Affinage

RALGDS

Ral guanine nucleotide dissociation stimulator · UniProt Q12967

Length
914 aa
Mass
100.6 kDa
Annotated
2026-06-10
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RALGDS is a Ras effector and guanine-nucleotide exchange factor that couples activated Ras to the Ral GTPase branch of Ras signaling, thereby controlling cell survival, oncogenic transformation, and regulated exocytosis (PMID:7935463, PMID:15766660). Its Ras-interacting domain adopts a ubiquitin-like fold and engages GTP-bound Ras through an inter-protein beta-sheet between the RalGDS beta-strand and the Ras switch I effector loop, binding only the active conformation and competing with Raf and NF1 for the same surface (PMID:7935463, PMID:9253406, PMID:9628477, PMID:10371160). Ras engagement recruits RalGDS to the plasma membrane—the RBD raising the membrane association rate while a second, switch-II-dependent contact (Ras Y64) and RalGDS clustering stabilize the productive complex—whereupon RalGDS catalyzes nucleotide exchange on RalA/RalB (PMID:11748241, PMID:28744424). Membrane recruitment and catalysis are gated by additional inputs: PDK1 binds the RalGDS N-terminus by a kinase-independent mechanism that relieves N-terminal autoinhibition of the catalytic domain, beta-arrestin sequesters RalGDS in an inactive cytosolic complex until receptor stimulation releases it, calmodulin binding through an N-terminal CaM-binding domain is required for Ca2+-stimulated Ral activation, and RILP recruits RalGDS to late endosomes to suppress RalA activity (PMID:11889038, PMID:12105416, PMID:18417737, PMID:26469971). Beyond exchange activity, RalGDS acts as a scaffold that bridges PDK1 and Akt (the latter via JIP1) to promote Akt phosphorylation and proliferation, a function genetically separable from Ral activation (PMID:18285454). Downstream, RalGDS-driven Ral signaling phosphorylates ATF2 Thr69 through a Ral-Src-p38 axis and promotes JNK/SAPK-dependent survival of transformed cells (PMID:12110590, PMID:15766660). Physiologically and pathologically, RalGDS is required for Ras-induced skin carcinogenesis, prostate cancer bone metastasis, endothelial Weibel-Palade body exocytosis, and load-induced cardiomyocyte autophagy and hypertrophy (PMID:15766660, PMID:17709381, PMID:18417737, PMID:23473774).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1994 High

    Established that RalGDS is a bona fide Ras effector by showing it binds selectively to GTP-Ras through the effector loop and competes with the canonical effectors Raf and NF1.

    Evidence Yeast two-hybrid, insect-cell co-IP, and in vitro binding/competition assays with GTP/GDP-loaded Ras

    PMID:7935463

    Open questions at the time
    • Did not identify the downstream GTPase target
    • Did not establish whether binding leads to catalytic output
  2. 1996 High

    Showed that receptor (EGF) signaling drives the Ras-RalGDS interaction and that cAMP/PKA biases Ras toward RalGDS by lowering Raf affinity, defining a context-dependent effector switch.

    Evidence Co-IP in COS cells, in vitro PKA kinase assay, GEF activity assay with forskolin

    PMID:8550624

    Open questions at the time
    • PKA phosphorylation of RalGDS itself had no functional consequence identified
    • Physiological setting of the cAMP switch not defined
  3. 1997 High

    Provided structural and genetic evidence that RalGDS uses a ubiquitin-like Ras-interacting domain and functions as an effector in cAMP/Ras-stimulated growth, distinguishing the Ral arm from the Raf arm.

    Evidence NMR structure with mutagenesis; effector-domain Ras mutant binding plus dominant-negative RalA microinjection and DNA synthesis assay

    PMID:9038168 PMID:9253406

    Open questions at the time
    • Atomic interface geometry not yet resolved
    • Direct demonstration of Ral exchange in the growth response absent
  4. 1998 High

    Crystal structures defined the Ras-RalGDS interface as an inter-protein beta-sheet at switch I plus a second contact at switch II, giving a structural basis for Ras-Ral cross-talk and effector discrimination.

    Evidence X-ray crystallography of the Ras-RalGDS RID complex at 2.1 A

    PMID:9628477

    Open questions at the time
    • Functional weight of the switch-II contact not yet tested in cells
    • Did not address membrane recruitment dynamics
  5. 1998 Medium

    Demonstrated a biological output for the Ral arm by showing RalGDS/RalA mediates Ras-dependent inhibition of myogenic SRF-driven transcription, separable from Raf.

    Evidence Ras effector-loop mutants, membrane-targeted and Ras-binding-defective RalGDS, luciferase reporter assays

    PMID:9651367

    Open questions at the time
    • Single-lab reporter readout
    • Endogenous RalGDS contribution not tested by loss-of-function
  6. 1999 High

    Refined the structural model with a second Ras-RalGDS RBD complex and extended Ral-pathway function to Ras-induced endoderm differentiation, linking RalGEF activity to a developmental program requiring basal MEK/ERK.

    Evidence X-ray crystallography, gel filtration, mutagenesis; Rlf-CAAX and dominant-negative RalA in F9 differentiation assay with MEK inhibitor

    PMID:10371160 PMID:10442634

    Open questions at the time
    • Mechanism of MEK/ERK cooperation with the Ral arm unresolved
    • Differentiation study used the RGL/Rlf GEF rather than RalGDS directly
  7. 2001 High

    Dissected the activation mechanism, showing membrane translocation via the RBD is necessary but not sufficient and that a switch-II (Ras Y64) interaction is additionally required, while Rap1 antagonizes activation by sequestering RalGDS in a long-lived complex.

    Evidence RalA-GTP loading assays, Ras/RalGDS mutant constructs, kinetic binding measurements, membrane-targeted RalGDS

    PMID:11748241

    Open questions at the time
    • Conformational basis of switch-II-dependent activation not resolved
    • In vivo relevance of Rap1 antagonism not tested
  8. 2001 Medium

    Identified transcriptional regulation of RalGDS, showing JAK/STAT3 signaling induces RalGDS expression to drive RalA activation, revealing cross-talk between cytokine and Ras/Ral pathways.

    Evidence RDA cloning, dominant-negative STAT3, JAK and Ras inhibitors, Ral-GTP loading assay in M1 leukemia cells

    PMID:11432872

    Open questions at the time
    • Single-lab study
    • Direct STAT3 occupancy of the RALGDS promoter not shown
  9. 2002 High

    Uncovered allosteric regulation by PDK1, which relieves RalGDS N-terminal autoinhibition through a kinase-independent interaction, integrating the PI3K-PDK1 and RalGEF effector pathways.

    Evidence Co-IP, kinase-dead PDK1, RalGDS N-terminal deletions, Ral-GTP loading assay

    PMID:11889038

    Open questions at the time
    • Structural basis of autoinhibition release not defined
    • Stoichiometry and cellular dynamics of the PDK1-RalGDS complex unresolved
  10. 2002 High

    Mapped specific RalGDS-dependent downstream outputs—choline kinase activation and ATF2 Thr69 phosphorylation via a Ral-Src-p38 axis—distinguishing them from Raf-MEK-ERK signaling.

    Evidence Ras effector-domain mutants, phospho-site-specific ATF2 antibodies, pathway mutants and inhibitors

    PMID:11840339 PMID:12110590

    Open questions at the time
    • Direct enzymatic link between Ral and Src/choline kinase not established
    • Endogenous RalGDS requirement not tested by knockout
  11. 2002 High

    Defined beta-arrestin as a negative regulator that holds RalGDS inactive in the cytosol and releases it for membrane translocation and Ras-independent Ral activation upon receptor stimulation.

    Evidence Yeast two-hybrid, co-IP from PMNs, translocation/fractionation assay, dominant-negative Ral, cytoskeletal readout

    PMID:12105416

    Open questions at the time
    • Structural basis of beta-arrestin sequestration unknown
    • Generality beyond fMLP/GPCR receptors not tested
  12. 2004 High

    Extended the RalGEF/p38 pathway to host-pathogen biology, showing it dictates cellular permissiveness to reovirus infection downstream of Ras.

    Evidence Ras effector-domain mutants, activated Rlf, dominant-negative RalA, p38 inhibitor, viral replication assay

    PMID:15263068

    Open questions at the time
    • Molecular target of p38 enabling viral replication unknown
    • Used the Rlf GEF as a tool rather than endogenous RalGDS
  13. 2005 High

    Provided in vivo proof that RalGDS is required for Ras-induced tumorigenesis, controlling survival rather than proliferation of transformed cells through JNK/SAPK activation.

    Evidence Ralgds-/- mice in DMBA/TPA skin carcinogenesis, transformation and survival assays, JNK activity measurement

    PMID:15766660

    Open questions at the time
    • Mechanism linking RalGDS to JNK not fully defined
    • Whether the survival role is Ral-dependent not isolated
  14. 2007 High

    Showed the RalGEF/Ral arm specifically drives prostate cancer bone metastasis, distinct from primary tumor growth and from Raf/PI3K signaling.

    Evidence Ras effector-domain mutants, RalA RNAi, intracardiac metastasis and subcutaneous growth assays

    PMID:17709381

    Open questions at the time
    • Effector(s) of RalA mediating bone-specific growth unknown
    • Direct requirement for RalGDS (vs other RalGEFs) not isolated
  15. 2008 High

    Revealed two regulatory and functional dimensions of RalGDS: a Ca2+/calmodulin requirement for Ral activation driving Weibel-Palade body exocytosis, and a scaffolding function bridging PDK1 and Akt (via JIP1) to promote Akt phosphorylation and proliferation independent of Ral exchange.

    Evidence RNAi, overexpression, dominant-negative and deletion mutants, calmodulin pulldown and CaM-peptide inhibitor, WPB exocytosis and Ral-GTP assays; reciprocal co-IP and domain mapping with phospho-Akt and proliferation readouts

    PMID:18285454 PMID:18417737

    Open questions at the time
    • How CaM binding couples to catalytic activation not structurally resolved
    • Whether scaffolding and GEF functions are spatially partitioned unclear
  16. 2013 High

    Established a physiological role for RalGDS in the heart, where it is required for load-induced cardiomyocyte autophagy and hypertrophy via RalB-mediated mTOR-dependent autophagy.

    Evidence Ralgds-/- mice with transverse aortic constriction, RalA/RalB RNAi in cardiomyocytes, autophagy markers and echocardiography

    PMID:23473774

    Open questions at the time
    • Upstream signal activating RalGDS under pressure overload unknown
    • Link between RalB and mTOR mechanistically undefined
  17. 2015 Medium

    Identified RILP as a spatial regulator that recruits RalGDS to late endosomes through its GEF domain to suppress RalA activity and tumor cell invasion.

    Evidence Co-IP, truncation mapping, immunofluorescence, RalA-GTP and invasion assays, RNAi

    PMID:26469971

    Open questions at the time
    • Single-lab study
    • How endosomal localization mechanistically dampens GEF activity unresolved
  18. 2017 Medium

    Resolved the membrane recruitment kinetics at single-molecule resolution, showing the RBD accelerates RalGDS membrane association while the REMCDC domain slows dissociation and Ras Y64 plus RalGDS clustering stabilize the Ral-engaged state.

    Evidence Single-molecule fluorescence imaging of GFP-tagged RalGDS domains in living HeLa cells with EGF stimulation

    PMID:28744424

    Open questions at the time
    • Single technique, single lab
    • Functional consequence of clustering for Ral exchange rate not quantified
  19. 2019 Medium

    Demonstrated in vivo that the RalGEF ortholog orchestrates two genetically separable outputs—GEF-dependent Ral activation and GEF-independent PI3K-PDK-AKT signaling—to reduce developmental stochasticity, mirroring the dual Ral/scaffold roles seen in mammals.

    Evidence C. elegans genetic epistasis with GEF-dead RGL-1 mutants and PI3K/PDK pathway double mutants, VPC fate scoring

    PMID:31086367

    Open questions at the time
    • Ortholog study; mammalian RalGDS not directly tested here
    • Molecular basis of the GEF-independent activity in this context not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs (PDK1 autoinhibition relief, CaM, beta-arrestin, RILP, clustering) are integrated to set RalGDS catalytic output in a given cellular context, and the structural basis of switch-II-dependent activation, remain unresolved.
  • No integrated structural model of autoinhibited vs activated RalGDS
  • Spatial/temporal coordination of GEF versus Akt-scaffold functions not resolved
  • Crosstalk hierarchy among regulators in vivo unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 1
Partners
AKT1ARRB2CALM1HRASPDPK1RALARALBRILP

Evidence

Reading pass · 23 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, but not with the GDP-bound form or an effector-loop mutant of Ras. In insect cells, RalGDS formed a complex with v-Ras but not with dominant-negative Ras. RalGDS inhibited both NF1 GAP activity toward Ras and the interaction of Raf with Ras in vitro, indicating it competes with Raf and NF1 for the Ras effector loop. Yeast two-hybrid, co-immunoprecipitation in insect cells, in vitro binding/competition assays with GTP/GDP-loaded Ras Molecular and cellular biology High 7935463
1996 EGF induces the interaction of c-Ras and RalGDS in mammalian COS cells in an effector-loop-dependent manner. Cyclic AMP-dependent protein kinase (PKA) phosphorylates RalGDS but does not alter its affinity for Ras or its GDP/GTP exchange activity toward Ral p24. PKA phosphorylation of (1-149)Raf reduces its affinity for Ras, thereby shifting Ras binding selectively toward RalGDS under cAMP-elevated conditions. Co-immunoprecipitation in COS cells, in vitro kinase assay (PKA phosphorylation), GEF activity assay, forskolin treatment The Journal of biological chemistry High 8550624
1997 RalGDS functions as an effector of Ras in cAMP-mediated growth stimulation in thyroid cells. A Ras effector-domain mutant (RasV12G37) defective in Raf-1 binding still bound RalGDS by yeast two-hybrid and co-immunoprecipitation. Microinjection of dominant-negative RalA (which sequesters RalGDS family members) reduced Ras-stimulated and cAMP-stimulated DNA synthesis. Yeast two-hybrid, co-immunoprecipitation in thyroid cell extracts, microinjection of dominant-negative RalA, DNA synthesis assay The Journal of biological chemistry High 9038168
1997 The Ras-interacting domain (RID) of RalGDS adopts an ubiquitin-like fold. Mutational analysis identified three residues in the RID critical for interaction with Ras. NMR structure determination, site-directed mutagenesis, binding assays Nature structural biology High 9253406
1998 Crystal structure (2.1 Å) of the Ras–RalGDS RID complex reveals that the beta-sheet of the RID joins the switch I region of Ras to form an extended beta-sheet, analogous to but geometrically distinct from the Rap-Raf complex. A second RID molecule also contacts the switch II region of Ras, providing a structural basis for cross-talk between the Ras and Ral pathways. X-ray crystallography at 2.1 Å resolution Nature structural biology High 9628477
1998 RalGDS mediates Ras-dependent inhibition of skeletal myogenesis. An H-Ras effector mutant (G12V,E37G) that binds RalGDS but not Raf inhibits muscle-specific reporter gene activity. Membrane-targeted RalGDS (RalGDS-CAAX) also inhibits alpha-actin-Luc and SRF-dependent transcription, while a RalGDS mutant defective in Ras interaction has no effect. RalGDS and activated RalA additionally inhibit the SRF-dependent component of H-Ras G12V,E37G-induced transcription. Transient transfection of Ras effector-loop mutants and RalGDS constructs, luciferase reporter assays, dominant-negative and constitutively active Ral constructs The Journal of biological chemistry Medium 9651367
1999 X-ray crystal structure of the Ras–RalGDS RBD (RGS-RBD) complex shows an inter-protein beta-sheet between Ras switch I and the RGS-RBD beta-strand, analogous to Rap-RafRBD but with markedly different interface side-chain interactions. Gel filtration confirms the complex is a 1:1 monomer. Mutational studies define interface residues contributing to binding affinity. X-ray crystallography, size-exclusion chromatography, site-directed mutagenesis with binding affinity measurements FEBS letters High 10371160
1999 RalGEFs (specifically Rlf/RGL) are required for Ras-induced primitive endoderm differentiation of F9 embryonal carcinoma cells. Constitutively active Rlf-CAAX is sufficient to induce differentiation; dominant-negative RalA completely abolishes Rlf-CAAX– and RasV12G37-induced differentiation. RalGEF-induced differentiation requires basal MEK/ERK activity (MEK inhibition blocks it), but Rlf-CAAX itself does not increase ERK activity. Ras effector-domain mutants, constitutively active RalGEF (Rlf-CAAX), dominant-negative RalA, MEK inhibitor (PD98059), morphological differentiation assay Oncogene Medium 10442634
2001 RalGDS activation by Ras involves membrane translocation (RBD-dependent) but additionally requires a Ras switch II interaction: Ras Y64W is impaired in RalGDS activation but not in RBD binding. An artificially membrane-targeted RalGDS lacking its RBD can still be activated by Ras, indicating the RBD is important but not sufficient. Rap1 antagonizes Ras-mediated RalGDS activation only when the RBD is intact, by forming a long-lived complex (KD ~0.6 μM) that sequesters RalGDS, whereas the Ras×RalGDS complex is short-lived (~0.1 s). RalA-GTP loading assay, Ras/RalGDS mutant constructs, kinetic binding measurements (surface plasmon resonance/stopped-flow), membrane-targeted RalGDS constructs The Journal of biological chemistry High 11748241
2002 Beta-arrestins bind RalGDS (identified by yeast two-hybrid and co-immunoprecipitation from human PMNs). Under basal conditions, RalGDS is held inactive in a cytosolic complex with beta-arrestin. Upon fMLP receptor stimulation, the complex dissociates, RalGDS translocates to the plasma membrane, and Ral is activated independently of Ras, driving cytoskeletal reorganization. Re-association of the complex correlates with Ral signal termination. Yeast two-hybrid screen, co-immunoprecipitation from PMNs, subcellular fractionation/translocation assay, dominant-negative Ral constructs, cytoskeletal phenotype readout Nature cell biology High 12105416
2002 PDK1 enhances RalGDS catalytic (GEF) activity by a kinase-independent mechanism. The non-catalytic N-terminus of PDK1 forms an EGF-induced complex with the N-terminus of RalGDS, relieving its auto-inhibitory effect on the catalytic domain. This represents cooperation between the PI3K-PDK1 Ras effector pathway and the RalGEF pathway to promote Ral activation. Co-immunoprecipitation, kinase-dead PDK1 constructs, Ral-GTP loading assay, N-terminal deletion mutants of RalGDS The EMBO journal High 11889038
2002 Ras regulates choline kinase activity through its direct effectors RalGDS and PI3K, but not through Raf-1. Ras effector-domain mutants specifically activating RalGDS (RasV12G37) or PI3K (RasV12C40), but not Raf (RasV12S35), activated choline kinase, establishing RalGDS as a required intermediary. Ras effector-loop mutants (RasV12G37, V12C40, V12S35), choline kinase activity assay Oncogene Medium 11840339
2002 Growth factors activate ATF2 Thr69 phosphorylation via a Ral-RalGDS-Src-p38 pathway, distinct from the Raf-MEK-ERK pathway that phosphorylates Thr71. Cooperation between ERK and p38 is required for full ATF2 dual-phosphorylation by growth factors such as insulin and EGF. Phosphorylation-site-specific ATF2 antibodies, dominant-negative and constitutively active pathway constructs, kinase inhibitors, Ras effector-domain mutants The EMBO journal High 12110590
2004 The Ras/RalGEF/p38 pathway dictates host cell permissiveness to reovirus infection. Ras effector-domain mutant RasV12G37 (retaining RalGEF signaling but not Raf or PI3K) renders NIH 3T3 cells permissive. Activated RalGEF (Rlf) alone confers permissiveness; dominant-negative RalA renders H-Ras cells resistant. p38 inhibition blocks reovirus replication downstream of RalGEF. Ras effector-domain mutants, activated RalGEF (Rlf) overexpression, dominant-negative RalA, p38/JNK inhibitors, viral replication assay Proceedings of the National Academy of Sciences of the United States of America High 15263068
2005 RalGDS is required for Ras-induced oncogenesis in vivo. RalGDS-knockout mice develop normally but show reduced tumor incidence, size, and malignant progression in multistage skin carcinogenesis. RalGDS does not regulate cell proliferation but controls survival of transformed cells, apparently through activation of the JNK/SAPK pathway. Ralgds-/- knockout mice, DMBA/TPA skin carcinogenesis model, tissue culture transformation assays, apoptosis/survival assays, JNK activity measurements in tumor-derived cells Cancer cell High 15766660
2007 Activation of the RalGEF/Ral pathway promotes prostate cancer bone metastasis. In DU145 cells, activation of the RalGEF pathway (RasV12G37) but not Raf/ERK or PI3K promotes bone metastasis. Loss of RalA in metastatic PC3 cells inhibits bone metastasis but not subcutaneous tumor growth, specifically suppressing expansive growth in bone. Ras effector-domain mutants, RalA RNAi knockdown, in vivo metastasis assay (intracardiac injection), subcutaneous tumor growth assay Molecular and cellular biology High 17709381
2008 RalGDS mediates thrombin- and epinephrine-induced exocytosis of Weibel-Palade bodies (WPBs) from endothelial cells. RNAi knockdown of RalGDS inhibits WPB exocytosis; overexpression promotes it; a dominant-negative exchange-domain-deleted RalGDS blocks WPB release. RalGDS binds calmodulin (CaM) via an N-terminal CaM-binding domain, and a cell-permeable peptide comprising this domain inhibits Ral activation and WPB exocytosis. RNAi knockdown, overexpression, dominant-negative mutant, calmodulin pulldown, cell-permeable peptide inhibitor, WPB exocytosis assay (VWF secretion), Ral-GTP loading assay Blood High 18417737
2008 RalGDS has a second function beyond Ral GEF activity: it promotes Akt phosphorylation by PDK1 by acting as a scaffold that brings PDK1 and Akt together. The N-terminus of RalGDS complexes PDK1 while the central region associates with Akt via JIP1. An N-terminally deleted RalGDS retains Ral activation but cannot promote Akt phosphorylation and fails to support cell proliferation. RNAi suppression of RalGDS, co-immunoprecipitation (PDK1/RalGDS, Akt/RalGDS via JIP1), deletion mutant analysis, phospho-Akt immunoblot, cell proliferation assay Molecular and cellular biology High 18285454
2013 RalGDS-mediated cardiomyocyte autophagy is required for load-induced cardiac hypertrophy. RalGDS-null hearts show blunted hypertrophic growth and suppressed autophagy in response to pressure-overload (TAC), while ventricular function is preserved and fetal gene program activation is unaffected. In NRCMs, RalB (a downstream target of RalGDS) specifically mediates mTOR-dependent autophagy. Ralgds-/- knockout mice, transverse aortic constriction (TAC) model, RalA/RalB RNAi in neonatal rat cardiomyocytes, autophagy markers (LC3, p62), echocardiography, fetal gene expression Journal of molecular and cellular cardiology High 23473774
2015 RILP (Rab7-interacting lysosomal protein) interacts with RalGDS via its N-terminal region binding to the GEF domain of RalGDS. RILP overexpression recruits RalGDS to late endosomal compartments and inhibits RalA activity and breast cancer cell invasion; RILP knockdown promotes invasion. The interaction is confirmed by co-immunoprecipitation and truncation analysis. Co-immunoprecipitation, truncation/deletion mapping, immunofluorescence microscopy, RalA-GTP loading assay, cell invasion assay, RNAi knockdown Cell death & disease Medium 26469971
2001 JAK/STAT3 activation in M1 myeloid leukemia cells induces RalGDS expression, leading to RalA-GTP activation. Dominant-negative STAT3 and the JAK inhibitor JAB/SOCS1 suppress both RalGDS expression and RalA activation. Full RalA activation also requires Ras activity, revealing cross-talk between the JAK/STAT3 and Ras/RalGDS/Ral pathways. Representational difference analysis (RalGDS cloning), dominant-negative STAT3, JAK inhibitor, Ras inhibitor, Ral-GTP loading assay The Journal of biological chemistry Medium 11432872
2017 Single-molecule fluorescence imaging shows that EGF-induced Ras activation increases the membrane density of RalGDS via its RBD (not the REMCDC domain). The RBD increases the RalGDS association rate to the membrane, while the REMCDC domain decreases the dissociation rate after Ras activation or Ral overexpression. Ras Y64 residue and RalGDS cluster formation on the membrane are involved in stabilizing RalGDS–Ral interaction upon Ras activation. Single-molecule fluorescence imaging, GFP-tagged RalGDS domain constructs in living HeLa cells, EGF stimulation, membrane density quantitation, rate constant measurements Biophysics and physicobiology Medium 28744424
2019 In C. elegans, the RalGEF ortholog RGL-1 plays two genetically separable roles in vulval cell fate patterning: (1) a canonical GEF-dependent promotion of 2° fate via RAL-1 activation, and (2) a non-canonical GEF-independent promotion of 1° fate that acts through the AGE-1/PI3K-PDK-1-AKT-1 cascade. Loss of RGL-1 increases VPC patterning error rates 15-fold, indicating RGL-1 orchestrates opposing modulatory cascades to reduce developmental stochasticity. C. elegans genetic epistasis, RGL-1 GEF-dead mutants, double-mutant analysis with PI3K/PDK pathway components, VPC 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 955 12850155
1994 ralGDS family members interact with the effector loop of ras p21. Molecular and cellular biology 254 7935463
1998 Structural basis for the interaction of Ras with RalGDS. Nature structural biology 222 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 186 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 159 15263068
2005 RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer cell 143 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
1999 Structural and biochemical analysis of Ras-effector signaling via RalGDS. FEBS letters 90 10371160
2011 The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery. Genes & cancer 89 21779498
2007 Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. Molecular and cellular biology 89 17709381
1991 RGDS tetrapeptide binds to osteoblasts and inhibits fibronectin-mediated adhesion. Bone 82 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
1997 RalGDS functions in Ras- and cAMP-mediated growth stimulation. The Journal of biological chemistry 67 9038168
2010 RalGDS family members couple Ras to Ral signalling and that's not all. Cellular signalling 66 20478380
2000 Pressure-induced local unfolding of the Ras binding domain of RalGDS. Nature structural biology 66 10876238
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 65 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 34 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
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 24 2349083
2021 Root meristem growth factor RGF, a sulfated peptide hormone in plants. Peptides 23 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
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 21 27428386
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 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
2010 Hydrogel cell patterning incorporating photocaged RGDS peptides. Biomedical microdevices 18 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 18 9516482
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
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
2021 Design of RGDS Peptide-Immobilized Self-Assembling β-Strand Peptide from Barnacle Protein. International journal of molecular sciences 12 33513895
2021 Evolution of RGF/GLV/CLEL Peptide Hormones and Their Roles in Land Plant Growth and Regulation. International journal of molecular sciences 12 34948169
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
2023 Functionalization of 3D printed polymeric bioresorbable stents with a dual cell-adhesive peptidic platform combining RGDS and YIGSR sequences. Biomaterials science 11 37198968
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
2021 RGDS-Modified Superporous Poly(2-Hydroxyethyl Methacrylate)-Based Scaffolds as 3D In Vitro Leukemia Model. International journal of molecular sciences 10 33673496
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

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