Affinage

RALA

Ras-related protein Ral-A · UniProt P11233

Length
206 aa
Mass
23.6 kDa
Annotated
2026-04-28
100 papers in source corpus 48 papers cited in narrative 48 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RALA is a Ras-related small GTPase that functions as a central signaling hub linking growth factor, calcium, and Ras-dependent inputs to vesicle trafficking, cytoskeletal remodeling, and transcriptional regulation. Cycling between GDP- and GTP-bound states under the control of RalGEFs (activated by Ras, Ca²⁺/calmodulin, β-arrestin release, Rab10, and RCC2/TD-60) and RalGAP complexes (inhibited by Akt-mediated phosphorylation), GTP-loaded RalA engages a suite of effectors: the exocyst complex (via Sec5 and Exo84) to drive GLUT4 vesicle tethering, Weibel-Palade body exocytosis, cytokinesis, exosome secretion, Frizzled-7 internalization, and membrane nanotube formation; RLIP76/RalBP1 to regulate Rac/Cdc42 signaling, JNK-FOXO activation, and heat-shock responses; phospholipase D1/D2 to generate phosphatidic acid for caveolae endocytosis, phagocytosis, and extracellular vesicle biogenesis; and filamin to promote filopodia downstream of Cdc42 (PMID:7477381, PMID:7673236, PMID:11744922, PMID:15920473, PMID:10051605, PMID:17765682, PMID:26459596, PMID:30853556, PMID:18756269, PMID:23770673). Aurora-A phosphorylates RalA at Ser194 to promote its translocation from the plasma membrane and enhance effector engagement during oncogenic growth (PMID:19901077). RalA is essential for Ras-driven tumorigenesis and anchorage-independent growth in pancreatic and lung cancer models, RalA-null mice exhibit exencephaly and embryonic lethality, and in obesity RalA drives mitochondrial fission by reversing Drp1-Ser637 phosphorylation in adipocytes (PMID:25219851, PMID:23063435, PMID:38286821).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1986 High

    The identity of RALA as a new Ras-related GTPase was established, revealing the existence of a distinct branch of the Ras superfamily with predicted membrane localization.

    Evidence cDNA cloning from simian B-lymphocyte library with sequence analysis identifying GTP-binding domains and C-terminal cysteine for prenylation

    PMID:3023062

    Open questions at the time
    • No effectors or upstream regulators identified
    • No functional role demonstrated
  2. 1990 High

    Biochemical characterization showed RalA possesses low intrinsic GTPase activity and slow GDP exchange, and that activating mutations analogous to oncogenic Ras mutations alter these properties, establishing RalA as a bona fide GTP-hydrolyzing molecular switch.

    Evidence In vitro GTPase and exchange assays with purified recombinant RalA; site-directed mutagenesis; NMR spectroscopy

    PMID:2108160

    Open questions at the time
    • No upstream activator (GEF) identified
    • No downstream effectors known
  3. 1991 Medium

    Discovery of a Ral-specific GAP in brain and testis demonstrated that RalA cycling is regulated by a dedicated GTPase-activating protein distinct from those acting on Ras, Rho, or Rap.

    Evidence Biochemical fractionation and in vitro GTPase assay with substrate specificity controls

    PMID:1903395

    Open questions at the time
    • Molecular identity of the GAP not determined
    • Single biochemical fractionation without molecular cloning
  4. 1995 High

    Identification of the first RalA effectors—phospholipase D and RLIP76/RalBP1—revealed that RalA connects to lipid signaling (PLD) and Rho-family GTPase regulation (via RLIP76's GAP activity toward Rac1/Cdc42), establishing two major downstream branches.

    Evidence Immunoprecipitation of PLD with RalA, deletion mutagenesis (PLD); yeast two-hybrid and in vitro pulldown with GAP activity assay (RLIP76)

    PMID:7477381 PMID:7673236

    Open questions at the time
    • Physiological contexts for PLD and RLIP76 signaling undefined
    • No structural detail on effector contacts
  5. 1996 High

    Epistasis experiments with constitutively active and dominant-negative RalA showed that Ral operates as a Ras effector pathway distinct from Raf, contributing to oncogenic transformation, and that prenylation of both Ras and RalA is required for efficient signal relay through RalGDS.

    Evidence Gain- and loss-of-function mutant overexpression in transformation assays; GDP/GTP exchange assays requiring prenylation

    PMID:8631302 PMID:8702675

    Open questions at the time
    • Identity and diversity of RalGEF proteins incompletely mapped
    • Whether Ral operates independently of Ras not resolved
  6. 1998 Medium

    Two Ras-independent activation modes for RalA were uncovered: Ca²⁺/PLC-dependent activation by LPA/EGF, and RalA scaffolding of an Arf–PLD complex, broadening the upstream inputs and mechanistic outputs of the pathway.

    Evidence Ral-GTP loading assays with dominant-negative Ras, Ca²⁺ ionophore, PLC inhibitor; GST-RalA pulldown identifying Arf co-association; Brefeldin A and dominant-negative Arf perturbation

    PMID:9520417 PMID:9663394

    Open questions at the time
    • Specific RalGEF linking Ca²⁺ to RalA not identified
    • Stoichiometry of the Ral-Arf-PLD complex undefined
  7. 1999 High

    RalA was placed downstream of Cdc42 in filopodium formation through direct GTP-dependent binding to filamin, and was shown to contribute to Ras-driven tumor invasion by controlling uPA and MMP expression.

    Evidence GTP-specific binding assay and filamin-deficient cell rescue; dominant-negative RalA blocking MMP overproduction and in vivo tumorigenesis

    PMID:10051605 PMID:10467419

    Open questions at the time
    • How Cdc42 activates RalA mechanistically not established
    • Filamin interaction structure unresolved
  8. 2002 High

    The exocyst subunit Sec5 was identified as a direct GTP-dependent effector of RalA, and β-arrestin was shown to sequester RalGDS until receptor stimulation, revealing a new effector arm (exocyst) and a Ras-independent activation mechanism (β-arrestin/GPCR).

    Evidence Yeast two-hybrid and co-immunoprecipitation confirming GTP-specific Sec5 binding with filopod functional readout; co-IP of β-arrestin/RalGDS from primary PMNs with Ral-GTP assay

    PMID:11744922 PMID:12105416

    Open questions at the time
    • Structural basis of RalA–Sec5 not yet determined at this time
    • Full set of exocyst subunits engaging RalA unknown
  9. 2003 High

    The crystal structure of the RalA·GppNHp–Sec5 complex at 2.1 Å revealed that Sec5 adopts an immunoglobulin-like fold contacting both switch regions of RalA, providing the first atomic-resolution view of how RalA recruits the exocyst.

    Evidence X-ray crystallography with ITC and mutagenesis validation

    PMID:12839989

    Open questions at the time
    • Structure of RalA with other effectors not yet solved
    • Mechanism of exocyst complex assembly upon RalA binding unknown
  10. 2005 High

    Crystal structure of RalA bound to Exo84's PH-fold Ral-binding domain showed that Sec5 and Exo84 compete for the same switch-region surface on RalA, establishing that RalA engages two distinct exocyst subunits in a mutually exclusive manner to potentially coordinate sequential trafficking steps.

    Evidence X-ray crystallography; competitive binding assay; mutagenesis

    PMID:15920473

    Open questions at the time
    • Functional consequence of Sec5 vs Exo84 engagement in specific trafficking events unclear
    • Full exocyst reconstitution with RalA not performed
  11. 2007 High

    RalA was established as a critical node in insulin-stimulated GLUT4 vesicle exocytosis: insulin activates RalA via PI3K, and RalA then bridges GLUT4 vesicles to the exocyst and the motor protein Myo1c for plasma membrane tethering.

    Evidence Ral-GTP pulldown, siRNA knockdown, co-IP with Myo1c, dominant-negative mutants, glucose transport assay in adipocytes

    PMID:17765682

    Open questions at the time
    • How RalA coordinates with Rab proteins on the same vesicle not resolved
    • Precise step at which RalA acts (tethering vs fusion) ambiguous
  12. 2006 High

    Systematic comparison in pancreatic cancer cells revealed that RalA is selectively required for anchorage-independent growth and tumor initiation, while RalB drives invasion and metastasis, demonstrating functional divergence despite >80% sequence identity.

    Evidence siRNA knockdown of RalA vs RalB across 10 cell lines; anchorage-independent growth; tail-vein metastasis model

    PMID:17174914

    Open questions at the time
    • Molecular basis of isoform-specific effector engagement unclear
    • Whether isoform divergence is tissue-dependent not fully tested
  13. 2008 Medium

    RalA was shown to tether the exocyst to the cytokinetic furrow during early cytokinesis and to regulate exocyst targeting to focal complexes during cell migration via Sec5–paxillin interaction, extending RalA-exocyst function to cell division and motility.

    Evidence RNAi knockdown with live cell imaging of cytokinesis stages; co-IP of exocyst-paxillin with RalA depletion

    PMID:18697830 PMID:18756269

    Open questions at the time
    • RalGEF identity at the furrow not determined
    • Whether RalA and RalB have sequential roles confirmed only partially
  14. 2009 High

    Aurora-A was identified as a kinase that phosphorylates RalA at Ser194, promoting RalA translocation from the plasma membrane and activating RalBP1-dependent effector signaling required for transformation—revealing a mitotic kinase input to Ral signaling.

    Evidence In vitro kinase assay; S194 mutagenesis; subcellular fractionation; tumor xenograft

    PMID:19901077

    Open questions at the time
    • Phosphatase opposing Aurora-A at Ser194 unknown
    • Whether Ser194 phosphorylation affects exocyst or PLD arms not tested
  15. 2010 High

    The molecular identity of the RalGAP complex (RGC1/RGC2) was established, and Akt2-mediated phosphorylation of RGC2 was shown to inhibit GAP activity, providing the mechanistic link between insulin/PI3K/Akt signaling and RalA activation for GLUT4 translocation.

    Evidence In vitro GAP assay; Akt2 phosphorylation site identification; siRNA knockdown; glucose uptake assay

    PMID:21148297

    Open questions at the time
    • Whether other kinases regulate RGC under different stimuli unclear
    • Structural basis of RGC catalysis unknown
  16. 2013 Medium

    A ROS-responsive pathway was delineated in which the RalGEF RLF activates RalA on a JIP1 scaffold, promoting assembly of a MLK3-MKK4-JNK cascade and FOXO activation—a mechanism conserved in C. elegans—linking RalA to oxidative stress and longevity signaling.

    Evidence Co-immunoprecipitation; RNAi knockdown; FOXO reporter assay; C. elegans epistasis

    PMID:23770673

    Open questions at the time
    • Direct binding between RalA and JIP1 not demonstrated in vitro
    • Physiological ROS levels required for this pathway not defined
  17. 2014 High

    Small-molecule inhibitors (RBC8, BQU57) that bind GDP-bound RalA and block effector engagement were developed and validated biophysically and in vivo, providing first chemical tools to pharmacologically target the Ral pathway.

    Evidence Virtual screening; ITC, SPR, TROSY-NMR binding confirmation; cell spreading and xenograft tumor growth inhibition

    PMID:25219851

    Open questions at the time
    • Selectivity over RalB not fully characterized
    • In vivo pharmacokinetics and therapeutic window undefined
  18. 2015 High

    RalA was placed in the chromosomal passenger complex (CPC) regulatory pathway through TD-60/RCC2 acting as a RalA GEF during mitosis, and in exosome biogenesis through localization to multivesicular bodies and requirement for MVB fusion with the plasma membrane.

    Evidence In vitro GEF assay with RCC2; RNAi and GTP-locked rescue of spindle phenotypes; EM and live imaging of MVBs in C. elegans; nanoparticle tracking in mammalian cells

    PMID:26158537 PMID:26459596

    Open questions at the time
    • Whether RalA directly associates with CPC components unknown
    • Step at which RalA acts in MVB biogenesis vs fusion not distinguished cleanly
  19. 2019 High

    In vivo genetic deletion in intestinal epithelium showed that RalA (and RalB) are required for Frizzled-7 internalization and intestinal stem cell maintenance, positioning Ral GTPases as essential regulators of Wnt receptor endocytosis in tissue homeostasis.

    Evidence Conditional KO mouse; Drosophila genetics; Frizzled-7 internalization assay; organoid culture

    PMID:30853556

    Open questions at the time
    • Effector pathway mediating Frizzled-7 internalization (exocyst vs PLD) not resolved
    • Whether RalA acts at internalization or recycling step unclear
  20. 2024 High

    In obesity, RalA activity increases in white adipocytes and drives mitochondrial fragmentation by reversing inhibitory Drp1-Ser637 phosphorylation, identifying a previously unrecognized metabolic role for RalA in controlling mitochondrial dynamics.

    Evidence Adipocyte-specific conditional RalA KO mouse; Drp1-Ser637 phosphorylation assay; mitochondrial imaging; metabolic phenotyping

    PMID:38286821

    Open questions at the time
    • Phosphatase recruited by RalA to dephosphorylate Drp1-Ser637 not identified
    • Whether this mechanism operates in other metabolically active tissues unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of RalA selectivity for specific effectors versus RalB, the identity of phosphatases that reverse Aurora-A and Akt regulatory inputs, how competing effector interactions (Sec5 vs Exo84 vs RLIP76 vs PLD) are spatiotemporally resolved within a single cell, and whether the metabolic (Drp1) function is a direct or indirect consequence of RalA effector engagement.
  • No structure of full exocyst with RalA
  • No phosphatase for Ser194 identified
  • Isoform-specific effector selection mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0003924 GTPase activity 3
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 4 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 6 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-1430728 Metabolism 4 R-HSA-382551 Transport of small molecules 3 R-HSA-1640170 Cell Cycle 2
Partners
EXO84FLNAMYO1CPLD1PLD2RALGDSRLIP76SEC5
Complex memberships
Exocyst complex

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 RALA was identified as a new RAS-related GTPase with GTP-binding domains and a C-terminal cysteine for membrane anchoring, predicting it to be a membrane-localized GTP-binding protein. cDNA cloning from simian B-lymphocyte library using synthetic oligonucleotide probe; sequence analysis The EMBO journal High 3023062
1990 Purified RalA protein binds and hydrolyzes GTP with low intrinsic GTPase activity (0.07 min-1 at 37°C) and slow GDP exchange; activating mutations (analogous to Ras Val12, Leu61) alter nucleotide exchange and GTPase activities, and NMR shows similar nucleotide-binding environment to p21Ras. In vitro biochemical assay with purified recombinant RalA; site-directed mutagenesis; NMR spectroscopy The Journal of biological chemistry High 2108160
1991 A cytosolic GTPase-activating protein (Ral-GAP) specific for RalA was identified in brain and testis; it stimulates RalA GTPase activity but not Ras, Rho, or Rap GTPase activity, demonstrating substrate specificity. Biochemical fractionation; in vitro GTPase activity assay The Journal of biological chemistry Medium 1903395
1995 RalA interacts with phospholipase D (PLD); a Ral-specific N-terminal region is required for PLD association and PLD activation downstream of v-Src. Dominant-negative RalA inhibits v-Src- and v-Ras-induced PLD activity. Immunoprecipitation of PLD with immobilized RalA; dominant-negative overexpression; deletion mutagenesis Nature High 7477381
1995 RLIP76 (RalBP1) was identified as a RalA effector that binds activated (GTP-bound) RalA via its effector domain, and functions as a GAP for Rac1 and CDC42 but not RhoA, bridging Ral to Rho pathways. Yeast two-hybrid screening; biochemical pulldown with purified proteins; GAP activity assay The Journal of biological chemistry High 7673236
1996 Constitutively active RalA enhances Ras- and Raf-induced oncogenic transformation, while dominant-negative RalA suppresses transformation by RasH and Raf, placing Ral as a downstream effector in a Ras signaling pathway distinct from Raf. Genetic epistasis; dominant-negative and constitutively active mutant overexpression; transformation assay in mammalian cells The EMBO journal High 8631302
1996 Post-translational modification (prenylation) of both Ras and RalA is required for efficient RalGDS-mediated GDP/GTP exchange on RalA, for RalGDS membrane redistribution, and for RalA binding to its effector RalBP1. In vitro GDP/GTP exchange assay; cell fractionation; co-immunoprecipitation The Journal of biological chemistry Medium 8702675
1998 RalA associates with an active PLD complex containing Arf proteins; the Ral-specific N-terminus is required for Arf association, and Arf is required for PLD activation in v-Src/v-Ras-transformed cells, demonstrating that RalA scaffolds a PLD-Arf complex. Pulldown with GST-RalA fusion; co-immunoprecipitation; Brefeldin A inhibitor study; dominant-negative Arf expression Proceedings of the National Academy of Sciences of the United States of America High 9520417
1998 RalA can be activated by a Ca2+-dependent, Ras-independent pathway triggered by LPA or EGF, involving phospholipase C activation; dominant-negative Ras did not block Ral-GTP loading. GTP-loading assay (Ral-GTP measurement) in Rat-2 fibroblasts; dominant-negative Ras; Ca2+ ionophore and PLC inhibitor Current biology : CB Medium 9663394
1999 GTP-bound RalA specifically binds filamin (an actin filament-crosslinking protein) and induces actin-rich filopodia; dominant-negative RalA or the RalA-binding domain of filamin blocks Cdc42-induced filopod formation. RalA does not generate filopodia in filamin-deficient cells, placing RalA downstream of Cdc42 in filopod production using filamin. GTP-specific binding assay; dominant-negative mutant expression; filamin-deficient cell rescue by transfection; fluorescence microscopy Proceedings of the National Academy of Sciences of the United States of America High 10051605
1999 Positions 36 and 37 in the effector domain of RalA determine specificity of RalA-RLIP76 interaction; mutating these residues converts Ral/Ras effector interaction specificity, despite no sequence homology between their binding domains. Sequence analysis; site-directed mutagenesis; binding assay The Journal of biological chemistry Medium 10364219
1999 RalA is required for v-Src- and v-Ras-induced urokinase-type plasminogen activator (uPA) and MMP-2/MMP-9 overproduction, and for tumor formation in mice; dominant-negative RalA blocks these effects. Dominant-negative RalA expression; zymogram for MMP activity; subcutaneous tumor injection in mice Oncogene Medium 10467419
2000 EGF activates c-Src through a RalA-dependent mechanism (but not beta2-adrenergic receptor signaling), leading to phosphorylation of Stat3 and cortactin but not Shc or Erk; RalA thus specifies c-Src substrate selectivity downstream of EGF receptor. Constitutively active RalA overexpression; dominant-negative mutants; phosphorylation assays The EMBO journal Medium 10675331
2000 RalA and PLD1 cooperate with EGF receptor to transform 3Y1 rat fibroblasts; EGF-induced PLD activation requires both Ras and RalA, while Erk activation is RalA-independent. Overexpression of active RalA increases PLD activity and induces transformation. Dominant-negative RalA; PLD activity assay; transformation assay; co-immunoprecipitation Molecular and cellular biology Medium 10611224
2000 Dominant-negative RalA inhibits chemotactic migration of skeletal myoblasts in response to bFGF, HGF, and IGF-1; active Ral mutant or RalGDS stimulates motility; RalA-mediated motility requires binding to RalBP1 and PLD. Dominant-negative and constitutively active mutant overexpression; effector mutant analysis; chemotaxis assay Molecular and cellular biology Medium 10848592
2001 RalA localizes to Weibel-Palade bodies in endothelial cells and is activated (GTP-loaded) by thrombin stimulation in a calmodulin-dependent manner; constitutively active RalA drives Weibel-Palade body exocytosis. Subcellular fractionation; GTP-loading assay; calmodulin inhibitor (trifluoperazine); dominant-active and dominant-negative RalA expression; immunofluorescence Arteriosclerosis, thrombosis, and vascular biology Medium 11397694
2002 The mammalian exocyst subunit Sec5 is a specific binding partner for GTP-bound RalA; inhibition of RalA-Sec5 interaction prevents filopod formation by TNF-α, IL-1, and active RalA/Cdc42, linking RalA-exocyst interaction to cytoskeletal remodeling. Yeast two-hybrid; co-immunoprecipitation; dominant-negative interference; filopod assay Nature cell biology High 11744922
2002 Pseudomonas ExoS ADP-ribosylates RalA at Arg52, inhibiting its ability to bind the RalBP1 effector; this identifies a post-translational modification that blocks RalA effector engagement. ADP-ribosylation assay; mass spectrometry for site identification; RalBP1-RBD binding assay in vitro and in cells Biochemistry Medium 12135390
2002 Beta-arrestins bind Ral-GDS and sequester it in an inactive cytosolic complex; upon fMLP receptor stimulation, beta-arrestin/Ral-GDS complexes dissociate, Ral-GDS translocates to plasma membrane, and activates RalA in a Ras-independent manner to drive cytoskeletal reorganization. Yeast two-hybrid; co-immunoprecipitation from PMNs; subcellular fractionation; Ral-GTP assay Nature cell biology High 12105416
2003 Crystal structure of RalA-GppNHp bound to the Sec5 Ral-binding domain at 2.1 Å reveals Sec5 adopts an immunoglobulin-like beta-sandwich fold and contacts both switch regions of RalA; key residues Sec5-Thr11, Arg27 and RalA-Glu38 are required for complex formation. X-ray crystallography; isothermal titration calorimetry; mutagenesis The EMBO journal High 12839989
2003 RalBP1 interacts with HSF1 in a multiprotein complex with HSP90 and alpha-tubulin; constitutively active RalA enhances heat-inducible HSP70 expression while dominant-negative RalA suppresses it; upon heat shock, RalA-GTP binds RalBP1, releasing HSF1 for nuclear translocation. Yeast two-hybrid; co-immunoprecipitation; cotransfection with RalA mutants; reporter assay The Journal of biological chemistry Medium 12621024
2004 RalA interacts with ZONAB (a Y-box transcription factor) in a GTP-dependent manner; the RalA-ZONAB complex increases with epithelial cell density and relieves ZONAB-mediated transcriptional repression; oncogenic Ras alleviates ZONAB repression in a RalA-dependent manner. Reverse Ras recruitment system; co-immunoprecipitation; transcriptional reporter assay The EMBO journal Medium 15592429
2004 RalA is associated with Weibel-Palade body dense granules in endothelial cells and is activated by cAMP-raising agents (epinephrine, forskolin) through a PKA-dependent mechanism; RalA activation is required for cAMP-mediated von Willebrand factor secretion. Cell-permeable peptide inhibition; PKA inhibitor (H-89); Ral-GTP loading assay; VWF secretion assay Arteriosclerosis, thrombosis, and vascular biology Medium 15130921
2005 Crystal structure of RalA bound to the Ral-binding domain (PH fold) of Exo84; Exo84 and Sec5 compete for the same binding site on active RalA via both switch regions; key interface residues were identified by mutagenesis. X-ray crystallography; mutagenesis; competitive binding assay The EMBO journal High 15920473
2005 RalA but not RalB promotes neurite branching in neurons via the exocyst complex; RalB promotes branching via phospholipase D; Ral-dependent branching is mediated by PKC-dependent phosphorylation of GAP-43. Active Ral overexpression; RNAi knockdown; dominant-negative mutants; effector-binding mutants; neuronal morphology assay The Journal of cell biology Medium 16330713
2006 RalA is required for tumor initiation in human pancreatic cancer cells (anchorage-independent growth and tumorigenesis), while RalB is required for invasion and metastasis; these are distinct and divergent functions of the two highly similar GTPases. siRNA knockdown of RalA vs RalB; anchorage-independent growth assay; invasion assay; tail-vein injection metastasis model Current biology : CB High 17174914
2007 Insulin activates RalA in a PI 3-kinase-dependent manner in adipocytes; RalA is present in Glut4 vesicles and interacts with the exocyst complex to tether vesicles to the plasma membrane; RalA also interacts with Myo1c (a molecular motor), regulated by calmodulin, to function as a cargo receptor for Glut4 vesicle trafficking. RalA-GTP pulldown; siRNA knockdown; dominant-negative mutants; co-immunoprecipitation; glucose transport assay Developmental cell High 17765682
2007 Activation of RalGEF/RalA pathway promotes prostate cancer metastasis specifically to bone; loss of RalA in PC3 cells inhibits bone metastasis but not subcutaneous tumor growth. RalA siRNA knockdown; in vivo bone metastasis assay; subcutaneous tumor growth comparison Molecular and cellular biology Medium 17709381
2008 RalA is required for tethering the exocyst to the cytokinetic furrow in early cytokinesis; RalB is then required for exocyst recruitment to the midbody for abscission; each Ral isoform is controlled by distinct RalGEF proteins. RNAi knockdown; live cell imaging; immunofluorescence of cytokinesis stages The EMBO journal Medium 18756269
2008 RalA (and RalB) control localization of the exocyst complex to focal complexes during cell migration by regulating interaction between Sec5 and paxillin; reduction of RalA or RalB by RNAi alters exocyst localization without disrupting steady-state exocyst assembly. RNAi knockdown; co-immunoprecipitation; immunofluorescence localization Journal of cell science Medium 18697830
2009 Aurora-A kinase phosphorylates RalA at Ser194, promoting RalA activation and translocation from the plasma membrane; this phosphorylation activates RalBP1 effector and is required for Aurora-A-enhanced transformed cell growth. Kinase assay; phosphorylation site mutagenesis (S194); subcellular fractionation; transformation assay; tumor xenograft Molecular and cellular biology High 19901077
2009 RalA mediates integrin-dependent membrane raft exocytosis via the exocyst complex; constitutively active RalA restores plasma membrane raft targeting to support anchorage-independent growth signaling. Dominant-active RalA; siRNA knockdown; membrane fractionation; growth signaling assay Current biology : CB Medium 20005108
2009 M-Sec induces membrane nanotube formation by interacting with RalA and the exocyst complex; blockage of M-Sec interaction with Ral or the exocyst attenuates nanotube formation. RNAi knockdown; dominant-negative interference; live cell imaging of nanotubes Nature cell biology Medium 19935652
2009 RalA and the exocyst complex associate with PAR-3 in a RalA-dependent manner during neuronal polarization; depletion of RalA or exocyst subunits inhibits axon formation, linking RalA-exocyst to PAR-3/aPKC polarity complex. Co-immunoprecipitation; RNAi knockdown; constitutively active RalA expression; neuronal morphology assay Journal of cell science Medium 19383721
2010 A Ral GAP complex (RGC1/RGC2) is identified as the GAP that activates RalA downstream of PI 3-kinase/Akt; Akt2 phosphorylates RGC2, inhibiting its GAP activity and thereby activating RalA for GLUT4 vesicle targeting in adipocytes. RGC identification and characterization; in vitro GTPase assay; Akt2 phosphorylation assay; siRNA knockdown; glucose uptake assay Molecular biology of the cell High 21148297
2010 RalA is a positive modulator of FcγR-mediated phagocytosis through PLD activation; RalA colocalizes with PLD1 and PLD2 at the phagocytic cup, and RalA co-immunoprecipitates with PLD isoforms in a stimulation-dependent manner. RNAi knockdown; PLD activity assay; co-immunoprecipitation; fluorescence microscopy of phagocytic cup Journal of immunology Medium 20679536
2012 RalA null mice develop exencephaly and embryonic lethality; double Rala/Ralb null embryos do not survive past gastrulation; in a KRAS-driven lung cancer model, either RalA or RalB alone is sufficient for tumor growth, but loss of both blocks tumor formation. Genetic knockout mice; Kras-driven lung cancer model; conditional deletion Current biology : CB High 23063435
2012 RALA is activated downstream of RalGAPα2 loss in bladder cancer; exogenous wild-type RalGAPα2 (but not a catalytically inactive mutant) reduces RalA activity, cell migration in vitro, and lung metastasis in vivo; Ralgapa2 knockout promotes tumor invasion in mice. RalGAPα2 expression rescue; in vitro migration assay; mouse tumor model; KO mouse Oncogene Medium 22450745
2013 ROS activates RalA via the exchange factor RLF, which is in complex with JIP1 scaffold and JNK; active RalA then promotes assembly and activation of MLK3-MKK4-JNK onto the JIP1 scaffold, leading to FOXO activation; this mechanism is conserved in C. elegans. Co-immunoprecipitation; RNAi knockdown; FOXO reporter/localization assay; C. elegans genetics The Journal of biological chemistry Medium 23770673
2014 Small molecules (RBC8, BQU57) bind the GDP-bound form of RalA/RalB, inhibit Ral-RALBP1 interaction, and inhibit Ral-mediated cell spreading and anchorage-independent growth; binding confirmed by ITC, SPR, and NMR spectroscopy. Structure-based virtual screening; ITC; SPR; TROSY NMR; cell spreading assay; xenograft tumor growth Nature High 25219851
2014 In skeletal muscle, GARNL1/RalGAPα1 is a major RalGAP catalytic subunit; insulin activates RalA by Akt-mediated phosphorylation of GARNL1 at Thr735, causing 14-3-3 binding and GAP inactivation; knockdown of GARNL1 increases RalA activity and GLUT4 translocation. RalGAPα1 identification; phosphorylation site mutagenesis; 14-3-3 binding assay; siRNA knockdown; GLUT4 translocation assay Cellular signalling High 24768767
2014 Rab10 is activated by AS160 inactivation downstream of Akt; active Rab10 recruits the RalGEF Rlf/Rgl2 to GLUT4 vesicle membranes, activating RalA and thereby promoting maximal glucose transport; RalA is downstream of Rab10 in this cascade. GTP-loading assays; overexpression of membrane-tethered Rlf to bypass Rab10; siRNA knockdown; glucose transport assay Molecular biology of the cell Medium 25103239
2015 TD-60/RCC2 exhibits GEF activity for RalA in vitro and in cells; TD-60 and RalA depletion cause spindle abnormalities and abnormal CPC accumulation; several TD-60-depletion phenotypes are rescued by GTP-locked RalA(Q72L), placing RalA in the CPC regulatory pathway. In vitro GEF assay; RNAi knockdown; GTP-locked rescue; immunofluorescence of mitotic cells Nature communications High 26158537
2015 RAL-1 (RalA ortholog in C. elegans) localizes to secretory multivesicular bodies (MVBs) and is required for both MVB biogenesis and fusion with the plasma membrane for exosome secretion; in mammalian cells, RalA and RalB are both required for exosome-like vesicle secretion. Live imaging; quantitative electron microscopy; RNAi knockdown in C. elegans; RalA/B knockdown in mammalian cells; nanoparticle tracking analysis The Journal of cell biology High 26459596
2016 RalA activates PLD2 in endothelial cells; phosphatidic acid produced by PLD2 facilitates caveolae-mediated endocytosis and vesicle trafficking; RalA co-immunoprecipitates with caveolin-1 and filamin A upon albumin stimulation. siRNA knockdown of RalA; PLD2 inhibition; co-immunoprecipitation; TIRF microscopy; PA biosensor The Journal of biological chemistry Medium 27510034
2019 RALA and RALB are required for internalization of the Wnt receptor Frizzled-7 in intestinal stem cells; genetic deletion of either reduces ISC function and Lgr5 positivity, while dual deletion causes rapid crypt death. Genetic KO mouse; Drosophila genetics; Frizzled-7 internalization assay; intestinal organoid culture Cell stem cell High 30853556
2021 RalA and RalB control biogenesis and secretion of pro-metastatic extracellular vesicles through phospholipase D1; RalA/B-depleted cells produce EVs with elevated MCAM/CD146, reducing organotropic EV targeting and pre-metastatic niche formation. RalA/B knockdown; EV nanoparticle tracking; in vivo EV uptake assay; proteomics of EVs eLife Medium 33404012
2024 RalA expression and activity are increased in white adipocytes after high-fat diet; RalA drives mitochondrial fragmentation by reversing the inhibitory Ser637 phosphorylation of Drp1, increasing fission; adipocyte-specific RalA deletion prevents fragmentation, reduces weight gain, and increases fatty acid oxidation. Conditional adipocyte-specific RalA KO mouse; Drp1-Ser637 phosphorylation assay; mitochondrial morphology imaging; metabolic phenotyping Nature metabolism High 38286821

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The small GTPase RalA targets filamin to induce filopodia. Proceedings of the National Academy of Sciences of the United States of America 358 10051605
2009 M-Sec promotes membrane nanotube formation by interacting with Ral and the exocyst complex. Nature cell biology 322 19935652
1996 Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. The EMBO journal 294 8631302
1995 Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. The Journal of biological chemistry 291 7673236
1998 All in the family? New insights and questions regarding interconnectivity of Ras, Rap1 and Ral. The EMBO journal 280 9843482
1995 Involvement of Ral GTPase in v-Src-induced phospholipase D activation. Nature 244 7477381
1986 The ral gene: a new ras related gene isolated by the use of a synthetic probe. The EMBO journal 240 3023062
2002 The exocyst complex binds the small GTPase RalA to mediate filopodia formation. Nature cell biology 208 11744922
2006 Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Current biology : CB 191 17174914
1996 Evidence for a Ras/Ral signaling cascade. Trends in biochemical sciences 179 8987400
2015 RAL-1 controls multivesicular body biogenesis and exosome secretion. The Journal of cell biology 176 26459596
2007 Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c. Developmental cell 171 17765682
1999 Ras caught in another affair: the exchange factors for Ral. Current opinion in genetics & development 127 10072355
2014 Discovery and characterization of small molecules that target the GTPase Ral. Nature 123 25219851
2005 Exo84 and Sec5 are competitive regulatory Sec6/8 effectors to the RalA GTPase. The EMBO journal 122 15920473
2009 Beta-arrestin/Ral signaling regulates lysophosphatidic acid-mediated migration and invasion of human breast tumor cells. Molecular cancer research : MCR 120 19609003
2000 An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity. The EMBO journal 120 10675331
2013 microRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN. Stem cells and development 112 24063364
2002 Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. Nature cell biology 112 12105416
1988 Expression of the ras-related ralA, rho12 and rab genes in adult mouse tissues. Oncogene 111 2457862
2005 RalA and RalB: antagonistic relatives in cancer cell migration. Cancer research 109 16103060
2024 Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation. Nature metabolism 107 38286821
2002 Regulation of choline kinase activity by Ras proteins involves Ral-GDS and PI3K. Oncogene 102 11840339
1998 Functional association between Arf and RalA in active phospholipase D complex. Proceedings of the National Academy of Sciences of the United States of America 102 9520417
2003 Structural basis of the interaction between RalA and Sec5, a subunit of the sec6/8 complex. The EMBO journal 98 12839989
2009 Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA. Molecular and cellular biology 97 19901077
2008 Distinct roles of RalA and RalB in the progression of cytokinesis are supported by distinct RalGEFs. The EMBO journal 96 18756269
2021 Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes. eLife 94 33404012
2014 RalR (a DNase) and RalA (a small RNA) form a type I toxin-antitoxin system in Escherichia coli. Nucleic acids research 93 24748661
1989 Identification of the ral and rac1 gene products, low molecular mass GTP-binding proteins from human platelets. The Journal of biological chemistry 91 2550440
2003 HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo. The Journal of biological chemistry 90 12621024
2007 Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. Molecular and cellular biology 89 17709381
2000 Phospholipase D and RalA cooperate with the epidermal growth factor receptor to transform 3Y1 rat fibroblasts. Molecular and cellular biology 88 10611224
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
2004 RalA interacts with ZONAB in a cell density-dependent manner and regulates its transcriptional activity. The EMBO journal 85 15592429
2010 A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action. Molecular biology of the cell 84 21148297
2000 Involvement of Ras and Ral in chemotactic migration of skeletal myoblasts. Molecular and cellular biology 84 10848592
2005 Ral GTPases regulate neurite branching through GAP-43 and the exocyst complex. The Journal of cell biology 83 16330713
2014 Ral small GTPase signaling and oncogenesis: More than just 15minutes of fame. Biochimica et biophysica acta 81 25219551
2016 DNA vaccination for cervical cancer; a novel technology platform of RALA mediated gene delivery via polymeric microneedles. Nanomedicine : nanotechnology, biology, and medicine 80 27979747
2008 Ral-regulated interaction between Sec5 and paxillin targets Exocyst to focal complexes during cell migration. Journal of cell science 80 18697830
2018 RAL GTPases: Biology and Potential as Therapeutic Targets in Cancer. Pharmacological reviews 78 29196555
2002 The role of Ral A in epidermal growth factor receptor-regulated cell motility. Cancer research 78 11861368
1999 Differential roles of Akt, Rac, and Ral in R-Ras-mediated cellular transformation, adhesion, and survival. Molecular and cellular biology 76 10454580
2019 DNA vaccination via RALA nanoparticles in a microneedle delivery system induces a potent immune response against the endogenous prostate cancer stem cell antigen. Acta biomaterialia 73 31299353
1999 RalA requirement for v-Src- and v-Ras-induced tumorigenicity and overproduction of urokinase-type plasminogen activator: involvement of metalloproteases. Oncogene 70 10467419
2007 Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Molecular and cellular biology 68 17875936
1999 Effector recognition by the small GTP-binding proteins Ras and Ral. The Journal of biological chemistry 68 10364219
2011 Activation and involvement of Ral GTPases in colorectal cancer. Cancer research 67 21199803
2007 Expression of ral GTPases, their effectors, and activators in human bladder cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 66 17606711
2012 Genetic deletion of RALA and RALB small GTPases reveals redundant functions in development and tumorigenesis. Current biology : CB 65 23063435
2010 RalGDS family members couple Ras to Ral signalling and that's not all. Cellular signalling 65 20478380
2009 RalA and the exocyst complex influence neuronal polarity through PAR-3 and aPKC. Journal of cell science 65 19383721
2006 Ral: mediator of membrane trafficking. The international journal of biochemistry & cell biology 65 16781882
1998 Ras-independent activation of Ral by a Ca(2+)-dependent pathway. Current biology : CB 65 9663394
2000 Ras-dependent regulation of c-Jun phosphorylation is mediated by the Ral guanine nucleotide exchange factor-Ral pathway. Molecular and cellular biology 63 11046144
2012 miR-181a post-transcriptionally downregulates oncogenic RalA and contributes to growth inhibition and apoptosis in chronic myelogenous leukemia (CML). PloS one 61 22442671
1997 Characterization of Ral GDP dissociation stimulator-like (RGL) activities to regulate c-fos promoter and the GDP/GTP exchange of Ral. The Journal of biological chemistry 61 9099691
2009 RalA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling. Current biology : CB 60 20005108
2018 DNA vaccination for cervical cancer: Strategic optimisation of RALA mediated gene delivery from a biodegradable microneedle system. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 56 29510205
2016 Dissolving microneedles for DNA vaccination: Improving functionality via polymer characterization and RALA complexation. Human vaccines & immunotherapeutics 53 27846370
2012 Downregulation of Ral GTPase-activating protein promotes tumor invasion and metastasis of bladder cancer. Oncogene 49 22450745
1991 Characterization of a GTPase-activating protein for the Ras-related Ral protein. The Journal of biological chemistry 49 1903395
2016 The Small GTPase Ral orchestrates MVB biogenesis and exosome secretion. Small GTPases 48 27875100
1986 Modification enhancement by the restriction alleviation protein (Ral) of bacteriophage lambda. Journal of molecular biology 48 3023633
2003 Elevated phospholipase D activity in H-Ras- but not K-Ras-transformed cells by the synergistic action of RalA and ARF6. Molecular and cellular biology 46 12509462
2007 R-Ras regulates exocytosis by Rgl2/Rlf-mediated activation of RalA on endosomes. Molecular biology of the cell 45 17344481
1990 Guanine nucleotide binding properties of the mammalian RalA protein produced in Escherichia coli. The Journal of biological chemistry 45 2108160
2012 Role of RalA downstream of Rac1 in insulin-dependent glucose uptake in muscle cells. Cellular signalling 43 22820503
2017 Ral signaling pathway in health and cancer. Cancer medicine 41 29047224
2015 TD-60 links RalA GTPase function to the CPC in mitosis. Nature communications 40 26158537
2004 Small GTP-binding protein Ral is involved in cAMP-mediated release of von Willebrand factor from endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 40 15130921
1996 Post-translational modifications of Ras and Ral are important for the action of Ral GDP dissociation stimulator. The Journal of biological chemistry 40 8702675
2019 Delivery of RALA/siFKBPL nanoparticles via electrospun bilayer nanofibres: An innovative angiogenic therapy for wound repair. Journal of controlled release : official journal of the Controlled Release Society 39 31676385
2006 The Ral/exocyst effector complex counters c-Jun N-terminal kinase-dependent apoptosis in Drosophila melanogaster. Molecular and cellular biology 39 17000765
2001 Small GTP-binding protein Ral modulates regulated exocytosis of von Willebrand factor by endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 39 11397694
2011 The Rap1-Rgl-Ral signaling network regulates neuroblast cortical polarity and spindle orientation. The Journal of cell biology 38 22084305
2014 A Rab10:RalA G protein cascade regulates insulin-stimulated glucose uptake in adipocytes. Molecular biology of the cell 37 25103239
2015 The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer. Acta pharmacologica Sinica 35 25557115
2012 Transcriptional signatures of Ral GTPase are associated with aggressive clinicopathologic characteristics in human cancer. Cancer research 35 22586063
2015 A rapid, membrane-dependent pathway directs furrow formation through RalA in the early Drosophila embryo. Development (Cambridge, England) 34 26092850
2012 PGE2 promotes renal carcinoma cell invasion through activated RalA. Oncogene 34 22580611
2014 GARNL1, a major RalGAP α subunit in skeletal muscle, regulates insulin-stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins. Cellular signalling 33 24768767
2014 κB-Ras proteins regulate both NF-κB-dependent inflammation and Ral-dependent proliferation. Cell reports 33 25220458
2005 The small G-protein RalA stimulates metastasis of transformed cells. Oncogene 33 15467745
2017 A family affair: A Ral-exocyst-centered network links Ras, Rac, Rho signaling to control cell migration. Small GTPases 32 28498728
2016 Phosphatidic Acid Produced by RalA-activated PLD2 Stimulates Caveolae-mediated Endocytosis and Trafficking in Endothelial Cells. The Journal of biological chemistry 31 27510034
2013 The small GTPase RALA controls c-Jun N-terminal kinase-mediated FOXO activation by regulation of a JIP1 scaffold complex. The Journal of biological chemistry 31 23770673
2020 κB-Ras and Ral GTPases regulate acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis. Nature communications 30 32641778
2012 Inhibition of RalA signaling pathway in treatment of non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 30 22498113
2007 Functional analysis of RalGPS2, a murine guanine nucleotide exchange factor for RalA GTPase. Experimental cell research 30 17462626
2002 ADP-ribosylation and functional effects of Pseudomonas exoenzyme S on cellular RalA. Biochemistry 30 12135390
1996 Association of Ral GTP-binding protein with human platelet dense granules. Biochemical and biophysical research communications 30 8769092
2019 RAL GTPases Drive Intestinal Stem Cell Function and Regeneration through Internalization of WNT Signalosomes. Cell stem cell 29 30853556
2018 Gene therapy with RALA/iNOS composite nanoparticles significantly enhances survival in a model of metastatic prostate cancer. Cancer nanotechnology 29 29899810
2016 Two-Step Forward Genetic Screen in Mice Identifies Ral GTPase-Activating Proteins as Suppressors of Hepatocellular Carcinoma. Gastroenterology 28 27178121
2012 Differential involvement of RalA and RalB in colorectal cancer. Small GTPases 28 22790202
2020 The RAL signaling network: Cancer and beyond. International review of cell and molecular biology 27 34074494
2010 Ral isoforms are implicated in Fc gamma R-mediated phagocytosis: activation of phospholipase D by RalA. Journal of immunology (Baltimore, Md. : 1950) 27 20679536
2020 Collagen/GAG scaffolds activated by RALA-siMMP-9 complexes with potential for improved diabetic foot ulcer healing. Materials science & engineering. C, Materials for biological applications 26 32993972