Affinage

RAPGEF2

Rap guanine nucleotide exchange factor 2 · UniProt Q9Y4G8

Length
1499 aa
Mass
167.4 kDa
Annotated
2026-06-10
29 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAPGEF2 (PDZ-GEF1/RA-GEF-2/NCS-Rapgef2) is a guanine nucleotide exchange factor that directly catalyzes nucleotide exchange on the small GTPases Rap1 and Rap2 — but not Ras — converting diverse upstream signals into Rap-dependent control of cell adhesion, junction integrity, migration, and ERK-driven gene expression (PMID:10608883, PMID:11524421). Its catalytic output is tuned by intramolecular and recruitment-based regulation: a cyclic nucleotide-binding domain that, unlike Epac, couples cAMP to activation rather than acting as a classical cAMP sensor, while a Ras-association (RA) domain binds GTP-Rap1 to drive a positive-feedback loop and binds GTP-loaded M-Ras to recruit the enzyme to membranes and amplify Rap1 activation at the plasma membrane and perinuclear/Golgi compartment (PMID:11359771, PMID:11524421, PMID:28948210). A neuronal/endocrine-enriched isoform, NCS-Rapgef2, arises from an alternative first exon and links GPCR-driven cAMP elevation to a Rap1→B-Raf→MEK→ERK cascade in neurons and endocrine cells, where mutation of a conserved CNBD residue uncouples cAMP from ERK while CNBD deletion renders the enzyme constitutively active (PMID:23800469, PMID:28948210). Through this Rap1-ERK axis NCS-Rapgef2 mediates cAMP-dependent neuritogenesis, fear-memory-associated Egr1 induction and hippocampal LTP, and cocaine-induced behavioral sensitization downstream of D1 receptors (PMID:23800469, PMID:38236296, PMID:33268547). RAPGEF2 is also assembled into membrane and junctional scaffolds — an S-SCAM/ARMS complex with the TrkA receptor at late endosomes that sustains NGF-induced Rap1/ERK signaling and neurite outgrowth, a JAM-A/ZO-2/afadin complex regulating epithelial tight-junction barrier function via Rap2, and a MAGI2 complex in podocytes maintaining glomerular integrity (PMID:17724123, PMID:23885123, PMID:31171376). Genetic studies establish broad in vivo roles in yolk-sac vascular morphogenesis and embryonic hematopoiesis, cortical neuronal migration and adherens-junction maintenance in radial glia, podocyte integrity, and G13-coupled integrin activation in platelets, all converging on Rap1 as confirmed by constitutively active Rap1 rescue (PMID:17826737, PMID:20595512, PMID:19453629, PMID:27390776, PMID:31171376, PMID:41949994). RAPGEF2 stability is controlled by IKKβ/CK1α phosphorylation triggering SCF-βTrCP-mediated proteasomal degradation, which limits Rap1 activity to permit cell migration (PMID:24290981).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Established RAPGEF2's core catalytic identity — that it is a GEF selective for Rap1 and Rap2 carrying a cAMP-binding-like domain that, unlike Epac, does not bind cyclic nucleotides.

    Evidence In vitro and in vivo GEF assays with domain deletion mutagenesis and cAMP/cGMP binding tests

    PMID:10608883

    Open questions at the time
    • How the cAMP-binding-like domain regulates activity if it does not bind cAMP was unresolved
    • No upstream activating signal identified at this stage
  2. 2001 High

    Defined the RA domain as a dual regulatory module — binding GTP-M-Ras to recruit RAPGEF2 to the plasma membrane and binding GTP-Rap1 to create a positive-feedback amplification loop at perinuclear/Golgi membranes.

    Evidence GST pulldown binding-specificity panels, RA-domain deletion, Rap1/B-Raf activation assays and co-localization in COS-7 cells

    PMID:11359771 PMID:11524421

    Open questions at the time
    • Physiological receptors triggering M-Ras activation not defined
    • In vivo significance of the feedback loop not yet tested
  3. 2007 High

    Connected RAPGEF2 to receptor signaling and immune adhesion by placing it in a TrkA/S-SCAM/ARMS late-endosomal complex for NGF-induced neurite outgrowth and in an M-Ras→Rap1 pathway for TNF-α-induced LFA-1 activation.

    Evidence Reciprocal Co-IP, endosomal fractionation and live imaging with neurite readout; siRNA and knockout-mouse splenocyte aggregation assays

    PMID:17538012 PMID:17724123

    Open questions at the time
    • Stoichiometry and assembly order of the tetrameric TrkA complex not resolved
    • Whether the same recruitment logic applies across cell types not addressed
  4. 2007 Medium

    Demonstrated an essential developmental requirement by showing RAPGEF2 knockout causes mid-gestation lethality with failed yolk-sac vascular plexus formation.

    Evidence Conventional knockout mice with embryo morphology and histology

    PMID:17826737

    Open questions at the time
    • Molecular effector linking RAPGEF2 loss to vascular failure not yet defined
    • Single-lab observation
  5. 2009 High

    Placed RAPGEF2 mechanistically upstream of Rap1 in vascular morphogenesis, showing it is needed for VE-cadherin junctional accumulation and that constitutively active Rap1 rescues the defect.

    Evidence Allantois explant culture, Rap1 activation probe, VE-cadherin staining and CA-Rap1 rescue

    PMID:19635461

    Open questions at the time
    • Receptor input driving RAPGEF2 in endothelium not identified
    • How Rap1 controls VE-cadherin localization not detailed
  6. 2009 High

    Revealed a CNS requirement, showing dorsal-telencephalon RAPGEF2 deletion causes cortical migration defects (band heterotopia), commissural agenesis, and lowered seizure threshold.

    Evidence Emx1-Cre conditional knockout with histology, retrograde tracing and EEG seizure measurement

    PMID:19453629

    Open questions at the time
    • Cellular mechanism of the migration defect not resolved at this stage
    • Downstream Rap1 effectors in neurons not yet defined
  7. 2010 High

    Defined RAPGEF2's role in embryonic hematopoiesis, linking its loss to impaired Rap1/B-Raf/ERK signaling and reduced Scl/Gata transcription factor expression, while showing adult hematopoiesis is independent.

    Evidence Conditional knockout mice, flow cytometry, colony assays, Rap1-GTP pulldown, ERK/B-Raf Western and RT-PCR

    PMID:20595512

    Open questions at the time
    • Direct link between ERK signaling and Scl/Gata transcription not mechanistically dissected
    • Why the requirement is embryo-restricted is unexplained
  8. 2013 High

    Established the long-sought cAMP-to-ERK function — that Rapgef2 couples GPCR cAMP elevation to Rap1→B-Raf→MEK→ERK and is directly enriched by cAMP affinity, plus defined its roles in tight-junction barrier function (via Rap2/JAM-A/ZO-2/afadin) and as a degradation target of IKKβ/CK1α/SCF-βTrCP controlling migration.

    Evidence cAMP-agarose affinity chromatography with loss/gain-of-function ERK readouts; reciprocal Co-IP with permeability assays; phospho-mutant rescue with metastasis assay

    PMID:23800469 PMID:23885123 PMID:24290981

    Open questions at the time
    • Whether cAMP binds RAPGEF2 directly or via a partner was not structurally resolved
    • Phospho-degron site geometry on RAPGEF2 not mapped
  9. 2014 High

    Identified Cdk5 as an upstream activating kinase, showing its phosphorylation of RapGEF2 is required for Rap1-driven N-cadherin upregulation in the cortical multipolar-to-bipolar transition.

    Evidence In utero electroporation, live imaging, Cdk5 kinase assay, Rap1 pulldown and N-cadherin staining

    PMID:25189171

    Open questions at the time
    • Cdk5 phosphosite(s) on RapGEF2 not mapped
    • Mechanism linking Rap1 to N-cadherin transcription/trafficking not defined
  10. 2016 High

    Showed RapGEF2 (with Rapgef6) maintains apical adherens junctions in radial glia cell-autonomously through Rap1, confirmed by CA-Rap1 rescue of the double-knockout phenotype.

    Evidence Conditional double knockout, Cre electroporation, CA-Rap1 rescue and adherens-junction marker immunostaining

    PMID:27390776

    Open questions at the time
    • Functional redundancy boundaries between RAPGEF2 and RAPGEF6 not delineated
    • Effector connecting Rap1 to AJ stability not identified
  11. 2017 High

    Resolved the structural basis of cAMP coupling, defining the NCS-Rapgef2 CNBD as required for cAMP-dependent ERK activation and identifying the tissue-restricted exon-1' isoform plus a distinct cAMP pharmacophore with selective agonists/inhibitors.

    Evidence CNBD point and deletion mutagenesis with reconstitution and conditional KO; cell-based pharmacological selectivity profiling of adenine derivatives

    PMID:28290664 PMID:28948210

    Open questions at the time
    • Direct in vitro cAMP binding to the CNBD not biochemically confirmed
    • Structural mechanism of how CNBD occupancy relieves autoinhibition not solved
  12. 2019 High

    Tied RAPGEF2 to podocyte biology and disease, showing it forms a Rap1-activating complex with MAGI2 disrupted by congenital nephrotic syndrome variants, with podocyte-specific deletion causing glomerulosclerosis.

    Evidence Co-IP, Rap1-GTP pulldown, podocyte conditional KO, siRNA in human podocytes and Rap1-agonist rescue

    PMID:31171376

    Open questions at the time
    • Whether RAPGEF2 mutations themselves cause human nephrotic syndrome not established
    • Cytoskeletal effector downstream of podocyte Rap1 not defined
  13. 2020 High

    Established NCS-Rapgef2 as the cAMP-ERK node for reward and nociceptive signaling, mediating D1-receptor-driven cocaine sensitization (independent of PKA/CREB) and OSM-primed sensory-neuron cAMP-ERK coupling.

    Evidence Region-specific AAV-Cre ablation with pERK/Egr-1 readouts and cocaine behavioral assays; pharmacological pathway dissection in sensory neurons

    PMID:32885411 PMID:33268547

    Open questions at the time
    • How NCS-Rapgef2-ERK signaling drives synaptic plasticity changes underlying sensitization not fully detailed
    • Sensory-neuron data rest on pharmacology, not genetics
  14. 2021 High

    Broadened the disease and endocrine relevance of RAPGEF2, implicating it in Aβ-induced synaptic loss via Rap2/JNK and in GLP-1 receptor→ERK signaling in beta cells.

    Evidence siRNA and in vivo AAV-shRNA knockdown in 3xTg-AD mice with spine/behavior readouts; shRNA knockdown with pERK and MEK-inhibitor analysis in INS-1/NS-1 cells

    PMID:33345400 PMID:33960038

    Open questions at the time
    • How Aβ upregulates RAPGEF2 mechanistically not defined
    • Switch between Rap1-ERK and Rap2-JNK output not explained
  15. 2024 High

    Demonstrated RapGEF2's role in hippocampal memory, showing it is required for cAMP-dependent ERK/Egr1 induction and LTP during fear conditioning, with selectivity for Egr1 over c-Fos.

    Evidence CamK2α-Cre conditional KO with pERK/Egr1 immunostaining, ex vivo LTP recording and fear-conditioning behavior

    PMID:38236296

    Open questions at the time
    • Basis of the Egr1-versus-c-Fos selectivity not resolved
    • Synaptic locus of RapGEF2 action not pinpointed
  16. 2026 High

    Extended RAPGEF2 function to hemostasis, placing it downstream of G13-coupled receptors to drive Rap1 and integrin αIIbβ3 activation for shear-dependent platelet adhesion, distinct from CalDAG-GEFI.

    Evidence Megakaryocyte-specific KO and double KO with CalDAG-GEFI, RAP1 pulldown, microfluidic shear adhesion and flow cytometry

    PMID:41949994

    Open questions at the time
    • Direct link between G13/GNA13 and RAPGEF2 recruitment not biochemically resolved
    • How shear stress selectively engages the RAPGEF2 arm not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single GEF integrates its multiple regulatory inputs (cAMP/CNBD, RA-domain feedback, Cdk5 and IKKβ/CK1α phosphorylation, scaffold recruitment) into context-specific Rap1 versus Rap2 output remains unresolved.
  • No structural model integrating CNBD, RA-domain and catalytic GEF domains
  • Determinants selecting Rap1-ERK versus Rap2-JNK signaling unknown
  • Whether cAMP binds the CNBD directly not biochemically confirmed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-109582 Hemostasis 1
Partners
CDK5GNA13JAMAMAGI2MRASRAP1RAP2TRKA
Complex memberships
JAM-A/ZO-2/afadin complexS-SCAM/ARMS/TrkA complex

Evidence

Reading pass · 23 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 activates both Rap1 and Rap2 in vitro and in vivo. It contains a domain related to cAMP-binding domains that acts as a negative regulatory domain, but unlike Epac, PDZ-GEF1 does not bind cAMP or cGMP. In vitro GEF assay, in vivo Rap1 activation assay, domain mutagenesis/deletion analysis, cAMP/cGMP binding assay The Journal of biological chemistry High 10608883
2001 RA-GEF-2 (RAPGEF2) stimulates guanine nucleotide exchange on Rap1 and Rap2 but not Ha-Ras. Its RA domain binds GTP-loaded M-Ras specifically (not other Ras family GTPases), recruiting RAPGEF2 to the plasma membrane where it activates Rap1 downstream of M-Ras. In vitro GEF assay, GST pulldown for RA domain binding specificity, co-localization in COS-7 cells, Rap1-GTP pulldown assay The Journal of biological chemistry High 11524421
2001 The RA domain of RA-GEF-1 (RAPGEF2) mediates binding to GTP-Rap1 and is required for translocation to the perinuclear/Golgi compartment, where it amplifies Rap1 activation in vivo and enhances B-Raf activation. Deletion of the RA domain abolishes in vivo but not in vitro GEF activity, revealing a positive feedback mechanism. RA domain deletion mutagenesis, Rap1 pulldown assay, B-Raf activation assay, subcellular co-localization with anti-TGN38 antibody in COS-7 cells The Journal of biological chemistry High 11359771
2007 PDZ-GEF1 (RAPGEF2) forms a tetrameric complex with synaptic scaffolding molecule (S-SCAM) and ARMS/Kidins220, which interacts directly with the TrkA neurotrophin receptor. Upon NGF binding and TrkA internalization to late endosomes, this complex induces sustained Rap1 and ERK activation leading to neurite outgrowth. PDZ-GEF1 is activated by GTP-Rap1 via a positive feedback mechanism at late endosomes. Co-immunoprecipitation, pulldown assays, subcellular fractionation/localization (endosome markers), live imaging, siRNA knockdown with neurite outgrowth readout The Journal of cell biology High 17724123
2007 RA-GEF-2 (RAPGEF2) mediates TNF-α-induced integrin (LFA-1) activation in splenocytes via an M-Ras→RA-GEF-2→Rap1 pathway. TNF-α activates M-Ras and Rap1 at the plasma membrane with concomitant recruitment of RA-GEF-2; knockdown or genetic knockout of RA-GEF-2 abolishes this Rap1 activation and LFA-1-mediated cell aggregation. siRNA knockdown in BAF3 cells, RA-GEF-2 knockout mice, Rap1-GTP pulldown, cell aggregation assay, subcellular fractionation Molecular biology of the cell High 17538012
2007 RA-GEF-1/RAPGEF2 knockout mice exhibit mid-gestation lethality (~E9.5) associated with severe defects in yolk sac blood vessel formation (failure of blood islands to coalesce into a vascular plexus), establishing an in vivo role in vascular morphogenesis. Conventional knockout mouse, embryo morphology analysis, histology Biochemical and biophysical research communications Medium 17826737
2009 RA-GEF-1/RAPGEF2 is required for Rap1 activation and VE-cadherin accumulation at endothelial cell-cell junctions during vascular plexus formation; constitutively active Rap1 rescues the vascular defects caused by RA-GEF-1 knockout, placing RA-GEF-1 upstream of Rap1 in vascular network formation. In vitro allantois explant culture, endothelial cell culture, Rap1 activation probe, VE-cadherin immunostaining, rescue with constitutively active Rap1 Biochemical and biophysical research communications High 19635461
2009 Conditional knockout of RA-GEF-1/RAPGEF2 in the dorsal telencephalon (Emx1-Cre) causes subcortical band heterotopia-like ectopic cortical mass, agenesis of commissures (corpus callosum, anterior commissure), and lowered seizure threshold, establishing a required role in cortical neuronal migration. Conditional knockout mice (Emx1-Cre), brain histology, retrograde tracing, EEG seizure threshold measurement The European journal of neuroscience High 19453629
2010 RapGEF2 conditional knockout mice die at ~E11.5 with yolk sac vascular defects and defective embryonic hematopoiesis. RapGEF2-null hematopoietic progenitors show impaired Rap1 activation, reduced B-Raf/ERK signaling, and decreased Scl/Gata transcription factor expression. Adult inducible deletion has no impact on hematopoiesis. Conditional knockout mice, flow cytometry (CD41, Flk1), colony formation assay, Rap1-GTP pulldown, Western blot for ERK/B-Raf signaling, RT-PCR for Scl/Gata Blood High 20595512
2013 Rapgef2 connects GPCR-mediated cAMP elevation to ERK activation via a Rap1→B-Raf→MEK pathway in neuroendocrine/neuronal cells, and is required for cAMP-dependent neuritogenesis. Rapgef2 is specifically eluted by cAMP from cAMP-agarose, indicating direct cAMP binding or interaction. cAMP-agarose affinity chromatography, siRNA knockdown (loss-of-function in NS-1 cells), gain-of-function in HEK293T cells, Western blot for ERK/B-Raf/MEK phosphorylation, neurite outgrowth assay Science signaling High 23800469
2013 JAM-A associates directly with ZO-2 and indirectly with afadin, forming a complex with PDZ-GEF1 that activates Rap2c to regulate epithelial tight junction barrier function and apical actomyosin contraction. siRNA knockdown of PDZ-GEF1 phenocopies JAM-A loss with enhanced paracellular permeability. Co-immunoprecipitation, siRNA knockdown, paracellular permeability assay, RhoA/myosin phosphorylation western blot Molecular biology of the cell High 23885123
2013 RAPGEF2 is phosphorylated by IKKβ and CK1α in response to pro-migratory factors, leading to proteasomal degradation via the SCF(βTrCP) ubiquitin ligase. Failure to degrade RAPGEF2 sustains Rap1 activity and inhibits HGF-induced cell migration and breast cancer metastasis. In vivo phosphorylation assay, kinase inhibitor studies, ubiquitin ligase genetic manipulation, degradation-resistant RAPGEF2 mutant expression, Rap1-GTP pulldown, cell migration assay, in vivo metastasis assay Developmental cell High 24290981
2014 RapGEF2 is phosphorylated by Cdk5, and this phosphorylation is required for RapGEF2-mediated Rap1 activation and N-cadherin upregulation during the multipolar-to-bipolar transition of cortical neurons. In utero electroporation knockdown of RapGEF2 blocks this polarity transition and radial migration. In utero electroporation, live imaging, Cdk5 kinase assay, Rap1-GTP pulldown, N-cadherin immunostaining, dominant-negative/constitutively active constructs Nature communications High 25189171
2016 Rapgef2 (and Rapgef6) act cell-autonomously through Rap1 to maintain apical adherens junctions in radial glia. Double knockout of Rapgef2 and Rapgef6 disrupts apical AJ structures, detaches radial glial cells, and disorganizes the radial glial fiber system; constitutively active Rap1(G12V) rescues the AJ disruption, placing Rapgef2/6 upstream of Rap1 in this pathway. Conditional knockout mice, intrauterine Cre electroporation, constitutively active Rap1 rescue, immunostaining for AJ markers (β-catenin, N-cadherin), cortical layer analysis eNeuro High 27390776
2017 NCS-Rapgef2 contains a cyclic nucleotide-binding domain (CNBD) that is required for cAMP-dependent ERK activation; mutation of a conserved CNBD residue abrogates cAMP-ERK coupling, whereas deletion of the CNBD results in constitutive ERK activation. NCS-Rapgef2 is encoded from an alternative first exon (exon 1') and is selectively expressed in neuronal and endocrine tissues. CNBD point mutagenesis and deletion mutagenesis, reconstitution in HEK293T cells, cAMP-ERK phosphorylation assay, tissue-specific mRNA and protein expression analysis, Rapgef2 CamK2α-Cre conditional KO mice, D1 receptor agonist ERK assay eNeuro High 28948210
2017 The cAMP-binding pharmacophore of NCS-Rapgef2 is distinct from those of PKA and Epac. N6-Phe-cAMP is a selective NCS-Rapgef2 agonist, and N6-phenyl-9-tetrahydrofuranyladenine is a selective NCS-Rapgef2 inhibitor without activity at PKA, Epac, or adenylate cyclase. Cell-based pharmacological assay (high-content microscopy for ERK/PKA-II activation), EC50/IC50 determination for adenine derivatives across cAMP effectors in NS-1 neuroendocrine cells ACS chemical neuroscience Medium 28290664
2019 RAPGEF2 forms a complex with MAGI2, and this interaction is lost when MAGI2 carries congenital nephrotic syndrome (CNS) variants. Co-expression of RapGEF2 with wild-type but not mutant MAGI2 enhances Rap1 activation in podocytes. Podocyte-specific RapGEF2 deletion in mice causes spontaneous glomerulosclerosis comparable to MAGI2 KO. Co-immunoprecipitation (MAGI2-RapGEF2 complex), Rap1-GTP pulldown, podocyte-specific conditional KO mice, siRNA knockdown in human podocytes, pharmacological Rap1 activation rescue Kidney international High 31171376
2020 NCS-Rapgef2 in nucleus accumbens D1-medium spiny neurons mediates cocaine-induced ERK phosphorylation and Egr-1/Zif268 upregulation via a D1 receptor→cAMP→NCS-Rapgef2→Rap1→B-Raf→MEK→ERK pathway. AAV-Cre-mediated NCS-Rapgef2 deletion in NAc eliminates cocaine-induced locomotor sensitization and conditioned place preference without affecting PKA/CREB phosphorylation. AAV-Synapsin-Cre injection for region-specific gene deletion, CamK2α-Cre conditional KO, pERK and Egr-1 immunostaining, cocaine behavioral tests (locomotor sensitization, CPP), ex vivo slice electrophysiology The Journal of neuroscience High 33268547
2020 In sensory neurons, cAMP-to-ERK signaling involves RapGEF2 (and PKA) but not Epac; Oncostatin M (OSM) priming enhances and prolongs this RapGEF2/PKA-dependent cAMP-ERK coupling in IB4/CaMKIIα-positive nociceptors. High-content microscopy for endogenous PKA-II and ERK activation, selective pharmacological inhibition of Rapgef2/Epac/PKA, OSM priming paradigm in primary sensory neuron cultures Journal of neurochemistry Medium 32885411
2021 RAPGEF2 upregulation mediates oligomeric Aβ-induced synaptic loss via activation of downstream Rap2 and JNK. siRNA silencing of RAPGEF2 blocks Aβ oligomer-induced dendritic spine loss in hippocampal neurons, and in vivo knockdown prevents cognitive deficits and excitatory synapse loss in 3xTg-AD mice. siRNA knockdown in primary hippocampal neurons, in vivo AAV-shRNA knockdown in 3xTg-AD mice, dendritic spine counting, Rap2/JNK activation western blot, behavioral testing (cognitive function), electron microscopy of synapses Neuropathology and applied neurobiology High 33345400
2021 GLP-1 receptor stimulation activates ERK via NCS-RapGEF2 in pancreatic beta cells (INS-1) and NS-1 neuroendocrine cells; shRNA-mediated RapGEF2 knockdown reduces exendin-4-induced ERK phosphorylation, establishing NCS-RapGEF2 as a component of the GLP-1R→cAMP→ERK pathway. shRNA knockdown, pERK western blot, MEK inhibitor (U0126), transduction of GLP1R into NS-1 cells, neurite outgrowth assay, transcriptome analysis of INS-1 cells Journal of neuroendocrinology Medium 33960038
2024 RapGEF2 is required for cAMP-dependent ERK activation and Egr1 (but not c-Fos) induction in hippocampal CA1/dentate gyrus during fear conditioning, and for cAMP-dependent long-term potentiation at perforant pathway and Schaffer collateral synapses. Context-dependent fear memory is impaired by hippocampal RapGEF2 ablation. CamK2α-Cre conditional KO mice, pERK and Egr1 immunostaining after fear conditioning, LTP recording in hippocampal slices ex vivo, behavioral fear conditioning assay Cellular and molecular life sciences High 38236296
2026 RAPGEF2 operates downstream of the G13 (GNA13)-coupled receptors (αIIbβ3 integrin, thromboxane receptor) in platelets to activate RAP1 and mediate integrin αIIbβ3-dependent platelet adhesion under shear stress. Megakaryocyte-specific RAPGEF2 knockout reduces RAP1 activation and integrin activation, especially under elevated shear stress conditions. Megakaryocyte-specific conditional KO mice (Rapgef2mKO), double KO with CalDAG-GEFI, RAP1-GTP pulldown, platelet aggregation assay, microfluidic adhesion under shear stress, flow cytometry for integrin activation 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 103 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 34 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
2018 A De Novo RAPGEF2 Variant Identified in a Sporadic Amyotrophic Lateral Sclerosis Patient Impairs Microtubule Stability and Axonal Mitochondria Distribution. Experimental neurobiology 12 30636905
2009 Impaired vascular development in the yolk sac and allantois in mice lacking RA-GEF-1. Biochemical and biophysical research communications 12 19635461
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

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