Affinage

RALA

Ras-related protein Ral-A · UniProt P11233

Length
206 aa
Mass
23.6 kDa
Annotated
2026-06-10
100 papers in source corpus 49 papers cited in narrative 48 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RALA is a Ras-related small GTPase that cycles between GDP- and GTP-bound states with intrinsically low GTPase activity, binds and hydrolyzes GTP, and is anchored to membranes via a C-terminal lipid modification (PMID:3023062, PMID:2108160, PMID:15530367). Nucleotide cycling is controlled by dedicated regulators: RalGDS-family GEFs require membrane co-localization with GTP-Ras (or Ras-independent recruitment through beta-arrestin) to load GTP onto lipid-modified RALA (PMID:9416833, PMID:12105416), TD-60/RCC2 acts as a mitotic GEF (PMID:26158537), and the RGC1/RGC2 (RalGAP) heterodimer stimulates GTP hydrolysis under control of Akt-mediated phosphorylation (PMID:21148297). In its GTP-bound state RALA engages a defined set of effectors through its switch regions: RLIP76/RalBP1, which couples RALA to Rac1/CDC42 GAP activity and to the AP2 endocytic machinery (PMID:7673236, PMID:7623849, PMID:10910768); the exocyst, where Sec5 and Exo84 bind competitively at overlapping sites (PMID:14978027, PMID:15920473); PLD1/PLD2 via a unique N-terminal region to generate phosphatidic acid (PMID:7477381, PMID:9520417); and filamin to drive filopodium formation downstream of Cdc42 (PMID:10051605). Through the exocyst, RALA directs polarized membrane trafficking that underlies cytokinetic furrow formation, neuronal polarity and synaptic plasticity, insulin- and feeding-stimulated GLUT4 translocation, integrin and membrane-raft delivery during migration, Wnt receptor (Frizzled-7) internalization, membrane-nanotube formation, and multivesicular-body/exosome biogenesis (PMID:11865051, PMID:17765682, PMID:18756269, PMID:19383721, PMID:20005108, PMID:26459596, PMID:30853556). Beyond trafficking, RALA drives transcriptional and metabolic programs—relieving ZONAB repression and inducing NF-κB/cyclin D1 (PMID:11027278, PMID:15592429)—and, upon Aurora A phosphorylation at Ser194, relocalizes to mitochondria to concentrate RalBP1 and drive DRP1-dependent mitochondrial fission (PMID:19901077, PMID:21822277, PMID:38286821). RALA is required for Ras-driven oncogenic transformation, anchorage-independent growth, and tumorigenesis, and is a target of structure-based small-molecule inhibitors (PMID:8631302, PMID:17174914, PMID:25219851).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1986 High

    Established RALA as a distinct Ras-related GTPase, defining a new branch of small GTPase signaling separate from the classical Ras genes.

    Evidence cDNA cloning and sequence analysis identifying a 206-residue protein with GTP-binding motifs and a C-terminal membrane-anchoring cysteine

    PMID:3023062

    Open questions at the time
    • No effectors or cellular function identified at isolation
    • Regulatory GEF/GAP machinery unknown
  2. 1991 High

    Defined the biochemical GTPase cycle and the first dedicated regulator, showing RALA is governed by its own GAP distinct from Ras/Rho/Rap regulators.

    Evidence In vitro GTPase and nucleotide-exchange assays on purified protein with activating mutants, plus biochemical fractionation of a brain/testis Ral-GAP

    PMID:1903395 PMID:2108160

    Open questions at the time
    • Molecular identity of the GAP not established
    • No GEF identified
    • No downstream effectors
  3. 1997 High

    Identified the first effectors (RLIP76/RalBP1) and the activating GEF logic, linking RALA to Rho-family regulation and placing it downstream of Ras at the membrane.

    Evidence Yeast two-hybrid, GST pulldowns, in vitro GAP assays, and liposome-reconstituted GDP-dissociation assays requiring GTP-Ras and lipid-modified Ral

    PMID:7623849 PMID:7673236 PMID:8702675 PMID:9237623 PMID:9416833

    Open questions at the time
    • Did not resolve full effector repertoire
    • Structural basis of effector selectivity unknown
  4. 1998 High

    Connected RALA to lipid signaling and oncogenic transformation, showing it activates PLD and potentiates Ras/Raf-driven transformation through a pathway parallel to ERK/JNK.

    Evidence Co-IP/GST pulldown of PLD1 with Arf, N-terminal deletion mapping, dominant-negative epistasis, and focus-formation/transformation assays

    PMID:10611224 PMID:7477381 PMID:8631302 PMID:9520417

    Open questions at the time
    • Effector responsible for NF-κB/cyclin D1 transcription left uncharacterized [#15]
    • Mechanistic link between PLD and transformation incomplete
  5. 1999 High

    Demonstrated RALA controls cytoskeletal and endocytic membrane events, binding filamin for filopodia and RLIP76/POB1 for receptor-selective endocytosis.

    Evidence GTP-specific pulldowns, filamin-deficient cell rescue, immunofluorescence, and ligand-internalization assays for EGF/insulin versus transferrin receptors

    PMID:10051605 PMID:10393179 PMID:10910768

    Open questions at the time
    • Both active and inactive RALA blocked endocytosis, complicating a simple switch model
    • Coupling to AP2/clathrin machinery only partially defined
  6. 2002 High

    Linked RALA to regulated exocytosis and synaptic vesicle dynamics in vivo through the exocyst, distinguishing GTP-dependent from Ca2+-dependent secretion.

    Evidence Transgenic dominant-inhibitory mice, synaptosomal secretion and RRP-refilling assays, and Sec6/8 exocyst co-IP

    PMID:11865051 PMID:12105416

    Open questions at the time
    • Precise exocyst subunit interface not yet mapped
    • Whether secretory defect reflects tethering versus fusion unresolved
  7. 2005 High

    Provided the structural basis of RALA effector engagement, showing nucleotide-state-dependent switch surfaces and competitive Sec5/Exo84 binding to active RALA.

    Evidence X-ray crystallography of RALA-GppNHp/RalA-GDP and of the Exo84 RBD-RalA complex with mutagenesis and competitive-binding biochemistry

    PMID:15530367 PMID:15920473

    Open questions at the time
    • Structural basis for effector choice in vivo not established
    • Does not explain spatial sorting between competing exocyst subunits
  8. 2008 High

    Resolved RALA-specific functions in cytokinesis and migration, showing it tethers the exocyst to the cleavage furrow and to focal complexes, distinct from RalB roles.

    Evidence siRNA knockdown with live imaging, spatial localization, Sec5-paxillin co-IP, and integrin trafficking/motility assays

    PMID:17174914 PMID:18697830 PMID:18756269

    Open questions at the time
    • GEFs specifying RalA versus RalB compartmentalization not all identified
    • Mechanism of furrow-specific exocyst tethering incomplete
  9. 2009 High

    Established the Aurora A-Ser194 phosphorylation switch that relocalizes RALA to mitochondria, and broadened its roles in neuronal polarity, synaptic plasticity, and intercellular communication.

    Evidence In vitro kinase assays with S194 mutagenesis, subcellular fractionation, exocyst-uncoupled mutants in neurons, AMPAR endocytosis/LTD electrophysiology, and TNT formation assays

    PMID:19383721 PMID:19823667 PMID:19901077 PMID:19935652

    Open questions at the time
    • Downstream mitochondrial targets not yet defined at this stage
    • How a single GTPase coordinates plasma-membrane versus mitochondrial pools unclear
  10. 2011 High

    Defined the mitochondrial fission mechanism, showing Aurora A-phosphorylated RALA scaffolds RalBP1 and cyclin B-CDK1 to phosphorylate DRP1-Ser616 and drive fission at mitosis.

    Evidence In vitro phosphorylation assays, S194 mutagenesis, localization, and mitochondrial fission/segregation assays with ATP readouts

    PMID:21822277

    Open questions at the time
    • Relationship between mitotic fission role and metabolic adipocyte role not connected
    • Stoichiometry of the RalBP1-cyclin B-CDK1-DRP1 assembly unresolved
  11. 2014 High

    Mapped the insulin-signaling input to RALA and validated it as a druggable target, defining the Rab10-Rlf-RALA cascade and RalGAP/Akt control of GLUT4 trafficking.

    Evidence In vitro GAP and Akt2 kinase assays, Rab10-Rlf membrane-tethering rescue, GLUT4/glucose-uptake assays, and structure-based inhibitor design with ITC/SPR/NMR and xenografts

    PMID:21148297 PMID:23770673 PMID:24389102 PMID:25103239 PMID:25219851

    Open questions at the time
    • JIP1/JNK-FOXO and mTORC1 crosstalk arms supported by single-lab Medium evidence
    • How RALA distinguishes GLUT4-vesicle from other exocyst cargoes unresolved
  12. 2015 High

    Identified TD-60/RCC2 as a mitotic GEF and uncovered an exocyst-independent RALA function in multivesicular-body and exosome biogenesis.

    Evidence In vitro GEF assay with GTP-locked RalA rescue of mitotic phenotypes, plus quantitative EM and exosome secretion assays in C. elegans and mammalian cells

    PMID:26158537 PMID:26459596

    Open questions at the time
    • The exocyst-independent MVB effector(s) not identified
    • How TD-60 GEF activity is restricted to mitosis unknown
  13. 2019 High

    Established physiological RALA functions in tissue homeostasis and disease, including Wnt-receptor internalization for intestinal stem cell maintenance and EV-mediated metastatic organotropism.

    Evidence Conditional knockouts in mouse and Drosophila, Frizzled-7 internalization and organoid assays, and in vivo EV organotropism with PLD1-dependent MVB regulation

    PMID:30853556 PMID:33404012

    Open questions at the time
    • RalA versus RalB division of labor in these contexts not fully separated
    • EV findings rest on single-lab Medium evidence
  14. 2024 High

    Demonstrated a metabolic mitochondrial-fission role in vivo, showing diet-induced RALA reverses inhibitory DRP1-Ser637 phosphorylation in white adipocytes to promote fragmentation and limit fatty acid oxidation.

    Evidence Adipocyte-specific RalA knockout mice with mitochondrial morphology imaging, DRP1 phospho-western blots, fatty acid oxidation assays, and metabolic phenotyping

    PMID:38286821

    Open questions at the time
    • Reconciliation with the mitotic Ser616 fission mechanism not addressed
    • Upstream kinase/phosphatase controlling Ser637 in this context unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RALA partitions a single GTP-bound pool among competing effectors and subcellular compartments to execute distinct exocyst-dependent trafficking, transcriptional, and mitochondrial programs remains unresolved.
  • No unified model for spatial/temporal effector selection
  • Identity of the effector mediating NF-κB/cyclin D1 transcription unknown
  • Exocyst-independent MVB effector(s) uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4 GO:0060089 molecular transducer activity 4 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 4 GO:0005739 mitochondrion 3 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 6 R-HSA-9609507 Protein localization 5 R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3
Partners
EXOC2/SEC5EXOC84/EXO84FLNAMYO1CPLD1RALBP1RALGDSRGC2
Complex memberships
exocyst

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 encoding a 206 amino acid protein with GTP-binding domains and a C-terminal cysteine for membrane anchoring, sharing >50% homology with H-ras/K-ras/N-ras. cDNA cloning using synthetic oligonucleotide probe, sequence analysis The EMBO journal High 3023062
1990 Purified RalA protein binds and hydrolyzes GTP with low GTPase activity (0.07 min-1 at 37°C) and exchanges GDP with t1/2 of 90 min; activating mutations analogous to Ras Val12 and Leu61 alter nucleotide exchange kinetics and GTPase activity but with less pronounced effects than in Ras. In vitro biochemical assay with purified recombinant protein, NMR, in vitro mutagenesis The Journal of biological chemistry High 2108160
1991 A GTPase-activating protein (Ral-GAP) for RalA was identified in brain and testis cytosol; it is distinct from Ras-GAP, NF1, Rho-GAP, and Rap-GAP, and fails to stimulate GTPase activity of Ral mutants analogous to GAP-insensitive Ras mutants. Biochemical fractionation, in vitro GTPase assay, chromatography The Journal of biological chemistry High 1903395
1995 RLIP76/RalBP1 was identified as a direct effector of activated (GTP-bound) RalA, requiring an intact effector domain of RalA for binding; RLIP76 also contains a GAP domain that acts on Rac1 and CDC42 (but not RhoA), linking Ral to Rho family GTPase regulation. Yeast two-hybrid screening, pulldown with purified proteins, in vitro GAP activity assay The Journal of biological chemistry High 7623849 7673236
1995 RalA is involved in v-Src-induced phospholipase D (PLD) activation: PLD activity co-precipitates with immobilized RalA; deletion of Ral-specific N-terminal amino acids abolishes RalA-PLD association; dominant-negative RalA inhibits v-Src- and v-Ras-induced PLD activity. Co-immunoprecipitation, GST pulldown, dominant-negative overexpression, PLD activity assay Nature High 7477381
1996 Constitutively activated RalA enhances the transforming activities of oncogenic RasH and Raf, while dominant-inhibitory RalA suppresses transformation by both, establishing Ral as a distinct downstream signaling pathway from Ras that potentiates oncogenic transformation. Focus formation assay, dominant-negative/constitutively active mutant overexpression in mammalian cells The EMBO journal High 8631302
1996 Post-translational modification (lipid modification) of RalA enhances RalGDS-stimulated GDP/GTP exchange activity on RalA and promotes RalA binding to RalBP1; modified Ras is required to regulate RalGDS membrane distribution. In vitro GDP dissociation assay, subcellular fractionation, co-immunoprecipitation in COS cells The Journal of biological chemistry Medium 8702675
1997 RalGDS (Ral GDP dissociation stimulator) requires membrane co-localization of GTP-Ras and lipid-modified Ral to activate Ral; Ras-GTP but not Ras-GDP stimulates RalGDS-mediated GDP dissociation from Ral in reconstituted liposomes. Liposome reconstitution assay, in vitro GDP dissociation assay, COS cell co-expression Oncogene High 9416833
1997 Post-translational modification of RalA is important for its membrane localization and for directing RalBP1 to the membrane; the interaction of Ral with RalBP1 does not affect RalBP1 GAP activity for Rac1 but recruits RalBP1 to membranes where its substrates reside. Subcellular fractionation, co-expression in COS cells, in vitro GAP activity assay FEBS letters Medium 9237623
1998 RalA forms a complex with PLD1 directly through its unique N-terminal region; Arf is present in active RalA-PLD1 complexes and is required for the increased PLD activity in v-Src/v-Ras transformed cells; deletion of 11 N-terminal amino acids of Ral abolishes both Arf association and PLD activity precipitation. GST pulldown from cell lysates, GTPγS activation, Brefeldin A inhibition, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 9520417
1999 GTP-bound RalA (but not other Ras-related GTPases tested in a GTP-specific manner) binds filamin, recruits filamin into filopodial cytoskeleton, and induces actin-rich filopodia in Swiss 3T3 cells; RalA acts downstream of Cdc42 in filopod formation and requires filamin (no filopodia in filamin-deficient cells; restored by filamin transfection). GTP-specific pulldown, dominant-negative/constitutively active mutant overexpression, filamin-deficient cell rescue experiment, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 10051605
1999 RalA and its effectors RalBP1 and POB1 regulate ligand-dependent endocytosis of EGF and insulin receptors (but not transferrin receptor); both constitutively active and dominant-negative RalA block EGF internalization; EGF and insulin activate Ral; POB1 EH domain binds Epsin and Eps15. Dominant-negative/constitutively active mutant expression, internalization assay, yeast two-hybrid, co-immunoprecipitation The EMBO journal High 10393179
1999 Dominant-negative RalA blocks v-Src- and v-Ras-induced overproduction of urokinase-type plasminogen activator (uPA) and MMP-2/MMP-9 (v-Src-induced), and completely blocks tumor formation by v-Src- and v-Ras-transformed NIH3T3 cells in vivo. Dominant-negative mutant expression, uPA and MMP assays, in vivo tumor formation assay Oncogene Medium 10467419
2000 RLIP76 interacts with the mu2 subunit of the AP2 endocytic adaptor complex; endogenous AP2 and RLIP76 form a complex in vivo; activated Ral interferes with transferrin receptor and EGF receptor endocytosis in HeLa cells, connecting Ral-RLIP76 signaling to the endocytic machinery. Yeast two-hybrid, co-immunoprecipitation, receptor endocytosis assay Journal of cell science Medium 10910768
2000 Activated RalA or PLD1 overexpression cooperates with the EGF receptor to transform 3Y1 rat fibroblasts; EGF-induced PLD activation in EGFR cells requires both Ras and RalA; EGF-induced ERK1/2 and JNK activation is Ras-dependent but RalA-independent, indicating divergent downstream pathways. Dominant-negative/activated mutant overexpression, transformation assay, PLD activity assay, kinase activity assay Molecular and cellular biology High 10611224
2000 Activated Ral expression in quiescent fibroblasts induces NF-κB-dependent gene expression and cyclin D1 transcription; this Ral-mediated NF-κB/cyclin D1 regulation is independent of PLD1 and RalBP1 association, suggesting an uncharacterized effector pathway. Constitutively active mutant overexpression, reporter gene assay (NF-κB, cyclin D1 promoter), dominant-negative mutants Molecular and cellular biology Medium 11027278
2000 The Ras/RalGEF/Ral pathway mediates chemotactic migration of skeletal myoblasts in response to bFGF, HGF, and IGF-1; dominant-negative Ral reduces chemotaxis; Ral's ability to stimulate motility requires binding to RalBP1 or PLD; Ral is activated by bFGF/HGF/IGF-1 through Ras- and Ca2+-mediated pathways. Dominant-negative/activated mutant expression, chemotaxis assay, effector-domain mutants, signaling pathway inhibitors Molecular and cellular biology Medium 10848592
2002 Ral-GDS is a beta-arrestin-binding protein; under basal conditions Ral-GDS is inactive in a complex with beta-arrestins in the cytosol; upon fMLP receptor stimulation, beta-arrestin–Ral-GDS complexes dissociate, Ral-GDS translocates to the plasma membrane with beta-arrestin, leading to Ras-independent RalA activation and cytoskeletal rearrangement. Yeast two-hybrid, co-immunoprecipitation from primary PMNs, subcellular fractionation, RalA activation assay Nature cell biology High 12105416
2002 Dominant-inhibitory Ral in transgenic mice suppresses protein kinase C-mediated enhancement of glutamate secretion and impairs refilling of the readily releasable pool of synaptic vesicles; active RalA binds the Sec6/8 (exocyst) complex. Transgenic mouse model, synaptosomal secretion assay, RRP refilling assay, co-immunoprecipitation Molecular and cellular biology High 11865051
2004 RalA interaction with the exocyst component Sec5 is essential for GTP-dependent (but not Ca2+-dependent) exocytosis in PC12 cells; point mutations abolishing RalA-Sec5 interaction (RalA E38R, Sec5 T11A) abolish GTP-dependent exocytosis; both pathways require SNARE proteins for final fusion. Permeabilized cell exocytosis assay, dominant-negative mutants, point mutagenesis, Botulinum neurotoxin SNARE cleavage The Journal of biological chemistry High 14978027
2004 RalA interacts with the transcription factor ZONAB (ZO-1-associated nucleic acid-binding protein) in a GTP-dependent manner; this interaction increases with epithelial cell density; RalA-ZONAB interaction relieves transcriptional repression by ZONAB; oncogenic Ras alleviates ZONAB repression in a RalA-dependent manner. Reverse Ras recruitment yeast two-hybrid, co-immunoprecipitation, reporter gene assay, dominant-negative expression The EMBO journal Medium 15592429
2004 Crystal structures of RalA-GppNHp and RalA-GDP were solved; structural analysis identified two surface sites for protein-protein interaction: one adjacent to switch I and one modulated by switch II (obstructed in GDP state); disordered switch regions observed in one asymmetric unit molecule. X-ray crystallography Structure High 15530367
2004 Ral, RalGDS, and PLD2 are constitutively associated with class I metabotropic glutamate receptors (mGluR1a, mGluR5a) and regulate their constitutive endocytosis; Ral and PLD2 colocalize with mGluRs in endocytic vesicles; RalBP1, PLD1, ARF1, and ARF6 are not required for this process. Co-immunoprecipitation, dominant-negative mutants, siRNA knockdown, colocalization by immunofluorescence, 1-butanol PLD inhibition The Journal of neuroscience Medium 15470141
2005 Crystal structure of the Ral-binding domain of Exo84 in complex with active RalA reveals that the Exo84 RBD adopts a pleckstrin homology domain fold; RalA interacts with Exo84 via both switch regions; Exo84 and Sec5 competitively bind to active RalA at overlapping sites. X-ray crystallography, mutagenesis binding studies, competitive binding biochemistry The EMBO journal High 15920473
2006 RalA (but not RalB) is required for anchorage-independent growth and tumorigenesis of pancreatic cancer cells; RalB is required for invasion and metastasis; both GTPases are more commonly activated in pancreatic tumor tissue. siRNA knockdown in panel of 10 cell lines, soft agar growth assay, tail-vein injection metastasis assay Current biology High 17174914
2007 RalA is activated by insulin in a PI3K-dependent manner; RalA is present in Glut4 vesicles, interacts with the exocyst complex, and is required for insulin-stimulated Glut4 translocation to the plasma membrane; RalA also interacts with the motor protein Myo1c, modulated by Calmodulin. Co-immunoprecipitation, dominant-negative/siRNA knockdown, Glut4 translocation assay, glucose uptake assay Developmental cell High 17765682
2008 RalA and RalB support distinct, non-overlapping steps of cytokinesis through the exocyst: RalA tethers the exocyst to the cytokinetic furrow in early cytokinesis, while RalB recruits the exocyst to the midbody for abscission; discrete RalGEF pairs specify each GTPase's subcellular compartmentalization. siRNA knockdown, live imaging, immunofluorescence localization, epistasis analysis The EMBO journal High 18756269
2008 Ral GTPases control localization of the exocyst to focal complexes during cell migration via Ral-regulated interaction between exocyst subunit Sec5 and paxillin; RNAi knockdown of either RalA or RalB altered exocyst localization, reduced integrin delivery to plasma membrane, and impaired tumor cell motility. RNAi knockdown, co-immunoprecipitation, confocal localization, integrin trafficking assay, motility assay Journal of cell science Medium 18697830
2009 Aurora A phosphorylates RalA at Ser194, promoting RalA activation, translocation from the plasma membrane to mitochondria and other compartments, and activation of the effector protein RalBP1; this Aurora A-RalA axis contributes to oncogenic transformation. In vitro kinase assay, phosphorylation site mutagenesis (S194), subcellular fractionation, transformation assay Molecular and cellular biology High 19901077
2009 RalA and the exocyst complex regulate neuronal polarity: RalA depletion or constitutively active RalA inhibit axon formation; constitutively active RalA that cannot interact with the exocyst has no effect on polarity; RalA-dependent association of exocyst with PAR-3 occurs during early polarization. siRNA knockdown, constitutively active/exocyst-binding mutant overexpression, co-immunoprecipitation, immunofluorescence in cultured neurons Journal of cell science Medium 19383721
2009 M-Sec induces membrane nanotube (TNT) formation by interacting with Ral GTPases and the exocyst complex (a downstream Ral effector); blockage of M-Sec interaction with Ral or the exocyst attenuates nanotube formation; M-Sec depletion reduces intercellular calcium flux propagation. Co-immunoprecipitation, RNAi knockdown, dominant-negative mutants, live imaging of TNT formation Nature cell biology High 19935652
2009 NMDAR activation stimulates RalA, which translocates RalBP1 to synapses; NMDAR activation also dephosphorylates RalBP1, promoting its interaction with PSD-95; both regulated interactions are required for NMDAR-dependent AMPA receptor endocytosis and LTD; basal RalA maintains surface AMPARs. Co-immunoprecipitation, dominant-negative mutants, AMPAR endocytosis assay, LTD electrophysiology PLoS biology High 19823667
2009 RalA mediates integrin-dependent membrane raft exocytosis through the exocyst complex; constitutively active RalA restores membrane raft targeting to promote anchorage-independent growth signaling; Ras-transformed pancreatic cancer cells show RalA-dependent constitutive PM raft targeting. Dominant-negative/constitutively active mutant overexpression, membrane fractionation, siRNA knockdown, lipid raft trafficking assay Current biology Medium 20005108
2010 A Ral GAP complex (RGC1/RGC2 heterodimer) directly stimulates GTP hydrolysis of RalA; insulin inhibits this GAP complex through Akt2-catalyzed phosphorylation of RGC2, linking PI3K/Akt signaling to RalA activation for GLUT4 translocation in adipocytes. In vitro GAP assay, in vitro kinase assay with Akt2, siRNA knockdown, glucose uptake assay Molecular biology of the cell High 21148297
2011 Aurora A phosphorylates RalA at Ser194, relocalizing it to mitochondria where it concentrates RalBP1 and DRP1; RALBP1 associates with cyclin B-CDK1 kinase activity that phosphorylates DRP1 on Ser616, driving mitochondrial fission at mitosis; loss of RALA or RALBP1 causes defective mitochondrial segregation and reduced ATP. In vitro phosphorylation assay, phosphorylation site mutagenesis, subcellular fractionation/immunofluorescence, siRNA knockdown, mitochondrial fission assay Nature cell biology High 21822277
2013 RalA (via the exocyst) promotes activity-dependent growth of postsynaptic membranes (SSR) in Drosophila; Ca2+ influx from synaptic activity activates Ral and recruits exocyst proteins to postsynaptic zones; constitutively active RalA in mammalian hippocampal neurons increases dendritic spine density in an exocyst-dependent manner. Constitutively active mutant expression, genetic epistasis (sec5 null), immunofluorescence, spine density analysis The EMBO journal High 23812009
2013 RalA promotes neuronal polarity in postnatal neural progenitors by facilitating direct binding between exocyst subunit Exo84 and the PDZ domain of Par6; blocking the Exo84-Par6 interaction impairs polarized migration of neural progenitors in vivo. Co-immunoprecipitation, in vivo postnatal electroporation, conditional genetic ablation, dominant-negative mutants Journal of cell science Medium 24284074
2013 RALA is activated by the exchange factor RLF following increased ROS; active RALA regulates assembly and activation of a MLK3-MKK4-JNK signaling module on the JIP1 scaffold, leading to JNK-mediated FOXO activation; this pathway is conserved in C. elegans (ral-1/jip-1 regulate DAF-16 nuclear translocation). Co-immunoprecipitation, kinase assay, dominant-negative mutants, RNAi in C. elegans, nuclear translocation assay The Journal of biological chemistry Medium 23770673
2014 RalGAP suppression activates RalB selectively (not RalA) and leads to Sec5- and exocyst-dependent engagement of mTORC1 and suppression of autophagy; Tsc1-Tsc2 loss activates RalA/B independently of Rheb-mTOR signaling, revealing crosstalk between Ral and mTOR networks. RNAi knockdown, epistasis analysis, mTORC1 activity assay, autophagy assay, C. elegans lifespan assay Molecular cell Medium 24389102
2014 Small molecules (RBC6, RBC8, RBC10, BQU57) were identified by structure-based virtual screening that bind to a site on GDP-bound RalA/B, inhibit Ral-RALBP1 interaction, inhibit Ral-mediated cell spreading and anchorage-independent growth, and inhibit tumor xenograft growth; BQU57 binding to RalB confirmed by ITC, SPR, and NMR. Virtual screening, ITC, SPR, TROSY-NMR, cell spreading assay, soft agar growth assay, xenograft tumor model Nature High 25219851
2014 In adipocytes, Rab10 is a GAP target of AS160/TBC1D4; once activated, Rab10 recruits the RalGEF Rlf/Rgl2 to Glut4-storage vesicle membranes, thereby activating RalA; RalA is downstream of Rab10 in insulin-stimulated Glut4 trafficking. Dominant-negative/constitutively active mutants, co-immunoprecipitation, siRNA knockdown, Glut4 translocation assay, membrane tethering rescue experiment Molecular biology of the cell Medium 25103239
2015 TD-60/RCC2 exhibits GEF activity for RalA in vitro and in cells; TD-60 or RalA depletion causes spindle abnormalities and abnormal centromeric CPC accumulation; mitotic phenotypes caused by TD-60 depletion are reverted by GTP-locked RalA (Q72L), demonstrating that TD-60 acts through RalA to regulate kinetochore-microtubule interactions. In vitro GEF activity assay, siRNA knockdown, RalA activation assay, immunofluorescence, rescue by constitutively active mutant Nature communications High 26158537
2015 RAL-1 (C. elegans RalA ortholog) localizes to the surface of secretory multivesicular bodies (MVBs); RAL-1 is required for MVB formation and MVB fusion with the plasma membrane; these functions do not require the exocyst complex; the t-SNARE SYX-5 colocalizes with constitutively active RAL-1 at the plasma membrane; mammalian RalA and RalB are both required for exosome secretion. Quantitative electron microscopy, RNAi knockdown, GFP-tagged protein localization, mammalian cell siRNA knockdown, exosome secretion assay The Journal of cell biology High 26459596
2016 Albumin stimulates RalA activation in endothelial cells; RalA knockdown abolishes BSA uptake; albumin induces association between RalA, caveolin-1, and filamin A; RalA activates PLD2, generating phosphatidic acid that facilitates caveolae-mediated endocytosis and transcytosis; RalA does not affect FilA-Cav1 complex formation. siRNA knockdown, co-immunoprecipitation, fluorescent BSA uptake assay, PA biosensor (GFP-PASS), TIRF microscopy, PLD2 inhibition The Journal of biological chemistry Medium 27510034
2018 RalA controls glucose uptake in brown adipose tissue in vivo; RalA is activated after feeding in brown adipose tissue; inhibition of RalA prevents Glut4 exocytosis; adipocyte-specific knockout of RalGAPB increases RalA activity and glucose uptake, protecting from metabolic disease. Conditional/tissue-specific knockout mice, pharmacological inhibition, Glut4 exocytosis assay, glucose tolerance test Proceedings of the National Academy of Sciences of the United States of America High 29915037
2019 RALA and RALB are required for efficient internalization of Wnt receptor Frizzled-7 in intestinal stem cells (ISCs); genetic deletion of Rala or Ralb reduces ISC function and Lgr5 positivity and impairs tissue regeneration; ablation of both genes causes rapid crypt death. Conditional genetic deletion (mouse and Drosophila), Frizzled-7 internalization assay, intestinal organoid assay, in vivo regeneration assay Cell stem cell High 30853556
2021 RalA and RalB control biogenesis and secretion of pro-metastatic extracellular vesicles (EVs) through phospholipase D1 regulation of MVB homeostasis; RalA/B depletion reduces EV levels of the adhesion molecule MCAM/CD146, which controls EV organotropism to the lungs. siRNA knockdown in mouse models, EV characterization, in vivo EV organotropism assay, co-immunoprecipitation, proteomics eLife Medium 33404012
2024 In white adipocytes, high-fat diet increases RalA expression and activity; activated RalA promotes mitochondrial fission by reversing inhibitory Ser637 phosphorylation of Drp1; targeted deletion of RalA in white adipocytes prevents mitochondrial fragmentation and reduces HFD-induced weight gain by increasing fatty acid oxidation. Adipocyte-specific conditional knockout mice, mitochondrial morphology imaging, Drp1 phosphorylation assay (western blot), fatty acid oxidation assay, 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 359 10051605
2009 M-Sec promotes membrane nanotube formation by interacting with Ral and the exocyst complex. Nature cell biology 330 19935652
2011 RALA and RALBP1 regulate mitochondrial fission at mitosis. Nature cell biology 306 21822277
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1998 All in the family? New insights and questions regarding interconnectivity of Ras, Rap1 and Ral. The EMBO journal 280 9843482
1995 Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases. Molecular and cellular biology 273 7623849
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
1999 Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors. The EMBO journal 199 10393179
2006 Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Current biology : CB 192 17174914
2015 RAL-1 controls multivesicular body biogenesis and exosome secretion. The Journal of cell biology 177 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 172 17765682
2000 RLIP76, an effector of the GTPase Ral, interacts with the AP2 complex: involvement of the Ral pathway in receptor endocytosis. Journal of cell science 152 10910768
2006 The metastasis-associated gene CD24 is regulated by Ral GTPase and is a mediator of cell proliferation and survival in human cancer. Cancer research 132 16488989
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2005 Exo84 and Sec5 are competitive regulatory Sec6/8 effectors to the RalA GTPase. The EMBO journal 123 15920473
2024 Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation. Nature metabolism 119 38286821
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
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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
2014 Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion. Molecular cell 99 24389102
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 95 33404012
2014 RalR (a DNase) and RalA (a small RNA) form a type I toxin-antitoxin system in Escherichia coli. Nucleic acids research 95 24748661
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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 Involvement of Ras and Ral in chemotactic migration of skeletal myoblasts. Molecular and cellular biology 86 10848592
2010 A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action. Molecular biology of the cell 85 21148297
2004 RalA interacts with ZONAB in a cell density-dependent manner and regulates its transcriptional activity. The EMBO journal 85 15592429
2000 Ral GTPases contribute to regulation of cyclin D1 through activation of NF-kappaB. Molecular and cellular biology 84 11027278
2014 Ral small GTPase signaling and oncogenesis: More than just 15minutes of fame. Biochimica et biophysica acta 83 25219551
2008 Ral-regulated interaction between Sec5 and paxillin targets Exocyst to focal complexes during cell migration. Journal of cell science 81 18697830
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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
1999 Differential roles of Akt, Rac, and Ral in R-Ras-mediated cellular transformation, adhesion, and survival. Molecular and cellular biology 76 10454580
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2004 Ral and phospholipase D2-dependent pathway for constitutive metabotropic glutamate receptor endocytosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 72 15470141
1999 RalA requirement for v-Src- and v-Ras-induced tumorigenicity and overproduction of urokinase-type plasminogen activator: involvement of metalloproteases. Oncogene 70 10467419
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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
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2012 Genetic deletion of RALA and RALB small GTPases reveals redundant functions in development and tumorigenesis. Current biology : CB 65 23063435
2009 RalA and the exocyst complex influence neuronal polarity through PAR-3 and aPKC. Journal of cell science 65 19383721
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2002 Ral-GTPase influences the regulation of the readily releasable pool of synaptic vesicles. Molecular and cellular biology 65 11865051
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
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
2002 PDK1 mediates growth factor-induced Ral-GEF activation by a kinase-independent mechanism. The EMBO journal 59 11889038
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2016 Dissolving microneedles for DNA vaccination: Improving functionality via polymer characterization and RALA complexation. Human vaccines & immunotherapeutics 54 27846370
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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
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