Affinage

RAP2A

Ras-related protein Rap-2a · UniProt P10114

Length
183 aa
Mass
20.6 kDa
Annotated
2026-06-10
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAP2A is a slowly cycling Ras-superfamily small GTPase that operates as a molecular switch transducing cytoskeletal and mechanical cues to cell growth, polarity, motility, and synaptic signaling pathways (PMID:10913189, PMID:30135582). It binds GTP with high affinity and has low intrinsic GTPase activity, and because canonical RAP1 GAPs act on it only weakly, its GTP-bound fraction remains high with a long half-life, making it a persistently "on" switch in adherent cells (PMID:1900290, PMID:1449497, PMID:10913189). Nucleotide loading is controlled by GEFs including PDZ-GEF1, the highly RAP2-selective RasGEF1A/1B (whose specificity is set by Phe39 in switch I), and Epac2 (PMID:10608883, PMID:19645719, PMID:28546426). The protein is dually lipidated—farnesylated at its C-terminal CAAX motif and palmitoylated—and palmitoylation targets it to Rab11-positive recycling endosomes where it recruits effectors (PMID:8424780, PMID:19061864). RAP2A signals through a dedicated set of GTP-dependent effectors of the germinal-center kinase family—MAP4K4, TNIK, and MINK—engaging their citron-homology domains (PMID:14966141, PMID:15342639, PMID:18930710). Through these kinases RAP2 functions as a central mechanotransducer in the Hippo pathway: low ECM stiffness or cytoskeletal perturbation activates RAP2 via PLCγ1/phosphatidic acid and PDZGEF, and active RAP2 stimulates MAP4K4/6/7 to drive LATS1/2 activation and YAP/TAZ inhibition (PMID:30135582, PMID:38574891). The same RAP2–TNIK/MINK module drives actin remodeling and AMPA-receptor removal underlying synaptic depression and dendrite restriction, and opposes Ras–ERK signaling in neurons in vivo (PMID:15342639, PMID:15953419, PMID:18701680). RAP2A activity is further tuned by ubiquitination: Nedd4-1 ubiquitinates RAP2A to inhibit TNIK and promote dendrite growth, while a Rab40b/Cullin5 complex ubiquitylates RAP2A to control its endosomal recycling and actin dynamics during cell migration (PMID:20159449, PMID:35293963). RAP2A also serves an apical polarity module linking LKB1-induced polarity to TNIK/MST4/Ezrin-dependent brush border formation, and acts in cell migration and matrix-stiffness-responsive contexts in vascular, immune, cartilage, and cardiac tissues (PMID:22797597, PMID:23213397, PMID:36366779, PMID:40332594).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1991 High

    Established the basic enzymology of RAP2A as a GTP-binding protein, defining it as an intrinsically slow switch and mapping active-site residues that control nucleotide handling.

    Evidence in vitro nucleotide binding/GTPase assays with purified recombinant protein and site-directed mutagenesis

    PMID:1900290

    Open questions at the time
    • Did not identify physiological GEFs or GAPs
    • No effectors known at this stage
  2. 1993 High

    Defined how RAP2A is anchored to membranes, showing it is farnesylated at its CAAX motif and palmitoylated—the first non-Ras superfamily member shown to be farnesylated—establishing the lipid basis for its distinctive localization.

    Evidence metabolic labeling, cell-free translation with [3H]mevalonolactone, HPLC isoprenoid identification, mutagenesis, subcellular fractionation

    PMID:1923507 PMID:8424780

    Open questions at the time
    • Functional consequence of dual lipidation for signaling not yet established
    • Precise endosomal compartment later refined
  3. 1997 High

    Provided atomic-level mechanism of the RAP2A switch by solving its structure in GDP, GTP, and GTPgammaS states, localizing conformational change to switch I/II.

    Evidence X-ray crystallography of three nucleotide states

    PMID:9312017

    Open questions at the time
    • No effector-bound structure
    • Structural basis of GAP resistance not resolved
  4. 2000 High

    Resolved why RAP2A behaves differently from RAP1: weak GAP sensitivity gives GTP-RAP2 a long half-life, and GTP-RAP2 can bind Raf-RBD and inhibit Ras-dependent transcription, framing RAP2 as a slow, Ras-antagonizing switch.

    Evidence GTP-loading and half-life measurements in 293T cells and in vitro, Raf-RBD pulldown, Elk1 reporter assay

    PMID:10913189

    Open questions at the time
    • Physiological relevance of Raf binding unclear
    • Dedicated RAP2 GAP not molecularly identified
  5. 1999 High

    Identified the first GEFs acting on RAP2 (PDZ-GEF1 and RalGEF interactions), beginning to map upstream activation despite RAP2 failing to activate Ral in vivo.

    Evidence in vitro GEF assays, yeast two-hybrid, co-IP, activation assays

    PMID:10085114 PMID:10608883

    Open questions at the time
    • RAP2-specific GEFs not yet defined
    • Downstream effector pathway incomplete
  6. 2004 High

    Defined the core RAP2-specific effector class by identifying MAP4K4 and TNIK as GTP-dependent CNH-domain effectors selective for RAP2 over RAP1/Ras, linking RAP2 to JNK signaling and actin/cell-spreading control.

    Evidence yeast two-hybrid, affinity purification/MS from brain, in vitro binding, JNK and cell-spreading assays

    PMID:14966141 PMID:15342639

    Open questions at the time
    • Recruitment to membranes and substrate repertoire of these kinases not fully mapped
    • MINK identified only later
  7. 2008 Medium

    Connected RAP2 lipidation to effector function and refined localization, showing palmitoylation targets RAP2 to recycling endosomes where it recruits TNIK, and extended the effector set to MINK controlling TANC1 phosphorylation.

    Evidence palmitoylation inhibitor treatment, fractionation, co-localization, in vitro phosphorylation, affinity purification/MS

    PMID:18930710 PMID:19061864

    Open questions at the time
    • Precise palmitoyl-transferase not identified
    • Quantitative dynamics of endosomal recruitment unresolved
  8. 2008 High

    Established RAP2 as a physiological regulator of synaptic plasticity and neuronal morphology in vivo, opposing Ras-ERK signaling and driving AMPA receptor removal and LTD.

    Evidence transgenic Rap2V12 mice, electrophysiology (LTP/LTD), spine morphometry, ERK phosphorylation, behavior; neuronal gain/loss of function

    PMID:15953419 PMID:17227435 PMID:18701680

    Open questions at the time
    • Endogenous activation triggers in vivo only partly defined
    • Effector usage (TNIK vs MINK) distinctions still being resolved
  9. 2009 High

    Identified RasGEF1A/1B as highly RAP2-selective GEFs and pinpointed Phe39 in switch I as the specificity determinant distinguishing RAP2 from RAP1 in both GEF and effector recognition.

    Evidence in vitro GEF assays with purified proteins and reciprocal site-directed mutagenesis

    PMID:19645719

    Open questions at the time
    • Tissue contexts where these GEFs operate not fully mapped
  10. 2010 High

    Revealed ubiquitination as a key regulatory layer, showing Nedd4-1 forms a complex with RAP2A and TNIK and ubiquitinates RAP2A to inhibit TNIK activity and promote dendrite growth in vivo.

    Evidence co-IP, ubiquitination assay, conditional Nedd4-1 knockout mice, neuronal morphometry

    PMID:20159449 PMID:21048137

    Open questions at the time
    • Whether ubiquitination alters localization vs effector binding not fully dissected
  11. 2012 High

    Placed RAP2A within an ordered apical-polarity signaling module linking LKB1/lipid signaling through PDZGEF to TNIK/MST4/Ezrin and brush border formation, and showed C-terminal hypervariable region confers RAP2A-selective activation.

    Evidence sequential siRNA epistasis, lipid analysis, phosphorylation and morphometric assays, chimeric protein analysis

    PMID:22797597 PMID:25203140

    Open questions at the time
    • Mechanism of HVR-driven selective activation at the molecular level not resolved
  12. 2018 High

    Defined RAP2 as the central mechanotransducer coupling ECM stiffness to the Hippo pathway, with low stiffness activating RAP2 via PLCγ1/phosphatidic acid/PDZGEF to stimulate MAP4K4/6/7 and inhibit YAP/TAZ.

    Evidence CRISPR knockout, RAP2 activation assays, co-IP with MAP4Ks, LATS1/2 kinase assays, YAP/TAZ reporters, transcriptomics

    PMID:30063210 PMID:30135582

    Open questions at the time
    • How the slow RAP2 switch achieves rapid stiffness responsiveness unclear
    • Cell-type generality of the GEF inputs incompletely mapped
  13. 2022 High

    Showed Rab40b/Cullin5-mediated ubiquitylation controls RAP2A activation and recycling from endolysosomes to lamellipodia, linking RAP2A trafficking to actin dynamics and cancer cell invasion.

    Evidence co-IP, ubiquitylation assay, Rab40b/Cullin5 KO, live confocal imaging, migration/invasion assays

    PMID:23213397 PMID:35293963

    Open questions at the time
    • Relationship between Rab40b/Cullin5 and Nedd4-1 ubiquitination not reconciled
    • Effectors at the leading edge incompletely defined
  14. 2024 High

    Generalized RAP2 as an integrator of broad cytoskeletal signals to Hippo, showing its deletion abrogates LATS1/2 activation by Rho inhibition, actin disruption, and microtubule stabilization, all acting upstream of MAP4K4/6/7.

    Evidence RAP2 and MAP4K4/6/7 CRISPR KO, pharmacological cytoskeletal perturbations, LATS1/2 kinase assays, RNA-seq

    PMID:38574891

    Open questions at the time
    • Direct sensor coupling RAP2 to cytoskeletal state not identified
    • How distinct perturbations converge on a single GTPase unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity of physiological RAP2A GAP(s) and the structural basis by which a slow, persistently GTP-loaded switch achieves dynamic, stimulus-specific output remain unresolved.
  • No purified RAP2A-specific GAP identified
  • No effector- or GEF-bound RAP2A structure
  • Mechanism reconciling slow cycling with rapid mechanoresponse unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4 GO:0060089 molecular transducer activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005768 endosome 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-9609507 Protein localization 3
Partners
LRP6MAP4K4MINK1NEDD4PDZ-GEF1RASGEF1BRPIP8TNIK
Complex memberships
Nedd4-1/TNIK/RAP2A complexRab40b/Cullin5 E3 ligase complex

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 RAP2A (rap2) encodes a 183 amino acid GTP-binding protein with ~46% identity to K-Ras; the putative effector domain differs by one amino acid from Ras, and the protein contains a C-terminal cysteine motif predicted to mediate membrane anchoring, suggesting possible interaction with Ras effectors. cDNA cloning, sequence homology analysis Oncogene Low 3045729
1991 Recombinant RAP2A protein binds GTP with higher affinity than GDP and exhibits low intrinsic GTPase activity (rate constant ~0.5×10⁻² min⁻¹). Site-directed mutagenesis showed: G12V reduces GDP dissociation and GTPase activity; S17N severely impairs GTP binding (Mg²⁺ coordination); T35A decreases GTP affinity and GTPase activity; T145I increases nucleotide dissociation rates. In vitro biochemical assay with purified recombinant protein; site-directed mutagenesis The Journal of biological chemistry High 1900290
1991 RAP2A protein is post-translationally modified by both palmitoylation and farnesylation (polyisoprenylation), processed from a soluble hydrophilic precursor to a hydrophobic membrane-bound form, and localizes to a low-density compartment overlapping with the endoplasmic reticulum—distinct from the plasma membrane localization of Ras proteins. Subcellular fractionation, sucrose density centrifugation, indirect immunofluorescence, metabolic labeling Oncogene High 1923507
1991 RAP2A overexpression (wild-type or G12V activated mutant) has neither transforming activity nor growth-promoting or growth-inhibitory effects in mammalian cells, and does not interfere with Ras-induced transformation—functionally distinct from RAP1A. Stable expression in mammalian cells, focus formation assay, colony growth assay International journal of cancer Medium 1833345
1991 RAP2A protein is phosphorylated neither in vitro nor in vivo by cAMP-dependent protein kinase (PKA) or protein kinase C (PKC), unlike RAP1A/RAP1B which are PKA substrates. In vitro kinase assay with purified PKA catalytic subunit; intact fibroblast labeling Biochemical and biophysical research communications High 1902091
1992 RAP2A GTPase activity is not stimulated by Ras-GAP and cannot compete with Ras for Ras-GAP interaction. Rap1-GAPm stimulates RAP2A GTPase but with 30–40-fold lower efficiency than on RAP1A. A specific RAP2-GAP activity was detected and partially purified from bovine brain cytosol but co-purified with a degraded form of rap1-GAP. GTPase activity assay with purified proteins; partial purification from bovine brain cytosol Biochemical and biophysical research communications Medium 1449497
1992 RAP2A (rap2p) localizes predominantly to specific granules in resting human neutrophils (membrane-bound, cytoplasmic face) and translocates to the plasma membrane upon neutrophil activation/degranulation, remaining membrane-bound throughout. Immunoblot of subcellular fractions, immunofluorescence microscopy, pronase protection assay The Journal of biological chemistry Medium 1556142
1993 RAP2A is farnesylated at its C-terminal CAAX motif (terminating in glutamine), making it the first non-Ras member of the Ras superfamily shown to be farnesylated. Mutation of the terminal glutamine to leucine switches the isoprenoid specificity to geranylgeranyl; mutation of the CAAX cysteine (C180S) abolishes isoprenoid incorporation entirely. In vitro translation with [³H]mevalonolactone, HPLC isoprenoid identification, site-directed mutagenesis The Biochemical journal High 8424780
1993 RAP2A localizes to gelatinase-containing (tertiary) granules in resting human neutrophils; RAP2B (not RAP2A) is the major RAP2 isoform in neutrophils. Immunoblot of subcellular fractions with specific antibodies FEBS letters Medium 8391995
1994 Epitope-tagged RAP2A colocalizes with Golgi complex markers in fibroblasts, a localization distinct from RAP1A/RAP1B which associate with late endosomes/lysosomes. Confocal immunofluorescence microscopy of transiently overexpressed epitope-tagged proteins; subcellular fractionation Journal of cell science Medium 7962206
1997 Crystal structures of RAP2A in complex with GDP, GTP, and GTPγS were solved. The RAP2A-GTP structure (first small G protein structure with natural GTP ligand) revealed that Tyr32 forms a hydrogen bond with the γ-phosphate of GTP and with Gly13; this interaction is absent in the GTPγS complex. Conformational changes between GDP and GTP states are confined to switch I and II regions. X-ray crystallography The EMBO journal High 9312017
1998 RPIP8 (Rap2-interacting protein 8) was identified as a specific effector of RAP2A. RPIP8 interacts with GTP-bound RAP2A (but not GDP-bound) and requires an intact effector domain of RAP2A. Co-immunoprecipitation from HIT-T15 cells confirmed the interaction with wild-type and activated RAP2A. Yeast two-hybrid screen, in vitro binding with purified proteins, co-immunoprecipitation European journal of biochemistry Medium 9523700
1999 PDZ-GEF1 functions as a guanine nucleotide exchange factor that activates both RAP1 and RAP2 in vivo and in vitro; it is the first GEF shown to act on RAP2. PDZ-GEF1 activity is regulated by a negative regulatory domain related to cAMP-binding domains but does not bind cAMP or cGMP. In vitro GEF assay with purified proteins, in vivo activation assay in 293T cells The Journal of biological chemistry High 10608883
1999 RalGEFs (RalGDS, RGL, Rlf) interact with GTP-bound RAP2A through their Ras/Rap interaction domain in yeast two-hybrid and in vitro assays. Activated RAP2A co-immunoprecipitates with RalGDS and Rlf from HeLa cells, and the complexes localize to the endoplasmic reticulum. However, overexpressed activated RAP2A does not activate Ral GTPase via RalGEFs in vivo. Yeast two-hybrid, in vitro binding, co-immunoprecipitation, confocal microscopy, Ral activation assay The Journal of biological chemistry Medium 10085114
1999 RAP2A directly binds actin filaments in a nucleotide state-independent manner (both GDP- and GTPγS-loaded forms bind equally). This interaction was demonstrated by co-sedimentation with purified F-actin, incorporation into reconstituted cytoskeleton, and binding to F-actin-coated surfaces. In vitro reconstitution, co-sedimentation with purified F-actin, Ni-Sepharose pulldown Journal of cellular biochemistry Medium 10572250
2000 RAP2A acts as a slowly responding molecular switch: its GTP-bound fraction exceeds 50% in adherent cells because GAPs for RAP1 (rap1GAPII, SPA-1) stimulate RAP2A GTPase with low efficiency, resulting in a long half-life for GTP-RAP2. Multiple RAP1 GEFs (C3G, Epac, CalDAG-GEFI, PDZ-GEF1, GFR) efficiently exchange nucleotide on RAP2 in cells and in vitro. GTP-RAP2 binds the Ras-binding domain of Raf and inhibits Ras-dependent Elk1 transcription. GTP-loading assays in 293T cells and in vitro, half-life measurement, Raf-RBD pulldown, reporter assay Molecular and cellular biology High 10913189
2002 Constitutively active RAP2 increases SDF-1 (CXCL12)-induced B cell migration, while expression of a Rap-specific GAP blocks both RAP1 and RAP2 activation and significantly reduces B cell migration toward SDF-1, placing RAP2 as a positive regulator of chemokine-directed B cell migration. Transfection of constitutively active RAP2 or dominant Rap-GAP, B cell migration assay Journal of immunology Medium 12133960
2004 MAP4K4 (isoform 3) was identified as a RAP2A effector. MAP4K4 interacts with RAP2 (but not RAP1 or Ras) through its C-terminal citron homology (CNH) domain in a GTP-dependent manner requiring the intact effector region of RAP2. Co-expression of RAP2 with MAP4K4 enhances JNK activation by MAP4K4. Yeast two-hybrid, in vitro binding assay, co-localization in cultured cells, JNK activation assay The Journal of biological chemistry Medium 14966141
2004 TNIK (Traf2- and Nck-interacting kinase) was identified as a specific RAP2 effector. TNIK interacts with RAP2 (but not RAP1 or Ras) through its CNH domain in a GTP-dependent manner. RAP2 promotes TNIK autophosphorylation, translocation to the detergent-insoluble cytoskeletal fraction, and enhances TNIK-mediated inhibition of cell spreading (F-actin disruption). RAP2 did not significantly enhance TNIK-induced JNK activation. Affinity chromatography from rat brain, LC-MS/MS identification, in vitro binding, co-localization, cell spreading assay The Journal of biological chemistry High 15342639
2005 RAP2 activity, stimulated by NR2A-containing NMDA receptor activation, depresses AMPA receptor-mediated synaptic transmission via JNK activation (not ERK1/2 or p38 MAPK), and controls synaptic removal of AMPA receptors with long cytoplasmic tails during depotentiation. Electrophysiology, dominant-negative/constitutively active RAP2 expression in neurons, pharmacological pathway dissection Neuron High 15953419
2005 PARG1 (a RhoGAP) interacts with RAP2 in a GTP-dependent manner through its ZPH region but not with Ras or RAP1; RAP2 suppresses the cytoskeletal (Rho-inactivating) effects of PARG1 in fibroblasts, identifying PARG1 as a putative RAP2 effector that regulates Rho. Yeast two-hybrid (C. elegans ortholog), in vitro binding, co-expression cytoskeletal assay Biochemical and biophysical research communications Low 15752761
2005 Xenopus Rap2 (XRap2) is required for Wnt/β-catenin signaling: XRap2 knockdown inhibits β-catenin stabilization and disrupts vesicular localization of Dishevelled (Dsh), thereby blocking Dsh-mediated β-catenin stabilization and Frizzled-induced Dsh phosphorylation and membrane recruitment. Morpholino knockdown in Xenopus embryos, ectopic expression, β-catenin stability assay, Dsh localization by immunofluorescence The EMBO journal Medium 15706349
2007 Constitutively active RAP2 expression in hippocampal pyramidal neurons causes decreased length and complexity of axonal and dendritic branches, loss of dendritic spines with increase in filopodia-like protrusions, and reduces AMPA receptor-mediated mEPSC amplitude and frequency, associated with reduced surface and total GluR2 levels. Neuronal transfection, morphometric analysis, electrophysiology (mEPSC recording), surface biotinylation Journal of neurochemistry Medium 17227435
2008 RAP2A requires palmitoylation for membrane-association and TNIK activation (farnesylated RAP2A, but not geranylgeranylated RAP2B, requires palmitoylation for membrane binding); all RAP2 isoforms require palmitoylation for TNIK-mediated suppression of cell spreading. RAP2 proteins localize to recycling endosomes (not Golgi or ER) in a palmitoylation-dependent manner, where they recruit TNIK. Palmitoylation inhibitor treatment, TNIK activation assay, co-localization by confocal microscopy, subcellular fractionation Biochemical and biophysical research communications Medium 19061864
2008 MINK is a RAP2 effector for phosphorylation of the postsynaptic scaffold TANC1. MINK interacts with RAP2 (not RAP1 or Ras) in a GTP-dependent manner requiring Phe39 in the RAP2 effector region. Both MINK and TNIK phosphorylate TANC1 under control of RAP2 in cultured cells. Affinity chromatography/MS, yeast two-hybrid, co-IP, in vitro phosphorylation assay Biochemical and biophysical research communications Medium 18930710
2008 Constitutively active RAP2 (Rap2V12) transgenic mice display fewer and shorter dendritic spines in CA1 hippocampal neurons, enhanced LTD at CA3-CA1 synapses, reduced basal ERK phosphorylation, impaired spatial learning, and defective fear extinction. This demonstrates that RAP2 opposes Ras-ERK signaling in vivo. Transgenic mouse generation, dendritic spine analysis, LTP/LTD electrophysiology, ERK phosphorylation assay, behavioral testing The Journal of neuroscience High 18701680
2008 RAP2 regulates Activin/Nodal receptor trafficking in Xenopus: in the absence of ligand, RAP2 directs internalized receptors into a recycling pathway preventing degradation and maintaining cell surface levels; upon ligand activation, RAP2 delays receptor turnover. RAP2 contributes to Smad2 activation by antagonizing Smad7. Morpholino knockdown, constitutively active/dominant-negative RAP2 expression, receptor trafficking assays, Smad2 phosphorylation assay in Xenopus embryos Developmental cell Medium 18606140
2009 RasGEF1A and RasGEF1B are highly specific GEFs for RAP2 (but not RAP1 or other Ras subfamily members). Using reciprocal site-directed mutagenesis, Phe39 in the switch I region of RAP2 was identified as the key specificity residue; Rap1(S39F) mutation allows RasGEF1B to exchange nucleotide on RAP1. In vitro GEF assay with purified proteins, site-directed mutagenesis of specificity residues The FEBS journal High 19645719
2010 Nedd4-1, TNIK, and RAP2A form a complex in neurons. Nedd4-1-mediated ubiquitination of RAP2A inhibits RAP2A function, which reduces TNIK family kinase activity and promotes dendrite growth. In Nedd4-1-deficient mice, dendrite formation is impaired, establishing a Nedd4-1/RAP2A/TNIK signaling pathway controlling neurite growth and arborization. Co-immunoprecipitation, ubiquitination assay, conditional knockout mouse analysis, morphometric analysis of neurons Neuron High 20159449
2010 MINK and TNIK are postsynaptic proteins whose clustering is bidirectionally regulated by RAP2 activation state. MINK antagonizes RAP2 signal transduction: Rap2-mediated removal of surface AMPA receptors from spines is abolished by MINK co-expression (but not TNIK). A MINK mutant unable to interact with RAP2 reduces dendritic branching in a RAP2-dependent manner, while equivalent TNIK truncation affects morphology independently of RAP2. Neuronal transfection, surface AMPA receptor assay, dendritic morphometry, dominant-negative constructs The Journal of neuroscience Medium 21048137
2011 RAP2 mediates FGF receptor 1 (FGFR1)-dependent smooth muscle cell (VSMC) migration during arteriogenesis. FGF-2 selectively increases RAP2 (not other Ras family members) activity in VSMCs. siRNA knockdown of RAP2 blocks FGF-2-induced VSMC migration without affecting proliferation. Dominant-negative RAP2 blocks arteriogenesis in vivo; constitutively active RAP2 enhances collateral vessel growth. siRNA knockdown, dominant-negative/constitutively active RAP2 expression, cell migration assay, in vivo rabbit arteriogenesis model Arteriosclerosis, thrombosis, and vascular biology Medium 21737786
2012 RAP2A links intestinal cell polarity to brush border formation through a signaling module: LKB1-induced apical polarity → apical PtdIns(4,5)P2 enrichment → phospholipase D1 recruitment → phosphatidic acid accumulation → PDZGEF activation → RAP2A activation → TNIK activation → MST4 activation → Ezrin activation → brush border formation. Single-cell polarity induction, lipid analysis, siRNA knockdown of pathway components, phosphorylation assays, morphometric analysis Nature cell biology High 22797597
2012 JAM-A trans-dimerization (between cells) activates RAP2: cells expressing cis-null JAM-A (which can only trans-dimerize) show enhanced RAP2 activity, while trans-null JAM-A mutants decrease RAP2 activity. Confluent cells permitting trans-dimerization have enhanced RAP2 activity versus sparse cells. Co-immunoprecipitation, RAP2 activation assay (GTP pulldown), mutagenesis, cell density manipulation Molecular biology of the cell Medium 24672055
2012 Rap2 GTPase participates in the recycling of the extended conformation of LFA-1 in migrating T lymphocytes. siRNA knockdown of RAP2 inhibits both LFA-1 internalization and re-exposure on the plasma membrane, resulting in intracellular accumulation of the extended form of LFA-1 and reduced migration. siRNA knockdown, biotinylated surface LFA-1 tracking, confocal microscopy, migration assay Biology open Medium 23213397
2013 RAP1 and RAP2 antagonistically control endothelial barrier resistance: RAP2 depletion enhances barrier resistance via the Rap2-specific activator RasGEF1C and the effector MAP4K4, establishing an independent pathway; simultaneous depletion of both Rap1 and Rap2 produces a combined neutral effect, demonstrating reciprocal antagonism. siRNA knockdown, electrical impedance measurement of HUVEC monolayer barrier resistance PloS one Medium 23469100
2013 RAP2 regulates the stability of Wnt receptor LRP6: RAP2 knockdown causes proteasome/lysosome-dependent LRP6 degradation. RAP2 and LRP6 physically associate. TNIK acts as downstream effector of RAP2 in controlling LRP6 stabilization and TNIK can rescue the inhibitory effects of RAP2 depletion on Wnt-dependent transcription. siRNA knockdown, co-immunoprecipitation, proteasome/lysosome inhibitor treatment, Wnt reporter assay Biochemical and biophysical research communications Medium 23743195
2014 RAP2A isoform specificity during intestinal brush border formation is determined by two mechanisms: (1) RAP2C is spatially segregated (not enriched at apical membrane); (2) RAP2B localizes like RAP2A at Rab11-positive apical recycling endosomes but is not equally activated. Selective activation of RAP2A is conferred by its C-terminal hypervariable region, independent of differential lipid modifications. Confocal microscopy, Rap2 activation assay, chimeric protein/mutagenesis analysis, subcellular fractionation PloS one Medium 25203140
2015 RAP2A is a novel transcriptional target of p53: upon DNA damage, p53 directly binds the RAP2A promoter and activates its transcription. Ectopic RAP2A expression enhances cancer cell migration and invasion, increases MMP2/MMP9 activity, and increases AKT phosphorylation; RAP2A inactivation has opposite effects. ChIP assay for p53 promoter binding, reporter assay, overexpression/siRNA knockdown, invasion assay, zymography, Western blot Cellular signalling Medium 25728512
2016 miR-9 and miR-124 synergistically target RAP2A: neither alone sufficiently suppresses RAP2A, but together they strongly reduce RAP2A expression. RAP2A diminishes dendritic complexity of mature neurons by decreasing pAKT and pGSK3β levels; miR-9/miR-124 co-expression promotes neuronal differentiation and dendritic branching by suppressing RAP2A. Luciferase reporter assay (3'UTR targeting), Western blot, RAP2A overexpression/knockdown, morphometric dendritic analysis Scientific reports Medium 27221778
2017 Epac2 is the upstream GEF and RAP2A is the obligate GEF substrate/effector mediating cAMP-dependent growth arrest through p38 MAP kinase activation in NS-1 neuroendocrine cells. This pathway is distinct from PKA- and RAPGEF2-mediated cAMP outputs in the same cells. Epac2 and RAP2A knockdown/overexpression, p38 phosphorylation assay, cell growth assay, pharmacological dissection of cAMP sensors The Journal of biological chemistry Medium 28546426
2018 RAP2 is a key mechanotransducer in the Hippo pathway: low ECM stiffness activates RAP2 through PLCγ1-mediated changes in PtdIns(4,5)P2/phosphatidic acid levels and PDZGEF1/PDZGEF2. Active RAP2 binds and stimulates MAP4K4, MAP4K6, MAP4K7, and ARHGAP29, leading to LATS1/2 activation and YAP/TAZ inhibition. RAP2 deletion blocks stiffness-dependent YAP/TAZ regulation and promotes aberrant cell growth. RAP2 knockout (CRISPR), RAP2 activation assay, Co-IP with MAP4Ks, LATS1/2 kinase assay, YAP/TAZ reporter assay, transcriptome analysis Nature High 30135582
2018 In C. elegans, RAP-2 and its effector TNIK (mig-15) act genetically downstream of Plexin (plx-1) to restrict presynaptic assembly and form tiled synaptic innervation. PLX-1 suppresses local RAP-2 activity; both constitutively GTP- and GDP-locked rap-2 mutants display tiling defects, indicating that RAP-2 nucleotide cycling (not simply active or inactive state) is critical for synapse inhibition. C. elegans genetics, constitutively active/GDP-locked mutations, epistasis analysis, synaptic marker imaging eLife High 30063210
2019 MIA-induced upregulation of ISG15 in offspring brain suppresses RAP2A ubiquitination via NEDD4 (reducing NEDD4-mediated ubiquitination of RAP2A), thereby causing RAP2A accumulation that impairs dendrite development and causes depressive-like behaviors. Upregulating NEDD4 abolished ISG15-induced dendrite impairments. AAV/lentiviral overexpression and silencing in rat brain, ubiquitination assay, confocal microscopy, Golgi staining, behavioral tests Biochimica et biophysica acta. Molecular basis of disease Medium 30826466
2022 The Rab40b/Cullin5 E3 ubiquitin ligase complex ubiquitylates RAP2A. This ubiquitylation regulates RAP2A activation and its recycling from the endolysosomal compartment to the lamellipodia of migrating breast cancer cells, controlling RAP2A-dependent actin dynamics at the leading edge and breast cancer cell migration/invasion. Co-IP, ubiquitylation assay, Rab40b/Cullin5 KO, confocal live imaging, cell migration/invasion assay The Journal of cell biology High 35293963
2022 RAP2A loss aggravates cartilage degradation in TMJ osteoarthritis via the Hippo/YAP pathway. RAP2A in chondrocytes directly regulates the Hippo/YAP pathway in response to matrix stiffness; conditional RAP2A KO mice show severe cartilage degeneration and RAP2A/Hippo/YAP signaling controls chondrocyte phenotype switch and matrix synthesis. Cre-loxP conditional KO mouse model, unilateral anterior crossbite TMJOA model, YAP pathway analysis, matrix stiffness assay Journal of dental research Medium 36366779
2024 RAP2 GTPase acts as a central integrator of cytoskeletal signals for Hippo signaling: RAP2 deletion abrogates LATS1/2 activation by RhoA inhibitors, actin disruptors, and microtubule-stabilizing agents (Taxol). RNA-seq revealed differential regulation of actin and microtubule networks by RAP2 deletion. RAP2 functions upstream of MAP4K4/6/7 in transducing cytoskeletal perturbations to LATS1/2. RAP2 and MAP4K4/6/7 CRISPR KO, pharmacological cytoskeletal perturbations, LATS1/2 kinase assay, RNA-seq The Journal of biological chemistry High 38574891
2025 RAP2A promotes cardiac fibrosis via the TNIK/Merlin/YAP signaling axis: RAP2A binds TNIK in myocardial fibroblasts and enhances TNIK expression; this activates downstream Merlin/YAP signaling to promote myofibroblast transformation, proliferation, and migration of cardiac fibroblasts. RAP2A deficiency relieves myocardial infarction in mice. Co-IP, RAP2A knockdown/KO mouse, CF proliferation/migration/phenotype assays, Merlin/YAP pathway analysis Cell biology and toxicology Medium 40332594

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1988 Human cDNAs rap1 and rap2 homologous to the Drosophila gene Dras3 encode proteins closely related to ras in the 'effector' region. Oncogene 356 3045729
2018 RAP2 mediates mechanoresponses of the Hippo pathway. Nature 317 30135582
2010 Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development. Neuron 176 20159449
2005 Rap2-JNK removes synaptic AMPA receptors during depotentiation. Neuron 176 15953419
2015 The low oxygen, oxidative and osmotic stress responses synergistically act through the ethylene response factor VII genes RAP2.12, RAP2.2 and RAP2.3. The Plant journal : for cell and molecular biology 154 25847219
1994 Association of Rap1a and Rap1b proteins with late endocytic/phagocytic compartments and Rap2a with the Golgi complex. Journal of cell science 148 7962206
2004 The Traf2- and Nck-interacting kinase as a putative effector of Rap2 to regulate actin cytoskeleton. The Journal of biological chemistry 143 15342639
1999 PDZ-GEF1, a guanine nucleotide exchange factor specific for Rap1 and Rap2. The Journal of biological chemistry 108 10608883
2000 RAP1 controls rhoptry targeting of RAP2 in the malaria parasite Plasmodium falciparum. The EMBO journal 104 10835342
2004 Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase. The Journal of biological chemistry 102 14966141
1992 Association of rap1 and rap2 proteins with the specific granules of human neutrophils. Translocation to the plasma membrane during cell activation. The Journal of biological chemistry 100 1556142
2002 The Rap GTPases regulate B cell migration toward the chemokine stromal cell-derived factor-1 (CXCL12): potential role for Rap2 in promoting B cell migration. Journal of immunology (Baltimore, Md. : 1950) 98 12133960
2000 Rap2 as a slowly responding molecular switch in the Rap1 signaling cascade. Molecular and cellular biology 96 10913189
2012 Rap2A links intestinal cell polarity to brush border formation. Nature cell biology 91 22797597
2015 The stability and nuclear localization of the transcription factor RAP2.12 are dynamically regulated by oxygen concentration. Plant, cell & environment 87 25438831
2008 Constitutively active Rap2 transgenic mice display fewer dendritic spines, reduced extracellular signal-regulated kinase signaling, enhanced long-term depression, and impaired spatial learning and fear extinction. The Journal of neuroscience : the official journal of the Society for Neuroscience 80 18701680
2007 Differential roles of Rap1 and Rap2 small GTPases in neurite retraction and synapse elimination in hippocampal spiny neurons. Journal of neurochemistry 73 17227435
2016 Oxygen Sensing via the Ethylene Response Transcription Factor RAP2.12 Affects Plant Metabolism and Performance under Both Normoxia and Hypoxia. Plant physiology 70 27372243
2010 MINK and TNIK differentially act on Rap2-mediated signal transduction to regulate neuronal structure and AMPA receptor function. The Journal of neuroscience : the official journal of the Society for Neuroscience 66 21048137
2012 RAP2.6L overexpression delays waterlogging induced premature senescence by increasing stomatal closure more than antioxidant enzyme activity. Plant molecular biology 65 22661072
2016 miR-9 and miR-124 synergistically affect regulation of dendritic branching via the AKT/GSK3β pathway by targeting Rap2a. Scientific reports 63 27221778
1997 Crystal structures of the small G protein Rap2A in complex with its substrate GTP, with GDP and with GTPgammaS. The EMBO journal 63 9312017
1999 Identification and characterization of potential effector molecules of the Ras-related GTPase Rap2. The Journal of biological chemistry 52 10085114
1991 The cAMP-dependent protein kinase phosphorylates the rap1 protein in vitro as well as in intact fibroblasts, but not the closely related rap2 protein. Biochemical and biophysical research communications 52 1902091
1998 Identification of a specific effector of the small GTP-binding protein Rap2. European journal of biochemistry 48 9523700
2018 Disrupting CD147-RAP2 interaction abrogates erythrocyte invasion by Plasmodium falciparum. Blood 42 29352039
2013 Rap1 and Rap2 antagonistically control endothelial barrier resistance. PloS one 41 23469100
2008 Rap2 function requires palmitoylation and recycling endosome localization. Biochemical and biophysical research communications 41 19061864
2008 MINK is a Rap2 effector for phosphorylation of the postsynaptic scaffold protein TANC1. Biochemical and biophysical research communications 37 18930710
1993 Prenyl group identification of rap2 proteins: a ras superfamily member other than ras that is farnesylated. The Biochemical journal 37 8424780
2012 A role for Rap2 in recycling the extended conformation of LFA-1 during T cell migration. Biology open 34 23213397
2006 Crystal structure of the RUN domain of the RAP2-interacting protein x. The Journal of biological chemistry 34 16928684
1990 Chromosome mapping of the human RAS-related RAP1A, RAP1B, and RAP2 genes to chromosomes 1p12----p13, 12q14, and 13q34, respectively. Cytogenetics and cell genetics 34 2108841
2005 Rap2 is required for Wnt/beta-catenin signaling pathway in Xenopus early development. The EMBO journal 33 15706349
1992 Generation of specific antibodies against the rap1A, rap1B and rap2 small GTP-binding proteins. Analysis of rap and ras proteins in membranes from mammalian cells. European journal of biochemistry 33 1628649
2015 Rap2a is a novel target gene of p53 and regulates cancer cell migration and invasion. Cellular signalling 32 25728512
2014 Trans-dimerization of JAM-A regulates Rap2 and is mediated by a domain that is distinct from the cis-dimerization interface. Molecular biology of the cell 32 24672055
1991 Effects of the ras-related rap2 protein on cellular proliferation. International journal of cancer 32 1833345
1991 Post-translational processing and subcellular localization of the Ras-related Rap2 protein. Oncogene 32 1923507
1993 Localization of rap1 and rap2 proteins in the gelatinase-containing granules of human neutrophils. FEBS letters 31 8391995
2008 Regulation of activin/nodal signaling by Rap2-directed receptor trafficking. Developmental cell 30 18606140
2005 PARG1, a protein-tyrosine phosphatase-associated RhoGAP, as a putative Rap2 effector. Biochemical and biophysical research communications 30 15752761
2009 RasGEF1A and RasGEF1B are guanine nucleotide exchange factors that discriminate between Rap GTP-binding proteins and mediate Rap2-specific nucleotide exchange. The FEBS journal 29 19645719
1991 The product of the rap2 gene, member of the ras superfamily. Biochemical characterization and site-directed mutagenesis. The Journal of biological chemistry 29 1900290
2018 ALTERED MERISTEM PROGRAM1 Restricts Shoot Meristem Proliferation and Regeneration by Limiting HD-ZIP III-Mediated Expression of RAP2.6L. Plant physiology 28 29884678
2019 Inflammation-dependent ISG15 upregulation mediates MIA-induced dendrite damages and depression by disrupting NEDD4/Rap2A signaling. Biochimica et biophysica acta. Molecular basis of disease 27 30826466
2011 Induction of smooth muscle cell migration during arteriogenesis is mediated by Rap2. Arteriosclerosis, thrombosis, and vascular biology 26 21737786
1991 Isoprenylation of rap2 proteins in platelets and human erythroleukemia cells. The Journal of biological chemistry 26 1900292
2018 Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans. eLife 24 30063210
2006 Nitric oxide produced in response to engagement of beta2 integrins on human neutrophils activates the monomeric GTPases Rap1 and Rap2 and promotes adhesion. The Journal of biological chemistry 24 16963453
2022 Ubiquitylation by Rab40b/Cul5 regulates Rap2 localization and activity during cell migration. The Journal of cell biology 23 35293963
2007 Rap2 regulates androgen sensitivity in human prostate cancer cells. The Prostate 23 17918750
2007 SPAR2, a novel SPAR-related protein with GAP activity for Rap1 and Rap2. Journal of neurochemistry 23 17961154
2017 Regulation of glioma migration and invasion via modification of Rap2a activity by the ubiquitin ligase Nedd4-1. Oncology reports 22 28405688
2020 The Suppression of miR-199a-3p by Promoter Methylation Contributes to Papillary Thyroid Carcinoma Aggressiveness by Targeting RAP2a and DNMT3a. Frontiers in cell and developmental biology 21 33365310
2017 Sumoylation stabilizes RACK1B and enhance its interaction with RAP2.6 in the abscisic acid response. Scientific reports 21 28272518
2017 Guanine nucleotide exchange factor Epac2-dependent activation of the GTP-binding protein Rap2A mediates cAMP-dependent growth arrest in neuroendocrine cells. The Journal of biological chemistry 20 28546426
1992 Regulation of the GTPase activity of the ras-related rap2 protein. Biochemical and biophysical research communications 19 1449497
2013 Over-expression of Rap2a inhibits glioma migration and invasion by down-regulating p-AKT. Cell biology international 18 24293123
2011 Rap2A Is Upregulated in Invasive Cells Dissected from Follicular Thyroid Cancer. Journal of thyroid research 18 22046576
2006 Biochemical characterization of RGS14: RGS14 activity towards G-protein alpha subunits is independent of its binding to Rap2A. The Biochemical journal 17 16246175
2013 Role of the Rap2/TNIK kinase pathway in regulation of LRP6 stability for Wnt signaling. Biochemical and biophysical research communications 16 23743195
1999 Interaction of the low-molecular-weight GTP-binding protein rap2 with the platelet cytoskeleton is mediated by direct binding to the actin filaments. Journal of cellular biochemistry 16 10572250
2020 lncRNA FLVCR1‑AS1 drives colorectal cancer progression via modulation of the miR‑381/RAP2A axis. Molecular medicine reports 15 33313944
2016 β-Arrestin 1-dependent regulation of Rap2 is required for fMLP-stimulated chemotaxis in neutrophil-like HL-60 cells. Journal of leukocyte biology 15 27493245
2004 Plasmodium falciparum: red blood cell binding studies using peptides derived from rhoptry-associated protein 2 (RAP2). Biochimie 15 14987794
2022 Loss of RAP2A Aggravates Cartilage Degradation in TMJOA via YAP Signaling. Journal of dental research 14 36366779
1999 Structure of the small G protein Rap2 in a non-catalytic complex with GTP. Proteins 14 10591105
2020 MiR-140 targets RAP2A to enable the proliferation of insulin-treated ovarian granulosa cells. Journal of ovarian research 13 32024547
2020 LINC00319-Mediated miR-3127 Repression Enhances Bladder Cancer Progression Through Upregulation of RAP2A. Frontiers in genetics 13 32194636
2019 Characterization of Brassica rapa RAP2.4-Related Proteins in Stress Response and as CUL3-Dependent E3 Ligase Substrates. Cells 13 30974760
2018 Phosphorylation of synaptic GTPase-activating protein (synGAP) by polo-like kinase (Plk2) alters the ratio of its GAP activity toward HRas, Rap1 and Rap2 GTPases. Biochemical and biophysical research communications 13 30049443
2016 RAP2.4a Is Transported through the Phloem to Regulate Cold and Heat Tolerance in Papaya Tree (Carica papaya cv. Maradol): Implications for Protection Against Abiotic Stress. PloS one 13 27764197
2015 PSD-Zip70 Deficiency Causes Prefrontal Hypofunction Associated with Glutamatergic Synapse Maturation Defects by Dysregulation of Rap2 Activity. The Journal of neuroscience : the official journal of the Society for Neuroscience 13 26490870
2021 Tumor suppressive role of miR-33a-5p in pancreatic ductal adenocarcinoma cells by directly targeting RAP2A. Cellular & molecular biology letters 12 34090323
2003 Cloning, expression, and genomic structure of a novel human Rap2 interacting gene (RPIP9). Biochemical genetics 12 12645870
1998 A study of antibody and T cell recognition of rhoptry-associated protein-1 (RAP-1) and RAP-2 recombinant proteins and peptides of Plasmodium falciparum in migrants and residents of the state of Rondonia, Brazil. The American journal of tropical medicine and hygiene 12 9715934
2019 The ACBP1-RAP2.12 signalling hub: A new perspective on integrative signalling during hypoxia in plants. Plant signaling & behavior 10 31397636
2014 Mechanisms of isoform specific Rap2 signaling during enterocytic brush border formation. PloS one 10 25203140
2021 Long Non-Coding RNA LINC01569 Promotes Proliferation and Metastasis in Colorectal Cancer by miR-381-3p/RAP2A Axis. Frontiers in oncology 9 34422671
2011 Molecular cloning and characterization of a novel ras-related protein (rap2) from Clonorchis sinensis. Parasitology research 9 21061020
2006 Rap2, but not Rap1 GTPase is expressed in human red blood cells and is involved in vesiculation. Biochimica et biophysica acta 9 16540189
2021 RAP2A promotes apoptosis resistance of hepatocellular carcinoma cells via the mTOR pathway. Clinical and experimental medicine 8 34018090
2024 Interplay of RAP2 GTPase and the cytoskeleton in Hippo pathway regulation. The Journal of biological chemistry 7 38574891
2022 Circ_0001667 Promotes Adriamycin Resistance and Malignant Progression via Targeting the miR-193a-5p/Rap2A Molecular Axis in Breast Cancer. Clinical breast cancer 7 36289041
2023 Artemisia carvifolia Buch silver nanoparticles downregulate the Rap2A gene in liver cancer. Scientific reports 6 38057542
2020 Social Stress-Induced Postsynaptic Hyporesponsiveness in Glutamatergic Synapses Is Mediated by PSD-Zip70-Rap2 Pathway and Relates to Anxiety-Like Behaviors. Frontiers in cellular neuroscience 5 31969804
1994 Characterization of the Ras-related RAP2A protein expressed in the baculovirus-insect cell system: processing of the protein in insect cells and comparison with the bacterially produced unprocessed form. Biochemical and biophysical research communications 5 8117305
2024 RAP-2 and CNH-MAP4 Kinase MIG-15 confer resistance in bystander epithelium to cell-fate transformation by excess Ras or Notch activity. Proceedings of the National Academy of Sciences of the United States of America 4 39739816
2022 TGF-β1-induced RAP2 regulates invasion in pancreatic cancer. Acta biochimica et biophysica Sinica 4 35538031
2021 Computational investigation of phytoalexins as potential antiviral RAP-1 and RAP-2 (Replication Associated Proteins) inhibitor for the management of cucumber mosaic virus (CMV): a molecular modeling, in silico docking and MM-GBSA study. Journal of biomolecular structure & dynamics 4 34463218
2020 Metformin Decreases Insulin Resistance in Type 1 Diabetes Through Regulating p53 and RAP2A in vitro and in vivo. Drug design, development and therapy 4 32606605
2014 [Identification analysis of eukaryotic expression plasmid Rap2a and its effect on the migration of lung cancer cells]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 4 25248704
2025 Rap2a promotes cardiac fibrosis and exacerbates myocardial infarction through the TNIK/Merlin/YAP axis. Cell biology and toxicology 3 40332594
2025 BRAF regulates circPSD3/miR-526b/RAP2A axis to hinder papillary thyroid carcinoma progression. BMC molecular and cell biology 2 39838328
2025 [Expression of Concern] lncRNA FLVCR1‑AS1 drives colorectal cancer progression via modulation of the miR‑381/RAP2A axis. Molecular medicine reports 2 41384308
2024 LINC00963 Represses Osteogenic Differentiation of hBMSCs via the miR-10b-5p/RAP2A/AKT Axis. International journal of sports medicine 2 39068933
2022 Simulated Microgravity Increases the Permeability of HUVEC Monolayer through Up-Regulation of Rap1GAP and Decreased Rap2 Activation. International journal of molecular sciences 2 35054818
2022 miR-33a-5p Targets RAP2A to Mediate the Sensitivity of Gastric Cancer Cells to 5-FU. Disease markers 2 36046374
2019 Data in support of Rap2a GTPase expression, activation and effects in LPS-mediated innate immune response and NF-κB activation. Data in brief 2 31193517

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