Affinage

RAP1A

Ras-related protein Rap-1A · UniProt P62834

Length
184 aa
Mass
21.0 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAP1A is a Ras-family small GTPase that cycles between GDP- and GTP-bound states to act as a signaling hub for cell adhesion, integrin activation, and vascular morphogenesis (PMID:11836528, PMID:16382154). It is geranylgeranylated at its C-terminus, a modification distinct from the farnesylation of H-Ras that is required for membrane association and downstream activity, and which depends on smgGDS engagement of its C-terminal polybasic region (PMID:1899909, PMID:1501882, PMID:36001955). RAP1A nucleotide cycling is governed by a dedicated regulatory circuit: a Rap1-specific GAP that stimulates its GTPase but does not act on Ras, with GAP specificity dictated by effector-domain residues including Thr35 (PMID:1904317, PMID:2160589). Structurally, GTP-loaded RAP1A engages effector Ras-binding domains through an antiparallel beta-sheet between its switch I region and the effector, the basis of its overlapping yet distinct effector repertoire relative to Ras (PMID:7791872). RAP1A binds tightly to Ras-GAP and to the Raf-1 cysteine-rich region, thereby competitively antagonizing Ras-driven Raf-1 activation and transformation; PKA phosphorylation at Ser-180 abolishes Raf-1 CRR binding and abrogates this suppressive function (PMID:2164710, PMID:9115221, PMID:9867809, PMID:2115210). Beyond Ras antagonism, RAP1A selectively engages effectors such as RalGEF, KRIT1, and AF-6/afadin (PMID:8636102, PMID:9285558, PMID:10922060). In leukocytes it drives inside-out activation of β1, β2, α4β1, and αLβ2 integrins through CalDAG-GEFI and effectors RIAM and Radil to control adhesion, polarization, chemotaxis, and selectin-dependent rolling (PMID:11836528, PMID:16382154, PMID:23565202, PMID:21480213, PMID:20048162). RAP1A associates with cytochrome b558 of the NADPH oxidase and supports phagocyte superoxide production through GDP/GTP cycling (PMID:1763330, PMID:1312373, PMID:1906890, PMID:7833480). In the endothelium and lymphatics it is the predominant isoform for junctional integrity and barrier function, is required for FGF2-induced angiogenesis and lymphatic development, and restrains store-operated calcium entry through Orai1 to limit inflammatory signaling (PMID:21776404, PMID:18625726, PMID:30354217, PMID:39324266). Mutations in the RAP1A-binding effector KRIT1 cause cerebral cavernous malformations, linking this pathway to cerebrovascular disease (PMID:10545614).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1990 High

    Establishing how Krev-1/Rap1A suppresses Ras transformation showed it acts by competing for Ras regulatory and effector interactions rather than by enzymatic activation.

    Evidence in vitro GTPase/competitive inhibition with purified proteins, plus Ras-Krev-1 chimera transformation assays in NIH 3T3 cells

    PMID:2115210 PMID:2164710

    Open questions at the time
    • Did not identify the dedicated GAP/GEF circuit
    • Did not establish the physiological effectors mediating suppression
  2. 1991 High

    Defining Rap1A's distinct regulatory and processing machinery established it as an autonomous GTPase circuit separate from Ras.

    Evidence purification of a Rap1-specific GAP from bovine brain, geranylgeranylation identified by mevalonate labeling, T35A mutant showing effector-domain control of GAP specificity, and chimera mapping of GAP-sensitivity residues

    PMID:1749934 PMID:1899909 PMID:1904317 PMID:2160589

    Open questions at the time
    • GEFs activating Rap1A in vivo not yet defined
    • Physiological output of the cycle not established
  3. 1991 High

    Identifying Ser-180 as the PKA phosphorylation site and the cytochrome b558 association provided the first regulated functional readouts of Rap1A in phagocytes.

    Evidence 32P-labeling, sequencing and S180 mutagenesis in neutrophils; stoichiometric co-purification with cytochrome b558 and nucleotide/phosphorylation-dependent binding; Golgi localization by immunofluorescence

    PMID:1763330 PMID:1900364 PMID:1908879

    Open questions at the time
    • Functional consequence of Ser-180 phosphorylation not yet mapped to a specific effector
    • Mechanism coupling Rap1A to oxidase assembly unresolved
  4. 1992 Medium

    Reconstitution and mutant studies established that Rap1A GDP/GTP cycling is functionally required for NADPH oxidase activation, not merely correlated with it.

    Evidence reconstitution of immunodepleted neutrophil cytosol with recombinant Krev-1, blocking-antibody experiments, dominant-negative/constitutively-active Rap1A in HL60 cells, and immunoEM cotranslocation with cytochrome b

    PMID:1312373 PMID:1906890 PMID:7833480

    Open questions at the time
    • GEF/GAP controlling oxidase-linked cycling not identified
    • Direct catalytic contribution of Rap1A to electron transfer unresolved
  5. 1996 High

    Quantitative effector binding distinguished the Rap1A and Ras effector repertoires, showing RalGEF binds Rap1A preferentially while Raf binds Ras.

    Evidence in vitro nucleotide-dissociation binding assays with KD measurements and D38A effector mutant

    PMID:8636102

    Open questions at the time
    • Cellular consequences of Rap1A-RalGEF engagement not addressed
    • In vivo relevance of effector partitioning not tested
  6. 1997 High

    Mapping Rap1A binding to the Raf-1 cysteine-rich region provided a structural mechanism for Ras antagonism, refined by the Rap1A-Raf RBD crystal structure.

    Evidence in vitro binding and Raf-1 kinase activation assays with mutagenesis; 2.2 Å crystal structure of GppNHp-Rap1A with Raf RBD

    PMID:7791872 PMID:9115221

    Open questions at the time
    • Whether CRR binding occurs at endogenous protein levels not shown
    • Structural basis of full-length Raf engagement incomplete
  7. 1999 High

    PKA phosphorylation at Ser-180 was shown to abolish Raf-1 CRR binding and Ras-suppressive function, linking cAMP signaling to control of Rap1A's anti-Ras activity.

    Evidence in vitro binding and S180E phosphomimetic mutant with Raf-1 kinase assay in COS-7 cells

    PMID:9867809

    Open questions at the time
    • In vivo kinetics of Ser-180 phosphorylation not quantified
    • Effect on other Rap1A effectors not examined
  8. 1999 Medium

    Two-hybrid and positional cloning identified KRIT1 as a specific Rap1A effector and tied the pathway to cerebral cavernous malformations.

    Evidence yeast two-hybrid screen and positional cloning with mutation identification in CCM1 families

    PMID:10545614 PMID:9285558

    Open questions at the time
    • Interaction validated mainly by two-hybrid
    • Mechanism by which Rap1A-KRIT1 signaling prevents malformations not established
  9. 2002 High

    Transgenic and knockout mouse studies reframed Rap1A's principal in vivo role from Ras antagonist to integrin activator controlling lymphocyte adhesion and polarization.

    Evidence constitutively active Rap1A transgenic T cells and homologous-recombination Rap1A knockout with adhesion and polarization assays

    PMID:11836528 PMID:16382154

    Open questions at the time
    • Effectors linking Rap1A to integrins not fully defined in these studies
    • Distinction from Rap1B not yet addressed
  10. 2007 High

    Clean Rap1a knockout established non-redundant, isoform-specific roles in myeloid/lymphoid adhesion, chemotaxis, phagocytosis, and superoxide production.

    Evidence Rap1a gene deletion with haptotaxis, chemotaxis, phagocytosis, and superoxide assays

    PMID:18056377

    Open questions at the time
    • Molecular basis of opposing adhesion/haptotaxis phenotypes unresolved
    • Compensation by Rap1b not fully delineated
  11. 2013 Medium

    Defining the upstream GEF cascades and effector adaptors clarified how Rap1A converts receptor signals into integrin activation during leukocyte trafficking.

    Evidence Gβγ-Rap1A-Radil complex co-IP and translocation imaging; CalDAG-GEFI/p38 epistasis in knockout mice with intravital microscopy; PI3Kγ-CalDAG-GEFI-RIAM epistasis in tumor recruitment models; KIF14-Radil tethering studies

    PMID:20048162 PMID:21480213 PMID:23209302 PMID:23565202

    Open questions at the time
    • Relative contributions of distinct GEFs in different cell types unresolved
    • Structural basis of Radil/RIAM recruitment not defined
  12. 2018 High

    Vascular and lymphatic genetic models established Rap1A as the predominant isoform for endothelial junction integrity, angiogenesis, and lymphatic development.

    Evidence FGF2 Matrigel/aortic-ring assays in Rap1a knockouts; isoform-specific knockdown with impedance and VE-cadherin imaging; conditional lymphatic-EC knockout with developmental phenotyping

    PMID:18625726 PMID:21776404 PMID:30354217

    Open questions at the time
    • Junctional effector(s) downstream of Rap1A only partly defined (AF-6)
    • Mechanism distinguishing Rap1A from Rap1B at junctions incompletely resolved
  13. 2020 High

    Structural and biochemical work defined how Rap1A allosterically activates PLCε, identifying a new direct effector mechanism.

    Evidence in vitro PLCε activity assays with RA2/PH/EF-hand mutagenesis and SAXS conformational analysis

    PMID:32948655

    Open questions at the time
    • High-resolution structure of the active complex lacking
    • Cellular signaling consequences of PLCε activation by Rap1A not mapped
  14. 2024 Medium

    Recent work expanded Rap1A's endothelial role to restraint of store-operated calcium entry and metabolic control of hepatic gluconeogenesis.

    Evidence EC-specific Rap1A knockout with patch-clamp CRAC current, Orai1 rescue, and NFAT assays; hepatocyte Rap1a silencing/overexpression with glucose production, actin polymerization, Akt/FoxO1 readouts and statin/geranylgeraniol rescue

    PMID:36001955 PMID:39324266

    Open questions at the time
    • Molecular link between Rap1A and Orai1 regulation not defined
    • Effectors mediating actin-dependent Akt/FoxO1 control in hepatocytes unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dozens of Rap1A effectors and isoform-specific functions are coordinated and spatially partitioned across cell types remains unresolved.
  • No unified map of effector selection across tissues
  • GEF/GAP determinants of context-specific Rap1A versus Rap1B output unknown
  • Structures of Rap1A bound to integrin-activation effectors (RIAM/Radil) lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1474244 Extracellular matrix organization 2
Partners
KRIT1MLLT4PLCE1RADILRAF1RALGDSRAP1GAPRASA1
Complex memberships
NADPH oxidase (cytochrome b558 complex)

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Crystal structure of Rap1A (GppNHp-bound) in complex with the Ras-binding domain (RBD) of c-Raf1 resolved to 2.2 Å, showing that RBD adopts a ubiquitin superfold and that the interaction is mediated by an antiparallel beta-sheet formed between RBD strands B1-B2 and Rap1A strands β2-β3, with switch I effector residues of Rap1A providing main-chain and side-chain contacts. X-ray crystallography (2.2 Å resolution) Nature High 7791872
1990 Rap1A-p21 (Krev-1 product) binds tightly to Ras-GAP in a GTP-dependent manner but is not activated by GAP; it competitively inhibits GAP-mediated Ras GTPase activity, suggesting the mechanism by which Krev-1 suppresses Ras transformation. In vitro GTPase activity assay, competitive inhibition kinetics with purified proteins Science High 2164710
1991 Rap1A is specifically activated (GTPase stimulated) by a dedicated Rap1-GAP purified from bovine brain (rap1GAP, 85–95 kDa); this GAP does not act on p21ras and is distinct from Ras-GAP, establishing a separate regulatory circuit for Rap1A. Biochemical purification from bovine brain, cDNA cloning, expression in Sf9 cells, in vitro GTPase stimulation assay Cell High 1904317
1991 Rap1A is geranylgeranylated (C20 isoprenoid) at its COOH terminus in insect cells, in contrast to H-Ras which carries a farnesyl (C15) group, indicating that Rap1A is modified by a prenyl transferase distinct from farnesyl transferase; this COOH-terminal modification is required for membrane association. [3H]mevalonate labeling, baculovirus/Sf9 expression, SDS-PAGE, biochemical characterization of prenyl group Molecular and cellular biology High 1899909
1991 Rap1A associates stoichiometrically with cytochrome b558 (the membrane component of the NADPH oxidase system) in human neutrophils; GTP-bound Rap1A binds more tightly than GDP-bound form; phosphorylation of Rap1A by cAMP-dependent protein kinase (PKA) inhibits this binding. Biochemical co-purification, GTP-γS binding, in vitro PKA phosphorylation, binding assay with purified components Science High 1763330
1991 Rap1A is phosphorylated by cAMP-dependent protein kinase (PKA) on serine-180 in human neutrophils; this was established by amino acid sequence analysis of the purified protein, immunoprecipitation with a Rap1A-specific antibody, and mutagenesis of Ser-180. Electroporated neutrophils, [γ-32P]ATP labeling, immunoprecipitation, amino acid sequencing, carboxypeptidase digestion, site-directed mutagenesis (S180 mutant) Journal of immunology High 1908879
1990 Ras-Krev-1 chimera studies mapped the transformation-suppressing activity of Krev-1/Rap1A to a small cluster of amino acids immediately surrounding the effector domain (residues 32–44), suggesting Krev-1 suppresses Ras transformation by competing for Ras effector interactions. Chimeric protein construction, NIH 3T3 transformation assay, focus formation Science High 2115210
1991 A recombinant Rap1A with a Thr35→Ala mutation is unresponsive to Rap-GAP stimulation of GTPase activity, whereas wild-type Rap1A is activated by cytosolic Rap-GAP but not by Ras-GAP, demonstrating that the effector domain mediates GAP specificity. Baculovirus expression, in vitro GTPase assay, site-directed mutagenesis (T35A) Molecular and cellular biology High 2160589
1996 Rap1A binds the Ras-binding domain of Ral-GEF (RGF-RBD) with high affinity (KD ~low nM range vs. ~1 µM for H-Ras), while H-Ras binds Raf-RBD with high affinity; binding of RGF-RBD to Rap1A is blocked by the D38A effector mutation and inhibits Rap-GAP interaction, indicating RalGEF is an effector of Rap1A rather than H-Ras. In vitro binding assay (guanine nucleotide dissociation inhibition), deletion mapping, mutagenesis (D38A), quantitative KD measurements The Journal of biological chemistry High 8636102
1997 Rap1A/Krev-1 binds strongly to a novel ankyrin repeat protein KRIT1 in a yeast two-hybrid screen; KRIT1 interacted with Krev-1 but only weakly with Ras, suggesting it is a specific Krev-1 effector. KRIT1 maps to 7q21-22 and is later identified as the CCM1 gene. Yeast two-hybrid screen of HeLa cDNA library, domain mapping Oncogene Medium 9285558
1999 Mutations in KRIT1, the Krev-1/Rap1A-binding protein identified by two-hybrid, cause cerebral cavernous malformations (CCM1), establishing a direct link between the Rap1A signaling pathway and cerebrovascular disease/angiogenesis. Positional cloning, mutation identification in 23 CCM1 families, yeast two-hybrid confirmation of KRIT1-Rap1A interaction Human molecular genetics Medium 10545614
1991 Rap1A proteins are localized to the Golgi complex in mammalian cells; they do not colocalize with Ras proteins on the plasma membrane; this localization is conferred by the C-terminal CAAX region and is distinct from Ras. Indirect immunofluorescence (anti-Rap1 peptide antibodies), subcellular fractionation Proceedings of the National Academy of Sciences of the United States of America Medium 1900364
1994 Rap1A and Rap1B proteins localize to late endocytic compartments (late endosomes/lysosomes) in fibroblasts, and also associate with phagosomes in macrophages, implicating Rap1A in late endocytic/phagocytic processes. Confocal immunofluorescence microscopy, subcellular fractionation, vaccinia T7 overexpression system Journal of cell science Medium 7962206
1992 Rap1A colocalizes with cytochrome b558 in plasma membrane and specific granule membranes of resting neutrophils; upon PMA stimulation, Rap1A cotranslocates with cytochrome b to the plasma membrane and to phagolysosomal membranes during phagocytosis. Subcellular fractionation, Western blotting, immunoelectron microscopy (double-labeling), quantitative ultrastructural analysis Blood High 1312373
1997 Rap1A binds the cysteine-rich region (CRR, residues 152-184) of Raf-1 with greatly enhanced affinity compared to Ha-Ras; this leads to co-association of Rap1A and Ha-Ras with Raf-1 N-terminus through CRR and RBD respectively, and Rap1A thereby interferes with Ras-dependent Raf-1 activation. In vitro binding assay, Sf9 baculovirus co-expression, Raf-1 kinase activation assay, mutagenesis (N26G, V45E, E31K) The Journal of biological chemistry High 9115221
1999 PKA phosphorylation of Rap1A at Ser-180 abolishes its binding to the Raf-1 cysteine-rich region (CRR) and prevents Rap1A from suppressing Ras-dependent Raf-1 activation; a phosphomimetic mutant S180E recapitulates this loss of suppressive function in COS-7 cells. In vitro binding assay, site-directed mutagenesis (S180E phosphomimetic), COS-7 cell co-transfection, Raf-1 kinase assay The Journal of biological chemistry High 9867809
2000 AF-6 (afadin) binds Rap1A through its first Ras-binding domain more efficiently than oncogenic Ha-, K-, or N-Ras; Rap1A and Ras both interact with full-length AF-6 in mammalian cells and a fraction of Rap1A colocalizes with AF-6 at the membrane; AF-6 also associates with the actin regulator profilin. In vitro binding assay, co-immunoprecipitation in mammalian cells, immunofluorescence colocalization, MDCK and MCF-7 cell dominant-active Rap1A expression Proceedings of the National Academy of Sciences of the United States of America Medium 10922060
2002 Constitutively active Rap1A in transgenic T cells does not antagonize Ras signaling or induce T cell anergy; instead, it enhances TCR-mediated responses and induces strong activation of β1 and β2 integrins via an avidity-modulation mechanism in vivo. Transgenic mouse model (constitutively active Rap1A in T cell lineage), T cell activation assays, integrin activation/adhesion assays Nature immunology High 11836528
2006 Genetic deletion of Rap1A in mice causes impaired integrin-mediated adhesion of primary T and B cells to ICAM and fibronectin substrates, and impaired polarization of T cells after CD3 stimulation, confirming a role for Rap1A in integrin regulation in vivo. Homologous recombination knockout mouse, adhesion assays on ICAM/fibronectin, T cell polarization assay Molecular and cellular biology High 16382154
2007 Rap1a-null mice show increased macrophage haptotaxis with decreased adhesion on fibronectin/vitronectin, reduced chemotaxis of lymphoid and myeloid cells to CXCL12/CCL21, increased FcR-mediated phagocytosis, and reduced fMLP-stimulated superoxide production in neutrophils, demonstrating non-redundant roles of Rap1a vs Rap1b. Rap1a gene deletion, macrophage haptotaxis/adhesion assays, chemotaxis assays, phagocytosis assay, superoxide production measurement Journal of immunology High 18056377
1999 RAP1A GTP/GDP cycling controls intracellular location of late endocytic compartments and contributes to myogenic differentiation; GDP-bound RAP1A clusters with acidic perinuclear structures and causes disturbances in cathepsin D maturation, while GTP-bound form inhibits and GDP-bound form promotes myotube formation. Stable cell lines expressing wild-type or mutant RAP1A, immunofluorescence, cathepsin D maturation assay, myogenic differentiation assay Experimental cell research Medium 9882515
2009 JAM-A forms a complex with Afadin and PDZ-GEF2 to activate Rap1A, which in turn regulates β1 integrin protein levels and epithelial cell migration; knockdown of Rap1A (but not Rap1B) specifically decreased β1 integrin levels and reduced cell migration. Co-immunoprecipitation, siRNA knockdown of Rap1A vs Rap1B, β1 integrin quantification, cell migration assay Molecular biology of the cell Medium 19176753
2008 Rap1a is required for FGF2-induced angiogenesis: rap1a−/− mice lack blood vessel growth into FGF2-containing Matrigel plugs and aortic rings fail to sprout; Rap1a/b knockdown in endothelial cells reduces adhesion, migration, tubular structure formation, and FGF2-induced ERK, p38, and Rac activation. Rap1a knockout mouse, Matrigel plug assay, aortic ring sprouting assay, siRNA knockdown in HMVECs, endothelial cell functional assays Molecular and cellular biology High 18625726
2011 Rap1A is the predominant isoform for endothelial junction formation and barrier function; Rap1A knockdown (not Rap1B) increases monolayer gaps and permeability; Rap1A localizes more strongly to junctions than Rap1B and co-immunoprecipitates more strongly with AF-6. miRNA-based isoform-specific knockdown, electrical impedance sensing, VE-cadherin immunostaining, GFP-tagged Rap1A/1B localization, co-immunoprecipitation Small GTPases Medium 21776404
1999 SHEP1, a novel SH2 domain-containing protein, directly couples activated EphB2 receptor to Rap1A and R-Ras (but not Ha-Ras or RalA) via its GEF-like domain, as demonstrated in a yeast two-hybrid screen and binding assays. Yeast two-hybrid screen, SH2 binding to phosphorylated EphB2, tyrosine phosphorylation of SHEP1 in cells expressing activated EphB2 The Journal of biological chemistry Low 10542222
1991 Rap1A (both GDP and GTP-bound forms) competitively inhibits the ability of Ras-GAP to block M2-muscarinic receptor-coupled K+ channel activation; a T35A effector-domain mutation abolishes this antagonism, confirming that the effector domain mediates Rap1A competition with GAP. Electrophysiology patch clamp, addition of purified Rap1A proteins, T35A mutagenesis The Journal of biological chemistry Medium 1939245
1991 Heterogeneous amino acids in Ras and Rap1A carboxyl-terminal to the effector region determine sensitivity to different GAPs: residues 61–65 of Ras confer Ras-GAP sensitivity, while a larger set of Rap1A residues mediates sensitivity to cytoplasmic Rap-GAP; sensitivity to membrane Rap-GAP requires yet other residues. Chimeric protein construction, in vitro GTPase assay with different GAPs, NIH 3T3 transformation assay Science Medium 1749934
1992 Purified recombinant Krev-1/Rap1A reconstitutes NADPH oxidase activity in immunodepleted neutrophil cytosol; H-Ras and yeast RAS proteins lack this activity; an antibody against the effector region (residues 31-43) of Krev-1 inhibits cell-free NADPH oxidase activation. Immunodepletion of cytosol, reconstitution with purified recombinant Krev-1, H-Ras controls, blocking antibody experiment The Journal of biological chemistry Medium 1906890
1992 Dominant-negative (N17) and constitutively active (V12, GTPase-defective) mutants of Rap1A both inhibit superoxide production in differentiated HL60 cells, while overexpression of wild-type Rap1A increases O2−production fourfold, establishing that cycling between GDP- and GTP-bound forms is required for continuous NADPH oxidase activation. Stable transfection of HL60 cells with Rap1A mutants, differentiation to neutrophil-like cells, superoxide production assay Blood Medium 7833480
2003 Active GTP-bound Rap1A translocates to the nucleus in squamous cell carcinoma cells, whereas inactive GDP-bound Rap1A is retained in the cytoplasm; nuclear translocation is induced by growth factors, as demonstrated by GFP-tagged constitutively active and inactive forms. GFP-tagging of active/inactive Rap1A, immunofluorescence, subcellular fractionation, immunohistochemistry on human cancer specimens Oncogene Medium 13679863
2010 Gβγ subunits of heterotrimeric G proteins form a complex with activated Rap1A and its effector Radil downstream of GPCR stimulation; Gβγ, activated Rap1A, and Radil promote translocation of Radil to the plasma membrane at sites of cell-matrix contact and are required for inside-out integrin activation. Co-immunoprecipitation, siRNA knockdown, integrin activation assay, live-cell imaging of Radil translocation The Journal of biological chemistry Medium 20048162
2012 KIF14 associates with the PDZ domain of the Rap1A effector Radil and tethers Radil on microtubules, negatively regulating Rap1A-mediated inside-out integrin activation; KIF14 depletion leads to increased cell spreading and altered focal adhesion dynamics. Co-immunoprecipitation, pulldown with PDZ domain, siRNA knockdown of KIF14, integrin activation assay, focal adhesion imaging, mouse xenograft The Journal of cell biology Medium 23209302
2013 PI3Kγ activates PLCγ → CalDAG-GEFI/II → Rap1A → RIAM pathway to induce integrin α4β1-mediated extravasation of myeloid cells; genetic depletion of Rap1A (but not constitutively active RapV12 which bypasses upstream signals) was sufficient to prevent integrin α4 activation and suppress myeloid cell recruitment to tumors. Genetic deletion/siRNA of pathway components in mouse, integrin activation assay, in vivo tumor inflammation model, epistasis analysis PloS one Medium 23565202
2012 cAMP-Epac2-Rap1A-RhoA signaling in microvascular smooth muscle cells induces translocation of α2C-adrenoceptors from the Golgi/perinuclear region to the cell surface; this effect is impaired in Rap1A-null mouse microVSM and rescued by constitutively active Rap1A. Pharmacological activation of Epac/cAMP, Rap1A-null mouse microVSM, constitutively active Rap1A rescue, α2C-AR localization imaging American journal of physiology. Cell physiology Medium 22621783
2013 cAMP-Rap1A signaling facilitates translocation of α2C-adrenoceptors to the cell surface via filamin-2; yeast two-hybrid identified filamin-2 as an α2C-AR binding partner; Rap1A stimulation caused α2C-ARs to colocalize with filamin-2 on intracellular filaments and at the plasma membrane; filamin-2 knockdown inhibited Rap1-induced receptor surface delivery. Yeast two-hybrid, co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown of filamin-2, confocal imaging American journal of physiology. Cell physiology Medium 23864608
2014 Rap1A mediates thrombin (PAR-1)-stimulated glioblastoma cell adhesion to fibronectin and proliferation via a RhoA-PLD-Rap1A-β1 integrin pathway; siRNA knockdown of Rap1A (but not Rap1B) reduces tumor mass by >70% in mouse xenograft; Rap1A knockdown reduces phospho-FAK and phospho-ERK. siRNA knockdown of Rap1A vs Rap1B, cell adhesion assay, FAK/ERK phosphorylation, β1 integrin neutralization, mouse xenograft model The Journal of biological chemistry Medium 24790104
2011 Rap1a activation by CalDAG-GEFI (Rasgrp2) and p38 MAPK (downstream of PLCγ2) is required for E-selectin-dependent slow leukocyte rolling and αLβ2 integrin activation; dominant-negative Rap1a blocked E-selectin-mediated slow rolling in Pik3cg−/− mice; Rasgrp2−/− mice lost E-selectin-dependent neutrophil recruitment. Intravital microscopy, Tat-fusion dominant-negative mutants, gene-deficient mice (Rasgrp2−/−, Pik3cg−/−), peritonitis model, biochemical studies European journal of immunology High 21480213
2018 Rap1A is required for lymphatic development: conditional knockout of Rap1a/b in lymphatic endothelial cells causes embryonic lethality with interstitial edema, blood-filled lymphatics, disrupted lymphovenous valves, and defective lymphangiogenesis; Rap1A/B knockdown disrupts junctional formation and impairs adrenomedullin-induced junctional tightening. Conditional knockout mouse (two independent lines), siRNA knockdown in human lymphatic endothelial cells, permeability assay, immunofluorescence Arteriosclerosis, thrombosis, and vascular biology High 30354217
2020 Rap1A allosterically activates phospholipase Cε (PLCε) by binding the RA2 domain; the PH domain and first two EF hands of PLCε are also required for Rap1A-mediated activation; hydrophobic residues on the RA2 surface are essential; SAXS shows Rap1A binding induces discrete conformational states in PLCε, providing the first structural evidence for allosteric activation. In vitro PLCε activity assay with purified proteins, mutagenesis (RA2 domain residues, PH, EF hands), small-angle X-ray scattering (SAXS), pulldown with purified proteins The Journal of biological chemistry High 32948655
2016 Phosphorylation in the polybasic region (PBR) of Rap1A does not detectably inhibit its prenylation or binding to SmgGDS-607 (unlike Rap1B where S179/S180 phosphorylation inhibits these interactions); GPCR activation suppresses Rap1A prenylation but does not diminish Rap1A membrane localization, revealing isoform-specific regulation of prenylation. Binding assays (SmgGDS-607 interaction), mutagenesis of PBR residues, prenylation assays, GPCR stimulation experiments Journal of molecular biology Medium 27760305
2022 Hepatocyte Rap1A activation suppresses gluconeogenic gene expression and hepatic glucose production via induction of actin polymerization that leads to Akt-mediated FoxO1 inhibition; Rap1A activity depends on geranylgeranylation for membrane localization; statins reduce Rap1A activity and stimulate hepatic gluconeogenesis; geranylgeraniol treatment restores Rap1A activity. Rap1a silencing and overexpression in hepatocytes, glucose production assay, actin polymerization assay, Akt/FoxO1 phosphorylation, statin treatment, geranylgeraniol rescue, obese mouse model Cell reports Medium 36001955
2024 Rap1A knockdown in endothelial cells increases store-operated calcium entry (SOCE) through Orai1 channels, enhancing NFAT1 nuclear translocation and pro-inflammatory cytokine expression; EC-specific Rap1A knockout mice show inflammatory lung phenotype with increased permeability; siRNA-mediated Orai1 knockdown normalizes SOCE, NFAT activity, and barrier function in Rap1A-depleted cells and mice. siRNA knockdown of Rap1A vs Rap1B, whole-cell patch clamp (CRAC current), NFAT translocation assay, cytokine ELISA, EC-specific conditional Rap1A knockout mouse, lipid-nanoparticle siRNA delivery Arteriosclerosis, thrombosis, and vascular biology High 39324266
2022 TRPM8 channel directly interacts with Rap1A via specific residues (E207 and Y240 on TRPM8; Y32 on Rap1A); this interaction traps Rap1A in GDP-bound inactive form and inhibits cell migration and adhesion in prostate cancer cells; point mutations at these sites disrupt PPI and abolish the functional effects. Active Rap1 pull-down assay, GST-pulldown, co-immunoprecipitation, proximity ligation assay (PLA), molecular modeling, site-directed mutagenesis, live-cell imaging, migration/adhesion assays Cancers Medium 35565390
1992 The C-terminal geranylgeranylated region of Rap1A/Krev-1 is essential for interaction with smg GDS (guanine nucleotide exchange factor); mapping by cross-linking identified residues 444-492 of smg GDS as the domain interacting with the C-terminal region of Rap1A; deletion of these residues abolishes GDS activity on Rap1A. Cross-linking, site-directed mutagenesis/deletion of smg GDS, GDS exchange activity assay Oncogene Medium 1501882

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue. Nature 510 7791872
1996 Differential interaction of the ras family GTP-binding proteins H-Ras, Rap1A, and R-Ras with the putative effector molecules Raf kinase and Ral-guanine nucleotide exchange factor. The Journal of biological chemistry 311 8636102
1999 Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Human molecular genetics 304 10545614
1990 Inhibition of GTPase activating protein stimulation of Ras-p21 GTPase by the Krev-1 gene product. Science (New York, N.Y.) 254 2164710
1991 Molecular cloning of a GTPase activating protein specific for the Krev-1 protein p21rap1. Cell 244 1904317
2002 Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling. Nature immunology 234 11836528
1997 Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22. Oncogene 180 9285558
2000 The junctional multidomain protein AF-6 is a binding partner of the Rap1A GTPase and associates with the actin cytoskeletal regulator profilin. Proceedings of the National Academy of Sciences of the United States of America 170 10922060
1994 Association of Rap1a and Rap1b proteins with late endocytic/phagocytic compartments and Rap2a with the Golgi complex. Journal of cell science 148 7962206
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
1991 Association of the Ras-antagonistic Rap1/Krev-1 proteins with the Golgi complex. Proceedings of the National Academy of Sciences of the United States of America 138 1900364
1991 Rap1A is a substrate for cyclic AMP-dependent protein kinase in human neutrophils. Journal of immunology (Baltimore, Md. : 1950) 111 1908879
1990 Identification of small clusters of divergent amino acids that mediate the opposing effects of ras and Krev-1. Science (New York, N.Y.) 105 2115210
1992 Microinjection of smg/rap1/Krev-1 p21 into Swiss 3T3 cells induces DNA synthesis and morphological changes. Molecular and cellular biology 104 1321333
1991 Inhibition of Rap1A binding to cytochrome b558 of NADPH oxidase by phosphorylation of Rap1A. Science (New York, N.Y.) 104 1763330
1991 The COOH-terminal domain of the Rap1A (Krev-1) protein is isoprenylated and supports transformation by an H-Ras:Rap1A chimeric protein. Molecular and cellular biology 103 1899909
2006 Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion. Molecular and cellular biology 100 16382154
2007 Rap1a null mice have altered myeloid cell functions suggesting distinct roles for the closely related Rap1a and 1b proteins. Journal of immunology (Baltimore, Md. : 1950) 98 18056377
1991 Purification of a plasma membrane-associated GTPase-activating protein specific for rap1/Krev-1 from HL60 cells. Proceedings of the National Academy of Sciences of the United States of America 95 1846040
2012 miR-337-3p and its targets STAT3 and RAP1A modulate taxane sensitivity in non-small cell lung cancers. PloS one 94 22723956
1999 A novel signaling intermediate, SHEP1, directly couples Eph receptors to R-Ras and Rap1A. The Journal of biological chemistry 94 10542222
1997 Coassociation of Rap1A and Ha-Ras with Raf-1 N-terminal region interferes with ras-dependent activation of Raf-1. The Journal of biological chemistry 90 9115221
1995 Function of wild-type or mutant Rac2 and Rap1a GTPases in differentiated HL60 cell NADPH oxidase activation. Blood 90 7833480
2008 Rap1a is a key regulator of fibroblast growth factor 2-induced angiogenesis and together with Rap1b controls human endothelial cell functions. Molecular and cellular biology 89 18625726
1992 RSR1, a ras-like gene homologous to Krev-1 (smg21A/rap1A): role in the development of cell polarity and interactions with the Ras pathway in Saccharomyces cerevisiae. Molecular and cellular biology 86 1732742
1994 Activated or dominant inhibitory mutants of Rap1A decrease the oxidative burst of Epstein-Barr virus-transformed human B lymphocytes. The Journal of biological chemistry 80 8034626
2011 Rap1a activation by CalDAG-GEFI and p38 MAPK is involved in E-selectin-dependent slow leukocyte rolling. European journal of immunology 79 21480213
1990 Tissue and subcellular distributions of the smg-21/rap1/Krev-1 proteins which are partly distinct from those of c-ras p21s. Molecular and cellular biology 76 2111441
2002 Consequences of mevalonate depletion. Differential transcriptional, translational, and post-translational up-regulation of Ras, Rap1a, RhoA, AND RhoB. The Journal of biological chemistry 74 11788600
1992 Subcellular distribution of the Rap1A protein in human neutrophils: colocalization and cotranslocation with cytochrome b559. Blood 74 1312373
1991 Resolution of a low molecular weight G protein in neutrophil cytosol required for NADPH oxidase activation and reconstitution by recombinant Krev-1 protein. The Journal of biological chemistry 69 1906890
2003 Rap1A and rap1B ras-family proteins are prominently expressed in the nucleus of squamous carcinomas: nuclear translocation of GTP-bound active form. Oncogene 68 13679863
1992 smg/rap1/Krev-1 p21s inhibit the signal pathway to the c-fos promoter/enhancer from c-Ki-ras p21 but not from c-raf-1 kinase in NIH3T3 cells. Oncogene 68 1323817
2012 KIF14 negatively regulates Rap1a-Radil signaling during breast cancer progression. The Journal of cell biology 67 23209302
2012 MiR-196a binding-site SNP regulates RAP1A expression contributing to esophageal squamous cell carcinoma risk and metastasis. Carcinogenesis 65 22859270
2016 Rap1A promotes ovarian cancer metastasis via activation of ERK/p38 and notch signaling. Cancer medicine 64 27925454
2015 MiR-203 down-regulates Rap1A and suppresses cell proliferation, adhesion and invasion in prostate cancer. Journal of experimental & clinical cancer research : CR 64 25636908
2011 Isoform-specific differences between Rap1A and Rap1B GTPases in the formation of endothelial cell junctions. Small GTPases 64 21776404
1989 Purification, identification, and characterization of two GTP-binding proteins with molecular weights of 25,000 and 21,000 in human platelet cytosol. One is the rap1/smg21/Krev-1 protein and the other is a novel GTP-binding protein. The Journal of biological chemistry 60 2507536
2018 miR-433 inhibits breast cancer cell growth via the MAPK signaling pathway by targeting Rap1a. International journal of biological sciences 59 29904277
2010 Vibrational Stark effect spectroscopy at the interface of Ras and Rap1A bound to the Ras binding domain of RalGDS reveals an electrostatic mechanism for protein-protein interaction. The journal of physical chemistry. B 58 20964430
2013 PI3-kinase γ promotes Rap1a-mediated activation of myeloid cell integrin α4β1, leading to tumor inflammation and growth. PloS one 56 23565202
1999 Effect of phosphorylation on activities of Rap1A to interact with Raf-1 and to suppress Ras-dependent Raf-1 activation. The Journal of biological chemistry 52 9867809
2014 The Ras-related protein, Rap1A, mediates thrombin-stimulated, integrin-dependent glioblastoma cell proliferation and tumor growth. The Journal of biological chemistry 51 24790104
2012 Cyclic AMP-Rap1A signaling activates RhoA to induce α(2c)-adrenoceptor translocation to the cell surface of microvascular smooth muscle cells. American journal of physiology. Cell physiology 51 22621783
1990 Biochemical characterization of baculovirus-expressed rap1A/Krev-1 and its regulation by GTPase-activating proteins. Molecular and cellular biology 51 2160589
2017 cAMP signaling increases histone deacetylase 8 expression via the Epac2-Rap1A-Akt pathway in H1299 lung cancer cells. Experimental & molecular medicine 46 28232663
2015 Rap1A Regulates Osteoblastic Differentiation via the ERK and p38 Mediated Signaling. PloS one 43 26599016
2010 G protein betagamma subunits regulate cell adhesion through Rap1a and its effector Radil. The Journal of biological chemistry 41 20048162
2002 Role of cAMP, PKA and Rap1A in thyroid follicular cell survival. Oncogene 41 11850806
2021 FABP4 activates the JAK2/STAT2 pathway via Rap1a in the homocysteine-induced macrophage inflammatory response in ApoE-/- mice atherosclerosis. Laboratory investigation; a journal of technical methods and pathology 38 34725437
1992 Reversion of middle T antigen-transformed Rat-2 cells by Krev-1: implications for the role of p21c-ras in polyomavirus-mediated transformation. Oncogene 36 1380149
2015 MiR-203 involves in neuropathic pain development and represses Rap1a expression in nerve growth factor differentiated neuronal PC12 cells. The Clinical journal of pain 35 24451631
1991 Heterogeneous amino acids in Ras and Rap1A specifying sensitivity to GAP proteins. Science (New York, N.Y.) 34 1749934
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
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
1991 Rap1A antagonizes the ability of Ras and Ras-Gap to inhibit muscarinic K+ channels. The Journal of biological chemistry 33 1939245
2019 miR-142-5p regulates pancreatic cancer cell proliferation and apoptosis by regulation of RAP1A. Pathology, research and practice 31 31047726
2000 Rap1A protein interferes with various MAP kinase activating pathways in skeletal myogenic cells. Oncogene 30 11146560
2020 miR-590-3p Alleviates diabetic peripheral neuropathic pain by targeting RAP1A and suppressing infiltration by the T cells. Acta biochimica Polonica 28 33332780
2013 Cyclic AMP-Rap1A signaling mediates cell surface translocation of microvascular smooth muscle α2C-adrenoceptors through the actin-binding protein filamin-2. American journal of physiology. Cell physiology 28 23864608
2016 Differences in the Phosphorylation-Dependent Regulation of Prenylation of Rap1A and Rap1B. Journal of molecular biology 27 27760305
2019 Role of miR-337-3p and its target Rap1A in modulating proliferation, invasion, migration and apoptosis of cervical cancer cells. Cancer biomarkers : section A of Disease markers 24 30883336
2004 Expression and significance of Rap1A in testes of azoospermic subjects. Asian journal of andrology 24 15064832
2018 Small GTPase Rap1A/B Is Required for Lymphatic Development and Adrenomedullin-Induced Stabilization of Lymphatic Endothelial Junctions. Arteriosclerosis, thrombosis, and vascular biology 23 30354217
2014 Modulation of angiotensin II-induced inflammatory cytokines by the Epac1-Rap1A-NHE3 pathway: implications in renal tubular pathobiology. American journal of physiology. Renal physiology 22 24553435
1992 Loss of heterozygosity at the human RAP1A/Krev-1 locus is a rare event in colorectal tumors. Cancer research 22 1345809
2019 MiR-501-3p functions as a tumor suppressor in non-small cell lung cancer by downregulating RAP1A. Experimental cell research 21 31805277
2021 Rap1a Overlaps the AGE/RAGE Signaling Cascade to Alter Expression of α-SMA, p-NF-κB, and p-PKC-ζ in Cardiac Fibroblasts Isolated from Type 2 Diabetic Mice. Cells 20 33806572
1992 Reconstitution of defective respiratory burst activity with partially purified human neutrophil cytochrome B in two genetic forms of chronic granulomatous disease: possible role of Rap1A. Blood 20 1315174
2019 Long noncoding RNA LINC00460 aggravates invasion and metastasis by targeting miR-30a-3p/Rap1A in nasopharyngeal carcinoma. Human cell 19 31414345
2016 miR-203a is involved in HBx-induced inflammation by targeting Rap1a. Experimental cell research 18 27780730
2019 MicroRNA-340-5p relieved chronic constriction injury-induced neuropathic pain by targeting Rap1A in rat model. Genes & genomics 17 30848438
2022 Hepatocyte Rap1a contributes to obesity- and statin-associated hyperglycemia. Cell reports 16 36001955
2019 Rap1A promotes esophageal squamous cell carcinoma metastasis through the AKT signaling pathway. Oncology reports 16 31545475
2018 Deletion of Rap1b, but not Rap1a or Epac1, Reduces Protein Kinase A-Mediated Thyroid Cancer. Thyroid : official journal of the American Thyroid Association 16 29882482
2012 Rap1a deficiency modifies cytokine responses and MAPK-signaling in vitro and impairs the in vivo inflammatory response. Cellular immunology 16 22695258
2010 Rap1A regulates generation of T regulatory cells via LFA-1-dependent and LFA-1-independent mechanisms. Cellular immunology 16 20864093
1997 Molecular dynamics on complexes of ras-p21 and its inhibitor protein, rap-1A, bound to the ras-binding domain of the raf-p74 protein: identification of effector domains in the raf protein. Journal of protein chemistry 16 9263124
1994 Partial growth suppression of human prostate cancer cells by the Krev-1 suppressor gene. The Prostate 16 8084835
1993 The Rap1A protein enhances protein kinase C activity in vitro. Biochemical and biophysical research communications 16 8216264
2018 miR-202 modulates the progression of neuropathic pain through targeting RAP1A. Journal of cellular biochemistry 15 30520098
1992 Co-deletions of the retinoblastoma gene and Wilms' tumor gene and rearrangement of the Krev-1 gene in a human insulinoma. Japanese journal of clinical oncology 15 1573790
2001 High-pressure NMR study of the complex of a GTPase Rap1A with its effector RalGDS. A conformational switch in RalGDS revealed from non-linear pressure shifts. FEBS letters 14 11602241
1997 Isolation and characterization of the krev-1 gene, a novel member of ras superfamily in Neurospora crassa: involvement in sexual cycle progression. Molecular & general genetics : MGG 14 9267439
1996 Differential up-regulation of Rap1a and Rap1b proteins during smooth muscle cell cycle. European journal of cell biology 14 8832211
2024 Rap1A Modulates Store-Operated Calcium Entry in the Lung Endothelium: A Novel Mechanism Controlling NFAT-Mediated Vascular Inflammation and Permeability. Arteriosclerosis, thrombosis, and vascular biology 13 39324266
2022 TRPM8-Rap1A Interaction Sites as Critical Determinants for Adhesion and Migration of Prostate and Other Epithelial Cancer Cells. Cancers 13 35565390
1999 RAP1A GTP/GDP cycles determine the intracellular location of the late endocytic compartments and contribute to myogenic differentiation. Experimental cell research 13 9882515
1990 A domain responsible for the transformation suppressor activity in Krev-1 protein. Japanese journal of cancer research : Gann 13 2116391
2020 microRNA-331-3p attenuates neuropathic pain following spinal cord injury via targeting RAP1A. Journal of biological regulators and homeostatic agents 12 32264665
2023 Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis. Cell communication and signaling : CCS 11 36691027
2023 Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure. Platelets 11 37139869
2021 Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade. Cells 11 34067282
2000 Use of an activation-specific probe to show that Rap1A and Rap1B display different sensitivities to activation by forskolin in rat1 cells. FEBS letters 11 10908723
2020 Long noncoding RNA CRNDE promotes proliferation, migration and invasion in prostate cancer through miR-101/Rap1A. Neoplasma 10 32182086
1992 The functional domain of the stimulatory GDP/GTP exchange protein (smg GDS) which interacts with the C-terminal geranylgeranylated region of rap1/Krev-1/smg p21. Oncogene 10 1501882
1992 Organization and chromosomal locations of Rap1a/Krev sequences in the mouse. Mammalian genome : official journal of the International Mammalian Genome Society 10 1617222
2023 Rap1A accelerates homocysteine-induced ANA-1 cells inflammation via synergy of FoxO1 and DNMT3a. Cellular signalling 9 36791985
2020 Functional and structural characterization of allosteric activation of phospholipase Cε by Rap1A. The Journal of biological chemistry 9 32948655

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