Ser587 on CalDAG-GEFI provided the molecular mechanism for cAMP/PKA-mediated inhibition of Rap1 activation and platelet function.

    Evidence In vitro kinase assay, mass spectrometry, phosphomimetic/alanine mutants in HEK293T and platelets

    PMID:23600630 PMID:23611601

    Open questions at the time
    • Structural basis of how phosphorylation inhibits GEF activity
    • Whether other kinases phosphorylate these sites in non-platelet contexts
  11. 2014 High

    Human missense mutations in the CDC25 domain (p.G248W) abolishing Rap1 exchange and reducing Rac1-GTP confirmed RASGRP2 as a causative gene for platelet-type bleeding disorders and demonstrated that rescue of patient megakaryocytes with wild-type RASGRP2 restores function.

    Evidence Whole-exome sequencing, in vitro GEF assay, flow-based thrombosis, megakaryocyte rescue transfection

    PMID:24958846

    Open questions at the time
    • Whether Rac1 activation is direct or entirely Rap1-dependent
  12. 2014 High

    Discovery that redox-sensitive vicinal cysteines in CalDAG-GEFI are targets for thiol-modifying agents (PAO, CLL2-1) that induce oligomerization and block GEF activity identified a druggable regulatory mechanism.

    Evidence PAO pull-down, non-reducing Western blot, purified recombinant protein GEF assay, CLL2-1 inhibition studies

    PMID:24352565 PMID:25451646

    Open questions at the time
    • Identity of specific cysteine residues modified
    • Physiological relevance of redox regulation in vivo
  13. 2016 High

    Structural mutagenesis of the C1 domain revealed that four residues render it unable to bind DAG/phorbol esters, distinguishing RasGRP2 from other RasGRP family members; restoring these residues recovered DAG binding and enhanced Rap1 activation.

    Evidence [3H]phorbol dibutyrate binding, lipid co-sedimentation, cell translocation, mutagenesis

    PMID:27022025

    Open questions at the time
    • Endogenous lipid ligand of the C1 domain not yet defined at this stage
  14. 2018 High

    HDX-MS and mutagenesis revealed the autoinhibition mechanism: at low calcium, an autoinhibitory linker between EF-hand and Cdc25 domains occludes the catalytic surface; calcium-induced conformational changes release this linker to enable Rap1B exchange.

    Evidence Purified recombinant CalDAG-GEFI, HDX-MS, EF-hand and linker mutagenesis, in vitro Rap1B GEF assay

    PMID:29622678

    Open questions at the time
    • Full atomic-resolution structure not available
    • Whether membrane association further modulates autoinhibitory conformation
  15. 2019 High

    Defining PIP2/PIP3 as the exclusive lipid ligands of the CalDAG-GEFI C1 domain resolved the longstanding question of how an atypical C1 domain controls membrane localization independently of DAG.

    Evidence Lipid co-sedimentation, molecular dynamics, C1 domain mutagenesis, subcellular fractionation

    PMID:31758832

    Open questions at the time
    • How PIP2/PIP3 binding is coordinated with acylation and F-actin binding for spatial Rap1 activation
  16. 2019 Medium

    Demonstration that RasGRP2 activates R-Ras in endothelial cells to suppress Bax-dependent apoptosis via PI3K–Akt expanded GEF substrate specificity beyond Rap1 to include a pro-survival signaling axis.

    Evidence Stable overexpression in HUVECs, Rap1 knockdown, R-Ras activation assay, Akt/Bax/HK-2 fractionation

    PMID:31723205

    Open questions at the time
    • Whether R-Ras activation by CalDAG-GEFI occurs in primary cells in vivo
    • No direct in vitro GEF assay for R-Ras
  17. 2022 Medium

    Identification of DARPP-32/PP1 and PP2A as phosphatases controlling CalDAG-GEFI phosphorylation downstream of D1 receptors in striatal neurons placed CalDAG-GEFI within dopaminergic signaling cascades, complementing its known PKA regulation.

    Evidence DARPP-32 KO mice, PP1/PP2A inhibitors, phospho-site-specific antibodies, D1 agonist stimulation of striatal slices

    PMID:36351540

    Open questions at the time
    • Functional consequences of individual phospho-site dephosphorylation on neuronal Rap1 activity
    • Whether CalDAG-GEFI regulates synaptic plasticity through Rap1 in this context
  18. 2021 High

    Conditional KO of CalDAG-GEFI in striatal neurons disrupted dendritic M1 muscarinic receptor signaling, temporal integration of EPSPs, and LTP induction, establishing a neuronal function for this GEF beyond hematopoietic cells.

    Evidence Conditional KO mice, dendritic electrophysiology, pharmacology, behavioral assays

    PMID:34371144

    Open questions at the time
    • Whether Rap1 is the relevant substrate for CalDAG-GEFI in striatal dendritic signaling
    • Downstream effectors linking CalDAG-GEFI to EPSP integration
  19. 2024 Medium

    Identification of CalDAG-GEFI as a GEF for LRRK2 expanded its substrate repertoire to a Parkinson's-disease-associated kinase, with genetic evidence of modulation of LRRK2-driven neurodegeneration in fly and mouse models.

    Evidence Co-IP, in vitro GTP loading assay for LRRK2, Drosophila and mouse LRRK2 neurodegeneration models

    PMID:39576856

    Open questions at the time
    • Whether CalDAG-GEFI acts on LRRK2 GTPase domain through the same Cdc25 catalytic mechanism as for Rap1
    • Physiological calcium concentrations at which LRRK2 exchange occurs
    • Independent replication needed
  20. 2024 Medium

    Discovery that NEDD4L ubiquitinates and destabilizes RASGRP2 identified the first E3 ubiquitin ligase regulating CalDAG-GEFI protein turnover.

    Evidence Co-IP, ubiquitination assay, NEDD4L knockdown in endothelial cells

    PMID:39260747

    Open questions at the time
    • Specific lysine residues ubiquitinated on RASGRP2
    • Proteasomal versus lysosomal degradation pathway not determined
    • In vivo relevance unconfirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution crystal or cryo-EM structure of full-length CalDAG-GEFI, alone and in complex with Rap1 and LRRK2, remains unavailable; how its multiple regulatory inputs (calcium, PIP2/PIP3, acylation, F-actin, PKA phosphorylation, redox modification, ubiquitination) are integrated at the structural level is unresolved.
  • No full-length atomic structure
  • Relative contribution of each regulatory input under physiological conditions
  • Whether CalDAG-GEFI GEF activity toward LRRK2 uses the same catalytic mechanism as for Rap1

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-109582 Hemostasis 5 R-HSA-168256 Immune System 4 R-HSA-112316 Neuronal System 2
Partners
BRAFLRRK2NEDD4LRAC1RAP1ARAP1B

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 RasGRP2 is targeted to the plasma membrane by N-terminal myristoylation and palmitoylation, and selectively catalyzes nucleotide exchange on N- and Ki-Ras (but not Ha-Ras) and on Rap1 in vivo; its GEF activity toward N-Ras is stimulated by diacylglycerol and inhibited by calcium. Cloning, in vivo GEF activity assays, subcellular localization studies, lipid analog treatment in NIH3T3 cells The Journal of biological chemistry High 10918068
2002 CalDAG-GEFI functions as a Rap1 exchange factor that enhances agonist-induced activation of Rap1b and fibrinogen binding to integrin αIIbβ3 in megakaryocytes, implicating it in inside-out integrin signaling. Retroviral overexpression in ES cell-derived megakaryocytes, Rap1 activation assay, fibrinogen binding flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 12239348
2001 CalDAG-GEFI forms a signaling complex with Rap1 and B-Raf downstream of M1 muscarinic acetylcholine receptors; calcium and diacylglycerol signals stimulate the sequential activation of CalDAG-GEFI, Rap1, and B-Raf, leading to MEK/ERK1/2 activation. Co-immunoprecipitation, antisense RNA knockdown, HA-tagged B-Raf activation assay in PC12D cells The Journal of biological chemistry High 11292831
2004 CalDAG-GEFI (RasGRP2) is crucial for Rap1-dependent integrin signaling in platelets; genetic ablation in mice severely impairs integrin-dependent platelet aggregation and thrombus formation. Genetic knockout mouse, platelet aggregation assays, Rap1 activation assay, in vivo thrombosis models Nature medicine High 15334074
2004 RasGRP2 subcellular localization is regulated by actin dynamics; induction of F-actin by Vav, Vav2, Dbl, or Rac1 translocates RasGRP2 from cytosol to membrane ruffles through direct association of its N-terminal 150 amino acids with F-actin, leading to regionalized Rap1 activation. Fluorescence microscopy, cytoskeletal disrupting drugs, Rac1 effector mutants, F-actin co-sedimentation biochemical assay The Journal of biological chemistry High 14988412
2007 CalDAG-GEFI controls activation of β1, β2, and β3 integrins in hematopoietic cells (neutrophils and platelets) via Rap1; CalDAG-GEFI-deficient neutrophils show defects in Rap1 activation, integrin-mediated adhesion and migration, recapitulating LAD-III syndrome. CalDAG-GEFI knockout mice, neutrophil adhesion and migration assays, Rap1 activation pull-down, intravital microscopy The Journal of clinical investigation High 17492052
2007 A splice junction mutation in the CalDAG-GEFI gene in human LAD-III patients reduces CalDAG-GEFI mRNA and protein in lymphocytes, neutrophils, and platelets, abrogating Rap1 activation and β1, β2, and β3 integrin activation (inside-out signaling). Human patient genetics, protein expression analysis, Rap1 activation assay, integrin activation flow cytometry, cell adhesion assays The Journal of experimental medicine High 17576779
2007 CalDAG-GEFI/Rap1 signaling selectively mediates SDF-1α- and PMA-induced LFA-1 activation (adhesion to ICAM-1) but not VLA-4 activation in primary human T cells; silencing CalDAG-GEFI blocks Rap1 activation and LFA-1-dependent adhesion without affecting VLA-4/VCAM-1 binding. siRNA knockdown of CalDAG-GEFI in human primary CD3+ T cells, Rap1 activation assay, cell adhesion assays to ICAM-1 and VCAM-1 Blood High 17702895
2008 CalDAG-GEFI and protein kinase C represent independent, synergizing pathways for Rap1 and αIIbβ3 activation in platelets; CalDAG-GEFI mediates rapid but reversible Rap1 activation, while PKC/Gαi/P2Y12 signaling mediates a second, sustained wave of Rap1 activation. CalDAG-GEFI knockout platelets, PKC inhibitor, Rap1 activation assay, aggregation assays, P2Y12 receptor pharmacology Blood High 18544684
2009 CalDAG-GEFI is the primary calcium sensor in platelets; through Rap1, it directly triggers integrin activation and ERK-dependent thromboxane A2 (TxA2) release; CalDAG-GEFI-dependent TxA2 generation provides feedback for PKC activation and granule release. CalDAG-GEFI knockout mice, Rap1 activation assay, TxA2 measurement, ERK activation assay, platelet aggregation and granule secretion assays Blood High 19628710
2011 CalDAG-GEFI (Rasgrp2) and p38 MAPK are key signaling intermediates between PLCγ2 and Rap1a activation downstream of E-selectin engagement; this pathway mediates integrin αLβ2-dependent slow leukocyte rolling and neutrophil recruitment into inflamed tissues. Rasgrp2-/- mice, dominant-negative Tat-fusion mutants, intravital microscopy, flow chamber, peritonitis model, biochemical Rap1 activation assay European journal of immunology High 21480213
2013 PKA phosphorylates CalDAG-GEFI at S587 (major site) and S116/S117 (minor sites); phosphorylation at these sites inhibits CalDAG-GEFI-mediated Rap1b activation and platelet aggregation, representing a mechanism for cAMP/PKA-mediated platelet inhibition. Radioactive phosphate incorporation assay, mass spectrometry, phospho-antibody development, phosphomutant expression in HEK293 cells and platelets, Rap1-GTP pull-down assay Journal of thrombosis and haemostasis : JTH High 23600630 23611601
2013 PKA phosphorylates CalDAG-GEFI at Ser116 and Ser586; a phospho-mimetic S587D mutant abolishes agonist-induced Rap1b activation, and a double Ser116/Ser586 alanine mutant abolishes cAMP-mediated inhibition of Rap1b, demonstrating these are the functional PKA phosphorylation sites. In vitro phosphorylation of purified recombinant CalDAG-GEFI by PKA catalytic subunit, serine-to-alanine and phosphomimetic mutants expressed in HEK293T cells and platelets, Rap1b activation assay, forskolin treatment The Biochemical journal High 23600630
2014 A missense mutation (cG742T) in RASGRP2 reduces CalDAG-GEFI-mediated Rap1 activation and αIIbβ3 inside-out signaling in human platelets and megakaryocytes; rescue experiments with wild-type RASGRP2 in cultured patient megakaryocytes correct the functional deficiency; reduced Rac1-GTP loading impairs thrombus formation and spreading. Whole-exome sequencing, HEK293T expression of mutant, Rap1 activation assay, flow cytometry for αIIbβ3 activation, flow-based thrombosis assay, Rac1-GTP assay, megakaryocyte rescue transfection The Journal of experimental medicine High 24958846
2013 Phenylarsine oxide (PAO) binds directly to vicinal dithiol (cysteine) residues in CalDAG-GEFI, inducing disulfide-linked oligomers and inhibiting CalDAG-GEFI-stimulated GTP loading of Rap1, thereby blocking platelet aggregation; this identifies redox-sensitive cysteines as functionally important in CalDAG-GEFI. Biotin-streptavidin pull-down of PAO-CalDAG-GEFI complex, Western blot under reducing/non-reducing conditions, purified recombinant protein GTP-binding assay, HEK293T overexpression system Thrombosis and haemostasis High 24352565
2016 The C1 domain of RasGRP2 has very weak phorbol ester/DAG binding affinity (Kd ~2890 nM) due to four residues (Asn7, Ser8, Ala19, Ile21); replacing these with the corresponding RasGRP1/3 residues restores potent phorbol ester binding and membrane translocation, and enhanced C1 domain membrane targeting increases Rap1 activation. Structural mutagenesis, [3H]phorbol 12,13-dibutyrate binding assays, lipid co-sedimentation, cell translocation assay, Rap1 activation assay, molecular modeling The Journal of biological chemistry High 27022025
2016 RASGRP2 mutations in the CDC25 catalytic domain (p.Ser381Phe, p.Arg113X) abolish nucleotide exchange activity of CalDAG-GEFI toward Rap1, causing impaired αIIbβ3 integrin activation in both platelets and neutrophils. Next-generation sequencing, in vitro GEF nucleotide exchange assay, flow cytometry for integrin activation, platelet aggregation Blood High 27235135
2018 CalDAG-GEFI is autoinhibited at low cytosolic calcium; calcium binding to canonical EF hands causes conformational rearrangements in an autoinhibitory linker connecting the Cdc25 and EF hand domains, freeing the catalytic surface to engage and activate Rap1B. An additional mutation (V406E) disrupting the autoinhibitory linker-Cdc25 interface restores GEF activity to EF hand variants. Purified recombinant CalDAG-GEFI, hydrogen-deuterium exchange mass spectrometry, EF hand calcium-binding residue mutagenesis, in vitro Rap1B GEF assay The Journal of biological chemistry High 29622678
2018 RasGRP2/Rap1 pathway mediates CD38-induced CLL cell migration; CD38 elevates intracellular Ca2+ to activate Rap1 via RasGRP2, and RasGRP2 is polarized in CLL cells with high CD38 expression; both Rap1 and RasGRP2 knockdown block CLL cell migration. siRNA knockdown of RasGRP2 and Rap1, Rap1 activation assay, cell migration assays, intracellular Ca2+ measurement, immunofluorescence localization Blood advances Medium 29970392
2019 The atypical C1 domain of CalDAG-GEFI interacts exclusively with phosphoinositides PIP2 and PIP3 (not DAG/phorbol esters) through a distinct phospholipid recognition motif; mutation of this motif abolishes lipid co-sedimentation and impairs membrane localization of CalDAG-GEFI in cells. Lipid co-sedimentation assays, molecular dynamics simulations, immunofluorescence, subcellular fractionation, C1 domain mutagenesis Journal of thrombosis and haemostasis : JTH High 31758832
2019 RasGRP2 activates R-Ras in addition to Rap1 in endothelial cells, and suppresses Bax activation-induced apoptosis via R-Ras–PI3K–Akt signaling, promoting hexokinase-2 translocation to mitochondria and blocking Bax mitochondrial translocation. RasGRP2 stable overexpression in HUVECs, Rap1 knockdown, R-Ras activation assay, Akt phosphorylation assay, Bax/HK-2 subcellular fractionation, flow cytometry for apoptosis Scientific reports Medium 31723205
2018 RASGRP2 is ectopically expressed in RA fibroblast-like synoviocytes (FLS), where it activates RAP-1 and subsequently promotes NF-κB signaling and actin dynamics, increasing FLS adhesion, migration, and IL-6 production; intra-articular RASGRP2 siRNA dampens experimental arthritis in rats. RASGRP2 transfection of FLS, RAP-1 activation assay, NF-κB reporter, migration/invasion assays, IL-6 ELISA, siRNA-mediated knockdown in rat collagen-induced arthritis model Annals of the rheumatic diseases Medium 30076153
2021 Genetic deletion of CalDAG-GEFI in mice disrupts dendritic M1 muscarinic receptor signaling in indirect pathway striatal spiny projection neurons, reduces temporal integration of EPSPs at dendritic glutamatergic synapses, and impairs activity-dependent LTP induction. Conditional CalDAG-GEFI knockout mice, electrophysiology (dendritic vs. somatic recordings), pharmacology, behavioral assays (psychostimulant-induced repetitive behaviors, sequence learning, cocaine self-administration) Neurobiology of disease High 34371144
2022 DARPP-32/PP1 regulates the PKA-dependent phosphorylation of Rasgrp2 at Ser116/Ser117 and Ser586 in striatal neurons downstream of D1 receptor activation; PP2A regulates all phosphorylation sites of Rasgrp2 including Ser554. DARPP-32 knockout mice, PP1 inhibitor (tautomycetin), PP1/PP2A inhibitor (okadaic acid), phospho-site specific antibodies, D1 receptor agonist stimulation of striatal slices Neurochemistry international Medium 36351540
2024 CalDAG-GEFI acts as a physiological GEF for LRRK2, interacting with LRRK2 and increasing its GDP-to-GTP exchange activity; CalDAG-GEFI modulates LRRK2-induced neurodegeneration in Drosophila and mouse LRRK2 models. Co-immunoprecipitation of CDGI and LRRK2, in vitro GTP loading/exchange assay for LRRK2, Drosophila genetic model of LRRK2 neurodegeneration, mouse model experiments Science advances Medium 39576856
2023 RASGRP2 suppresses LUAD cell proliferation and induces mitochondrial-dependent apoptosis; cytological experiments showed that RASGRP2 regulates mitochondrial membrane potential. Clone formation assay, EdU proliferation assay, flow cytometry for apoptosis, fluorescence microscopy of mitochondrial membrane potential in LUAD cell lines Frontiers in immunology Low 36817422
2014 CLL2-1, a 1,4-phenanthrenequinone, inhibits CalDAG-GEFI function through thiol modification of redox-sensitive cysteines, inducing CalDAG-GEFI oligomerization and blocking Rap1 activation and platelet aggregation; in a purified recombinant protein system, CLL2-1 directly inhibited CalDAG-GEFI-stimulated GTP binding to Rap1. Western blot under reducing/non-reducing conditions, purified recombinant protein GTP-binding assay, HEK293T overexpression, flow cytometry, platelet aggregation assay Free radical biology & medicine Medium 25451646
2010 CalDAG-GEFI is colocalized with axons and axon terminals of striatal projection neurons in the substantia nigra, as shown by subcellular fractionation of the substantia nigra with monoclonal antibodies against CalDAG-GEFI. In situ hybridization, subcellular fractionation, monoclonal antibody immunostaining The Journal of comparative neurology Low 11503142
2024 NEDD4L interacts with RASGRP2 and ubiquitinates it, destabilizing RASGRP2 protein and reducing its expression in endothelial cells; NEDD4L knockdown reduces HG+oxLDL-induced endothelial dysfunction, an effect reversed by RASGRP2 downregulation. Co-IP assay, ubiquitination assay, NEDD4L knockdown, RASGRP2 overexpression/knockdown, cell viability/apoptosis/migration/angiogenesis assays, Western blot Biochimica et biophysica acta. Molecular cell research Medium 39260747

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nature medicine 307 15334074
2007 Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. The Journal of clinical investigation 153 17492052
2002 Megakaryocytes derived from embryonic stem cells implicate CalDAG-GEFI in integrin signaling. Proceedings of the National Academy of Sciences of the United States of America 150 12239348
2009 CalDAG-GEFI is at the nexus of calcium-dependent platelet activation. Blood 121 19628710
2007 A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. The Journal of experimental medicine 116 17576779
2000 Characterization of RasGRP2, a plasma membrane-targeted, dual specificity Ras/Rap exchange factor. The Journal of biological chemistry 110 10918068
2008 CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin alphaIIbbeta3 in platelets. Blood 107 18544684
2007 Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin mediated human T-cell adhesion. Blood 100 17702895
2014 Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding. The Journal of experimental medicine 99 24958846
2011 Rap1a activation by CalDAG-GEFI and p38 MAPK is involved in E-selectin-dependent slow leukocyte rolling. European journal of immunology 79 21480213
2016 Novel mutations in RASGRP2, which encodes CalDAG-GEFI, abrogate Rap1 activation, causing platelet dysfunction. Blood 65 27235135
2001 A CalDAG-GEFI/Rap1/B-Raf cassette couples M(1) muscarinic acetylcholine receptors to the activation of ERK1/2. The Journal of biological chemistry 62 11292831
2011 CalDAG-GEFI deficiency protects mice in a novel model of Fcγ RIIA-mediated thrombosis and thrombocytopenia. Blood 53 21652673
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
2004 F-actin-dependent translocation of the Rap1 GDP/GTP exchange factor RasGRP2. The Journal of biological chemistry 44 14988412
2011 Relative contributions of stromal interaction molecule 1 and CalDAG-GEFI to calcium-dependent platelet activation and thrombosis. Journal of thrombosis and haemostasis : JTH 40 21848641
2010 CalDAG-GEFI and platelet activation. Platelets 40 20218908
2019 The inhibition of Bax activation-induced apoptosis by RasGRP2 via R-Ras-PI3K-Akt signaling pathway in the endothelial cells. Scientific reports 39 31723205
2013 Phosphorylation of CalDAG-GEFI by protein kinase A prevents Rap1b activation. Journal of thrombosis and haemostasis : JTH 36 23611601
2017 Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding. Blood 33 28637664
2018 Calcium-RasGRP2-Rap1 signaling mediates CD38-induced migration of chronic lymphocytic leukemia cells. Blood advances 30 29970392
2010 CalDAG-GEFI down-regulation in the striatum as a neuroprotective change in Huntington's disease. Human molecular genetics 29 20147317
2013 Phosphorylation of the guanine-nucleotide-exchange factor CalDAG-GEFI by protein kinase A regulates Ca(2+)-dependent activation of platelet Rap1b GTPase. The Biochemical journal 28 23600630
2001 Guanine nucleotide exchange factors CalDAG-GEFI and CalDAG-GEFII are colocalized in striatal projection neurons. The Journal of comparative neurology 28 11503142
2017 Identification of two novel mutations in RASGRP2 affecting platelet CalDAG-GEFI expression and function in patients with bleeding diathesis. Platelets 25 28762304
2023 RASGRP2 is a potential immune-related biomarker and regulates mitochondrial-dependent apoptosis in lung adenocarcinoma. Frontiers in immunology 21 36817422
2016 CalDAG-GEFI Deficiency Reduces Atherosclerotic Lesion Development in Mice. Arteriosclerosis, thrombosis, and vascular biology 20 26988592
2018 Ectopic RASGRP2 (CalDAG-GEFI) expression in rheumatoid synovium contributes to the development of destructive arthritis. Annals of the rheumatic diseases 19 30076153
2007 Calcium diacylglycerol guanine nucleotide exchange factor I (CalDAG-GEFI) gene mutations in a thrombopathic Simmental calf. Veterinary pathology 19 18039909
2014 CalDAG-GEFI deficiency protects mice from FcγRIIa-mediated thrombotic thrombocytopenia induced by CD40L and β2GPI immune complexes. Journal of thrombosis and haemostasis : JTH 18 25287077
2019 RASGRP2 Suppresses Apoptosis via Inhibition of ROS Production in Vascular Endothelial Cells. TheScientificWorldJournal 17 30692874
2019 RASGRP2 gene variations associated with platelet dysfunction and bleeding. Platelets 17 30849270
2017 Marked bleeding diathesis in patients with platelet dysfunction due to a novel mutation in RASGRP2, encoding CalDAG-GEFI (p.Gly305Asp). Platelets 17 28726538
2017 Phenotype analysis and clinical management in a large family with a novel truncating mutation in RASGRP2, the CalDAG-GEFI encoding gene. Research and practice in thrombosis and haemostasis 17 30046681
2016 Structural Basis for the Failure of the C1 Domain of Ras Guanine Nucleotide Releasing Protein 2 (RasGRP2) to Bind Phorbol Ester with High Affinity. The Journal of biological chemistry 17 27022025
2016 Mice Expressing Low Levels of CalDAG-GEFI Exhibit Markedly Impaired Platelet Activation With Minor Impact on Hemostasis. Arteriosclerosis, thrombosis, and vascular biology 16 27417588
2021 CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors. Neurobiology of disease 15 34371144
2018 Calcium-induced structural rearrangements release autoinhibition in the Rap-GEF CalDAG-GEFI. The Journal of biological chemistry 15 29622678
2021 The Role of RASGRP2 in Vascular Endothelial Cells-A Mini Review. International journal of molecular sciences 14 34681791
2021 RasGRP2 inhibits glyceraldehyde-derived toxic advanced glycation end-products from inducing permeability in vascular endothelial cells. Scientific reports 13 33536515
2010 Identification of the gene regulatory region in human rasgrp2 gene in vascular endothelial cells. Biological & pharmaceutical bulletin 10 20606303
2019 Subcellular localization of Rap1 GTPase activator CalDAG-GEFI is orchestrated by interaction of its atypical C1 domain with membrane phosphoinositides. Journal of thrombosis and haemostasis : JTH 8 31758832
2019 Novel variants in FERMT3 and RASGRP2-Genetic linkage in Glanzmann-like bleeding disorders. Pediatric blood & cancer 7 31724816
2014 CLL2-1, a chemical derivative of orchid 1,4-phenanthrenequinones, inhibits human platelet aggregation through thiol modification of calcium-diacylglycerol guanine nucleotide exchange factor-I (CalDAG-GEFI). Free radical biology & medicine 7 25451646
2021 Mutations in RASGRP2 gene identified in patients misdiagnosed as Glanzmann thrombasthenia patients. Blood cells, molecules & diseases 6 33711653
2021 [Expression of RASGRP2 in Lung Adenocarcinoma and Its Effect 
on Immune Microenvironment]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 5 34157800
2021 CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2. International journal of molecular sciences 4 34830306
2020 Severe Bleeding Diathesis in Siblings with Platelet Dysfunction due to a Novel Nonsense RASGRP2 Mutation. TH open : companion journal to thrombosis and haemostasis 4 33376940
2024 NEDD4L-mediated RASGRP2 suppresses high-glucose and oxLDL-induced vascular endothelial cell dysfunctions by activating Rap1 and R-Ras. Biochimica et biophysica acta. Molecular cell research 3 39260747
2023 RasGRP2 Attenuates Oxygen Deprivation-Induced Autophagy in Vascular Endothelial Cells. Biological & pharmaceutical bulletin 3 37914354
2019 A novel missense variant in the RASGRP2 gene in patients with moderate to severe bleeding disorder. Platelets 3 32609603
2017 The Guanine-Nucleotide Exchange Factor Caldag Gefi Fine-Tunes Functional Properties of Regulatory T Cells. European journal of microbiology & immunology 3 28690878
2013 Identification of CalDAG-GEFI as an intracellular target for the vicinal dithiol binding agent phenylarsine oxide in human platelets. Thrombosis and haemostasis 3 24352565
2025 RasGRP2 Attenuates TAGE Modification of eNOS in Vascular Endothelial Cells. Biological & pharmaceutical bulletin 2 40101981
2023 The CalDAG-GEFI/Rap1/αIIbβ3 axis minimally contributes to accelerated platelet clearance in mice with constitutive store-operated calcium entry. Platelets 2 36683325
2022 DARPP-32/protein phosphatase 1 regulates Rasgrp2 as a novel component of dopamine D1 receptor signaling in striatum. Neurochemistry international 2 36351540
2025 Identification of novel RASGRP2 mutations in patients with platelet dysfunction. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis 1 40651280
2024 CalDAG-GEFI acts as a guanine nucleotide exchange factor for LRRK2 to regulate LRRK2 function and neurodegeneration. Science advances 1 39576856
2013 Rasgrp2 regulates the permissiveness of NIH3T3 cells to a herpes simplex virus 1 mutant with inactivated ICP34.5 gene. Acta virologica 1 23530823
2024 A splice mutation in RASGRP2 gene in the patient with recurrent epistaxis and nasal vascular malformation. Platelets 0 39512176
2023 [Study on the Role of RASGRP2 in Vascular Endothelial Cells]. Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 0 37914339