Affinage

RAPGEF2

Rap guanine nucleotide exchange factor 2 · UniProt Q9Y4G8

Length
1499 aa
Mass
167.4 kDa
Annotated
2026-04-28
29 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAPGEF2 is a guanine nucleotide exchange factor selective for Rap1 and Rap2 that transduces diverse upstream signals—including cAMP, M-Ras-GTP, Cdk5 phosphorylation, and G13-coupled receptor activation—into Rap-dependent control of cell adhesion, migration, junction integrity, and ERK-mediated gene expression across vascular, hematopoietic, epithelial, and neuronal lineages (PMID:10608883, PMID:11524421, PMID:25189171, PMID:41949994). A neuron- and neuroendocrine-specific isoform (NCS-Rapgef2) directly binds cAMP through a cyclic nucleotide-binding domain pharmacologically distinct from PKA and Epac, coupling Gs-linked GPCRs (D1 dopamine, GLP-1, VIPR) to Rap1→B-Raf→MEK→ERK signaling that drives neuritogenesis, synaptic long-term potentiation, and cocaine-induced behavioral plasticity (PMID:23800469, PMID:28948210, PMID:38236296, PMID:33268547). RAPGEF2 protein levels are regulated by IKKβ/CK1α-triggered SCF(βTrCP)-mediated proteasomal degradation, which controls the magnitude of Rap1 signaling during cell migration and metastasis (PMID:24290981). Conditional loss of RAPGEF2 in the developing cortex causes subcortical band heterotopia and commissural agenesis through disruption of Rap1-dependent adherens junctions in radial glia and Cdk5-dependent neuronal migration (PMID:19453629, PMID:27390776, PMID:25189171).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    Establishing that PDZ-GEF1 is a Rap1/Rap2-specific GEF with an RCBD that negatively regulates activity—but, unlike Epac, does not bind cAMP—defined the protein's catalytic selectivity and raised the question of what ligand, if any, engages the RCBD.

    Evidence In vitro GEF assays, in vivo Rap activation, and cAMP/cGMP binding assays in transfected cells

    PMID:10608883

    Open questions at the time
    • Identity of physiological ligand for the RCBD remained unknown
    • In vivo relevance not tested
    • No structural information on RCBD
  2. 2001 High

    Demonstration that the RA domain binds GTP-loaded M-Ras and recruits RAPGEF2 to the plasma membrane for Rap1 activation, and that GTP-Rap1 feeds back through the RA domain for perinuclear enrichment, established dual modes of regulated membrane targeting and a positive feedback amplification mechanism.

    Evidence GST pulldowns, fluorescence colocalization, Rap1 activation assays, RA-domain deletion mutagenesis in COS-7 cells

    PMID:11359771 PMID:11524421

    Open questions at the time
    • Relative contribution of M-Ras vs. Rap1 feedback in physiological settings unclear
    • No structural basis for RA domain selectivity
  3. 2007 High

    Two studies showed RAPGEF2 operates in tissue-specific signaling complexes: in neurons it assembles with S-SCAM/ARMS at TrkA-containing late endosomes for sustained Rap1→ERK signaling and neurite outgrowth, while in hematopoietic cells it mediates TNFα-induced M-Ras→Rap1→LFA-1 integrin activation—establishing cell-type-specific upstream inputs and functional outputs.

    Evidence Co-IP, subcellular fractionation, siRNA/KO in hippocampal neurons; siRNA/KO, Rap1 pulldown, cell aggregation in hematopoietic cells

    PMID:17538012 PMID:17724123

    Open questions at the time
    • Direct interaction surfaces within the TrkA endosomal complex undefined
    • How TNFα activates M-Ras upstream of RAPGEF2 not resolved
  4. 2009 High

    Conditional knockout in dorsal telencephalon and allantois explants revealed essential non-redundant roles of RAPGEF2 in cortical neuron migration (loss causes subcortical band heterotopia) and VE-cadherin-dependent vascular morphogenesis, placing Rap1 downstream by constitutive-Rap1 rescue.

    Evidence Emx1-Cre conditional KO mice with EEG, retrograde tracing; KO allantois explants with constitutively active Rap1 rescue

    PMID:19453629 PMID:19635461

    Open questions at the time
    • Which Rap1 effectors mediate cortical migration vs. vascular plexus formation not distinguished
    • Whether RAPGEF6 partially compensates in single KO unclear
  5. 2010 High

    Deletion of RapGEF2 causing embryonic lethality with impaired yolk sac vasculature and hematopoietic progenitor loss, accompanied by reduced Rap1→B-Raf→ERK signaling and Scl/Gata expression, defined a Rap1→ERK→transcription factor axis in embryonic hematopoiesis.

    Evidence Conditional KO mice, colony-forming assays, ERK/B-Raf signaling analysis, flow cytometry

    PMID:20595512

    Open questions at the time
    • Whether RAPGEF2 acts in endothelial vs. hematopoietic lineage not fully dissected
    • Direct substrates of B-Raf/ERK controlling Scl/Gata not identified
  6. 2013 High

    Three advances resolved distinct regulatory axes: (1) cAMP directly engages RAPGEF2 (via affinity chromatography) to couple GPCRs to Rap1→ERK in neurons/neuroendocrine cells; (2) JAM-A/ZO-2/afadin complex uses RAPGEF2 to activate Rap2c for epithelial tight junction regulation; (3) IKKβ/CK1α phosphorylation triggers SCF(βTrCP)-mediated degradation of RAPGEF2 to limit Rap1 during migration.

    Evidence cAMP-agarose chromatography, siRNA, reconstitution in NS-1/HEK293T; reciprocal Co-IP, KO mice, paracellular permeability; in vitro kinase assay, MS phosphosite mapping, degradation-resistant mutants, in vivo metastasis assay

    PMID:23800469 PMID:23885123 PMID:24290981

    Open questions at the time
    • Kd of cAMP for RAPGEF2 CNBD not measured by isothermal methods
    • Relationship between IKKβ-mediated degradation and the cAMP-responsive isoform unclear
    • Whether Rap2c vs. Rap1 activation through RAPGEF2 at junctions is context-dependent
  7. 2014 High

    Cdk5 phosphorylation of RAPGEF2 was shown to be required for the multipolar-to-bipolar transition of migrating cortical neurons via Rap1→N-cadherin, providing a kinase-specific mechanism linking cell-cycle exit to migratory competence.

    Evidence Cdk5 kinase assay, in utero electroporation with live imaging, dominant-negative and knockdown experiments, N-cadherin co-IP

    PMID:25189171

    Open questions at the time
    • Specific Cdk5 phosphorylation site(s) on RAPGEF2 that activate GEF activity not fully mapped
    • Whether Cdk5 phosphorylation and IKKβ phosphorylation compete on the same or different residues unknown
  8. 2016 High

    Double knockout of Rapgef2/Rapgef6 in radial glia demonstrated that these GEFs maintain apical adherens junctions cell-autonomously via Rap1, with constitutive Rap1 fully rescuing the phenotype—resolving the functional redundancy question between the two paralogs in this context.

    Evidence Conditional double-KO mice, in utero electroporation, constitutively active Rap1 rescue, AJ marker immunofluorescence

    PMID:27390776

    Open questions at the time
    • Relative quantitative contributions of RAPGEF2 vs. RAPGEF6 to total Rap1-GTP not measured
    • How Rap1 mechanistically stabilizes apical AJs not resolved
  9. 2017 High

    Identification of the NCS-Rapgef2 isoform (driven from alternative exon 1') and mutagenesis of its CNBD established that a single residue in the cyclic nucleotide-binding pocket is required for cAMP→ERK coupling, and that this domain has a pharmacophore distinct from PKA and Epac—opening possibilities for selective pharmacological targeting.

    Evidence CNBD point mutagenesis and deletion in HEK293T cells, AAV-Cre region-specific KO in mouse striatum, selective cAMP analog screening in NS-1 cells

    PMID:28290664 PMID:28948210

    Open questions at the time
    • Crystal structure of the NCS-Rapgef2 CNBD with cAMP not available
    • In vivo selectivity of pharmacological inhibitor not tested
  10. 2020 High

    Region-specific deletion of NCS-Rapgef2 in nucleus accumbens D1-MSNs blocked cocaine-induced ERK phosphorylation, Egr-1 induction, locomotor sensitization, and conditioned place preference independently of PKA/CREB, establishing NCS-Rapgef2 as the non-redundant cAMP→ERK effector underlying drug-induced behavioral plasticity.

    Evidence AAV-Cre regional KO in adult NAc, CamK2α-Cre::Rapgef2-flox mice, pERK/Egr-1 immunostaining, locomotor sensitization and CPP behavioral assays

    PMID:33268547

    Open questions at the time
    • Whether NCS-Rapgef2 is required for other psychostimulant or opioid responses not examined
    • Downstream ERK nuclear targets beyond Egr-1 not characterized
  11. 2021 Medium

    RAPGEF2 was implicated in two additional pathological contexts: (1) its upregulation in Alzheimer's disease activates Rap2→JNK to mediate Aβ-induced synapse loss, and (2) it couples GLP-1/VIP receptors to ERK in beta cells—broadening its pathophysiological relevance beyond neurons.

    Evidence siRNA/shRNA knockdown in cultured neurons and 3xTg-AD mice, Rap2/JNK assays; shRNA knockdown in INS-1 cells, ERK phosphorylation readout

    PMID:33345400 PMID:33960038

    Open questions at the time
    • Mechanism of RAPGEF2 upregulation in AD not identified
    • Whether Rap2→JNK pathway in AD is independent of or interacts with Rap1→ERK unclear
    • Functional consequence of RAPGEF2 loss in beta-cell insulin secretion not tested
  12. 2024 High

    Conditional hippocampal KO showed that RAPGEF2 is required for cAMP-dependent LTP at both perforant pathway and Schaffer collateral synapses, and for fear conditioning-induced ERK phosphorylation and Egr1 (but not c-Fos) induction—establishing it as a synapse-specific plasticity effector controlling contextual fear memory.

    Evidence CamK2α-Cre::Rapgef2-flox conditional KO, ex vivo LTP recordings, pERK/Egr1 immunostaining after fear conditioning, behavioral testing

    PMID:38236296

    Open questions at the time
    • Whether RAPGEF2 acts pre- or post-synaptically at these synapses not resolved
    • Whether spatial memory and other hippocampus-dependent tasks are also affected not tested
  13. 2026 High

    RAPGEF2 was identified as a non-redundant Rap1-GEF downstream of G13-coupled receptors in platelets, required for integrin αIIbβ3 activation, aggregation, and shear-stress adhesion—establishing a new upstream input (Gα13) and a hemostatic function distinct from CalDAG-GEFI.

    Evidence Megakaryocyte-specific conditional KO, Rapgef2/CalDAG-GEFI double KO, RAP1 activation and integrin activation assays, in vivo thrombus assays

    PMID:41949994

    Open questions at the time
    • How G13 biochemically activates RAPGEF2 (direct interaction vs. intermediate) not resolved
    • Whether RAPGEF2 contributes to pathological thrombosis in human disease not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for cAMP binding to the NCS-Rapgef2 CNBD and how it differs from PKA/Epac; how multiple upstream phosphorylation events (Cdk5, IKKβ/CK1α) are integrated on the same protein; and whether RAPGEF2 selectively activates Rap1 vs. Rap2 in different cellular contexts or whether substrate selectivity is constitutive.
  • No crystal or cryo-EM structure of RAPGEF2 or its CNBD
  • Quantitative cAMP binding affinity not determined by biophysical methods
  • Context-dependent Rap1 vs. Rap2 selectivity mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 4 R-HSA-112316 Neuronal System 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-109582 Hemostasis 1 R-HSA-168256 Immune System 1
Partners
AFDNCDK5GNA13KIDINS220MAGI2MRASRAP1RAP2
Complex memberships
JAM-A/ZO-2/afadin junctional complexS-SCAM/ARMS/TrkA endosomal complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PDZ-GEF1 (RAPGEF2) is a guanine nucleotide exchange factor that specifically activates Rap1 and Rap2 both in vivo and in vitro. It contains a domain related to cAMP-binding domains (RCBD) that serves as a negative regulatory domain, but unlike Epac, it does not interact with cAMP or cGMP. In vitro GEF assay, in vivo Rap1 activation assay, cAMP/cGMP binding assay The Journal of biological chemistry High 10608883
2001 RA-GEF-2 (RAPGEF2) stimulates guanine nucleotide exchange of Rap1 and Rap2 but not Ha-Ras. Its RA domain binds M-Ras in a GTP-dependent manner, and it colocalizes with activated M-Ras at the plasma membrane, increasing GTP-Rap1 levels there. In vitro GEF assay, GST pulldown, colocalization by fluorescence microscopy, Rap1 pull-down (activation) assay in COS-7 cells The Journal of biological chemistry High 11524421
2001 RA-GEF-1 (RAPGEF2 paralog/ortholog) is translocated from cytoplasm to the perinuclear/Golgi compartment by binding to GTP-Rap1 via its RA domain, creating a positive feedback amplification loop. Deletion of the RA domain abolishes this translocation and reduces in vivo but not in vitro GEF activity, as well as B-Raf activation. RA domain deletion mutagenesis, in vitro GEF assay, Rap1 pull-down assay, B-Raf co-immunoprecipitation, fluorescence microscopy of subcellular localization in COS-7 cells The Journal of biological chemistry High 11359771
2007 PDZ-GEF1 (RAPGEF2) forms a tetrameric complex with synaptic scaffolding molecule and ARMS (ankyrin repeat-rich membrane spanning protein), which interacts with the TrkA neurotrophin receptor at late endosomes. This complex is activated by GTP-Rap1 via positive feedback and induces sustained Rap1 and ERK activation, leading to neurite outgrowth. Co-immunoprecipitation, subcellular fractionation/late endosome localization, dominant-negative and knockdown experiments, live imaging in hippocampal neurons, ERK/Rap1 activation assays The Journal of cell biology High 17724123
2007 RA-GEF-2 (RAPGEF2) is specifically responsible for TNF-α-triggered Rap1 activation and LFA-1 integrin activation in hematopoietic cells, operating through an M-Ras → RA-GEF-2 → Rap1 pathway at the plasma membrane. M-Ras activation recruits RA-GEF-2 to the plasma membrane. siRNA knockdown, Rap1 activation pull-down assay, LFA-1-mediated cell aggregation assay, RA-GEF-2 knockout mice, subcellular localization by fluorescence microscopy Molecular biology of the cell High 17538012
2009 RA-GEF-1 (RAPGEF2) loss-of-function in the dorsal telencephalon causes heterotopic cortical mass resembling subcortical band heterotopia, agenesis of commissures, and epilepsy susceptibility, demonstrating a crucial role in neural migration in vivo. Conditional knockout mice (Emx1-Cre × RA-GEF-1flox/flox), retrograde tracing, electroencephalography The European journal of neuroscience High 19453629
2009 RA-GEF-1 (RAPGEF2) is required for VE-cadherin accumulation at endothelial cell-cell junctions and vascular plexus formation. Constitutively active Rap1 rescues the vascular defects in RA-GEF-1 knockout allantois explants, placing Rap1 downstream of RA-GEF-1 in vascular morphogenesis. RA-GEF-1 knockout explant culture, Rap1 activation visualization (FRET probe), constitutively active Rap1 rescue experiment, VE-cadherin immunostaining Biochemical and biophysical research communications High 19635461
2010 RapGEF2 is required for embryonic hematopoiesis; its deletion causes embryonic lethality at ~E11.5 with yolk sac vascular defects and impaired CD41+ cell maintenance. At the molecular level, RapGEF2 loss impairs Rap1 activation and downstream B-Raf/ERK signaling, and reduces Scl/Gata transcription factor expression in hematopoietic progenitors. Conditional knockout mice, Rap1 activation assay, colony-forming assay, ERK/B-Raf signaling analysis, flow cytometry Blood High 20595512
2013 Rapgef2 connects GPCR-mediated cAMP elevation to ERK activation via a Rap1→B-Raf→MEK→ERK pathway in neuronal and neuroendocrine cells. Rapgef2 is enriched by cAMP-agarose affinity chromatography and specifically eluted by cAMP, indicating direct cAMP interaction. Rapgef2 knockdown blocks cAMP- and ERK-dependent neuritogenesis. cAMP-agarose affinity chromatography, loss-of-function (siRNA in NS-1 cells), gain-of-function (overexpression in HEK293T cells), ERK/Rap1 activation assays, neuritogenesis assay Science signaling High 23800469
2013 JAM-A associates directly with ZO-2 and indirectly with afadin, and this complex along with PDZ-GEF1 (RAPGEF2) activates Rap2c to regulate epithelial tight junction barrier function and apical actomyosin contraction via RhoA and myosin phosphorylation. Co-immunoprecipitation, siRNA knockdown, paracellular permeability assay, RhoA/myosin phosphorylation assay, JAM-A knockout mice Molecular biology of the cell High 23885123
2013 RAPGEF2 is phosphorylated by IKKβ and CK1α in response to motility-promoting factors, targeting it for SCF(βTrCP) ubiquitin ligase-mediated proteasomal degradation. Failure to degrade RAPGEF2 results in sustained Rap1 activity and inhibits HGF-induced cell migration and metastasis. In vitro kinase assay, mass spectrometry phosphosite identification, proteasome inhibitor experiments, degradation-resistant mutant expression, in vivo metastasis assay in breast cancer cells Developmental cell High 24290981
2014 RapGEF2 is phosphorylated by Cdk5 during neuronal radial migration, which is required for the multipolar-to-bipolar transition via a Rap1/N-cadherin pathway. Specific expression of RapGEF2 in the intermediate zone and its Cdk5-dependent activation are essential for proper cortical neuron migration. In utero electroporation, live imaging, Cdk5 kinase assay, dominant-negative/knockdown experiments, Rap1 activation assay, N-cadherin co-immunoprecipitation Nature communications High 25189171
2016 Rapgef2 (and Rapgef6) act cell-autonomously via Rap1 to maintain apical adherens junctions in radial glial cells in the developing cerebral cortex. Double knockout causes disruption of apical AJs, detachment of radial glial cells, and ectopic cortical mass; rescue by constitutively active Rap1(G12V) confirms the Rapgef2→Rap1 pathway. Conditional double-knockout mice, intrauterine Cre electroporation, constitutively active Rap1 rescue, immunofluorescence for AJ markers (E-cadherin, β-catenin) eNeuro High 27390776
2017 NCS-Rapgef2, a neuron/endocrine-specific isoform of Rapgef2 initiated from an alternative exon 1', links cAMP elevation to ERK activation. A single residue mutation in its cyclic nucleotide-binding domain (CNBD) abolishes cAMP-ERK coupling, while deletion of the CNBD causes constitutive ERK activation. NCS-Rapgef2 is required specifically for D1 dopamine receptor-dependent ERK phosphorylation in striatal MSNs and corticolimbic neurons. CNBD point mutagenesis, CNBD deletion, reconstitution in HEK293T cells, AAV-Cre region-specific KO in mouse brain, ERK phosphorylation immunostaining, D1 agonist pharmacology eNeuro High 28948210
2017 The cyclic nucleotide-binding domain (CNBD) of NCS-Rapgef2 has a distinct pharmacophore from PKA and Epac; N6-Phe-cAMP selectively activates NCS-Rapgef2 (EC50 ~256 μM) while N6-phenyl-9-tetrahydrofuranyladenine selectively inhibits it without affecting PKA, Epac, or adenylate cyclase. Cell-based pharmacological assays (ERK phosphorylation, cAMP elevation, neuritogenesis) in NS-1 neuroendocrine cells; high-content screening ACS chemical neuroscience Medium 28290664
2019 MAGI2 forms a protein complex with RapGEF2 in podocytes; this interaction is abolished by MAGI2 congenital nephrotic syndrome variants. The MAGI2-RapGEF2 complex is required for Rap1 activation and downstream signaling in podocytes; podocyte-specific RapGEF2 deletion causes spontaneous glomerulosclerosis. Co-immunoprecipitation, podocyte-specific conditional KO mice, Rap1 activation assay, pharmacological Rap1 rescue, human kidney section immunostaining Kidney international High 31171376
2020 NCS-Rapgef2 in nucleus accumbens D1 medium spiny neurons is required for cocaine-induced ERK phosphorylation and Egr-1/Zif268 upregulation, and for cocaine-induced locomotor sensitization and conditioned place preference, operating independently of PKA/CREB signaling. AAV-Cre region-specific KO in adult mouse NAc, immunofluorescence for pERK and Egr-1, behavioral assays (locomotor sensitization, CPP), CamK2α-Cre::Rapgef2fl/fl mice The Journal of neuroscience High 33268547
2020 In sensory neurons, cAMP-to-ERK signaling involves RapGEF2 (and PKA) but not Epac. OSM-induced hyperalgesic priming enhances and prolongs this RapGEF2-dependent cAMP→ERK pathway in IB4/CaMKIIα-positive neurons. High-content microscopy-based ERK/PKA activation assay in cultured sensory neurons, siRNA knockdown of RapGEF2/Epac/PKA, selective pharmacological inhibitors Journal of neurochemistry Medium 32885411
2021 RAPGEF2 upregulation in Alzheimer's disease activates downstream Rap2 and JNK. In hippocampal neurons, oligomeric Aβ increases RAPGEF2 levels and causes dendritic spine loss; silencing RAPGEF2 blocks Aβ oligomer-induced synapse loss. In vivo knockdown of RAPGEF2 in the AD hippocampus prevents cognitive deficits and loss of excitatory synapses. siRNA knockdown in cultured neurons, in vivo AAV-shRNA hippocampal knockdown in 3xTg-AD mice, dendritic spine counting, synaptic marker immunofluorescence, behavioral testing, Rap2/JNK activation assays Neuropathology and applied neurobiology Medium 33345400
2021 NCS-RapGEF2 mediates GLP-1 receptor (and VIPR1/2)-stimulated cAMP→ERK activation in neuroendocrine NS-1 cells and pancreatic INS-1 beta cells. shRNA-mediated RapGEF2 knockdown reduces exendin-4-induced ERK phosphorylation in INS-1 cells. Receptor transduction in NS-1 cells, MEK-ERK inhibitor (U0126), RapGEF2-shRNA knockdown, ERK phosphorylation assay, transcriptome analysis Journal of neuroendocrinology Medium 33960038
2024 RapGEF2 is required for cAMP-dependent ERK activation and Egr1 (but not c-Fos) induction during fear conditioning in hippocampus, and for cAMP-dependent long-term potentiation at perforant pathway and Schaffer collateral synapses. RapGEF2 deletion in hippocampus impairs contextual fear memory. CamK2α-Cre::Rapgef2fl/fl conditional KO, pERK and Egr1 immunostaining after fear conditioning, ex vivo LTP recording in hippocampal slices, behavioral fear conditioning assay Cellular and molecular life sciences High 38236296
2026 RAPGEF2 operates downstream of G13 (GNA13)-coupled receptors (including αIIbβ3 and the thromboxane receptor) in platelets to activate RAP1 and promote integrin αIIbβ3-mediated aggregation and platelet adhesion under shear stress. Megakaryocyte-specific Rapgef2 KO and combined Rapgef2/CalDAG-GEFI double KO demonstrate that RAPGEF2 acts as a non-redundant RAP-GEF in this context. Megakaryocyte-specific conditional KO mice, RAP1 activation assay, integrin activation flow cytometry, platelet aggregation assay, ex vivo and in vivo shear stress adhesion assay, double-KO epistasis Blood High 41949994

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 PDZ-GEF1, a guanine nucleotide exchange factor specific for Rap1 and Rap2. The Journal of biological chemistry 108 10608883
2013 JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function. Molecular biology of the cell 102 23885123
2007 Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late endosomes, leading to sustained activation of Rap1 and ERK and neurite outgrowth. The Journal of cell biology 97 17724123
2001 Identification and characterization of RA-GEF-2, a Rap guanine nucleotide exchange factor that serves as a downstream target of M-Ras. The Journal of biological chemistry 80 11524421
2014 Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex. Nature communications 68 25189171
2012 DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth. International journal of epidemiology 60 22422452
2013 Rapgef2 connects GPCR-mediated cAMP signals to ERK activation in neuronal and endocrine cells. Science signaling 53 23800469
2001 RA-GEF-1, a guanine nucleotide exchange factor for Rap1, is activated by translocation induced by association with Rap1*GTP and enhances Rap1-dependent B-Raf activation. The Journal of biological chemistry 52 11359771
2007 The M-Ras-RA-GEF-2-Rap1 pathway mediates tumor necrosis factor-alpha dependent regulation of integrin activation in splenocytes. Molecular biology of the cell 44 17538012
2009 Dorsal telencephalon-specific RA-GEF-1 knockout mice develop heterotopic cortical mass and commissural fiber defect. The European journal of neuroscience 36 19453629
2013 Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2. Developmental cell 32 24290981
2010 RapGEF2 is essential for embryonic hematopoiesis but dispensable for adult hematopoiesis. Blood 31 20595512
2017 NCS-Rapgef2, the Protein Product of the Neuronal Rapgef2 Gene, Is a Specific Activator of D1 Dopamine Receptor-Dependent ERK Phosphorylation in Mouse Brain. eNeuro 25 28948210
2016 Crucial Role of Rapgef2 and Rapgef6, a Family of Guanine Nucleotide Exchange Factors for Rap1 Small GTPase, in Formation of Apical Surface Adherens Junctions and Neural Progenitor Development in the Mouse Cerebral Cortex. eNeuro 25 27390776
2007 Defective vascular morphogenesis and mid-gestation embryonic death in mice lacking RA-GEF-1. Biochemical and biophysical research communications 23 17826737
2019 Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2. Kidney international 22 31171376
2020 Cocaine-Dependent Acquisition of Locomotor Sensitization and Conditioned Place Preference Requires D1 Dopaminergic Signaling through a Cyclic AMP, NCS-Rapgef2, ERK, and Egr-1/Zif268 Pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 21 33268547
2020 Oncostatin M induces hyperalgesic priming and amplifies signaling of cAMP to ERK by RapGEF2 and PKA. Journal of neurochemistry 20 32885411
2021 RAPGEF2 mediates oligomeric Aβ-induced synaptic loss and cognitive dysfunction in the 3xTg-AD mouse model of Alzheimer's disease. Neuropathology and applied neurobiology 18 33345400
2014 Critical function of RA-GEF-2/Rapgef6, a guanine nucleotide exchange factor for Rap1, in mouse spermatogenesis. Biochemical and biophysical research communications 13 24491570
2009 Impaired vascular development in the yolk sac and allantois in mice lacking RA-GEF-1. Biochemical and biophysical research communications 12 19635461
2018 A De Novo RAPGEF2 Variant Identified in a Sporadic Amyotrophic Lateral Sclerosis Patient Impairs Microtubule Stability and Axonal Mitochondria Distribution. Experimental neurobiology 11 30636905
2017 Differential Pharmacophore Definition of the cAMP Binding Sites of Neuritogenic cAMP Sensor-Rapgef2, Protein Kinase A, and Exchange Protein Activated by cAMP in Neuroendocrine Cells Using an Adenine-Based Scaffold. ACS chemical neuroscience 8 28290664
2024 The guanine nucleotide exchange factor RapGEF2 is required for ERK-dependent immediate-early gene (Egr1) activation during fear memory formation. Cellular and molecular life sciences : CMLS 7 38236296
2021 Cyclic AMP-dependent activation of ERK via GLP-1 receptor signalling requires the neuroendocrine cell-specific guanine nucleotide exchanger NCS-RapGEF2. Journal of neuroendocrinology 5 33960038
2018 Correction: Jiang et al., NCS-Rapgef2, the Protein Product of the Neuronal Rapgef2 Gene, Is a Specific Activator of D1 Dopamine Receptor-Dependent ERK Phosphorylation in Mouse Brain (eNeuro September/October 2017, 4(5) e0248-17.2017 1-17 https://doi.org/10.1523/ENEURO.0248-17.2017). eNeuro 1 30406181
2006 Biochemistry of the Rap-specific guanine nucleotide exchange factors PDZ-GEF1 and -2. Methods in enzymology 1 16757323
2026 Rare heterozygous de novo variants in RAPGEF2 are associated with a neurodevelopmental disorder. Genetics in medicine : official journal of the American College of Medical Genetics 0 41556274
2026 A Novel G13-RAPGEF2-RAP1 Signaling Pathway Critical for Platelet Adhesion. Blood 0 41949994