Affinage

RAPGEF6

Rap guanine nucleotide exchange factor 6 · UniProt Q8TEU7

Length
1601 aa
Mass
179.4 kDa
Annotated
2026-06-10
15 papers in source corpus 10 papers cited in narrative 10 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

RAPGEF6 (RA-GEF-2/PDZ-GEF2) is a guanine nucleotide exchange factor that activates the Rap1 and Rap2 GTPases to control cell-cell junction maturation, cell-matrix adhesion, and cell migration (PMID:11524421, PMID:18585005, PMID:19176753). It catalyzes nucleotide exchange on Rap1 and Rap2 but not Ha-Ras, and its RA domain binds GTP-loaded M-Ras specifically, recruiting the GEF to the plasma membrane where it locally elevates active Rap1 (PMID:11524421). This M-Ras–RAPGEF6–Rap1 module drives TNF-α–triggered LFA-1 integrin activation in splenocytes, a requirement confirmed by knockout mice (PMID:17538012). At epithelial junctions RAPGEF6 acts within a JAM-A–Afadin scaffold, where its association with Afadin depends on JAM-A and the resulting Rap1A activation maintains β1 integrin levels and supports cell migration, while activating Rap1A and Rap1B for distinct outputs—adherens junction maturation versus E-cadherin regulation (PMID:18585005, PMID:19176753). The C-terminal PPDY motif of RAPGEF6 binds the WW domain of the co-chaperone BAG3, and RAPGEF6 is required downstream of BAG3 for integrin-mediated adhesion to fibronectin (PMID:20800573). RAPGEF6 also operates downstream of desmoglein-2 to restrain Rap1 activity and cell spreading (PMID:34168237). In vivo, RAPGEF6 acts redundantly with RAPGEF2 through Rap1 to maintain apical adherens junctions in cortical radial glia (PMID:27390776), is required for N-cadherin junction integrity during spermatogenesis (PMID:24491570), and supports amygdala-dependent fear behavior and neuronal morphology (PMID:26057047).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2001 High

    Established RAPGEF6 as a Rap-specific GEF and defined how it is targeted to the plasma membrane, answering both its catalytic specificity and its upstream activator.

    Evidence In vitro GEF assays, GTP-dependent domain-binding specificity tests, and colocalization in COS-7 cells

    PMID:11524421

    Open questions at the time
    • Physiological receptor inputs upstream of M-Ras not yet defined
    • No structural basis for RA domain–M-Ras selectivity
  2. 2007 High

    Placed RAPGEF6 in a signaling chain from a physiological stimulus to integrin function, showing M-Ras→RAPGEF6→Rap1 mediates TNF-α–induced LFA-1 activation.

    Evidence siRNA knockdown, genetic knockout mice, cell aggregation and Rap1 activation assays in splenocytes

    PMID:17538012

    Open questions at the time
    • How the TNF-α receptor connects to M-Ras activation is unresolved
    • Direct membrane recruitment mechanism beyond M-Ras binding not dissected
  3. 2008 High

    Demonstrated that RAPGEF6 routes distinct Rap1 isoforms to distinct adhesion outputs, resolving how one GEF supports both junction maturation and cadherin regulation.

    Evidence siRNA knockdown with constitutively active Rap1A rescue and E-cadherin quantification in A549 cells

    PMID:18585005

    Open questions at the time
    • Molecular basis of Rap1A versus Rap1B selectivity unknown
    • Single cell-line context
  4. 2009 High

    Identified the scaffold that positions RAPGEF6 at junctions, defining a JAM-A→Afadin/RAPGEF6→Rap1A→β1 integrin migration pathway.

    Evidence Reciprocal co-immunoprecipitation, siRNA knockdown epistasis, and migration/β1 integrin readouts

    PMID:19176753

    Open questions at the time
    • Whether RAPGEF6 binds Afadin directly or via JAM-A not distinguished
    • Quantitative stoichiometry of the complex unknown
  5. 2010 Medium

    Mapped a direct PPDY–WW interaction linking RAPGEF6 to the co-chaperone BAG3, placing RAPGEF6 downstream of BAG3 in adhesion control.

    Evidence Co-IP, domain-deletion mutants, in vitro binding, and adhesion assays on fibronectin

    PMID:20800573

    Open questions at the time
    • Functional consequence of BAG3 binding for GEF activity not measured
    • Single-lab finding
  6. 2014 Medium

    Extended RAPGEF6 function to a whole-organism adhesion phenotype, showing it maintains N-cadherin junctions required for spermatogenesis.

    Evidence Genetic knockout mice with histology, sperm parameters, and N-cadherin immunolocalization

    PMID:24491570

    Open questions at the time
    • Direct link between Rap1 activity and N-cadherin junction maintenance in testes not established
    • Cell type responsible not pinpointed
  7. 2015 Medium

    Revealed a neural role for RAPGEF6 in amygdala-dependent behavior and neuronal structure.

    Evidence Knockout mice analyzed by fear conditioning, cFOS IHC, dendritic morphology, and LTP electrophysiology

    PMID:26057047

    Open questions at the time
    • Molecular pathway connecting RAPGEF6 to synaptic phenotypes not defined
    • Whether effects are Rap1-dependent untested
  8. 2016 High

    Showed RAPGEF6 acts redundantly with RAPGEF2 via Rap1 to maintain apical adherens junctions in radial glia, resolving its developmental role through in vivo epistasis.

    Evidence Conditional/double knockout mice with in utero Cre transduction and constitutively active Rap1 rescue

    PMID:27390776

    Open questions at the time
    • Upstream cue activating Rapgef2/6 in radial glia unknown
    • Basis of functional redundancy between the two GEFs not dissected
  9. 2021 Medium

    Placed RAPGEF6 downstream of desmoglein-2 in restraining Rap1 activity and cell spreading, extending its input repertoire to desmosomal cadherins.

    Evidence Dsg2 knockout cells with Rap1 activity assays, spreading measurement, and RAPGEF6 knockdown

    PMID:34168237

    Open questions at the time
    • How Dsg2 loss elevates RAPGEF6/Rap1 activity mechanistically unclear
    • Role of the implicated TGFβ arm not integrated
  10. 2025 Low

    Linked RAPGEF6 to macrophage inflammatory and necroptotic responses, a distinct functional context from its adhesion roles.

    Evidence Lentiviral shRNA stable knockdown in RAW264.7 macrophages with LPS stimulation and NF-κB/necroptosis readouts

    PMID:41081959

    Open questions at the time
    • Pathway placement inferred from downstream markers without mechanistic reconstitution
    • No demonstration that GEF/Rap1 activity mediates the effect
    • Single knockdown model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RAPGEF6 selects between Rap1A and Rap1B and integrates its multiple upstream inputs (M-Ras, JAM-A/Afadin, BAG3, Dsg2) into context-specific outputs remains unresolved.
  • No structural model of substrate or activator selection
  • Mechanistic basis for tissue-specific output unknown
  • Direct GEF activity not connected to neural or inflammatory phenotypes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1500931 Cell-Cell communication 2
Partners
BAG3DSG2F11RMLLT4MRAS
Complex memberships
JAM-A–Afadin–PDZ-GEF2 junctional complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 RA-GEF-2 (RAPGEF6) is a guanine nucleotide exchange factor that stimulates nucleotide exchange on both Rap1 and Rap2, but not Ha-Ras. Its RA domain binds M-Ras in a GTP-dependent manner (but not other Ras family GTPases tested, including Ha-Ras, N-Ras, Rap1A, Rap2A, R-Ras, RalA, Rin, Rit, or Rheb). Upon coexpression with activated M-Ras, RA-GEF-2 colocalizes with it at the plasma membrane and increases GTP-bound Rap1 there, in contrast to the related RA-GEF-1, which acts in perinuclear/Golgi compartments. In vitro GEF assay, domain-specific binding assays, subcellular colocalization in COS-7 cells, coexpression experiments The Journal of biological chemistry High 11524421
2007 The M-Ras → RA-GEF-2 → Rap1 pathway mediates TNF-α-triggered LFA-1 integrin activation in hematopoietic/splenocyte cells. Activated M-Ras induces LFA-1-mediated cell aggregation that is abrogated by knockdown of RA-GEF-2 or Rap1. TNF-α activates LFA-1 in a manner dependent on M-Ras, RA-GEF-2, and Rap1 and recruits RA-GEF-2 to the plasma membrane. Genetic deletion of RA-GEF-2 in mice confirmed its requirement for TNF-α-stimulated, Rap1-mediated LFA-1 activation in splenocytes. siRNA knockdown, genetic knockout mice, cell aggregation assays, Rap1 activation assays, subcellular localization experiments Molecular biology of the cell High 17538012
2008 PDZ-GEF2 (RAPGEF6) is required for maturation of adherens junctions in lung carcinoma A549 cells. Knockdown of PDZ-GEF2 results in persistence of adhesion zippers at cell-cell contacts. Constitutively active Rap1A rescues junction maturation in the absence of PDZ-GEF2, placing Rap1A downstream of PDZ-GEF2 in this process. PDZ-GEF2 knockdown also reduces E-cadherin levels (an effect mimicked by Rap1B but not Rap1A siRNA), indicating PDZ-GEF2 activates both Rap1A (junction maturation) and Rap1B (E-cadherin regulation) for distinct functions. siRNA knockdown, constitutively active Rap1A rescue, immunofluorescence microscopy, E-cadherin level measurement Cellular signalling High 18585005
2009 JAM-A forms a physical complex with Afadin and PDZ-GEF2 at tight junctions in epithelial cells. This complex is functionally required: loss of JAM-A, Afadin, or PDZ-GEF2 (but not ZO-1 or PDZ-GEF1) similarly decreases active Rap1, β1 integrin protein levels, and cell migration. Association of PDZ-GEF2 with Afadin is dependent on JAM-A expression. Downstream, Rap1A (but not Rap1B) knockdown phenocopies the decrease in β1 integrin and migration, establishing JAM-A → Afadin/PDZ-GEF2 → Rap1A → β1 integrin → cell migration as the functional pathway. Co-immunoprecipitation, siRNA knockdown, cell migration assays, β1 integrin quantification Molecular biology of the cell High 19176753
2010 BAG3 directly interacts with PDZGEF2 (RAPGEF6) via binding of the PPDY motif at the C-terminus of PDZGEF2 to the WW domain of BAG3, both in vitro and in vivo. PDZGEF2 activates Rap1 and increases integrin-mediated cell adhesion. BAG3 overexpression increases cell adhesion, but this effect is lost when PDZGEF2 is knocked down, demonstrating that PDZGEF2 is required downstream of BAG3 for cell adhesion regulation. Co-immunoprecipitation, domain deletion mutants, in vitro binding assay, siRNA knockdown, cell adhesion assay on fibronectin Biochemical and biophysical research communications Medium 20800573
2014 RA-GEF-2/Rapgef6 is required for spermatogenesis in mice. Knockout of RA-GEF-2 results in testicular atrophy, hypospermatogenesis, reduced sperm concentration and motility, abnormal sperm morphology, and male infertility. Loss of RA-GEF-2 causes reduced expression and disrupted junctional localization of N-cadherin in testes, suggesting the Rapgef6-Rap1 pathway maintains N-cadherin-dependent cell junctions necessary for testicular differentiation. Genetic knockout mice, histological analysis, sperm parameter measurement, N-cadherin immunolocalization Biochemical and biophysical research communications Medium 24491570
2015 Deletion of Rapgef6 in mice impairs amygdala function, evidenced by reduced fear conditioning and anxiolysis, reduced cFOS phosphorylation in hippocampus and amygdala after fear conditioning, reduced spine density and primary dendrite number in CA3 pyramidal neurons, and enhanced long-term potentiation at cortico-amygdala synapses. Genetic knockout mice, fear conditioning behavioral assays, cFOS immunohistochemistry, dendritic morphology analysis, electrophysiology (LTP measurement) Translational psychiatry Medium 26057047
2016 Rapgef2 and Rapgef6 act redundantly and cell-autonomously through a Rap1 pathway to maintain apical surface adherens junctions in radial glial cells during mouse cerebral cortex development. Double knockout (Rapgef2/6-dKO) causes greater disruption of apical AJs, RGC detachment, and radial glial fiber disorganization than single Rapgef2 knockout alone, affecting both early-born and late-born neurons. Cotransduction of constitutively active Rap1(G12V) suppresses AJ disruption and RGC detachment caused by Rapgef2 loss, placing Rap1 downstream of Rapgef2/6 in this pathway. Conditional and double genetic knockout mice, intrauterine Cre transduction, constitutively active Rap1 rescue, immunohistochemistry for AJ markers, confocal microscopy eNeuro High 27390776
2021 Desmoglein-2 (Dsg2) controls cell spreading and focal adhesion phosphorylation through a PDZ-GEF2/Rap1 signaling axis. Cells lacking Dsg2 show elevated Rap1 activity and increased spreading on fibronectin and collagen, even in single cells (independent of cell-cell adhesion). PDZ-GEF2 was implicated as mediating Dsg2-dependent Rap1 activation, with downstream TGFβ signaling also involved. Dsg2 knockout cells, Rap1 activity assay, cell spreading area measurement, focal adhesion phosphorylation assay, siRNA for PDZ-GEF2 Scientific reports Medium 34168237
2025 Stable knockdown of RAPGEF6 in RAW264.7 macrophages attenuates LPS-induced inflammatory responses and oxidative stress by inhibiting NF-κB-mediated necroptosis. Lentiviral shRNA stable knockdown, LPS stimulation, NF-κB pathway assays, necroptosis readouts Functional & integrative genomics Low 41081959

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Junctional adhesion molecule A interacts with Afadin and PDZ-GEF2 to activate Rap1A, regulate beta1 integrin levels, and enhance cell migration. Molecular biology of the cell 146 19176753
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
2010 BAG3 directly associates with guanine nucleotide exchange factor of Rap1, PDZGEF2, and regulates cell adhesion. Biochemical and biophysical research communications 61 20800573
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
2006 Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia. Human molecular genetics 43 17030554
2008 The RapGEF PDZ-GEF2 is required for maturation of cell-cell junctions. Cellular signalling 40 18585005
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
2008 Association of haplotypes spanning PDZ-GEF2, LOC728637 and ACSL6 with schizophrenia in Han Chinese. Journal of medical genetics 21 18718982
2015 Deletion of Rapgef6, a candidate schizophrenia susceptibility gene, disrupts amygdala function in mice. Translational psychiatry 18 26057047
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
2019 Novel Polymorphisms in RAPGEF6 Gene Associated with Egg-Laying Rate in Chinese Jing Hong Chicken using Genome-Wide SNP Scan. Genes 11 31137587
2021 Desmoglein-2 harnesses a PDZ-GEF2/Rap1 signaling axis to control cell spreading and focal adhesions independent of cell-cell adhesion. Scientific reports 10 34168237
2019 A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs. PLoS genetics 7 31647804
2025 Novel ETV6::RAPGEF6 fusion gene in chronic eosinophilic leukemia: compiling evidence on the role of IL3 overexpression in tumorigenesis. Annals of hematology 2 39923209
2025 RAPGEF6 is a key biomarker with temporal characteristics in sepsis and exacerbates inflammation and oxidative stress by NF-κB-mediated necroptosis. Functional & integrative genomics 0 41081959

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