Affinage

RRAS

Ras-related protein R-Ras · UniProt P10301

Length
218 aa
Mass
23.5 kDa
Annotated
2026-06-14
100 papers in source corpus 68 papers cited in narrative 68 extracted findings
Cross-family judge vs UniProt: Affinage preferred

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

R-Ras (RRAS) is a membrane-anchored Ras-family small GTPase whose principal cellular role is the positive control of integrin ligand-binding affinity and the resulting programs of cell adhesion, spreading, and migration ("inside-out" signaling) (PMID:8620538). It cycles between GDP- and GTP-bound states under the control of a broad set of GEFs — including RasGRF, C3G, the CalDAG-GEF/RasGRP family, Epac1, and AND-34/BCAR3 — and GAPs including p120RasGAP, NF-1, and a dedicated ~98-kDa R-Ras GAP (PMID:8530488, PMID:10777492, PMID:16754664). Unlike classical Ras, active R-Ras does not drive the Raf–MEK–ERK axis but instead signals through PI 3-kinase to activate Akt, and this PI3K branch is essential for both its transforming activity and its pro-adhesive, pro-survival functions (PMID:8999998, PMID:10454580). Membrane targeting and effector engagement depend on C-terminal palmitoylation (C213) and geranylgeranylation, which direct Golgi exit, focal-adhesion localization, and productive PI3K coupling (PMID:12890755, PMID:22751447). Beyond PI3K, GTP-bound R-Ras engages distinct effectors to remodel the cytoskeleton and traffic integrins: RLIP76/RalBP1 and an Arf6 cascade, the proline-rich/Nck adaptor link, PLCε-driven membrane protrusion, and a RIN2→Rab5→TIAM1→Rac1 module that drives endocytosis of active β1 integrins (PMID:10671570, PMID:16537651, PMID:16966426, PMID:22825554). R-Ras activity is suppressed by tyrosine phosphorylation at Y66 by EphB2 and Src, and by plexin receptors that act as direct R-Ras GAPs: plexin-B1 (with Rnd1), plexin-D1 (with Rnd2), and plexin-C1 (Rnd-independent) inactivate R-Ras in response to semaphorins to mediate growth cone collapse and repulsive guidance through sequential loss of PI3K signaling, Akt dephosphorylation, GSK-3β and PTEN activation (PMID:10570155, PMID:11682467, PMID:15297673, PMID:19136556, PMID:16799460, PMID:20610402). In the vasculature R-Ras stabilizes endothelial barriers by maintaining VE-cadherin junctions, suppressing VEGFR2 internalization and autophosphorylation, and dampening p38MAPK–HSP27 signaling, and it promotes endothelial lumenogenesis via Akt-dependent microtubule stabilization (PMID:25645912, PMID:27029009, PMID:29170374); its endothelial expression is set transcriptionally by FOXF1 and repressed by cAMP/CREB3 (PMID:29775418, PMID:37137915).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1987 High

    Established R-Ras as a bona fide membrane-associated, lipid-modified GTP-binding protein analogous to H-Ras, defining its biochemical identity.

    Evidence Metabolic [3H]palmitate labeling, membrane fractionation, and GTP-binding/autokinase assays on expressed protein

    PMID:3313005

    Open questions at the time
    • No cellular function assigned
    • Effectors and regulators unidentified
  2. 1989 High

    Showed R-Ras GTPase activity is controlled by the canonical 125-kDa rasGAP via its effector domain, placing R-Ras within Ras-family regulatory logic while hinting at lipid-modulated regulation.

    Evidence In vitro GTPase-activating assays with mammalian extracts and defined phospholipids

    PMID:2491843 PMID:2513485

    Open questions at the time
    • Physiological GAP not yet identified
    • Functional consequence of GAP regulation unknown
  3. 1993 High

    Linked R-Ras to apoptosis regulation by identifying a physical Bcl-2 interaction through its C-terminus, the first effector-type partner.

    Evidence Yeast two-hybrid and co-immunoprecipitation from human cell extracts

    PMID:8232588

    Open questions at the time
    • Functional direction of Bcl-2 interaction not resolved here
    • GTP-dependence not established
  4. 1994 High

    Defined R-Ras as a transforming GTPase that engages Raf-1 and RalGDS in a GTP-dependent manner and cooperates with c-raf-1, raising the question of which effectors are physiological.

    Evidence Yeast two-hybrid, in vitro binding with purified proteins, site-directed mutagenesis and NIH3T3 transformation assays

    PMID:7809086 PMID:8002932 PMID:8084601 PMID:8108110

    Open questions at the time
    • Whether Raf/RalGDS binding is physiologically relevant unresolved
    • No distinct R-Ras-specific effector identified
  5. 1995 High

    Resolved the apoptosis question by placing Bcl-2 downstream of R-Ras and identified a dedicated R-Ras-specific GAP, distinguishing R-Ras regulation from classical Ras.

    Evidence IL-3-withdrawal apoptosis assays with Bcl-2 epistasis; GST-R-Ras affinity purification and reconstituted GAP assays

    PMID:7744959 PMID:8530488

    Open questions at the time
    • Identity/cloning of the R-Ras-specific GAP only partially defined
    • Apoptosis pathway intermediates between R-Ras and Bcl-2 unclear
  6. 1996 High

    Identified the defining cellular function of R-Ras — control of integrin ligand-binding affinity (inside-out signaling) — and showed its weak/nonspecific binding to Raf/RalGDS argues against those as primary effectors.

    Evidence Activated/dominant-negative R-Ras with integrin affinity and adhesion assays; quantitative solution binding measurements

    PMID:8620538 PMID:8636102

    Open questions at the time
    • Downstream effector for integrin control not yet identified
    • Mechanism connecting R-Ras to integrin cytoplasmic tail unknown
  7. 1997 High

    Established PI 3-kinase/Akt as the central R-Ras effector branch, distinguishing it from the Ras-Raf-MAPK axis.

    Evidence Co-transfection PI3K lipid product and PKB/Akt kinase assays with wortmannin

    PMID:8999998

    Open questions at the time
    • Direct vs indirect PI3K activation not fully resolved
    • Link from PI3K to integrin affinity not yet mapped
  8. 1999 High

    Showed R-Ras activity is suppressed by EphB2-mediated phosphorylation at Y66 and recruited to EphB2 via SHEP1, defining an anti-adhesive regulatory input, while effector-loop mutagenesis dissociated transformation from adhesion/survival and pinned both PI3K-dependent functions.

    Evidence Y66F mutagenesis with EphB2 activation and adhesion rescue; yeast two-hybrid/co-IP for SHEP1; systematic effector-loop mutants with PI3K/Akt inhibitors

    PMID:10352023 PMID:10359597 PMID:10454580 PMID:10542222 PMID:10570155

    Open questions at the time
    • SHEP1 GEF exchange activity on R-Ras not directly demonstrated
    • How PI3K vs PKC branches diverge for invasion incompletely defined
  9. 2000 High

    Mapped the regulator landscape of R-Ras (multiple GEFs and GAPs) and identified non-PI3K outputs — a GTP-independent Nck/proline-rich link, cAMP/Epac activation, and JNK/MLK3 and PLD activation — broadening its effector repertoire.

    Evidence In vitro and cell-based GEF/GAP assays; GST-SH3 pulldowns and adhesion mutants; Epac in vitro GEF assay; JNK kinase assays with MLK3 dominant-negatives

    PMID:10671570 PMID:10777492 PMID:10777559 PMID:10801791 PMID:10835426 PMID:10896938 PMID:11134082 PMID:16754664

    Open questions at the time
    • Which GEF/GAP pairs operate in which cell context unresolved
    • Some PI3K-dependence findings conflict across cell types
  10. 2001 High

    Confirmed R-Ras suppression by Src at Y66 and extended its function to Rap1-dependent phagocytic integrin activation, reinforcing adhesion control over mitogenic output.

    Evidence In vitro and cellular Src kinase assays, Y66F rescue, co-IP; microinjection and macrophage phagocytosis assays

    PMID:11257001 PMID:11682467

    Open questions at the time
    • Interplay between Src and EphB2 phosphorylation at Y66 not resolved here
    • Role of Rap1 vs R-Ras in phagocytosis not separated
  11. 2003 High

    Defined the membrane-targeting determinants (C-terminal HVR, palmitoylation at C213) required for focal-adhesion localization and showed active R-Ras enhances FAK/p130Cas adhesion signaling; introduced ORP3 as an interacting adhesion regulator.

    Evidence H-Ras/R-Ras chimeras, C213A mutagenesis, fractionation, immunofluorescence; phospho-FAK/p130Cas immunoblotting; co-IP and siRNA of ORP3

    PMID:12529399 PMID:12890755 PMID:18270267

    Open questions at the time
    • Mechanism by which ORP3 modulates R-Ras unresolved
    • How palmitoylation gates effector access not yet defined
  12. 2004 High

    Established plexin receptors as direct R-Ras GAPs requiring Rnd1, revealing the mechanism (intramolecular C1–C2 release, ligand-induced clustering) and a neuronal function in semaphorin-induced growth cone collapse; in parallel, defined R-Ras leading-edge control of Rac/Rho balance via PI3K.

    Evidence Reconstituted R-Ras GAP assays, domain dissection, antibody-induced clustering, growth cone collapse in hippocampal neurons; Rho/Rac pull-downs with activity imaging and effector mutants

    PMID:15297673 PMID:15525681 PMID:15601954

    Open questions at the time
    • Direct R-Ras effectors mediating Rac/Rho balance not all identified
    • Whether plexin GAP activity operates outside neurons not addressed
  13. 2005 Medium

    Identified the unique N-terminal extension as required for Rac activation and showed R-Ras as a required downstream mediator of EphB2 in glioma, connecting receptor signaling to invasive behavior.

    Evidence N-terminal truncation mutants with Rac pull-downs; R-Ras siRNA with glioma adhesion/invasion assays and EphB2 co-IP

    PMID:15772154 PMID:16049340

    Open questions at the time
    • Effector coupling N-terminus to Rac unidentified
    • How R-Ras both promotes and is inhibited downstream of Eph reconciled
  14. 2006 High

    Established a coherent semaphorin/plexin→R-Ras-off pathway (PI3K loss→Akt dephosphorylation→GSK-3β→CRMP-2; β1 integrin suppression), defined dual Eph inactivation (Y66 + p120RasGAP), and identified R-Ras-specific effectors RLIP76 and PLCε plus endosomal RalA signaling and axon-specification via ILK.

    Evidence Plexin-B1 GAP assays with Akt/GSK-3β/PTEN readouts; Eph mutant dissection; direct GTP-dependent RLIP76 binding with Arf6 epistasis; PLCε co-IP/siRNA; FRET endosomal activity imaging; ILK siRNA and rescue in primary neurons

    PMID:16522685 PMID:16537651 PMID:16702230 PMID:16799460 PMID:16966426 PMID:17107957 PMID:17344481

    Open questions at the time
    • How a single GTPase coordinates opposing migratory outputs across cell types unresolved
    • Quantitative effector partitioning (RLIP76 vs PLCε vs PI3K) undefined
  15. 2007 Medium

    Showed RalGDS-family effector RalA acts downstream on endosomes for exocytosis, and that Notch-1 intracellular domain activates R-Ras to drive β1 integrin adhesion independently of CSL transcription, expanding upstream activators.

    Evidence FRET activity probes and shRNA exocytosis assays; γ-secretase inhibitors, Notch mutants and R-Ras GTP-loading with integrin assays

    PMID:17344481 PMID:17664272

    Open questions at the time
    • GEF coupling Notch to R-Ras not identified
    • Direct vs indirect Notch–R-Ras link unresolved
  16. 2010 High

    Defined an ER-based activation mechanism (Fam38A/Piezo1→R-Ras→Ca2+/calpain→talin cleavage→β1 integrin), the DHHC19 palmitoyltransferase as R-Ras-specific, plexin-D1/Rnd2 GAP activity, and endosomal trafficking of active integrins via Rab11.

    Evidence Four-step siRNA epistasis with Ca2+/calpain assays; substrate-specific palmitoylation assays; plexin-D1/Rnd2 GAP and co-IP; live-cell imaging and integrin endocytosis assays

    PMID:19136556 PMID:20016066 PMID:20074548 PMID:20167113 PMID:20385769 PMID:20610402

    Open questions at the time
    • How ER-localized R-Ras integrates with plasma-membrane pool unclear
    • Plexin subfamily Rnd-requirement logic only partially explained
  17. 2012 High

    Defined the R-Ras→RIN2→Rab5→TIAM1→Rac1 module coupling active-integrin endocytosis to endothelial adhesion, and identified afadin as the effector for R-Ras-controlled axon branching, mechanistically integrating trafficking and cytoskeletal outputs.

    Evidence Co-IP, integrin endocytosis and Rab5 GEF assays, Rac1 activation, siRNA; endogenous R-Ras/afadin co-IP and domain mutants in cortical neurons

    PMID:22593211 PMID:22825554

    Open questions at the time
    • How R-Ras switches RIN2 from GEF to adaptor structurally undefined
    • Generality of afadin pathway beyond cortical neurons untested
  18. 2011 Medium

    Identified the R-Ras/filamin A complex as a regulator of fibronectin matrix assembly and endothelial barrier integrity, mechanistically linking R-Ras to VE-cadherin junction stability and Src restraint.

    Evidence Yeast two-hybrid/co-IP/GST pulldowns with FLNa repeat-3 mutants; siRNA with permeability (TEER, FITC-dextran) and VE-cadherin/Src phospho-analysis

    PMID:20585650 PMID:21660952

    Open questions at the time
    • Whether FLNa binding is GTP-dependent not established
    • Mechanism by which R-Ras restrains Src at junctions unclear
  19. 2015 High

    Defined R-Ras as a suppressor of VEGFR2 endocytosis and autophosphorylation in endothelium, providing a junction-stabilizing, anti-permeability mechanism validated in knockout mice.

    Evidence VEGFR2 internalization and five-site phospho-analysis, R-Ras siRNA, VE-cadherin epistasis, R-Ras knockout tumor vasculature

    PMID:25645912

    Open questions at the time
    • Direct effector mediating VEGFR2 trafficking suppression unidentified
    • Relationship to RIN2/Rab5 endocytic module unresolved
  20. 2016 Medium

    Extended endothelial R-Ras control to the VEGF→p38MAPK–HSP27 axis, showing R-Ras dampens migration-promoting signaling, and showed RASA1/p120RasGAP tumor suppression operates specifically through R-Ras GAP activity.

    Evidence p38/HSP27 phospho-immunoblotting with SB203580 rescue; RASA1 GAP assays and melanoma-mutant colony formation with RalA readout

    PMID:26993606 PMID:27029009

    Open questions at the time
    • Mechanistic link from R-Ras to p38 not defined
    • How RASA1 mutations select for R-Ras hyperactivity in tumors unclear
  21. 2017 High

    Showed R-Ras–Akt signaling stabilizes microtubules to drive endothelial lumenogenesis, a function distinct from VEGF-Akt, validated in vivo, sharpening the role of the PI3K–Akt branch in vascular morphogenesis.

    Evidence Constitutively active/dominant-negative R-Ras, microtubule stability and 3D lumen assays, Akt inhibition, knockout-mouse ischemia model

    PMID:29170374

    Open questions at the time
    • Microtubule-binding effector downstream of Akt unidentified
    • Why VEGF-Akt fails to phenocopy R-Ras-Akt undefined
  22. 2014 High

    Provided structural definition of GTP-bound R-Ras sequestration by SHANK SPN domains, with autism-related mutations disrupting the interaction, linking R-Ras to integrin restraint and neurological disease.

    Evidence Crystal structure of SHANK3 N-terminus, affinity measurements, SHANK silencing and SPN point-mutant functional assays; ORP3-P/VAPA interaction mapping with R-Ras activation

    PMID:25447204 PMID:28263956

    Open questions at the time
    • Whether SHANK sequestration operates physiologically in neurons in vivo not established
    • ORP3-VAPA to R-Ras activation mechanism not reconstituted
  23. 2019 Medium

    Connected the CalDAG-GEF RasGRP2 to endothelial R-Ras–PI3K–Akt anti-apoptotic signaling acting through hexokinase-2 mitochondrial translocation, extending R-Ras survival functions into the vasculature.

    Evidence Rap1/R-Ras pull-downs, siRNA epistasis, Akt/Bax/HK-2 localization and apoptosis assays

    PMID:31723205

    Open questions at the time
    • Relative contributions of Rap1 vs R-Ras not fully separated
    • Mechanism linking Akt to HK-2 translocation undefined
  24. 2022 Medium

    Defined a focal-adhesion lipid–GAP circuit (PI3KC2α→PI(3,4)P2→RASA3→R-Ras-off) controlling adhesion turnover and metastasis, providing a spatially localized inactivation mechanism.

    Evidence PI3KC2α knockdown/overexpression, PI(3,4)P2 and RASA3 localization, R-Ras GTP-loading, focal-adhesion turnover and in vivo metastasis assays

    PMID:35098698

    Open questions at the time
    • Generality across cancer types untested
    • How RASA3 selectivity for R-Ras is achieved unclear
  25. 2023 High

    Established FOXF1 as a direct transcriptional activator of RRAS in endothelium and showed cAMP/CREB3 represses RRAS, identifying transcriptional control as a determinant of endothelial R-Ras-dependent barrier function and fibrosis.

    Evidence scRNA-seq, promoter analysis, endothelial Foxf1 knockout and nanoparticle rescue; cAMP/CREB3 siRNA with permeability and Miles assays

    PMID:29775418 PMID:37137915

    Open questions at the time
    • Direct FOXF1 promoter occupancy details limited
    • How transcriptional and post-translational regulation are integrated unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis by which R-Ras partitions among its many effectors (PI3K, RLIP76, PLCε, RIN2, afadin, RalGDS/RalA) in a given subcellular compartment, and how palmitoylation/phosphorylation and localized GAPs choreograph context-specific output, remains unresolved.
  • No structural model of R-Ras effector selection
  • Quantitative effector partitioning across compartments undefined
  • In vivo essentiality of individual effector branches untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 5 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005768 endosome 3 GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-5357801 Programmed Cell Death 2
Partners
FLNAMRAS-GAPPLCE1RAF1RALGDSRASA1RIN2RLIP76

Evidence

Reading pass · 68 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 R-Ras p23 protein is palmitoylated (3H-palmitate labeling) and associates with the P100 membrane fraction; it exhibits GTP-binding activity analogous to H-Ras p21, and a threonine 85 substitution mutant undergoes GTP-dependent phosphorylation (autokinase activity analogous to H-Ras T59 mutants). Immunoprecipitation, metabolic labeling with [3H]palmitate, membrane fractionation, GTP-dependent phosphorylation assay in E. coli-expressed protein Molecular and cellular biology High 3313005
1989 R-Ras (p23) interacts with the same 125-kDa rasGAP protein as p21ras (not with the 29-kDa rhoGAP), demonstrating that R-Ras GTPase activity is stimulated by the canonical rasGAP in a manner dependent on the effector domain. GTPase-activating assay using mammalian cytoplasmic extracts, GTPase activity measurements The Journal of biological chemistry High 2491843
1989 Certain phospholipids inhibit the interaction between R-Ras and its GTPase-activating protein (GAP), with inhibitory lipids differing from those blocking ras-GAP interaction, suggesting lipid-mediated regulation of R-Ras GAP interaction. In vitro GTPase-activating assay with defined lipids added Molecular and cellular biology Medium 2513485
1993 Bcl-2 physically associates with R-Ras p23; the C-terminal 60 amino acids of R-Ras are sufficient for this interaction, which was detected by yeast two-hybrid and co-immunoprecipitation from human cell extracts. Yeast two-hybrid screen, co-immunoprecipitation from human cell extracts Nature High 8232588
1994 R-Ras directly interacts with Raf-1 in a GTP-dependent manner; this interaction requires the N-terminal regulatory domain (aa 1–256) of Raf-1 and the effector domain of R-Ras, as demonstrated by yeast two-hybrid and direct in vitro binding with purified proteins. Yeast two-hybrid, in vitro binding assay with purified R-Ras and Raf-1 Ras-binding domain (aa 51–131) The Biochemical journal High 8002932
1994 R-Ras interacts with RalGDS (Ral guanine nucleotide dissociation stimulator) in a GTP-dependent manner via the RalGDS Ras-binding domain (RBD), identified by yeast two-hybrid screening; direct GTP-dependent interaction confirmed with purified proteins in vitro; RalGDS-RBD and Raf-1 RBD compete for binding to R-Ras. Yeast two-hybrid library screen, in vitro binding assay with purified proteins Proceedings of the National Academy of Sciences of the United States of America High 7809086
1994 R-Ras interacts with the catalytic domain of rasGAP and with the GAP-related domain of neurofibromin in vitro, and stimulates c-fos expression when microinjected into Swiss 3T3 cells, but unlike Ras does not induce DNA synthesis, membrane ruffling, oocyte maturation, or PC12 differentiation. In vitro binding assays, microinjection into fibroblasts, gene expression assays Oncogene Medium 8108110
1994 Oncogenic activation of R-Ras by point mutations at codon 38 (analogous to Ras codon 12) or codon 87 (analogous to codon 61) confers transforming capacity; R-Ras cooperates with c-raf-1 in NIH3T3 transformation, suggesting interaction with the Raf signaling pathway. Site-directed mutagenesis, NIH3T3 focus formation assay, soft-agar colony assay, in vivo tumor assay, co-transfection with c-raf-1 Oncogene High 8084601
1995 A novel ~98-kDa R-Ras-specific GTPase-activating protein (R-Ras GAP) was purified from bovine brain; it binds GTP-bound R-Ras but not GDP-R-Ras, effector-domain-mutant R-Ras, Ha-Ras, or RalA; its GAP-related domain stimulates GTPase activity of R-Ras and weakly of Ha-Ras, but not Rap1 or Rho. GST-R-Ras affinity chromatography, GTPase activity assay with recombinant GAP domain, protein purification and cDNA cloning The Journal of biological chemistry High 8530488
1995 Activated R-Ras (38V) promotes apoptosis upon growth factor withdrawal via a Bcl-2-suppressible mechanism; Bcl-2 does not alter R-Ras GTP/GDP ratio or inhibit R-Ras-mediated Raf-1 activation, placing Bcl-2 downstream of R-Ras in the cell death pathway. Stable transfection of R-Ras(38V), IL-3 withdrawal apoptosis assay, co-transfection with Bcl-2, in vitro GTPase assay, Raf-1 kinase assay in Sf9 cells The Journal of cell biology High 7744959
1996 Expression of constitutively active R-Ras increases integrin ligand-binding affinity without changing integrin surface expression; dominant-negative R-Ras reduces adhesion of endogenous cells, establishing R-Ras as a regulator of integrin activation (inside-out signaling). Stable transfection of activated/dominant-negative R-Ras mutants, integrin ligand-binding affinity assays, cell adhesion assays, fibronectin matrix assembly assay Cell High 8620538
1996 R-Ras binds to the Raf-1 RBD and RalGDS RBD with weak affinity and no specificity compared to H-Ras/Raf or Rap1A/RalGDS interactions; biochemical solution binding assays show Rap1A, not R-Ras, is the likely physiological effector of RalGDS. Solution binding assays (quantitative affinity measurements), guanine nucleotide dissociation inhibition assay The Journal of biological chemistry High 8636102
1997 R-Ras activates PI 3-kinase in vitro and elevates PI 3-kinase lipid products in cells, and activates PKB/Akt through a PI 3-kinase-dependent mechanism; unlike Ras, R-Ras does not activate Raf or MAP kinase in cells. Co-transfection assays, PI 3-kinase lipid product measurements, PKB/Akt kinase assays, MAP kinase assays, PI 3-kinase inhibitor (wortmannin) Current biology : CB High 8999998
1999 EphB2 receptor tyrosine kinase phosphorylates tyrosine 66 in the R-Ras effector domain upon activation, reducing integrin activity and cell adhesion; an R-Ras Y66F mutant resistant to phosphorylation renders cells unresponsive to EphB2-mediated anti-adhesion. EphB2 activation assays, phosphorylation mapping by site-directed mutagenesis (Y66F), cell adhesion assays, transfection rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 10570155
1999 SHEP1 (SH2 domain-containing Eph receptor-binding protein 1) directly links activated EphB2 to R-Ras: SHEP1's SH2 domain binds the phosphorylated juxtamembrane region of EphB2, and SHEP1's Ras-GEF-like domain binds R-Ras and Rap1A (but not Ha-Ras or RalA). Yeast two-hybrid screen, co-immunoprecipitation, domain-mapping experiments The Journal of biological chemistry Medium 10542222
1999 Activated R-Ras (38V) and TC21 promote integrin-mediated migration and invasion of breast epithelial cells through integrin alpha2 (but not alpha5) cytoplasmic domain-dependent signaling, via a combination of PI 3-kinase and PKC (but not MAPK) pathways. Stable transfection, integrin cytoplasmic domain chimeras, cell migration and invasion assays, pharmacological pathway inhibitors The Journal of cell biology High 10352023
1999 GTP-bound R-Ras antagonizes the Ras/Raf-initiated integrin suppression pathway without competing for common downstream effectors or inhibiting Ras/Raf-induced MAP kinase activation, suggesting distinct downstream effectors. CHO cell transfection, integrin affinity assays, MAP kinase activation assays, dominant-negative/constitutively active mutant expression Molecular biology of the cell Medium 10359597
1999 R-Ras effector domain mutants (S61, G63, C66) dissociate transforming activity from cell adhesion/survival promotion; PI 3-kinase (but not MEK-dependent MAPK) is essential for R-Ras oncogenicity; Akt inhibition blocks R-Ras pro-survival effects; dominant-negative Rac and Ral suppress R-Ras-induced cell adhesion. Effector loop mutagenesis, transformation assays, dominant-negative kinase co-expression, PI3K inhibitor LY294002, cell adhesion/survival assays in 32D cells Molecular and cellular biology High 10454580
2000 R-Ras guanine nucleotide exchange is promoted by RasGRF, C3G, CalDAG-GEFI, CalDAG-GEFII (RasGRP), and CalDAG-GEFIII both in 293T cells and in vitro; R-Ras GTPase activity is stimulated by Gap1(m), p120 GAP, NF-1, and R-Ras GAP (but not by exchange factors or GAPs for classical Ras exclusively). GTP/GDP ratio measurements in 293T cells, in vitro GEF assays, GAP activity assays The Journal of biological chemistry High 10777492
2000 CalDAG-GEFIII (also called CalDAG-GEFIII) promotes guanine nucleotide exchange on R-Ras (as well as Ha-Ras and Rap1) both in 293T cells and in vitro, demonstrating that R-Ras is a substrate of this calcium/DAG-regulated GEF. GTP/GDP ratio assay in 293T cells, in vitro GEF assay with purified proteins The Journal of biological chemistry High 10835426
2000 AND-34 (BCAR3 homolog) exhibits GEF activity on R-Ras (as well as RalA and Rap1A) in cells; its GEF activity is regulated by binding to p130Cas, with overexpression of p130Cas inhibiting AND-34's Ral GEF activity. GTP/GDP exchange assay in cells, co-immunoprecipitation, dominant-negative construct co-expression The Journal of biological chemistry Medium 10896938
2000 Activated R-Ras, PI 3-kinase, PKCε, and Rac1 can each restore cell spreading inhibited by tac-β1 dominant-negative integrin; R-Ras-mediated rescue of cell spreading requires intact integrin β cytoplasmic domains and PI 3-kinase activity (blocked by LY294002), placing R-Ras upstream of PI 3-kinase in integrin-dependent spreading. Tac-β1 dominant-negative expression, PI 3-kinase inhibitor LY294002, cell spreading area measurements, co-expression of signaling mutants The Journal of cell biology Medium 11134082
2000 Ha-Ras activates α5β1 integrin via PI 3-kinase p110δ, while R-Ras activates α5β1 via a distinct PI 3-kinase-independent pathway; R-Ras effector loop mutations affecting cell adhesion do not correlate with PI3K activity. Integrin adhesion assays in mast cells, wortmannin inhibition, effector loop mutants, PI3K co-immunoprecipitation, Akt phosphorylation assays The Journal of biological chemistry Medium 10801791
2000 R-Ras contains a proline-rich motif that binds the second SH3 domain of the adaptor protein Nck in a GTP-independent manner; mutations in this proline-rich site suppress R-Ras-mediated cell adhesion without affecting GTP binding. GST-SH3 pulldown, yeast two-hybrid, co-immunoprecipitation from transfected cells, site-directed mutagenesis, cell adhesion assay The Journal of biological chemistry High 10671570
2001 R-Ras activates Rap1-dependent αMβ2 integrin-mediated phagocytosis in macrophages but does not activate ERK, JNK, or p38 MAPK pathways; microinjection of activated R-Ras into PC12 cells induces cell spreading rather than differentiation. Microinjection of constitutively active R-Ras into fibroblasts and PC12 cells, phagocytosis assay in macrophage cell line, MAP kinase assays Journal of cell science Medium 11257001
2001 Activated Src kinase (v-Src and Src527) phosphorylates R-Ras at tyrosine 66 in vitro and in cells, suppressing integrin activity; R-Ras and Src co-immunoprecipitate in temperature-sensitive v-Src cells at the permissive temperature; R-Ras Y66F mutant confers partial resistance to Src-mediated loss of adhesion. In vitro kinase assay, endogenous R-Ras phosphorylation in Src-transformed cells, co-immunoprecipitation, site-directed mutagenesis (Y66F), cell adhesion assay The Journal of biological chemistry High 11682467
2002 Toxin B variants from toxin A-negative C. difficile strains glucosylate R-Ras (a post-translational modification), causing cell detachment from ECM and blocking EGF-mediated ERK phosphorylation; constitutively active R-Ras expression protects cells against cytopathic effect, confirming R-Ras as the functional target. Glucosylation assay, constitutively active R-Ras rescue transfection, cell adhesion/detachment assay, ERK phosphorylation assay The Journal of biological chemistry High 12496290
2003 Activated R-Ras promotes focal adhesion formation and dramatically enhances FAK and p130Cas phosphorylation upon collagen stimulation or α2β1 integrin clustering; this signaling is partially PI 3-kinase dependent but Src-independent and distinct from canonical integrin signaling. Stable transfection of R-Ras(38V), phospho-FAK and p130Cas immunoblotting, Src and PI3K inhibitors, integrin clustering experiments Molecular and cellular biology Medium 12529399
2003 The C-terminal hypervariable region (aa 175–218) of R-Ras contains a focal adhesion targeting signal; palmitoylation at C213 is required for Golgi exit and plasma membrane targeting; activated R-Ras (but not dominant-negative R-Ras) localizes to focal adhesions in a GTP-dependent manner. H-Ras/R-Ras chimera analysis, palmitoylation site mutagenesis (C213A), subcellular fractionation, immunofluorescence localization Journal of cell science High 12890755
2003 ORP3 (OSBP-related protein 3) interacts with R-Ras; siRNA knockdown of ORP3 phenocopies constitutively active R-Ras (enhanced β1 integrin activity, altered actin); ORP3 overexpression reduces β1 integrin activity; ORP3 is phosphorylated when cells lose adhesive contacts. Co-immunoprecipitation, siRNA knockdown, β1 integrin activity assay (FACS), phagocytosis assay, actin cytoskeleton analysis Journal of cell science Medium 18270267
2004 Plexin-B1 directly stimulates the intrinsic GTPase activity of R-Ras; this GAP activity requires the interaction of Plexin-B1 with Rnd1 (a Rho-family GTPase); R-Ras inactivation by the Plexin-B1–Rnd1 complex is essential for Sema4D-induced growth cone collapse in hippocampal neurons. R-Ras GTPase activity assay (GAP assay), co-immunoprecipitation of Plexin-B1 and Rnd1, Sema4D-induced growth cone collapse assay in primary hippocampal neurons, dominant-negative constructs Science (New York, N.Y.) High 15297673
2004 The Plexin-B1 cytoplasmic domain contains C1 and C2 R-Ras GAP-homologous domains; Rnd1 disrupts an intramolecular C1–C2 interaction to open the GAP domains; Sema4D-induced receptor clustering activates R-Ras GAP activity; deletion of the extracellular domain causes ligand-independent clustering and constitutive R-Ras GAP activity. Domain deletion and mutagenesis of Plexin-B1, antibody-induced clustering of recombinant cytoplasmic domain, R-Ras GTPase activation assay, COS-7 cell contraction assay, hippocampal neurite outgrowth assay The Journal of neuroscience : the official journal of the Society for Neuroscience High 15601954
2004 Constitutively active R-Ras (38V) decreases Rac activity and increases Rho activity at the cell periphery; dominant-negative R-Ras shows the converse; endogenous R-Ras localizes and is preferentially activated at the leading edge; R-Ras effects on migration are mediated by PI 3-kinase (effector mutant uncoupling PI3K binding rescues migration). Rho/Rac activity assays (pull-down), localization by immunofluorescence with activity probe, siRNA knockdown, PI3K-uncoupling effector mutant, cell migration assays Molecular biology of the cell High 15525681
2005 The unique N-terminal 26-amino-acid extension of R-Ras is required for Rac activation and Rac-dependent cell spreading; truncated R-Ras lacking this N-terminus fails to activate Rac and stimulates more β3-integrin-dependent migration; the N-terminus does not affect subcellular localization or cell adhesion. N-terminal truncation mutants, Rac-GTP pull-down assay, cell spreading assay, migration assay in 32D cells Molecular biology of the cell Medium 15772154
2005 EphB2 activates R-Ras, which becomes associated with the receptor and highly phosphorylated; siRNA depletion of R-Ras abrogates EphB2 effects on glioma cell adhesion, proliferation, and invasion, confirming R-Ras as a required downstream mediator of EphB2 in glioma. siRNA knockdown of R-Ras, EphB2 activation experiments, cell adhesion/invasion assays, R-Ras co-immunoprecipitation with EphB2, phosphorylation analysis The American journal of pathology Medium 16049340
2006 Sema4D/Plexin-B1 suppresses R-Ras activity in hippocampal neurons, leading to dephosphorylation of Akt and activation of GSK-3β; constitutively active Akt or GSK-3 inhibitors block Sema4D-induced growth cone collapse; Plexin-B1 R-Ras GAP activity is required for downstream Akt dephosphorylation, GSK-3β activation, and CRMP-2 phosphorylation. R-Ras GTPase activity assay, Akt and GSK-3β phosphorylation immunoblotting, pharmacological inhibitors (GSK-3 inhibitors, PI3K activators), siRNA/dominant-negative constructs in hippocampal neurons EMBO reports High 16799460
2006 Sema4D/Plexin-B1 R-Ras GAP activity suppresses β1 integrin activation and cell migration in response to ECM; knockdown or dominant-negative inhibition of R-Ras alone is sufficient to suppress β1 integrin activation and migration, establishing R-Ras as a required mediator between ECM and β1 integrin activation. R-Ras siRNA knockdown, R-Ras-specific GAP overexpression, β1 integrin activation assay, cell migration assay, PI3K activation assay The Journal of cell biology High 16702230
2006 R-Ras drives membrane protrusion through PLCε: R-Ras co-precipitates with PLCε and increases PLCε activity; siRNA knockdown of PLCε reduces ruffling lamellipod formation; PLC inhibitors and intracellular Ca2+ chelation block R-Ras-mediated membrane protrusions and spreading. TIRF microscopy, co-immunoprecipitation, PLCε activity assay, siRNA knockdown of PLCε, pharmacological PLC inhibitors, Ca2+ chelation Journal of cell science Medium 16537651
2006 Eph receptors inactivate R-Ras through two mechanisms: (1) phosphorylation at tyrosine 66 via EphB2, and (2) increased GTP hydrolysis through p120RasGAP; retraction of cell periphery depends only on p120RasGAP-mediated inactivation, while ephrin-inhibited migration and growth cone collapse require both mechanisms. R-Ras mutants resistant to p120RasGAP and/or Y66 phosphorylation, COS cell retraction assay, cell migration assay, growth cone collapse assay in primary neurons Journal of cell science High 16522685
2006 RLIP76 (RalBP1) is a novel R-Ras-specific effector: it binds R-Ras directly in a GTP-dependent manner but not H-Ras or Rap1A; RLIP76 is required for adhesion-induced Rac activation, cell spreading, and migration; RLIP76 regulates Rac through an Arf6 GTPase cascade. R-Ras interactome database mining, direct binding assay, GTP-dependence test, siRNA knockdown of RLIP76, Rac and Arf6 activity assays, cell spreading/migration assays The Journal of cell biology High 16966426
2006 R-Ras activates JNK in 293T and NIH 3T3 cells through the C3G GEF pathway; constitutively active R-Ras (Val-38) activates JNK, whereas dominant-negative R-Ras (Asn-43) inhibits v-Crk-induced JNK activation; R-Ras-mediated JNK activation requires mixed lineage kinase 3 (MLK3). JNK activity assays, dominant-negative R-Ras expression, v-Crk oncogene transfection, MLK3 dominant-negative inhibition, flat-reversion of transformed NIH 3T3 cells The Journal of biological chemistry Medium 10777559
2006 R-Ras controls axon specification in hippocampal neurons: it localizes to the prospective axon, activates PI 3-kinase to recruit ILK to the membrane, and ILK inactivates GSK-3β, leading to axon formation; R-Ras knockdown blocks GSK-3β inactivation and axon formation. Immunofluorescence localization, R-Ras siRNA knockdown, ILK siRNA knockdown, ILK membrane targeting construct, GSK-3β phosphorylation immunoblotting, axon formation assay in primary hippocampal neurons The Journal of biological chemistry High 17107957
2006 Cyclic AMP activates R-Ras through Epac (exchange protein directly activated by cAMP) via G protein-coupled receptors; Epac1 directly interacts with R-Ras and catalyzes GDP/GTP exchange in vitro; activated R-Ras specifically mediates GPCR-stimulated phospholipase D activation. Epac-specific cAMP analog, Epac1 siRNA knockdown, dominant-negative Rap GTPases, in vitro GEF assay (Epac1 + R-Ras), phospholipase D activity assay The Journal of biological chemistry High 16754664
2006 R-Ras GAP is transcriptionally downregulated by NGF during PC12 neurite formation, allowing R-Ras activation to promote neurite growth; R-Ras GAP homozygous mutant mice die at E12.5–13.5 from hemorrhage due to underdeveloped adherens junctions in capillary endothelial cells. Stable R-Ras GAP overexpression in PC12 cells, NGF stimulation, neurite formation assay, R-Ras GAP knockin/knockout mouse generation, embryonic histology The Journal of biological chemistry Medium 17179160
2007 R-Ras is enriched on early and recycling endosomes; endosomal R-Ras activity is higher than at the plasma membrane and correlates with accumulation of the Rgl2/Rlf GEF for RalA, leading to high endosomal RalA activity; R-Ras or RalA shRNA suppresses calcium-triggered exocytosis in PC12 cells. FRET-based R-Ras activity probe (subcellular), anti-R-Ras antibody localization, shRNA knockdown of R-Ras and RalA, calcium-triggered exocytosis assay in PC12 cells Molecular biology of the cell Medium 17344481
2007 Mammalian Notch-1 intracellular domain (released by γ-secretase cleavage) activates R-Ras and thereby activates β1 integrins, independently of CSL-mediated transcription; Notch-1 reverses H-Ras/Raf-mediated integrin suppression without affecting ERK; Delta-like ligand-4 stimulates R-Ras-dependent α5β1 integrin adhesion. γ-secretase inhibitor, Notch mutants (inefficient cleavage, ankyrin repeat deletion, PEST domain truncation), R-Ras GTP-loading assay, integrin activation assay, Delta-like ligand-4 stimulation The Journal of biological chemistry Medium 17664272
2008 Transcription factor 8 (TCF8) activates R-Ras by binding CalDAG-GEFIII (an R-Ras GEF) in the cytosol, not through transcriptional regulation; TCF8-activated R-Ras suppresses endothelial tube formation. Co-immunoprecipitation of TCF8 and CalDAG-GEFIII, R-Ras GTP-loading assay, siRNA knockdown, tube formation assay in HUVECs Biochemical and biophysical research communications Low 19116136
2009 Plexin-D1 exhibits R-Ras GAP activity requiring Rnd2 (not Rnd1); Sema3E/Plexin-D1 inhibits axon outgrowth of cortical neurons requiring Rnd2 and R-Ras downregulation; Plexin-C1 exhibits R-Ras GAP activity independently of any Rnd protein. R-Ras GTPase activity assay, co-immunoprecipitation of Rnd2 with Plexin-D1, Rnd2 siRNA, cell migration inhibition assay, cortical neuron axon outgrowth assay The Journal of biological chemistry High 19136556
2010 Fam38A (Piezo1 precursor) localizes at the ER and recruits R-Ras to the ER, where R-Ras activates calpain by increasing Ca2+ release from ER stores; calpain then cleaves talin to activate β1 integrins; siRNA knockdown of Fam38A, R-Ras, calpain, or talin each block integrin activation. siRNA knockdown of Fam38A/R-Ras/calpain/talin, Ca2+ release measurement, calpain activity assay, β1 integrin activation assay, subcellular co-localization (confocal) Journal of cell science High 20016066
2010 Sema3E activates Plexin-D1 to inactivate R-Ras and stimulate Arf6, causing disassembly of integrin adhesive structures and inhibition of endothelial cell adhesion; R-Ras inactivation controls integrin activation status while Arf6 stimulation controls integrin intracellular trafficking. R-Ras GTP-loading assay, Arf6 activation assay, integrin adhesion and fibrillar adhesion assays, dominant-negative R-Ras/Arf6 constructs, endothelial cell retraction assay Molecular and cellular biology Medium 20385769
2010 Sema4D/Plexin-B1 R-Ras GAP activity promotes dephosphorylation and activation of PTEN (at Ser-380) through inhibition of casein kinase 2α; PTEN activation contributes to growth cone collapse downstream of R-Ras inactivation. PTEN phosphorylation immunoblotting, PTEN phosphatase activity assay, phospho-mimic/phospho-resistant PTEN mutants, casein kinase 2α activity assay, growth cone collapse assay in hippocampal neurons The Journal of biological chemistry High 20610402
2010 R-Ras colocalizes with and is endocytosed from membrane ruffles, trafficking via Rab11-positive vesicles; active R-Ras promotes ruffle formation and β1 integrin endocytosis; dominant-negative R-Ras and R-Ras siRNA prevent β1 integrin accumulation in ruffles and impair β1-integrin-mediated adhesion. GFP-R-Ras live-cell imaging, Rab11 co-localization, siRNA knockdown, β1 integrin endocytosis assay, TIRF microscopy BMC cell biology Medium 20167113
2010 DHHC19 is a palmitoyl transferase that specifically palmitoylates R-Ras (not H-Ras, N-Ras, K-Ras4A, RhoB, or Rap2); DHHC19 co-expression increases R-Ras palmitoylation approximately 2-fold, enhances R-Ras membrane and raft/caveolae association, and increases cell viability. Palmitoylation assay (metabolic labeling), membrane fractionation, raft/caveolae isolation, co-transfection in COS7 cells, cell viability assay Biochimica et biophysica acta Medium 20074548
2010 R-Ras interacts with filamin A (FLNa) via FLNa repeat 3; active R-Ras colocalizes with FLNa and coordinately increases cell migration and fibronectin matrix assembly; siRNA knockdown of endogenous R-Ras impairs FLNa-dependent fibronectin matrix assembly. Yeast two-hybrid screen, co-immunoprecipitation, GST-FLNa pulldown, FLNaΔ3 deletion mutant, co-localization immunofluorescence, siRNA knockdown, cell migration and fibronectin assembly assays PloS one Medium 20585650
2011 R-Ras interacts with FLNa (repeat 3) in endothelial cells; co-knockdown of R-Ras and FLNa promotes vascular permeability, disorganizes VE-cadherin at adherens junctions, and increases Src (Y416) and VE-cadherin (Y731) phosphorylation; dominant-negative R-Ras-induced permeability is blocked by Src inhibitor PP2. Co-immunoprecipitation, FLNaΔ3 rescue experiments, siRNA knockdown, transendothelial electrical resistance, FITC-dextran permeability assay, VE-cadherin immunostaining Journal of cellular physiology Medium 21660952
2012 R-Ras-GTP binds RIN2 (Ras and Rab5 interacting protein) and converts it from a Rab5 GEF to an adaptor that binds Rab5-GTP; this promotes selective endocytosis of ligand-bound/active β1 integrins; the R-Ras/RIN2/Rab5 module then activates Rac1 via TIAM1 on early endosomes to drive endothelial cell adhesion. Co-immunoprecipitation of R-Ras with RIN2, active integrin endocytosis assay, Rac1 activation assay, TIAM1 localization, RIN2 siRNA, Rab5 GEF activity assay, dominant-negative constructs Cell research High 22825554
2012 Palmitoylation of R-Ras is required for exit from the Golgi in post-Golgi vesicle membranes and trafficking to the plasma membrane; geranylgeranylation is required for membrane anchorage; palmitoylation-deficient R-Ras blocks membrane ruffling, PI3K interaction, PtdIns(3,4,5)P3 enrichment at plasma membrane, and R-Ras-dependent cell spreading. Palmitoylation-deficient mutant analysis, GFP-tagged R-Ras vesicle trafficking by live-cell imaging, Rab11 co-localization, PI3K co-immunoprecipitation, PtdIns(3,4,5)P3 reporter, cell spreading assay Small GTPases Medium 22751447
2012 R-Ras controls axon branching in cortical neurons through afadin: active R-Ras induces translocation of afadin to membranes via afadin's RA (Ras-association) domains; afadin RA domain and F-actin binding domain are required for axon branching; R-Ras and afadin interact endogenously during axon development. Co-immunoprecipitation of endogenous R-Ras and afadin, afadin domain deletion mutants, siRNA knockdown of afadin, R-Ras constitutively active expression, subcellular localization analysis in cortical neurons Molecular biology of the cell Medium 22593211
2014 ORP3-hyperphosphorylated form (ORP3-P) selectively interacts with the ER membrane protein VAPA via FFAT-like and canonical FFAT motifs; ORP3-VAPA complexes are targeted to PM sites via the ORP3 PH domain; ORP3-VAPA co-expression induces R-Ras activation and downstream AktS473 phosphorylation and β1 integrin activity. ORP3 mutagenesis (FFAT motif), co-immunoprecipitation of ORP3-P with VAPA, β1 integrin activity assay, Akt phosphorylation, VAPA co-expression Experimental cell research Medium 25447204
2014 SHANK1 and SHANK3 limit integrin activation by sequestering GTP-bound R-Ras (and Rap1) via the SHANK SPN domain (revealed as a Ras-association domain by crystal structure); autism-related SHANK3 SPN mutations (R12C and L68P) disrupt G-protein interaction and fail to inhibit integrin activation along the Rap1-RIAM-talin axis. Crystal structure of SHANK3 N-terminal region, affinity measurements of SPN-R-Ras interaction, SHANK3 silencing (increased Rap1 activity, cell spreading/migration/invasion), SPN point mutant functional rescue assays in cancer cells and neurons Nature cell biology High 28263956
2015 R-Ras suppresses internalization/endocytosis of VEGFR2 in endothelial cells, thereby strongly inhibiting VEGF-induced autophosphorylation at all five major tyrosine sites; this suppression is partially dependent on VE-cadherin; silencing R-Ras increases VEGFR2 phosphorylation and R-Ras knockout mice show elevated VEGFR2 phosphorylation in tumor vasculature. VEGFR2 internalization assay, VEGFR2 phosphorylation immunoblotting (5 sites), R-Ras siRNA, R-Ras knockout mouse tumor model, VE-cadherin knockdown epistasis The Journal of biological chemistry High 25645912
2016 R-Ras strongly suppresses VEGF-dependent activation of p38MAPK and downstream HSP27 phosphorylation in endothelial cells; silencing R-Ras by siRNA increases VEGF-induced membrane protrusion and migration, effects reversed by p38MAPK inhibitor SB203580, establishing R-Ras as a regulator of the p38MAPK-HSP27 axis. p38MAPK and HSP27 phosphorylation immunoblotting, R-Ras siRNA, p38MAPK inhibitor SB203580, cell migration assay, membrane protrusion assay Journal of vascular research Medium 27029009
2016 RASA1 (p120RasGAP) exerts its tumor-suppressive function specifically through its GAP activity toward R-Ras; RASA1 mutants (Y472H, L481F) found in melanoma lack GAP activity toward R-Ras; wild-type RASA1 suppresses soft agar colony formation via R-Ras; R-Ras promotes RalA activation among downstream effectors. Soft-agar colony formation assay, RASA1 GAP activity assay toward R-Ras, RASA1 point mutant expression, RalA activation assay Oncotarget Medium 26993606
2017 R-Ras-Akt signaling stabilizes the microtubule cytoskeleton in endothelial cells, promoting endothelial lumenogenesis; VEGF-A-activated Akt does not similarly stabilize microtubules or drive lumen formation; R-Ras-Akt pathway is required in vivo for lumenization of new capillaries in ischemic muscle. R-Ras constitutively active and dominant-negative expression, microtubule stability assay, 3D lumen formation assay, R-Ras knockout mouse ischemia model, Akt inhibitor Nature communications High 29170374
2018 Prolonged cAMP elevation transcriptionally represses RRAS gene expression in endothelial cells via a CREB3-dependent mechanism, disrupting VE-cadherin at adherens junctions and increasing vascular permeability; cAMP-induced plasma leakage from microvessels in mouse skin is mediated by RRAS repression. RT-PCR and immunoblotting of R-Ras upon cAMP elevation, CREB3 siRNA, R-Ras rescue transduction, VE-cadherin localization, TEER and FITC-dextran permeability assay, in vivo Miles assay in mice FASEB journal High 29775418
2019 RasGRP2 (CalDAG-GEF) activates R-Ras (in addition to Rap1) in endothelial cells; the R-Ras-PI3K-Akt signaling pathway activated by RasGRP2 suppresses Bax-activation-induced apoptosis by promoting translocation of hexokinase-2 from cytoplasm to mitochondria. Rap1 and R-Ras GTP pull-down assays, Rap1 siRNA knockdown, R-Ras siRNA knockdown, Akt phosphorylation, Bax translocation assay, HK-2 localization, apoptosis assay Scientific reports Medium 31723205
2022 PI3KC2α synthesizes PI(3,4)P2 at focal adhesions, which recruits RASA3 (RasGAP); RASA3 at focal adhesions inactivates R-RAS, increasing focal adhesion turnover, cell migration, and invasion; inhibiting PI3KC2α or lowering RASA3 activity reduces metastasis in PI3KC2α-overexpressing breast cancer models. PI3KC2α knockdown/overexpression, PI(3,4)P2 localization at focal adhesions, RASA3 co-localization and recruitment assay, R-RAS GTP-loading assay, focal adhesion turnover assay, in vivo metastasis model Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 35098698
2023 FOXF1 directly activates the RRAS gene promoter through transcriptional activation in endothelial cells; endothelial-specific Foxf1 inhibition impairs R-Ras signaling and increases collagen deposition; nanoparticle delivery of Foxf1 cDNA decreases pulmonary fibrosis, with the mechanism involving FOXF1-dependent R-Ras transcription. Single-cell RNA-sequencing, FOXF1 promoter luciferase/ChIP (implied by 'direct transcriptional activation'), endothelial-specific Foxf1 knockout mouse, R-Ras signaling analysis, nanoparticle Foxf1 delivery in bleomycin mouse model Nature communications Medium 37137915

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Integrin activation by R-ras. Cell 379 8620538
2004 The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science (New York, N.Y.) 332 15297673
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
1994 Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proceedings of the National Academy of Sciences of the United States of America 257 7809086
1993 Bcl-2 associates with the ras-related protein R-ras p23. Nature 228 8232588
1987 Structure of the human and murine R-ras genes, novel genes closely related to ras proto-oncogenes. Cell 217 3098437
1997 R-Ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways. Current biology : CB 203 8999998
1989 Identification of distinct cytoplasmic targets for ras/R-ras and rho regulatory proteins. The Journal of biological chemistry 189 2491843
2010 Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum. Journal of cell science 177 20016066
1999 An Eph receptor regulates integrin activity through R-Ras. Proceedings of the National Academy of Sciences of the United States of America 171 10570155
2010 Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras. Molecular and cellular biology 138 20385769
2000 Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. The Journal of biological chemistry 136 10777492
1999 R-Ras signals through specific integrin alpha cytoplasmic domains to promote migration and invasion of breast epithelial cells. The Journal of cell biology 135 10352023
1995 R-Ras promotes apoptosis caused by growth factor deprivation via a Bcl-2 suppressible mechanism. The Journal of cell biology 133 7744959
2005 Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays. Cancer research 128 15781621
2005 EphB2/R-Ras signaling regulates glioma cell adhesion, growth, and invasion. The American journal of pathology 128 16049340
2000 CalDAG-GEFIII activation of Ras, R-ras, and Rap1. The Journal of biological chemistry 125 10835426
2000 Activated R-ras, Rac1, PI 3-kinase and PKCepsilon can each restore cell spreading inhibited by isolated integrin beta1 cytoplasmic domains. The Journal of cell biology 122 11134082
2014 MiR-124 governs glioma growth and angiogenesis and enhances chemosensitivity by targeting R-Ras and N-Ras. Neuro-oncology 118 24861879
2003 Oxidized phospholipid-induced endothelial cell/monocyte interaction is mediated by a cAMP-dependent R-Ras/PI3-kinase pathway. Arteriosclerosis, thrombosis, and vascular biology 114 12805072
2014 Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Human molecular genetics 113 24705357
2006 Sema4D/plexin-B1 activates GSK-3beta through R-Ras GAP activity, inducing growth cone collapse. EMBO reports 110 16799460
1994 R-Ras induces malignant, but not morphologic, transformation of NIH3T3 cells. Oncogene 110 7936652
2004 Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 108 15601954
2005 R-Ras is a global regulator of vascular regeneration that suppresses intimal hyperplasia and tumor angiogenesis. Nature medicine 107 16286923
2017 SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras. Nature cell biology 100 28263956
2012 The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling. Cell research 98 22825554
1999 A novel signaling intermediate, SHEP1, directly couples Eph receptors to R-Ras and Rap1A. The Journal of biological chemistry 94 10542222
2001 Analysis of R-Ras signalling pathways. Journal of cell science 89 11257001
2006 Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta(1) integrin activity. The Journal of cell biology 88 16702230
2023 Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling. Nature communications 86 37137915
2000 p130Cas regulates the activity of AND-34, a novel Ral, Rap1, and R-Ras guanine nucleotide exchange factor. The Journal of biological chemistry 86 10896938
1999 The small GTP-binding protein R-Ras can influence integrin activation by antagonizing a Ras/Raf-initiated integrin suppression pathway. Molecular biology of the cell 85 10359597
2009 Different requirement for Rnd GTPases of R-Ras GAP activity of Plexin-C1 and Plexin-D1. The Journal of biological chemistry 82 19136556
1994 Oncogenic activation of human R-ras by point mutations analogous to those of prototype H-ras oncogenes. Oncogene 82 8084601
2008 The R-Ras interaction partner ORP3 regulates cell adhesion. Journal of cell science 79 18270267
2004 R-Ras controls membrane protrusion and cell migration through the spatial regulation of Rac and Rho. Molecular biology of the cell 78 15525681
2007 Mammalian NOTCH-1 activates beta1 integrins via the small GTPase R-Ras. The Journal of biological chemistry 76 17664272
1999 Differential roles of Akt, Rac, and Ral in R-Ras-mediated cellular transformation, adhesion, and survival. Molecular and cellular biology 76 10454580
2014 OSBP-related protein 3 (ORP3) coupling with VAMP-associated protein A regulates R-Ras activity. Experimental cell research 74 25447204
1994 R-ras interacts with rasGAP, neurofibromin and c-raf but does not regulate cell growth or differentiation. Oncogene 67 8108110
2006 The small GTPase R-Ras regulates organization of actin and drives membrane protrusions through the activity of PLCepsilon. Journal of cell science 66 16537651
1989 Inhibition by phospholipids of the interaction between R-ras, rho, and their GTPase-activating proteins. Molecular and cellular biology 65 2513485
2006 Cyclic AMP-dependent and Epac-mediated activation of R-Ras by G protein-coupled receptors leads to phospholipase D stimulation. The Journal of biological chemistry 64 16754664
1987 Heterologous expression and characterization of the human R-ras gene product. Molecular and cellular biology 64 3313005
2006 RLIP76 (RalBP1) is an R-Ras effector that mediates adhesion-dependent Rac activation and cell migration. The Journal of cell biology 63 16966426
2006 Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion. Journal of cell science 62 16522685
1994 The Ras-related protein R-ras interacts directly with Raf-1 in a GTP-dependent manner. The Biochemical journal 61 8002932
1995 A novel GTPase-activating protein for R-Ras. The Journal of biological chemistry 60 8530488
2000 Crk activation of JNK via C3G and R-Ras. The Journal of biological chemistry 58 10777559
2016 Ghrelin induces colon cancer cell proliferation through the GHS-R, Ras, PI3K, Akt, and mTOR signaling pathways. European journal of pharmacology 56 26879868
2003 R-Ras promotes focal adhesion formation through focal adhesion kinase and p130(Cas) by a novel mechanism that differs from integrins. Molecular and cellular biology 55 12529399
2003 The C-terminal end of R-Ras contains a focal adhesion targeting signal. Journal of cell science 54 12890755
2002 R-Ras glucosylation and transient RhoA activation determine the cytopathic effect produced by toxin B variants from toxin A-negative strains of Clostridium difficile. The Journal of biological chemistry 53 12496290
2001 Activated SRC oncogene phosphorylates R-ras and suppresses integrin activity. The Journal of biological chemistry 53 11682467
2000 Distinct mechanisms of alpha 5beta 1 integrin activation by Ha-Ras and R-Ras. The Journal of biological chemistry 50 10801791
2010 Semaphorin 4D/Plexin-B1 stimulates PTEN activity through R-Ras GTPase-activating protein activity, inducing growth cone collapse in hippocampal neurons. The Journal of biological chemistry 49 20610402
2010 R-Ras regulates migration through an interaction with filamin A in melanoma cells. PloS one 48 20585650
2006 R-Ras controls axon specification upstream of glycogen synthase kinase-3beta through integrin-linked kinase. The Journal of biological chemistry 48 17107957
2002 Involvement of R-Ras and Ral GTPases in estrogen-independent proliferation of breast cancer cells. Oncogene 48 12386818
1999 Signal transduction elements of TC21, an oncogenic member of the R-Ras subfamily of GTP-binding proteins. Oncogene 46 10557073
2007 R-Ras regulates exocytosis by Rgl2/Rlf-mediated activation of RalA on endosomes. Molecular biology of the cell 45 17344481
2005 The unique N-terminus of R-ras is required for Rac activation and precise regulation of cell migration. Molecular biology of the cell 45 15772154
2000 R-Ras contains a proline-rich site that binds to SH3 domains and is required for integrin activation by R-Ras. The Journal of biological chemistry 45 10671570
2000 The effector loop and prenylation site of R-Ras are involved in the regulation of integrin function. Oncogene 45 11042683
1997 R-Ras is regulated by activators and effectors distinct from those that control Ras function. Oncogene 45 9010215
2011 R-Ras interacts with filamin a to maintain endothelial barrier function. Journal of cellular physiology 44 21660952
2020 Prostaglandin E2 breaks down pericyte-endothelial cell interaction via EP1 and EP4-dependent downregulation of pericyte N-cadherin, connexin-43, and R-Ras. Scientific reports 43 32636414
2017 R-Ras-Akt axis induces endothelial lumenogenesis and regulates the patency of regenerating vasculature. Nature communications 42 29170374
2019 The inhibition of Bax activation-induced apoptosis by RasGRP2 via R-Ras-PI3K-Akt signaling pathway in the endothelial cells. Scientific reports 39 31723205
2012 A genome-scale RNA-interference screen identifies RRAS signaling as a pathologic feature of Huntington's disease. PLoS genetics 38 23209424
1997 An activated mutant of R-Ras inhibits cell death caused by cytokine deprivation in BaF3 cells in the presence of IGF-I. Oncogene 37 9349502
2016 R-Ras Inhibits VEGF-Induced p38MAPK Activation and HSP27 Phosphorylation in Endothelial Cells. Journal of vascular research 36 27029009
2017 A thirty-year quest for a role of R-Ras in cancer: from an oncogene to a multitasking GTPase. Cancer letters 35 28610953
2010 Palmitoylation of R-Ras by human DHHC19, a palmitoyl transferase with a CaaX box. Biochimica et biophysica acta 35 20074548
2003 R-Ras promotes tumor growth of cervical epithelial cells. Cancer 35 12548599
2010 R-Ras regulates beta1-integrin trafficking via effects on membrane ruffling and endocytosis. BMC cell biology 34 20167113
2005 R-ras as a key player for signaling pathway of plexins. Molecular neurobiology 33 16385138
2005 The COOH-terminal end of R-Ras alters the motility and morphology of breast epithelial cells through Rho/Rho-kinase. Cancer research 32 15695393
2016 Lack of R-Ras Leads to Increased Vascular Permeability in Ischemic Retinopathy. Investigative ophthalmology & visual science 31 27654416
2012 R-Ras controls axon branching through afadin in cortical neurons. Molecular biology of the cell 30 22593211
2018 R-Ras1 and R-Ras2 Are Essential for Oligodendrocyte Differentiation and Survival for Correct Myelination in the Central Nervous System. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 29720552
2005 R-Ras fills another GAP in semaphorin signalling. Trends in cell biology 29 15695091
2015 R-Ras protein inhibits autophosphorylation of vascular endothelial growth factor receptor 2 in endothelial cells and suppresses receptor activation in tumor vasculature. The Journal of biological chemistry 27 25645912
1998 Synergistic action of R-Ras and IGF-1 on Bcl-xL expression and caspase-3 inhibition in BaF3 cells: R-Ras and IGF-1 control distinct anti-apoptotic kinase pathways. FEBS letters 27 9804182
2018 Prolonged activation of cAMP signaling leads to endothelial barrier disruption via transcriptional repression of RRAS. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 29775418
2006 Versatile roles of R-Ras GAP in neurite formation of PC12 cells and embryonic vascular development. The Journal of biological chemistry 26 17179160
2022 Phosphoinositide Conversion Inactivates R-RAS and Drives Metastases in Breast Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 25 35098698
2021 Oxysterol binding protein-like 3 (OSBPL3) is a novel driver gene that promotes tumor growth in part through R-Ras/Akt signaling in gastric cancer. Scientific reports 25 34584127
2017 An Oncogenic ALK Fusion and an RRAS Mutation in KRAS Mutation-Negative Pancreatic Ductal Adenocarcinoma. The oncologist 25 28167572
2008 Transcription factor 8 activates R-Ras to regulate angiogenesis. Biochemical and biophysical research communications 25 19116136
2012 Palmitoylation regulates vesicular trafficking of R-Ras to membrane ruffles and effects on ruffling and cell spreading. Small GTPases 24 22751447
2011 R-Ras is required for murine dendritic cell maturation and CD4+ T-cell priming. Blood 24 22174156
2006 R-Ras promotes metastasis of cervical cancer epithelial cells. Cancer immunology, immunotherapy : CII 24 16862428
2016 Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation. Oncotarget 22 26993606
2003 C-terminal sequences in R-Ras are involved in integrin regulation and in plasma membrane microdomain distribution. Biochemical and biophysical research communications 22 14623256
2015 Girdin/GIV regulates transendothelial permeability by controlling VE-cadherin trafficking through the small GTPase, R-Ras. Biochemical and biophysical research communications 21 25869066
2006 H-Ras, R-Ras, and TC21 differentially regulate ureteric bud cell branching morphogenesis. Molecular biology of the cell 21 16467383
2006 The R-Ras GTPase mediates cross talk between estrogen and insulin signaling in breast cancer cells. Molecular and cellular biology 20 16914723
2014 An increase in tolerogenic dendritic cell and natural regulatory T cell numbers during experimental autoimmune encephalomyelitis in Rras-/- mice results in attenuated disease. Journal of immunology (Baltimore, Md. : 1950) 18 24771856

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