Affinage

RALGDS

Ral guanine nucleotide dissociation stimulator · UniProt Q12967

Length
914 aa
Mass
100.6 kDa
Annotated
2026-04-28
100 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RALGDS is a guanine nucleotide exchange factor (GEF) for Ral GTPases (RalA and RalB) and a direct effector of Ras, serving as a critical signaling node that translates Ras activation into cytoskeletal reorganization, regulated exocytosis, autophagy, stress-kinase signaling, and cell survival. GTP-loaded Ras recruits RALGDS to the plasma membrane through an inter-protein β-sheet interaction between Ras switch I and the RALGDS Ras-binding domain (RBD), while PDK1 relieves autoinhibition of the catalytic CDC25 domain in a kinase-independent manner, and beta-arrestins regulate RALGDS cytosol-to-membrane translocation upon GPCR stimulation (PMID:9628477, PMID:11889038, PMID:12105416). Beyond its GEF activity, RALGDS scaffolds PDK1 and Akt (via JIP1) to promote Akt phosphorylation and cell survival independently of Ral exchange, and signals through Ral to JNK/p38 and Src to control ATF2 phosphorylation and tumor cell survival (PMID:18285454, PMID:12110590, PMID:15766660). RALGDS knockout mice are viable but show markedly reduced Ras-driven tumor incidence and impaired load-induced cardiac autophagy, establishing RALGDS as essential for Ras-dependent oncogenesis and stress-responsive membrane trafficking in vivo (PMID:15766660, PMID:23473774).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1994 High

    Establishing that RALGDS is a direct, GTP-dependent effector of Ras resolved how the Ral-GEF pathway connects to the canonical Ras switch and competes with Raf and NF1 for the Ras effector loop.

    Evidence Yeast two-hybrid, in vitro binding, co-immunoprecipitation, and NF1-competition assay with insect-cell-expressed proteins

    PMID:7935463

    Open questions at the time
    • Structural basis of the Ras–RalGDS interaction was unknown
    • In vivo relevance of the Ras–RalGDS axis was not yet tested
    • How GEF activity is regulated beyond Ras binding was unclear
  2. 1996 High

    Demonstration that PKA phosphorylates Raf-1 to reduce its Ras affinity without affecting RalGDS exchange activity revealed a signal-switching mechanism that reroutes Ras output from Raf toward RalGDS under cAMP-elevating conditions.

    Evidence In vitro kinase assay, co-immunoprecipitation in COS cells, GDP/GTP exchange assay, Ras T35A effector-loop mutant, forskolin treatment

    PMID:8550624

    Open questions at the time
    • Whether PKA-mediated pathway switching operates in physiological tissues was untested
    • Direct phosphorylation sites on RalGDS were not mapped
  3. 1997 High

    NMR structure of the RalGDS Ras-interacting domain and demonstration that RalGDS mediates Ras-dependent, Raf-independent proliferation in thyrocytes established the structural and functional autonomy of the Ras–RalGDS arm.

    Evidence NMR structure determination with mutagenesis; dominant-negative RalA microinjection blocking cAMP/Ras-induced DNA synthesis in thyroid cells

    PMID:9038168 PMID:9253406

    Open questions at the time
    • Full atomic detail of the Ras–RalGDS complex was still lacking
    • Downstream targets of RalA activation in this context were unidentified
  4. 1998 High

    Crystal structures of the Ras–RalGDS RBD complex at 2.1 Å revealed an inter-protein β-sheet mediated by Ras switch I, providing the atomic framework for understanding effector selectivity among Ras targets.

    Evidence X-ray crystallography at 2.1 Å resolution, confirmed by independent structure with mutagenesis and gel filtration (1999)

    PMID:10371160 PMID:9628477

    Open questions at the time
    • How the catalytic CDC25 domain is autoinhibited and activated was unresolved
    • Role of the Ras switch II contact observed in the crystal remained functionally untested
  5. 2001 High

    Dissection of RBD-dependent versus RBD-independent activation mechanisms showed that membrane recruitment via the RBD is important but not sufficient, and that Rap1 antagonizes RalGDS by sequestering the RBD in a kinetically trapped complex, resolving a long-standing question about Rap1–Ras cross-talk.

    Evidence In vivo Ral-GTP loading with RBD-defective/CAAX-targeted RalGDS, Ras Y64W mutant, stopped-flow fluorescence kinetics

    PMID:11748241

    Open questions at the time
    • Identity of the non-RBD Ras contact site on RalGDS was not mapped
    • Whether Rap1 antagonism operates in vivo was unconfirmed
  6. 2002 High

    Multiple studies in 2002 established that RalGDS integrates diverse regulatory inputs (PDK1 scaffolding, beta-arrestin sequestration) and diverse outputs (ATF2 via Src/p38, choline kinase, Ral-driven cytoskeletal reorganization), positioning it as a multifunctional signaling hub rather than a simple Ras-to-Ral relay.

    Evidence PDK1 kinase-dead mutant co-IP and domain mapping with Ral-GTP assay; beta-arrestin yeast two-hybrid, co-IP from PMNs, translocation assays; Ras effector-domain mutant epistasis for ATF2 phosphorylation and choline kinase activity

    PMID:11840339 PMID:11889038 PMID:12105416 PMID:12110590

    Open questions at the time
    • Whether PDK1 scaffolding and beta-arrestin regulation converge on the same pool of RalGDS was unknown
    • Structural basis of autoinhibition relief by PDK1 was not determined
  7. 2005 High

    RALGDS knockout mice showed reduced tumor incidence and impaired JNK-dependent survival of transformed cells in a Ras-driven carcinogenesis model, providing the first in vivo genetic proof that RALGDS is essential for Ras-mediated oncogenesis.

    Evidence Ralgds-null mice subjected to DMBA/TPA multistage skin carcinogenesis, with tumor burden quantification, apoptosis assays, and JNK pathway analysis

    PMID:15766660

    Open questions at the time
    • Whether RalGDS is required for tumor maintenance versus initiation was not distinguished
    • Contribution of individual Ral isoforms (RalA vs RalB) in vivo was not resolved
  8. 2007 High

    The RalGEF pathway was shown to specifically promote bone metastasis of prostate cancer cells through RalA, distinct from subcutaneous tumor growth, establishing tissue-microenvironment specificity for RalGDS signaling.

    Evidence Ras effector-domain mutants in DU145 cells, RalA shRNA in PC3 cells, intracardiac injection metastasis model

    PMID:17709381

    Open questions at the time
    • Bone microenvironment signals activating RalGDS were not identified
    • Whether RalB also contributes to metastasis in this model was not tested
  9. 2008 High

    Discovery that RALGDS scaffolds PDK1 and Akt (via JIP1) to promote Akt phosphorylation independently of its GEF activity, and that it drives Weibel-Palade body exocytosis through calmodulin-dependent Ral activation, revealed two additional non-canonical functions separable from Ral exchange.

    Evidence Domain-separation mutants and RNAi for PDK1–Akt scaffolding with phospho-Akt readout; RNAi, dominant-negative GEF-dead RalGDS, CaM-binding domain peptide for WPB exocytosis (VWF release)

    PMID:18285454 PMID:18417737

    Open questions at the time
    • Whether JIP1 is the sole mediator of Akt recruitment was not confirmed
    • Calmodulin-binding site on RalGDS was mapped only by peptide competition, not structurally
  10. 2013 Medium

    RALGDS-null cardiomyocytes showed impaired autophagy and blunted hypertrophic growth under pressure overload, linking RALGDS–RalB signaling to mTOR-dependent autophagy and cardiac stress adaptation beyond oncogenesis.

    Evidence Ralgds knockout mice with TAC pressure-overload, RalA/RalB siRNA in neonatal cardiomyocytes, autophagy markers (LC3, beclin), echocardiography

    PMID:23473774

    Open questions at the time
    • Exocyst-dependent membrane trafficking mechanism in cardiomyocytes was inferred but not directly demonstrated
    • Whether RalGDS GEF or scaffolding activity mediates the cardiac phenotype was not distinguished
  11. 2015 Medium

    RILP was identified as a negative regulator that recruits RalGDS to late endosomes and inhibits its GEF activity, suppressing RalA-dependent breast cancer cell invasion and revealing compartment-specific regulation of RalGDS.

    Evidence Co-immunoprecipitation, domain mapping, immunofluorescence, RalA-GTP pull-down, Matrigel invasion assay

    PMID:26469971

    Open questions at the time
    • Whether RILP-mediated endosomal sequestration operates in non-transformed cells was not tested
    • Structural basis of RILP inhibition of the GEF domain was not resolved
  12. 2017 Medium

    Single-molecule imaging directly visualized RalGDS membrane recruitment kinetics, showing that the RBD mediates initial Ras-dependent translocation while the REMCDC catalytic domain reduces dissociation rate, providing a biophysical framework for two-step membrane engagement.

    Evidence Single-molecule TIRF microscopy in living HeLa cells with domain deletion mutants and EGF stimulation

    PMID:28744424

    Open questions at the time
    • Whether membrane clustering reflects oligomerization or lipid-domain partitioning was not resolved
    • Kinetic measurements were in a single overexpression system
  13. 2019 Medium

    Genetic analysis in C. elegans demonstrated that the RalGDS ortholog RGL-1 has genetically separable GEF-dependent (promoting Ral-mediated 2° fate) and GEF-independent (promoting PI3K–PDK-1–AKT-mediated 1° fate) activities, confirming evolutionary conservation of dual signaling modes.

    Evidence C. elegans RGL-1 deletion and domain mutants, genetic epistasis with pathway components, vulval fate scoring

    PMID:31086367

    Open questions at the time
    • Whether the mammalian GEF-independent PDK1–Akt scaffolding function is fully orthologous to the worm pathway was not tested
    • Direct biochemical interaction between RGL-1 and worm PDK-1 was not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full structural model of autoinhibited full-length RALGDS, the conformational change upon PDK1 or Ras engagement, and the relative quantitative contributions of GEF-dependent versus scaffolding functions in specific disease contexts remain unresolved.
  • No full-length RALGDS structure exists
  • Quantitative partitioning of GEF versus scaffolding functions in vivo is unknown
  • Whether therapeutic targeting of the RBD–Ras interface is feasible has not been explored structurally

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 2 R-HSA-5653656 Vesicle-mediated transport 1 R-HSA-9612973 Autophagy 1
Partners
ARRB1ARRB2CALM1HRASPDPK1RALARALBRILP

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 RALGDS interacts directly with the GTP-bound (active) form of Ras p21 through the effector loop of Ras, competing with NF1 and Raf for binding to the effector loop; it does not interact with the GDP-bound form or effector-loop mutants of Ras. Yeast two-hybrid, in vitro binding with insect-cell-expressed proteins, co-immunoprecipitation, in vitro competition assay with NF1 GTPase-activating activity Molecular and cellular biology High 7935463
1996 Protein kinase A (PKA) phosphorylates RalGDS (without altering its GDP/GTP exchange activity for Ral) and also phosphorylates Raf-1 (reducing Raf-1 affinity for Ras), thereby selectively shifting Ras signaling from Raf toward RalGDS; EGF-induced Ras–RalGDS interaction in COS cells requires an intact effector loop on Ras. In vitro kinase phosphorylation assay, co-immunoprecipitation in COS cells, GDP/GTP exchange assay, use of effector-loop mutant Ras (T35A), forskolin treatment The Journal of biological chemistry High 8550624
1997 RalGDS functions as an effector of Ras in cAMP-mediated (TSH-induced) growth stimulation in thyrocytes, downstream of Ras but independent of Raf-1/MEK; microinjection of dominant-negative RalA (which sequesters RalGDS family members) inhibited Ras- and cAMP-induced DNA synthesis. Yeast two-hybrid (identifies RalGDS as Ras effector-domain mutant V12G37 binding partner), co-immunoprecipitation in thyroid cell extracts, microinjection of dominant-negative RalA protein, DNA synthesis assay The Journal of biological chemistry High 9038168
1997 The three-dimensional structure of the Ras-interacting domain (RID) of RalGDS was determined; mutational analysis identified three residues in the RID critical for interaction with Ras. NMR structure determination; site-directed mutagenesis of RID residues, binding assays Nature structural biology High 9253406
1998 Crystal structure of the Ras–RalGDS RID complex at 2.1 Å resolution revealed that the beta-sheet of the RID joins the switch I region of Ras to form an extended beta-sheet, and a second RID molecule contacts the switch II region of Ras, explaining cross-talk between Ras and Ral pathways and effector specificity. X-ray crystallography at 2.1 Å resolution Nature structural biology High 9628477
1998 RalGDS (via a membrane-targeted CAAX construct) inhibits skeletal myogenesis independently of Raf, acting on SRF-dependent transcription; however, a Ras effector-loop mutant that retains RalGDS interaction (H-Ras G12V,E37G) also inhibits an SRF-independent myogenic reporter, indicating an additional Ras effector beyond RalGDS is required for full myogenic inhibition. Expression of constitutively active and dominant-negative constructs, luciferase reporter assays for muscle-specific promoters (alpha-actin-Luc, troponin I-Luc), co-expression in C3H10T1/2 cells The Journal of biological chemistry Medium 9651367
1999 X-ray crystal structure of the Ras–RalGDS RBD complex confirmed inter-protein beta-sheet interaction via switch I; mutational analysis of interface residues quantified their contribution to binding affinity; gel filtration showed the complex is monomeric. X-ray crystallography, site-directed mutagenesis, gel filtration FEBS letters High 10371160
1999 In C. elegans, the RalGEF ortholog (Rlf/RGL-1) is required for Ras-induced primitive endoderm differentiation of F9 embryonal carcinoma cells; constitutively active RalGEF (Rlf-CAAX) is sufficient to induce differentiation in a Ral-dependent manner that also requires basal MEK/ERK activity. Expression of constitutively active Rlf-CAAX and dominant-negative Ral, inhibitor of MEK (PD98059), differentiation morphology assay Oncogene Medium 10442634
2001 The Ras-binding domain (RBD) of RalGDS is important but not sufficient for Ras-stimulated Ral activation; an artificially membrane-targeted RalGDS lacking its RBD can still be activated by Ras via its switch II region (Y64W mutation in Ras impairs this). Rap1 blocks Ras-mediated RalGDS signaling only when RalGDS contains an intact RBD (by forming a long-lived competing complex), explaining Rap1 antagonism. In vivo Ral-GTP loading assay, point-mutation analysis (RBD-defective RalGDS, CAAX membrane targeting, Ras Y64W), kinetic analysis of complex formation by stopped-flow fluorescence The Journal of biological chemistry High 11748241
2001 JAK/STAT3 pathway activation induces RalGDS expression, and RalGDS expression leads to RalA activation in M1 myeloid leukemia cells; full RalA activation also requires Ras activity, revealing cross-talk between JAK/STAT3 and Ras/RalGDS/Ral pathways. Representational difference analysis to clone RalGDS, dominant-negative STAT3 expression, JAK inhibitor (JAB/SOCS1), Ras inhibitor, Ral-GTP pull-down assay The Journal of biological chemistry Medium 11432872
2002 Beta-arrestins bind RalGDS and maintain it in an inactive cytosolic complex; upon fMLP receptor stimulation, beta-arrestin–RalGDS complexes dissociate and both translocate to the plasma membrane, activating Ral signaling in a Ras-independent manner to mediate cytoskeletal reorganization; re-association of the complex inactivates Ral signaling. Yeast two-hybrid screening, co-immunoprecipitation from PMNs, subcellular fractionation/translocation assays, Ral-GTP activation assay Nature cell biology High 12105416
2002 PDK1 enhances RalGDS catalytic (GEF) activity in a kinase-independent manner: the non-catalytic N-terminus of PDK1 forms an EGF-induced complex with the N-terminus of RalGDS, relieving its autoinhibitory effect on the catalytic domain, thereby providing a second mechanism (beyond Ras-mediated membrane redistribution) for Ral-GEF activation. Co-immunoprecipitation, dominant-negative PDK1 kinase-dead mutant, deletion mapping of PDK1–RalGDS interaction domains, in vivo Ral-GTP assay, EGF stimulation The EMBO journal High 11889038
2002 RalGDS mediates Ras-dependent activation of ATF2 Thr69 phosphorylation via a RalGDS–Src–p38 pathway, while Raf–MEK–ERK phosphorylates ATF2 Thr71; cooperation of both pathways is required for full ATF2 activation by growth factors. Ras effector-loop mutants (G12V/G37 selectively activates RalGEF path), dominant-negative constructs, phospho-specific antibodies for ATF2 Thr69/Thr71, in vivo kinase assays The EMBO journal High 12110590
2002 RalGDS and PI3K (but not Raf) mediate Ras-dependent activation of choline kinase; RalGDS and PI3K also provide opposing regulatory inputs to phospholipase D downstream of oncogenic Ras. Ras effector-domain mutants (G12V/S35 Raf-only, G12V/C40 PI3K-only, G12V/G37 RalGEF-only), choline kinase activity assay, phospholipase D activity assay Oncogene Medium 11840339
2004 The Ras/RalGEF/p38 pathway is required for reovirus oncolysis: Ras mutant V12G37 (which signals only through RalGEFs) supports reovirus infection; dominant-negative RalA blocks infection; chemical inhibition of p38 (but not JNK) prevents reovirus replication in Ras-transformed cells. NIH 3T3 cells expressing Ras effector-domain mutants, activated RalGEF (Rlf) expression, dominant-negative RalA, p38 and JNK chemical inhibitors, reovirus replication assay Proceedings of the National Academy of Sciences of the United States of America High 15263068
2004 RalGDS mediates Ras-induced upregulation of ST6Gal I (beta-galactoside alpha2,6-sialyltransferase) via the RalGEF signal, specifically through the housekeeping promoter P3; this was shown using Ras effector-domain mutants that selectively activate individual Ras pathways. Ras effector-domain mutants (H-RasV12S35, H-RasV12C40, H-RasV12G37), RT-PCR, sialyltransferase activity assay, 5'-RACE, inducible H-RasV12 expression system European journal of biochemistry Medium 15355339
2005 RalGDS knockout mice are viable and develop normally but show markedly reduced tumor incidence, size, and malignant progression in Ras-driven multistage skin carcinogenesis; RalGDS controls survival (via the JNK/SAPK pathway) rather than proliferation of transformed cells. Ralgds knockout mice, DMBA/TPA skin carcinogenesis model, cell proliferation assays, cell survival/apoptosis assays, JNK/SAPK pathway analysis in tumor-derived cells Cancer cell High 15766660
2007 Activation of the RalGEF pathway (but not Raf/ERK or PI3K) promotes prostate cancer bone metastasis; loss of RalA in metastatic PC3 cells inhibits bone metastasis but not subcutaneous tumor growth, implicating Ral-dependent expansion in the bone microenvironment. Ras effector-domain mutants expressed in DU145 cells, in vivo bone metastasis model, RalA shRNA knockdown in PC3 cells, intracardiac injection metastasis assay Molecular and cellular biology High 17709381
2008 RalGDS promotes Akt phosphorylation by PDK1 through a second, GEF-independent scaffolding function: RalGDS brings PDK1 (via its N-terminus) and Akt (via its central region, through intermediary JIP1) together; suppression of RalGDS blocks EGF- and insulin-induced Akt phosphorylation and inhibits cell proliferation. Co-immunoprecipitation, RNAi knockdown of RalGDS, deletion mutants of RalGDS separating GEF activity from Akt activation, phospho-Akt immunoblot, proliferation assay Molecular and cellular biology High 18285454
2008 RalGDS mediates exocytosis of Weibel-Palade bodies (WPBs) from endothelial cells: RNAi knockdown of RalGDS inhibits thrombin- and epinephrine-induced WPB exocytosis; overexpression promotes it; a GEF-dead RalGDS acts as dominant negative. RalGDS binds calmodulin (CaM) via an N-terminal CaM-binding domain, and this CaM association is required for Ral activation and WPB exocytosis. RNAi knockdown, overexpression, dominant-negative GEF-dead RalGDS, cell-permeable CaM-binding domain peptide, Ral-GTP pull-down, WPB exocytosis (VWF release) assay Blood High 18417737
2013 RalGDS-null cardiomyocytes show impaired load-induced autophagy and blunted hypertrophic growth in response to pressure overload (TAC); specifically RalB (downstream of RalGDS) is required for mTOR-dependent cardiomyocyte autophagy, linking RalGDS to exocyst-dependent membrane trafficking in cardiac remodeling. Ralgds knockout mice, TAC pressure-overload model, RalA/RalB siRNA knockdown in neonatal rat cardiomyocytes, autophagy markers (LC3, beclin), echocardiography Journal of molecular and cellular cardiology Medium 23473774
2015 RILP (Rab7-interacting lysosomal protein) interacts with the GEF domain of RalGDS through RILP's N-terminal region, recruits RalGDS to late endosomal compartments, and inhibits RalGDS GEF activity toward RalA, thereby suppressing breast cancer cell invasion. Co-immunoprecipitation, truncation/domain mapping, immunofluorescence microscopy, RalA-GTP pull-down, Matrigel invasion assay, RNAi knockdown Cell death & disease Medium 26469971
2017 Single-molecule fluorescence imaging showed that RalGDS translocates from the cytoplasm to the plasma membrane upon EGF-induced Ras activation via its RBD (not the REMCDC catalytic domain); the REMCDC domain reduces the dissociation rate from the membrane after Ras activation or Ral hyperexpression; RalGDS clusters at the membrane and the Y64 residue of Ras participates in stabilizing the RalGDS–membrane interaction. Single-molecule total internal reflection fluorescence (TIRF) microscopy in living HeLa cells, EGF stimulation, domain deletion mutants (RBD vs. REMCDC), kinetic analysis of membrane association/dissociation Biophysics and physicobiology Medium 28744424
2019 In C. elegans, the RalGDS ortholog RGL-1 has two genetically separable activities: a canonical GEF-dependent activity that activates RAL-1 to promote 2° vulval cell fate, and a non-canonical GEF-independent activity that promotes 1° fate via the PI3K-PDK-1-AKT cascade; these opposing activities reduce developmental stochasticity. C. elegans genetics, RGL-1 deletion and domain mutants, epistasis with dominant-negative and activated pathway components, vulval cell fate scoring PLoS genetics Medium 31086367

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes. Journal of molecular biology 952 12850155
1994 ralGDS family members interact with the effector loop of ras p21. Molecular and cellular biology 253 7935463
1998 Structural basis for the interaction of Ras with RalGDS. Nature structural biology 220 9628477
2002 Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38. The EMBO journal 185 12110590
2004 Reovirus oncolysis: the Ras/RalGEF/p38 pathway dictates host cell permissiveness to reovirus infection. Proceedings of the National Academy of Sciences of the United States of America 158 15263068
2005 RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer cell 141 15766660
2006 Presentation of RGDS epitopes on self-assembled nanofibers of branched peptide amphiphiles. Biomacromolecules 119 16768407
1996 RalGDS-like factor (Rlf) is a novel Ras and Rap 1A-associating protein. Oncogene 117 8710374
2002 Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. Nature cell biology 112 12105416
2004 Temperature-responsive cell culture surfaces enable "on-off" affinity control between cell integrins and RGDS ligands. Biomacromolecules 103 15003013
2005 Covalent immobilization of RGDS on hydrogel surfaces to direct cell alignment and migration. Journal of controlled release : official journal of the Controlled Release Society 102 16290119
2002 Regulation of choline kinase activity by Ras proteins involves Ral-GDS and PI3K. Oncogene 102 11840339
1990 Elegantin and albolabrin purified peptides from viper venoms: homologies with the RGDS domain of fibrinogen and von Willebrand factor. Biochimica et biophysica acta 94 2191722
1994 Activation of the alpha 4 beta 1 integrin through the beta 1 subunit induces recognition of the RGDS sequence in fibronectin. The Journal of cell biology 92 7517944
2007 Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. Molecular and cellular biology 89 17709381
1999 Structural and biochemical analysis of Ras-effector signaling via RalGDS. FEBS letters 89 10371160
2011 The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery. Genes & cancer 88 21779498
1991 RGDS tetrapeptide binds to osteoblasts and inhibits fibronectin-mediated adhesion. Bone 81 1793678
1987 Fibroblast adhesion to RGDS shows novel features compared with fibronectin. The Journal of cell biology 76 3611194
1997 Three-dimensional structure of the Ras-interacting domain of RalGDS. Nature structural biology 72 9253406
1992 Selective inactivation of the Arg-Gly-Asp-Ser (RGDS) binding site in von Willebrand factor by site-directed mutagenesis. The Journal of biological chemistry 68 1737795
2000 Pressure-induced local unfolding of the Ras binding domain of RalGDS. Nature structural biology 66 10876238
1997 RalGDS functions in Ras- and cAMP-mediated growth stimulation. The Journal of biological chemistry 66 9038168
2010 RalGDS family members couple Ras to Ral signalling and that's not all. Cellular signalling 65 20478380
1996 Regulation of interaction of ras p21 with RalGDS and Raf-1 by cyclic AMP-dependent protein kinase. The Journal of biological chemistry 65 8550624
1995 The cDNA sequence of human endothelial cell multimerin. A unique protein with RGDS, coiled-coil, and epidermal growth factor-like domains and a carboxyl terminus similar to the globular domain of complement C1q and collagens type VIII and X. The Journal of biological chemistry 64 7629143
2009 Synthetic RGDS peptide attenuates lipopolysaccharide-induced pulmonary inflammation by inhibiting integrin signaled MAP kinase pathways. Respiratory research 62 19272161
2002 PDK1 mediates growth factor-induced Ral-GEF activation by a kinase-independent mechanism. The EMBO journal 59 11889038
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
2003 Adhesion and migration of marrow-derived osteoblasts on injectable in situ crosslinkable poly(propylene fumarate-co-ethylene glycol)-based hydrogels with a covalently linked RGDS peptide. Journal of biomedical materials research. Part A 56 12734821
1996 Functional role of sialyl Lewis X and fibronectin-derived RGDS peptide analogue on tumor-cell arrest in lungs followed by extravasation. International journal of cancer 56 8631600
1996 Identification of a novel RalGDS-related protein as a candidate effector for Ras and Rap1. The Journal of biological chemistry 56 8939933
1989 Mechanism of fibronectin-mediated cell migration: dependence or independence of cell migration susceptibility on RGDS-directed receptor (integrin). Experimental cell research 56 2544438
2004 RGDS peptide induces caspase 8 and caspase 9 activation in human endothelial cells. Blood 55 14982875
1995 Recombinant domain III of perlecan promotes cell attachment through its RGDS sequence. The Journal of biological chemistry 55 7814401
2002 rgf encodes a novel two-component signal transduction system of Streptococcus agalactiae. Infection and immunity 54 11953380
2000 A novel RalGEF-like protein, RGL3, as a candidate effector for rit and Ras. The Journal of biological chemistry 52 10869344
1988 Ganglioside-dependent adhesion events of human neuroblastoma cells regulated by the RGDS-dependent fibronectin receptor and proteoglycans. Experimental cell research 52 2966069
1990 Fibronectin fragments containing the RGDS cell-binding domain mediate monocyte migration into the rabbit lung. A potential mechanism for C5 fragment-induced monocyte lung accumulation. The Journal of clinical investigation 51 2212000
2009 The integrin-blocking peptide RGDS inhibits airway smooth muscle remodeling in a guinea pig model of allergic asthma. American journal of respiratory and critical care medicine 50 20019343
2004 Ras oncogene induces beta-galactoside alpha2,6-sialyltransferase (ST6Gal I) via a RalGEF-mediated signal to its housekeeping promoter. European journal of biochemistry 49 15355339
2008 Guanine exchange factor RalGDS mediates exocytosis of Weibel-Palade bodies from endothelial cells. Blood 45 18417737
1993 Cell-attachment activities of surface immobilized oligopeptides RGD, RGDS, RGDV, RGDT, and YIGSR toward five cell lines. Journal of biomaterials science. Polymer edition 45 8476793
2017 Enhanced articular cartilage by human mesenchymal stem cells in enzymatically mediated transiently RGDS-functionalized collagen-mimetic hydrogels. Acta biomaterialia 44 28087486
1998 A role for RalGDS and a novel Ras effector in the Ras-mediated inhibition of skeletal myogenesis. The Journal of biological chemistry 43 9651367
2010 Effects of RGDS sequence genetically interfused in the silk fibroin light chain protein on chondrocyte adhesion and cartilage synthesis. Biomaterials 42 20643479
2001 The activation of RalGDS can be achieved independently of its Ras binding domain. Implications of an activation mechanism in Ras effector specificity and signal distribution. The Journal of biological chemistry 42 11748241
2002 Involvement of phosphatidylinositol 3-kinase, but not RalGDS, in TC21/R-Ras2-mediated transformation. The Journal of biological chemistry 41 11788587
1987 A second cell-binding domain on fibronectin (RGDS-independent) for neurite extension of human neuroblastoma cells. Experimental cell research 41 2951267
2007 RGDS peptides immobilized on titanium alloy stimulate bone cell attachment, differentiation and confer resistance to apoptosis. Journal of biomedical materials research. Part A 39 17503524
2012 RGDS-functionalized polyethylene glycol hydrogel-coated magnetic iron oxide nanoparticles enhance specific intracellular uptake by HeLa cells. International journal of nanomedicine 38 22619531
1991 Synthesis and cell attachment activity of bioactive oligopeptides: RGD, RGDS, RGDV, and RGDT. Journal of biomedical materials research 37 1724445
2008 RalGDS couples growth factor signaling to Akt activation. Molecular and cellular biology 36 18285454
2007 Evaluation of L929 fibroblast attachment and proliferation on Arg-Gly-Asp-Ser (RGDS)-immobilized chitosan in serum-containing/serum-free cultures. Journal of bioscience and bioengineering 33 17697986
2003 Arg-Gly-Asp-Ser (RGDS) peptide stimulates transforming growth factor beta1 transcription and secretion through integrin activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 12824296
2015 Distinct sensitivities to phosphate deprivation suggest that RGF peptides play disparate roles in Arabidopsis thaliana root development. The New phytologist 30 25856240
2010 Intracellular targets of RGDS peptide in melanoma cells. Molecular cancer 29 20412563
1988 Glycoprotein IIb-IIIa and RGD(S) are not important for fibronectin-dependent platelet adhesion under flow conditions. Blood 29 2968824
2014 The bioactivity of composite Fmoc-RGDS-collagen gels. Biomaterials science 28 32481893
1999 Interdependent action of RalGEF and Erk in Ras-induced primitive endoderm differentiation of F9 embryonal carcinoma cells. Oncogene 27 10442634
1993 Interaction of human malignant melanoma tumor spheroids with endothelium and reconstituted basement membrane: modulation by RGDS. International journal of cancer 26 8509226
1997 RGDS tetrapeptide and hippocampal in vitro kindling in rats: evidence for integrin-mediated physiological stability. Neuroscience letters 25 9300641
2015 Soft PEG-Hydrogels with Independently Tunable Stiffness and RGDS-Content for Cell Adhesion Studies. Macromolecular bioscience 24 26097013
1990 The antithrombotic effect of KRDS, a lactotransferrin peptide, compared with RGDS. Nouvelle revue francaise d'hematologie 23 2349083
2021 Root meristem growth factor RGF, a sulfated peptide hormone in plants. Peptides 22 33901628
2006 Effects of CD44 antibody-- or RGDS peptide--immobilized magnetic beads on cell proliferation and chondrogenesis of mesenchymal stem cells. Journal of biomedical materials research. Part A 22 16565960
1991 Antiplatelet and antithrombotic effects of platelet glycoprotein IIb/IIIa (GPIIb/IIIa) inhibition by arginine-glycine-aspartic acid-serine (RGDS) and arginine-glycine-aspartic acid (RGD) (O-me)Y (SC-46749). The Journal of pharmacology and experimental therapeutics 21 2005585
1990 Synthetic RGDS-containing peptides of von Willebrand factor inhibit platelet adhesion to collagen. Thrombosis and haemostasis 21 2084945
2016 RGDS- and TAT-Conjugated Upconversion of NaYF4:Yb(3+)/Er(3+)&SiO2 Nanoparticles: In Vitro Human Epithelioid Cervix Carcinoma Cellular Uptake, Imaging, and Targeting. ACS applied materials & interfaces 20 27428386
2016 Control of fibrotic changes through the synergistic effects of anti-fibronectin antibody and an RGDS-tagged form of the same antibody. Scientific reports 19 27484779
2012 Role of electrostatics in differential binding of RalGDS to Rap mutations E30D and K31E investigated by vibrational spectroscopy of thiocyanate probes. The journal of physical chemistry. B 19 22738401
2005 RalGDS comes of age. Cancer cell 19 15766656
2017 Single-molecule fluorescence imaging of RalGDS on cell surfaces during signal transduction from Ras to Ral. Biophysics and physicobiology 18 28744424
2016 RGDS- and SIKVAVS-Modified Superporous Poly(2-hydroxyethyl methacrylate) Scaffolds for Tissue Engineering Applications. Macromolecular bioscience 18 27460202
2015 RILP suppresses invasion of breast cancer cells by modulating the activity of RalA through interaction with RalGDS. Cell death & disease 18 26469971
2013 RalGDS-dependent cardiomyocyte autophagy is required for load-induced ventricular hypertrophy. Journal of molecular and cellular cardiology 18 23473774
1993 Inhibition of tumor metastasis by Arg-Gly-Asp-Ser (RGDS) peptide conjugated with sulfated chitin derivative, SCM-chitin-RGDS. Clinical & experimental metastasis 18 8222396
2010 Hydrogel cell patterning incorporating photocaged RGDS peptides. Biomedical microdevices 17 20213214
1998 Interactions of the amino acid residue at position 31 of the c-Ha-Ras protein with Raf-1 and RalGDS. The Journal of biological chemistry 17 9516482
2014 Conserved electrostatic fields at the Ras-effector interface measured through vibrational Stark effect spectroscopy explain the difference in tilt angle in the Ras binding domains of Raf and RalGDS. Physical chemistry chemical physics : PCCP 16 25127074
2001 JAK/STAT3-dependent activation of the RalGDS/Ral pathway in M1 mouse myeloid leukemia cells. The Journal of biological chemistry 16 11432872
1995 Antimetastatic activities of synthetic Arg-Gly-Asp-Ser (RGDS) and Arg-Leu-Asp-Ser (RLDS) peptide analogues and their inhibitory mechanisms. Biological & pharmaceutical bulletin 16 8787788
2013 The RalGEF/Ral pathway: evaluating an intervention opportunity for Ras cancers. The Enzymes 15 25034103
2011 RGDS-fuctionalized alginates improve the survival rate of encapsulated embryonic stem cells during cryopreservation. Cryo letters 15 22020461
2002 Modulation of phospholipase D by Ras proteins mediated by its effectors Ral-GDS, PI3K and Raf-1. International journal of oncology 15 12168089
1992 Keratinocyte migration is partially supported by the cell-binding domain of fibronectin and is RGDS-dependent. The Journal of investigative dermatology 15 1431231
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
2000 The human RGL (RalGDS-like) gene: cloning, expression analysis and genomic organization. Biochimica et biophysica acta 14 10760592
1994 Tetrafibricin has a high selectivity for GPIIb/IIIa: comparison of the effects of tetrafibricin and RGDS on GPIIb/IIIa and the vitronectin receptor. Biochemical and biophysical research communications 13 7524499
2005 RGDS and DGEA-induced [Ca2+]i signalling in human dermal fibroblasts. Biochimica et biophysica acta 12 16199103
1997 Studies on tumor-promoting activity of polyethylene: inhibitory activity of metabolic cooperation on polyethylene surfaces is markedly decreased by surface modification with collagen but not with RGDS peptide. Journal of biomedical materials research 12 9138073
2021 Design of RGDS Peptide-Immobilized Self-Assembling β-Strand Peptide from Barnacle Protein. International journal of molecular sciences 11 33513895
2021 Evolution of RGF/GLV/CLEL Peptide Hormones and Their Roles in Land Plant Growth and Regulation. International journal of molecular sciences 11 34948169
2019 Developmental fidelity is imposed by genetically separable RalGEF activities that mediate opposing signals. PLoS genetics 11 31086367
2015 RGDS covalently surfaced nanodiamond as a tumor targeting carrier of VEGF-siRNA: synthesis, characterization and bioassay. Journal of materials chemistry. B 11 32262925
2012 Synthetic RGDS peptide attenuates mechanical ventilation-induced lung injury in rats. Experimental lung research 11 22452721
2023 Functionalization of 3D printed polymeric bioresorbable stents with a dual cell-adhesive peptidic platform combining RGDS and YIGSR sequences. Biomaterials science 10 37198968
2017 Contribution of the RgfD Quorum Sensing Peptide to rgf Regulation and Host Cell Association in Group B Streptococcus. Genes 10 28067833
2015 Preparation and Characterization of RGDS/Nanodiamond as a Vector for VEGF-siRNA Delivery. Journal of biomedical nanotechnology 10 26301301
2007 Physico-chemical and thermodynamic aspects of fibroblastic attachment on RGDS-modified chitosan membranes. Colloids and surfaces. B, Biointerfaces 10 17904828