Affinage

RALBP1

RalA-binding protein 1 · UniProt Q15311

Length
655 aa
Mass
76.1 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 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

RALBP1 (RLIP76) is a multifunctional Ral effector that couples Ras-family GTPase signaling to membrane transport, endocytosis, and cytoskeletal remodeling (PMID:7673236, PMID:20696399). It binds activated RalA/RalB through a coiled-coil Ral-binding domain that contacts both nucleotide-sensitive switch regions, competing with the Sec5 and Exo84 exocyst effectors for Ral occupancy (PMID:20696399, PMID:33214225), and its juxtaposed RhoGAP domain inactivates Rac1 and CDC42 but not RhoA (PMID:7673236, PMID:21915608). Independently of its Ral-binding and GAP functions, RLIP76 is a non-ABC ATP-dependent transporter built from two ATP-binding sites and a membrane-anchoring domain that exports glutathione-electrophile conjugates (GS-HNE, LTC4, DNP-SG) and xenobiotics including doxorubicin; reconstitution requires intact N- and C-terminal ATPase fragments, and this activity is the predominant glutathione-conjugate efflux route in human erythrocytes (PMID:10924126, PMID:11300797, PMID:11437348, PMID:15610018). This transport activity underlies acquired oxidative-stress resistance, drug resistance, and is mechanistically required for clathrin-dependent endocytosis and downstream EGF receptor signaling, with RLIP76-null mice resistant to chemical carcinogenesis (PMID:11522795, PMID:21220488). RLIP76 also functions as a scaffold: as a GTP-dependent effector of R-Ras it recruits the Arf6 GEF ARNO to Rab11 recycling endosomes to activate Arf6 and Rac1, driving cell spreading and migration (PMID:16966426, PMID:25450693, PMID:26498519); in neurons it is recruited to synapses by RalA and binds PSD-95 to drive NMDAR-dependent AMPA receptor endocytosis during long-term depression (PMID:19823667); and at mitosis it is recruited with DRP1 to mitochondria where associated cyclin B–CDK1 phosphorylates DRP1-Ser616 to drive mitochondrial fission (PMID:21822277). Through these activities RLIP76 supports tumor proliferation, invadopodium formation, angiogenesis, and HIF-1-driven glycolysis (PMID:22331470, PMID:22902412, PMID:24928198, PMID:35998001). Its transport activity is regulated by PKCα phosphorylation and is directly inhibited by p53 (PMID:16087181, PMID:21411502).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1995 High

    Established RALBP1 as a direct effector of activated RalA that also carries Rho-family GAP activity, defining it as a node linking Ral and Rho signaling.

    Evidence Two-hybrid screen with purified-protein GAP assays against Rac1, CDC42, and RhoA

    PMID:7673236

    Open questions at the time
    • Cellular consequences of Rac1/CDC42 inactivation not defined
    • Did not address any transport or scaffolding function
  2. 2000 High

    Revealed that RLIP76 is identical to the DNP-SG ATPase and is an ATP-dependent transporter of glutathione conjugates and doxorubicin, a function entirely separate from its Ral effector role.

    Evidence cDNA cloning, recombinant purification, proteoliposome reconstitution transport assays, and drug-resistance transfection in K562 cells

    PMID:10924126

    Open questions at the time
    • Structural basis of substrate recognition unknown
    • Relationship between transport and Ral binding undefined
  3. 2000 High

    Connected the Ral–RLIP76 pathway to clathrin-mediated endocytosis by identifying the AP2 adaptor subunit Mu2 as a partner.

    Evidence Two-hybrid, endogenous Co-IP, and receptor endocytosis assays in HeLa cells expressing activated Ral

    PMID:10910768

    Open questions at the time
    • Did not show whether transport activity is required for endocytosis
    • Direct AP2-Mu2 interface not mapped
  4. 2001 High

    Defined the bipartite ATPase architecture (two ATP-binding sites) required for transport, showing reconstitution needs both N- and C-terminal fragments.

    Evidence Deletion mutagenesis, 8-azido-ATP photoaffinity labeling, and proteoliposome reconstitution of doxorubicin/colchicine transport

    PMID:11300797

    Open questions at the time
    • No atomic structure of the transport module
    • Stoichiometry of the functional transporter unresolved
  5. 2001 High

    Quantified RLIP76 as the dominant glutathione-conjugate/doxorubicin transporter in native erythrocyte membranes, distinguishing it from MRP1 and Pgp.

    Evidence Antibody immunotitration of transport in erythrocyte inside-out vesicles

    PMID:11437348

    Open questions at the time
    • Contribution in other tissues not quantified in this study
  6. 2001 High

    Demonstrated that RLIP76-mediated GS-HNE efflux is the mechanistic basis of stress-induced apoptosis resistance, linking the transporter to cellular stress adaptation.

    Evidence Stress-induced expression, GS-HNE efflux assays, and anti-RLIP76 surface-coating loss-of-function with apoptosis readouts across cell lines

    PMID:11522795

    Open questions at the time
    • Transcriptional control of stress induction not defined
  7. 2004 High

    Mapped the membrane-anchoring domain (residues 154–219) needed for membrane incorporation, surface expression, and transport.

    Evidence Deletion mutagenesis, partitioning assays, reconstitution, and confocal colocalization with HER2/Neu

    PMID:15610018

    Open questions at the time
    • Topology of membrane insertion not resolved
  8. 2005 High

    Identified PKCα phosphorylation at T297/S509 as a positive regulator of transport activity, providing a signaling input to drug efflux.

    Evidence In vitro PKCα phosphorylation, site mutagenesis, and transport assays comparing NSCLC vs SCLC RLIP76

    PMID:15386349 PMID:16087181

    Open questions at the time
    • In vivo phosphorylation stoichiometry not measured
    • Structural effect of phosphorylation on transport unknown
  9. 2006 High

    Established RLIP76 as a GTP-dependent R-Ras effector required for adhesion-induced Rac and Arf6 activation, driving cell spreading and migration.

    Evidence GTP-dependent pulldowns, siRNA knockdown with spreading/migration assays, and Arf6 rescue epistasis

    PMID:16966426

    Open questions at the time
    • Mechanism linking RLIP76 to Arf6 activation not yet molecular
  10. 2009 High

    Defined a neuronal role: RalA-driven synaptic recruitment and dephosphorylation-dependent PSD-95 binding control AMPAR endocytosis during LTD.

    Evidence Co-IP, dephosphorylation-binding assays, siRNA rescue, and LTD electrophysiology

    PMID:19823667

    Open questions at the time
    • Phosphatase responsible for dephosphorylation not identified
    • Link to the transport/endocytosis machinery not resolved
  11. 2010 High

    Solved the Ral-binding domain structure, showing a coiled-coil that engages both RalB switch regions and competes with exocyst effectors.

    Evidence NMR/X-ray structures of RBD and RBD–RalB complex with interface mutagenesis and affinity measurements

    PMID:20696399 PMID:21915608

    Open questions at the time
    • Functional consequences of effector competition in cells not quantified
  12. 2011 High

    Demonstrated that GS-E transport activity is mechanistically required for clathrin-dependent endocytosis and EGF signaling, and that RLIP76 loss confers carcinogenesis resistance in vivo.

    Evidence Mutant rescue in RLIP76(-/-) MEFs, CDE assays, EGF signaling blots, and chemical carcinogenesis in knockout mice

    PMID:21220488

    Open questions at the time
    • Molecular link between glutathione-conjugate flux and clathrin machinery unresolved
  13. 2011 High

    Defined the mitotic mitochondrial-fission axis in which Aurora A–phosphorylated RalA recruits RLIP76 and DRP1, with associated cyclin B–CDK1 phosphorylating DRP1-Ser616.

    Evidence Phospho-specific antibodies, mitochondrial fractionation, live imaging, CDK1 kinase co-purification, and siRNA epistasis

    PMID:21822277

    Open questions at the time
    • How RLIP76 physically tethers cyclin B–CDK1 to DRP1 not defined
  14. 2012 High

    Separated RLIP76 functions in cancer, showing its ATPase (not GAP) activity drives RalB-dependent invadopodium formation and tumor angiogenesis.

    Evidence Domain-specific rescue in PDAC invadopodium assays and RLIP76(-/-) mouse tumor vasculature with isolated endothelial cell assays

    PMID:22331470 PMID:22902412

    Open questions at the time
    • Transport substrate relevant to invadopodia/angiogenesis not identified
  15. 2014 Medium

    Identified ARNO (cytohesin-2) as an N-terminal partner and dissected phosphosite-controlled steps for Arf6 versus Rac1 activation in spreading and migration.

    Evidence Domain mapping, point mutation (Ser29/30, Ser62), Co-IP, and GTPase activation/cell motility assays

    PMID:25450693

    Open questions at the time
    • Single lab
    • Kinases controlling these serines not identified
  16. 2015 Medium

    Showed RLIP76 acts as a recycling-endosome scaffold bridging activated R-Ras and ARNO to localize Arf6 activation, integrating earlier transport and migration findings.

    Evidence Co-IP, domain mapping, Rab11 colocalization, and Arf6/migration rescue assays

    PMID:26498519

    Open questions at the time
    • Single lab
    • Relationship to the transport-dependent endocytosis role not reconciled
  17. 2022 Medium

    Linked RLIP76 to hypoxic metabolism by showing it directly binds and stabilizes HIF-1α to activate GLUT1/LDHA and promote glioma glycolysis.

    Evidence Co-IP, ubiquitination assays, siRNA with GLUT1/LDHA blots, and xenografts

    PMID:35998001

    Open questions at the time
    • Single lab
    • Mechanism by which RLIP76 blocks HIF-1α ubiquitination unresolved
    • Apparent tension with earlier report that RLIP76 does not affect HIF-1α expression/localization (24928198) not reconciled
  18. 2023 Medium

    Revealed a non-effector GTPase-regulatory mode in which a Reps1–Ralbp1 complex selectively stabilizes GTP-bound RalA on exocytic vesicles to promote surface protein delivery.

    Evidence Co-IP, GTP-dependent binding, surface protein measurements, and exocyst epistasis

    PMID:36812304

    Open questions at the time
    • Single study
    • Structural basis of GTP-state stabilization unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RLIP76's distinct activities — glutathione-conjugate transport, RhoGAP, Ral/R-Ras effector scaffolding, and GTP-state stabilization — are spatially and temporally coordinated within a single protein remains unresolved.
  • No full-length structure integrating transport, GAP, and Ral-binding modules
  • Mechanistic link between glutathione-conjugate flux and clathrin endocytosis unexplained
  • Physiological hierarchy among transport vs scaffold functions in vivo undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140657 ATP-dependent activity 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005768 endosome 2 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005739 mitochondrion 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-382551 Transport of small molecules 3 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-112316 Neuronal System 1 R-HSA-1640170 Cell Cycle 1
Partners
ARNOPSD95RALARALBREPS1REPS2RRASTP53

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 RLIP76 (RLIP1) was identified as a direct effector of activated RalA via its effector domain; it also contains a RhoGAP domain that displays GAP activity toward Rac1 and CDC42 but not RhoA, and this GAP region is not required for RalA binding. Two-hybrid screen, purified protein biochemical GAP assay, binding studies with purified RalA The Journal of biological chemistry High 7673236
2000 RLIP76 is identical to the previously characterized DNP-SG ATPase and catalyzes ATP-dependent transport of glutathione conjugates (GS-HNE, LTC4, DNP-SG) and doxorubicin when reconstituted into proteoliposomes; it has inherent ATPase activity stimulated by these substrates; transfection into K562 cells confers doxorubicin resistance. cDNA cloning and sequencing; E. coli expression and purification; ATPase assays; proteoliposome reconstitution transport assays; cell transfection with drug resistance/efflux readout Biochemistry High 10924126
2000 RLIP76 interacts with Mu2, the medium chain of the AP2 clathrin adaptor complex, both in vitro and in vivo as an endogenous complex; activated Ral interferes with transferrin receptor and EGF receptor endocytosis in HeLa cells, linking the Ral-RLIP76 pathway to clathrin-mediated endocytosis. Two-hybrid assay; co-immunoprecipitation of endogenous proteins; receptor endocytosis assay in cells expressing activated Ral Journal of cell science High 10910768
1997 RalBP1 binds a novel ~85 kDa EH-domain protein, Reps1, at a site distinct from the Ral-binding site; Reps1 is tyrosine-phosphorylated in response to EGF and can associate with SH3 domains of Crk and Grb2. Two-hybrid cloning; in-cell EGF stimulation/phosphorylation assay; SH3 domain binding assay The Journal of biological chemistry Medium 9395447
2001 RLIP76 has two ATP-binding sites: (69)GKKKGK(74) in the N-terminal fragment and (418)GGIKDLSK(425) in the C-terminal fragment; mutation of K74 or K425 to Met abrogates ATPase activity and ATP binding; transport of doxorubicin and colchicine can be reconstituted by co-mixing N- and C-terminal fragments but not by either alone or by the ATPase-dead mutants. Deletion mutagenesis; photoaffinity labeling with 8-azido-ATP; ATPase assays; proteoliposome reconstitution transport assays Biochemistry High 11300797
2001 RLIP76 is the predominant ATP-dependent transporter of glutathione conjugates (GS-HNE, LTC4, DNP-SG) and doxorubicin in human erythrocytes; anti-RLIP76 antibodies inhibit ~70% of transport in inside-out vesicles, whereas anti-MRP1 or anti-Pgp antibodies have no effect. Western blot; immunohistochemistry; antibody-mediated inhibition of transport in erythrocyte inside-out vesicles Archives of biochemistry and biophysics High 11437348
2001 Mild oxidative or heat stress induces RLIP76 expression in K562 and multiple other cell lines, leading to increased GS-HNE efflux; cells pre-conditioned with stress acquire resistance to 4-HNE- and H2O2-mediated apoptosis; coating cells with anti-RLIP76 IgG (blocking GS-HNE efflux) abrogates this protection, demonstrating that RLIP76-mediated GS-HNE transport is the mechanistic basis of acquired stress resistance. Western blot (induction); GS-HNE efflux assay; cell surface antibody coating; apoptosis/caspase-3 and JNK activation assays The Journal of biological chemistry High 11522795
2004 Amino acids 154–219, and specifically the segment 171–185, constitute the membrane-anchoring domain of RLIP76; deletion of this region reduces hydrophobicity, membrane incorporation into liposomes, and transport activity toward doxorubicin and DNP-SG; the region co-localizes with HER2/Neu at the cell surface and is necessary for surface expression. Deletion mutagenesis; detergent/aqueous partitioning assay; proteoliposome reconstitution; confocal immunohistochemistry; siRNA depletion of endogenous RLIP76 in transfected cells Biochemistry High 15610018
2005 PKCα phosphorylates RLIP76 at T297 and S509; phosphorylation at T297 increases doxorubicin transport activity approximately 2-fold and confers sensitivity to tryptic cleavage at R293; RLIP76 from NSCLC (primarily phosphorylated) has ~2-fold higher specific activity for doxorubicin transport than SCLC RLIP76. Deletion mutant analysis; in vitro PKCα phosphorylation; transport activity assays with purified RLIP76 from cell lines; tryptic digest analysis FEBS letters High 16087181
2004 PKCα phosphorylates RLIP76 and increases its LTC4 transport activity 2–3-fold; proteoliposomes reconstituted with RLIP76 catalyze ATP-dependent LTC4 transport (Km ATP ~5.1 mM; Km LTC4 ~210 nM; Vmax ~3.2 nmol/min/mg); anti-RLIP76 antibodies inhibit 67–81% of LTC4 transport in cancer cell membrane vesicles. In vitro PKCα phosphorylation; proteoliposome reconstitution transport assays; antibody immunotitration of transport in cell membrane vesicles International journal of cancer High 15386349
2006 RLIP76 is a direct effector of R-Ras (binds R-Ras in a GTP-dependent manner) but does not associate with H-Ras or Rap1A; RLIP76 is required for adhesion-induced Rac activation and resulting cell spreading and migration; RLIP76 mediates these effects through adhesion-induced Arf6 GTPase activation, and activated Arf6 can bypass the requirement for RLIP76. GTP-dependent pulldown/binding assay; siRNA knockdown with cell spreading and migration assays; epistasis by Arf6 activation rescue The Journal of cell biology High 16966426
2008 HSF-1 causes specific, saturable inhibition of RLIP76 transport activity; combined HSF-1 and POB1 binding causes nearly complete inhibition; RLIP76 sequesters HSF-1 in the cellular cytoskeleton, and membrane-bound RLIP76 activity is inhibited by HSF-1. In vitro transport inhibition assays with purified proteins; over-expression of HSF-1/POB1 with apoptosis readout in lung cancer cells The Journal of biological chemistry Medium 18474607
2005 POB1 (REPS2) directly inhibits RLIP76-mediated doxorubicin and DNP-SG transport in a concentration-dependent manner through direct binding to RLIP76; a POB1 deletion mutant lacking the RLIP76-binding domain does not inhibit transport and does not cause apoptosis upon liposomal delivery to cancer cells. Purified protein transport inhibition assay; liposomal delivery of POB1 with apoptosis and drug efflux readouts; deletion mutant analysis Biochemical and biophysical research communications Medium 15707977
2009 Cdc2 (CDK1) directly inhibits RLIP76-mediated transport of doxorubicin and DNP-SG in a concentration-dependent manner in reconstituted proteoliposomes; liposomal delivery of cdc2 to H358 cells increases intracellular doxorubicin accumulation and induces apoptosis. Purified protein transport inhibition assay in reconstituted liposomes; liposomal cdc2 delivery with intracellular drug accumulation and apoptosis assays Cancer letters Medium 19375851
2009 RalBP1 is translocated to synapses upon NMDA receptor activation via stimulation of RalA; NMDAR activation also dephosphorylates RalBP1, promoting its interaction with the postsynaptic scaffolding protein PSD-95; both the RalA interaction and the PSD-95 interaction are required for NMDAR-dependent AMPA receptor endocytosis and LTD, and together they are sufficient to induce AMPAR endocytosis in the absence of NMDAR activation. Co-immunoprecipitation; NMDAR activation/dephosphorylation assays; siRNA knockdown with AMPAR endocytosis and LTD electrophysiology readouts; rescue experiments PLoS biology High 19823667
2010 The Ral-binding domain (RBD) of RLIP76 forms a coiled-coil motif; the RBD-RalB complex structure reveals that RLIP76 contacts both nucleotide-sensitive switch regions of RalB; RLIP76 competes with Sec5 and Exo84 exocyst components for Ral binding with similar affinities in vitro. NMR structure determination of RBD alone; X-ray/NMR co-structure of RBD–RalB complex; mutagenesis of RalB interface residues with affinity measurements Structure High 20696399
2011 Aurora A phosphorylates RALA at Ser194 during mitosis, relocalizing RALA to mitochondria where it concentrates RALBP1 and DRP1; RALBP1 is associated with cyclin B–CDK1 kinase activity that phosphorylates DRP1 Ser616; disrupting RALA or RALBP1 abolishes mitochondrial fission at mitosis, causes improper mitochondrial segregation, and reduces ATP levels. Phospho-specific antibodies; mitochondrial fractionation; siRNA knockdown with live imaging and mitochondrial fission/DRP1 localization readouts; CDK1 kinase activity co-purification assay Nature cell biology High 21822277
2011 RLIP76-mediated glutathione-conjugate (GS-E) transport is required for clathrin-dependent endocytosis (CDE); RLIP76 mutants deficient in GS-E binding fail to rescue CDE in RLIP76(-/-) MEFs; RLIP76 depletion blocks downstream EGF signaling in a CDE-dependent manner; RLIP76(-/-) mice are resistant to chemical carcinogenesis (benzo[a]pyrene, DMBA, phorbol esters), and this resistance can be restored by topical RLIP76 protein application. RLIP76 mutant analysis in knockout MEFs; CDE assay; EGF signaling Western blots; in vivo chemical carcinogenesis in RLIP76(-/-) mice Molecular cancer therapeutics High 21220488
2012 RalB-dependent invadopodium formation in PDAC cells requires RalBP1/RLIP76 but not the Sec5/Exo84 exocyst effectors; the requirement for RalBP1 is independent of its RhoGAP activity but depends on its ATPase function, identifying a novel RalB→RalBP1(ATPase) signaling axis for invadopodium formation. siRNA knockdown of Ral effectors; invadopodium formation assay; RalBP1 domain-specific rescue (ATPase mutant vs GAP mutant) Molecular and cellular biology High 22331470
2012 RLIP76 is required for angiogenesis and neovascularization of solid tumors; in RLIP76(-/-) mice tumor vascular volumes are diminished, vessels are fewer, shorter and narrower; endothelial cells from RLIP76(-/-) mice show defects in migration, proliferation, and cord formation in vitro. RLIP76(-/-) mouse tumor implantation; X-ray microcomputed tomography of tumor vasculature; isolated endothelial cell functional assays (migration, proliferation, Matrigel cord formation) Cancer research High 22902412
2012 RalBP1 is detected in the nucleus of interphase cells via nuclear localization sequences in the N-terminal third of the protein; a C-terminal coiled-coil mediates nuclear retention in Xenopus embryos; RalBP1 localizes to the actin cytoskeleton in an active Ral-dependent manner; during mitosis it associates with the mitotic spindle and centrosome, a localization negatively regulated by active Ral. Immunolocalization of endogenous RalBP1; deletion mutant analysis; live imaging in Xenopus embryos; cell-cycle staging FASEB journal Medium 22319010
2011 RLIP76 in glioma cells promotes proliferation and suppresses apoptosis through a Rac1-JNK signaling mechanism; constitutively active Rac1 rescues the effects of RLIP76 siRNA; the ATPase function of RLIP76 (not its RhoGAP activity) modulates Rac1 protein levels by regulating Rac1 ubiquitylation and degradation. Stable siRNA knockdown; constitutively active Rac1 rescue; Western blot for Rac1 ubiquitylation; JNK signaling assays; xenograft model Carcinogenesis Medium 23276796
2014 RLIP76 N-terminus (residues 1–180) binds ARNO (cytohesin-2, an Arf6 GEF); Ser29/Ser30 mutation blocks ARNO interaction and prevents RLIP76-dependent Arf6 activation, PI3K activation, cell spreading, and migration; Ser62 mutation blocks Rac1 activation without affecting ARNO interaction or Arf6 activation, indicating a second step in the pathway. Domain deletion and point mutation analysis; Co-IP; Arf6 and Rac1 activation assays; cell spreading and migration assays Biochemical and biophysical research communications Medium 25450693
2015 RLIP76 acts as a scaffold at recycling endosomes (Rab11-positive) by binding activated R-Ras via residues 180–192 and ARNO via the N-terminal domain (residues 1–180); RLIP76 recruits ARNO to recycling endosomes to activate Arf6, thereby promoting cell spreading and migration. Co-IP; domain-deletion mutant analysis; Rab11 colocalization imaging; Arf6 activation assay; cell spreading/migration assays with rescue Biochemical and biophysical research communications Medium 26498519
2014 RLIP76 is required for HIF-1 transcriptional activity and VEGF expression/secretion in carcinoma and melanoma cells; RLIP76-depleted tumor conditioned medium cannot stimulate endothelial cell proliferation, migration, or Matrigel cord formation, and this is rescued by recombinant VEGF; RLIP76 is required for PI3-kinase activation that regulates HIF-1 activity, but does not affect HIF-1α expression or nuclear localization. siRNA knockdown; HIF-1 luciferase reporter assay; VEGF ELISA; conditioned medium transfer experiment with endothelial cell functional assays; PI3K activity assay FASEB journal Medium 24928198
2007 Mass spectrometry identified 14 phosphorylation sites in RalBP1; 10 of the first 100 N-terminal residues are phosphorylated (9 Ser, 1 Thr); overexpression of RalB produces the largest changes in phosphorylation at S463 and S645. Mass spectrometric phosphoprotein mapping in UMUC-3 and 293T cells; RalB overexpression with comparative phosphorylation analysis Biochemical and biophysical research communications Medium 17706599
2011 p53 forms a specific, saturable complex with RLIP76 (shown by co-immunoprecipitation and immunofluorescence colocalization); p53 inhibits both basal and PKCα-stimulated RLIP76-mediated transport of GS-HNE and doxorubicin; loss of p53 in neuroblastoma results in RLIP76 overexpression and enhanced transport activity. Co-immunoprecipitation of purified proteins; immunofluorescence colocalization; in vitro transport inhibition assay; comparison of p53-WT vs p53-mutant cell lines Cancer prevention research Medium 21411502
2006 PKCα-mediated mitogenesis requires RLIP76 as a downstream effector; RLIP76(-/-) MEFs are resistant to PKCα depletion-mediated growth inhibition and to the PKCα-dependent mitogen PMA; restoration of RLIP76 in RLIP76(-/-) MEFs rescues sensitivity to both effects. RLIP76(-/-) MEFs; PKCα depletion; PMA treatment; rescue with exogenous RLIP76 protein via liposomal delivery Biochemical and biophysical research communications Medium 16890208
2020 Affinity maturation of the RLIP76 Ral-binding domain identified substitutions that improve Ral binding >20-fold; two 1.5 Å co-crystal structures of tight-binding mutants with RalB defined key interface interactions; NMR confirmed the binding site of resulting stapled peptides on RalB; these peptides competed with multiple Ral-effector interactions in cellular lysates. Directed evolution/affinity maturation; X-ray co-crystallography (1.5 Å); NMR chemical shift mapping; competitive binding assays in cellular lysates The Journal of biological chemistry High 33214225
2023 Reps1 and Ralbp1 form a binary complex that recognizes vesicle-bound RalA in the exocytic pathway; RalA binding causes Reps1 release and formation of a Ralbp1–RalA binary complex; Ralbp1 selectively stabilizes GTP-bound RalA (GTP state stabilization), thereby promoting exocytosis and surface protein levels; this is distinct from classical effector function. Co-IP; GTP-dependent binding assays; surface protein level measurements; epistasis with exocyst complex Science advances Medium 36812304
2022 RLIP76 directly binds HIF-1α in the nucleus and stabilizes it by alleviating HIF-1α ubiquitination under hypoxia, thereby activating HIF-1α target glycolytic genes GLUT1 and LDHA to promote glioma glycolysis and tumor development. Co-immunoprecipitation of RLIP76 and HIF-1α; ubiquitination assay; siRNA knockdown with GLUT1/LDHA Western blots; in vivo xenograft Molecular neurobiology Medium 35998001
2011 RBD structure of RLIP76 reveals its coiled-coil binds both switch regions of RalB; the juxtaposed RhoGAP and RBD domains are held in fixed orientation by a rigid linker, allowing simultaneous engagement of Rho-family and Ral GTPases at the membrane. NMR resonance assignments; structural analysis of GAP-GBD di-domain Biomolecular NMR assignments Medium 21915608

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 RALA and RALBP1 regulate mitochondrial fission at mitosis. Nature cell biology 306 21822277
1995 Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. The Journal of biological chemistry 292 7673236
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
2001 Accelerated metabolism and exclusion of 4-hydroxynonenal through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative stress. The Journal of biological chemistry 151 11522795
2000 Novel function of human RLIP76: ATP-dependent transport of glutathione conjugates and doxorubicin. Biochemistry 137 10924126
1997 An Eps homology (EH) domain protein that binds to the Ral-GTPase target, RalBP1. The Journal of biological chemistry 106 9395447
2003 Transport of glutathione conjugates and chemotherapeutic drugs by RLIP76 (RALBP1): a novel link between G-protein and tyrosine kinase signaling and drug resistance. International journal of cancer 100 12866021
2007 Regression of lung and colon cancer xenografts by depleting or inhibiting RLIP76 (Ral-binding protein 1). Cancer research 95 17483352
2006 Regression of melanoma in a murine model by RLIP76 depletion. Cancer research 94 16489041
2005 RLIP76 is a major determinant of radiation sensitivity. Cancer research 83 16024601
2008 RLIP76 and Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 77 18628450
2005 RLIP76 transports vinorelbine and mediates drug resistance in non-small cell lung cancer. Cancer research 71 15705900
2001 Functional reassembly of ATP-dependent xenobiotic transport by the N- and C-terminal domains of RLIP76 and identification of ATP binding sequences. Biochemistry 65 11300797
2009 RLIP76: a target for kidney cancer therapy. Cancer research 64 19417134
2007 Autoantibodies to the C-terminal subunit of RLIP76 induce oxidative stress and endothelial cell apoptosis in immune-mediated vascular diseases and atherosclerosis. Blood 63 17993611
2006 RLIP76 (RalBP1) is an R-Ras effector that mediates adhesion-dependent Rac activation and cell migration. The Journal of cell biology 63 16966426
2002 RLIP76, a novel transporter catalyzing ATP-dependent efflux of xenobiotics. Drug metabolism and disposition: the biological fate of chemicals 63 12433796
2005 Depletion of RLIP76 sensitizes lung cancer cells to doxorubicin. Biochemical pharmacology 59 15950949
2011 Glutathione-conjugate transport by RLIP76 is required for clathrin-dependent endocytosis and chemical carcinogenesis. Molecular cancer therapeutics 58 21220488
2001 RLIP76 is the major ATP-dependent transporter of glutathione-conjugates and doxorubicin in human erythrocytes. Archives of biochemistry and biophysics 57 11437348
2012 The RalB small GTPase mediates formation of invadopodia through a GTPase-activating protein-independent function of the RalBP1/RLIP76 effector. Molecular and cellular biology 56 22331470
2008 Regression of prostate cancer xenografts by RLIP76 depletion. Biochemical pharmacology 56 19073149
2005 RLIP76, a non-ABC transporter, and drug resistance in epilepsy. BMC neuroscience 56 16188027
2003 Role of RLIP76 in lung cancer doxorubicin resistance: II. Doxorubicin transport in lung cancer by RLIP76. International journal of oncology 56 12632060
2011 Gender disparity in susceptibility to oxidative stress and apoptosis induced by autoantibodies specific to RLIP76 in vascular cells. Antioxidants & redox signaling 55 21671802
2010 RalBP1 is necessary for metastasis of human cancer cell lines. Neoplasia (New York, N.Y.) 54 21170262
2009 Regulated RalBP1 binding to RalA and PSD-95 controls AMPA receptor endocytosis and LTD. PLoS biology 54 19823667
2010 Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer. International journal of cancer 53 19626587
2012 RALBP1/RLIP76 depletion in mice suppresses tumor growth by inhibiting tumor neovascularization. Cancer research 51 22902412
2012 RLIP76 is overexpressed in human glioblastomas and is required for proliferation, tumorigenesis and suppression of apoptosis. Carcinogenesis 51 23276796
2008 Hsf-1 and POB1 induce drug sensitivity and apoptosis by inhibiting Ralbp1. The Journal of biological chemistry 51 18474607
2003 Role of RLIP76 in lung cancer doxorubicin resistance: III. Anti-RLIP76 antibodies trigger apoptosis in lung cancer cells and synergistically increase doxorubicin cytotoxicity. International journal of oncology 51 12632061
2008 RLIP76: A novel glutathione-conjugate and multi-drug transporter. Biochemical pharmacology 50 18983828
2003 Role of RLIP76 in lung cancer doxorubicin resistance: I. The ATPase activity of RLIP76 correlates with doxorubicin and 4-hydroxynonenal resistance in lung cancer cells. International journal of oncology 49 12527936
2008 RLIP76 in defense of radiation poisoning. International journal of radiation oncology, biology, physics 47 18793957
2004 Identification of membrane-anchoring domains of RLIP76 using deletion mutant analyses. Biochemistry 46 15610018
2005 POB1 over-expression inhibits RLIP76-mediated transport of glutathione-conjugates, drugs and promotes apoptosis. Biochemical and biophysical research communications 43 15707977
2007 The non-ABC drug transporter RLIP76 (RALBP-1) plays a major role in the mechanisms of drug resistance. Current drug metabolism 42 17504221
2011 RLIP76, a glutathione-conjugate transporter, plays a major role in the pathogenesis of metabolic syndrome. PloS one 40 21931813
2010 RLIP76: a versatile transporter and an emerging target for cancer therapy. Biochemical pharmacology 40 20097178
2013 Knockdown of RLIP76 expression by RNA interference inhibits invasion, induces cell cycle arrest, and increases chemosensitivity to the anticancer drug temozolomide in glioma cells. Journal of neuro-oncology 39 23292182
2004 RLIP76 (RALBP1)-mediated transport of leukotriene C4 (LTC4) in cancer cells: implications in drug resistance. International journal of cancer 39 15386349
2012 RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer. PloS one 37 22509328
2010 The RalB-RLIP76 complex reveals a novel mode of ral-effector interaction. Structure (London, England : 1993) 36 20696399
2007 Doxorubicin transport by RALBP1 and ABCG2 in lung and breast cancer. International journal of oncology 36 17273774
2015 RLIP76-dependent suppression of PI3K/AKT/Bcl-2 pathway by miR-101 induces apoptosis in prostate cancer. Biochemical and biophysical research communications 33 26067553
2005 The role of PKCalpha and RLIP76 in transport-mediated doxorubicin-resistance in lung cancer. FEBS letters 31 16087181
2016 Upregulation of miR-124 by physcion 8-O-β-glucopyranoside inhibits proliferation and invasion of malignant melanoma cells via repressing RLIP76. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 30 27657824
2014 RLIP76 regulates HIF-1 activity, VEGF expression and secretion in tumor cells, and secretome transactivation of endothelial cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 24928198
2009 Functional reconstitution of RLIP76 catalyzing ATP-dependent transport of glutathione-conjugates. International journal of oncology 24 19082490
2021 RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease. Cells 23 34831336
2002 Transport functions and physiological significance of 76 kDa Ral-binding GTPase activating protein (RLIP76). Acta biochimica Polonica 23 12545192
2017 miR-340 suppresses tumor growth and enhances chemosensitivity of colorectal cancer by targeting RLIP76. European review for medical and pharmacological sciences 22 28682430
2011 Targeting p53-null neuroblastomas through RLIP76. Cancer prevention research (Philadelphia, Pa.) 22 21411502
2009 Increased expression of cdc2 inhibits transport function of RLIP76 and promotes apoptosis. Cancer letters 22 19375851
2006 Mitogenic and drug-resistance mediating effects of PKCalpha require RLIP76. Biochemical and biophysical research communications 22 16890208
2002 Functional reconstitution of Ral-binding GTPase activating protein, RLIP76, in proteoliposomes catalyzing ATP-dependent transport of glutathione conjugate of 4-hydroxynonenal. Acta biochimica Polonica 22 12422239
2013 RLIP76 protein knockdown attenuates obesity due to a high-fat diet. The Journal of biological chemistry 21 23821548
2007 Lack of support for a role for RLIP76 (RALBP1) in response to treatment or predisposition to epilepsy. Epilepsia 21 17437410
2018 2'-Hydroxyflavanone inhibits in vitro and in vivo growth of breast cancer cells by targeting RLIP76. Molecular carcinogenesis 20 30136444
2008 Diminished drug transport and augmented radiation sensitivity caused by loss of RLIP76. FEBS letters 20 18789326
2019 RALBP1 regulates oral cancer cells via Akt and is a novel target of miR-148a-3p and miR-148b-3p. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 19 31336396
2016 Pharmacogenetics of ABCB5, ABCC5 and RLIP76 and doxorubicin pharmacokinetics in Asian breast cancer patients. The pharmacogenomics journal 19 26975227
2014 The RLIP76 N-terminus binds ARNO to regulate PI 3-kinase, Arf6 and Rac signaling, cell spreading and migration. Biochemical and biophysical research communications 19 25450693
2012 Dynamics of the subcellular localization of RalBP1/RLIP through the cell cycle: the role of targeting signals and of protein-protein interactions. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 22319010
2018 2'-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer. Oncotarget 18 29719590
2001 Purification and functional reconstitution of intact ral-binding Gtpase activating protein, RLIP76, in artificial liposomes. Acta biochimica Polonica 18 11732624
2017 RalBP1 and p19-VHL play an oncogenic role, and p30-VHL plays a tumor suppressor role during the blebbishield emergency program. Cell death discovery 17 28580172
2015 RLIP76 regulates Arf6-dependent cell spreading and migration by linking ARNO with activated R-Ras at recycling endosomes. Biochemical and biophysical research communications 17 26498519
2015 RLIP76 blockade by siRNA inhibits proliferation, enhances apoptosis, and suppresses invasion in HT29 colon cancer cells. Cell biochemistry and biophysics 15 25213293
2015 Inflammation Modulates RLIP76/RALBP1 Electrophile-Glutathione Conjugate Transporter and Housekeeping Genes in Human Blood-Brain Barrier Endothelial Cells. PloS one 15 26406496
2014 Structure and function of RLIP76 (RalBP1): an intersection point between Ras and Rho signalling. Biochemical Society transactions 14 24450627
2007 Mass spectroscopic phosphoprotein mapping of Ral binding protein 1 (RalBP1/Rip1/RLIP76). Biochemical and biophysical research communications 13 17706599
2007 The association between polymorphisms in RLIP76 and drug response in epilepsy. Pharmacogenomics 13 18086001
2022 Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer's Disease? International journal of molecular sciences 12 35682775
2015 RLIP76 Targeted Therapy for Kidney Cancer. Pharmaceutical research 12 26021465
2023 Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module. Science advances 11 36812304
2023 The role of RLIP76 in oxidative stress and mitochondrial dysfunction: Evidence based on autopsy brains from Alzheimer's disease patients. Biochimica et biophysica acta. Molecular basis of disease 11 37926360
2019 A potential function of RLIP76 in the ovarian corpus luteum. Journal of ovarian research 11 30999946
2015 Early Steps of Jaagsiekte Sheep Retrovirus-Mediated Cell Transformation Involve the Interaction between Env and the RALBP1 Cellular Protein. Journal of virology 11 26041289
2013 Down-regulation of RalBP1 expression reduces seizure threshold and synaptic inhibition in mice. Biochemical and biophysical research communications 10 23485460
2017 RLIP76 Inhibition: A Promising Developmental Therapy for Neuroblastoma. Pharmaceutical research 9 28386633
2016 RLIP76 increases apoptosis through Akt/mTOR signaling pathway in gastric cancer. Oncology reports 9 27572296
2014 Knockdown of RLIP76 expression by RNA interference inhibits proliferation, enhances apoptosis, and increases chemosensitivity to daunorubicin in U937 leukemia cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 9 24839008
2016 RLIP76 Depletion Enhances Autophagic Flux in U251 Cells. Cellular and molecular neurobiology 8 27473470
2024 Pterostilbene and 6-shogaol exhibit inhibitory effects on sunitinib resistance and motility by suppressing the RLIP76-initiated Ras/ERK and Akt/mTOR pathways in renal cancer cells. European journal of pharmacology 7 38325792
2021 RLIP76: A Structural and Functional Triumvirate. Cancers 7 34064388
2013 Emerging treatments in lung cancer - targeting the RLIP76 molecular transporter. Lung Cancer (Auckland, N.Z.) 7 25419163
2021 Haploinsufficiency Interactions between RALBP1 and p53 in ERBB2 and PyVT Models of Mouse Mammary Carcinogenesis. Cancers 6 34283045
2020 Affinity maturation of the RLIP76 Ral binding domain to inform the design of stapled peptides targeting the Ral GTPases. The Journal of biological chemistry 6 33214225
2010 RLIP76 (RalBP1): The first piece of the structural puzzle. Small GTPases 6 21686269
2022 The ABCB1, ABCC2 and RALBP1 polymorphisms are associated with carbamazepine response in epileptic patient: a systematic review. Acta neurologica Belgica 5 35325436
2017 RLIP76 silencing inhibits cell proliferation and invasion in melanoma cell line A375. European review for medical and pharmacological sciences 5 28537681
2015 Overexpression of RLIP76 Required for Proliferation in Meningioma Is Associated with Recurrence. PloS one 5 25993541
2012 Identification and characterization of the RLIP/RALBP1 interacting protein Xreps1 in Xenopus laevis early development. PloS one 5 22413001
2022 Crucial Role of RLIP76 in Promoting Glycolysis and Tumorigenesis by Stabilization of HIF-1α in Glioma Cells Under Hypoxia. Molecular neurobiology 4 35998001
2016 Downregulation of RLIP76 is associated with vincristine resistance in human colorectal cancer HCT-8/VCR cells. International journal of oncology 4 27633085
2015 [Role and clinical significance of RLIP76 in regulation of multi-drug resistance of small cell lung cancer]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 4 26462890
2008 1H, 13C and 15N resonance assignments for the active conformation of the small G protein RalB in complex with its effector RLIP76. Biomolecular NMR assignments 4 19636899
2011 1H, 13C and 15N resonance assignments of the GTPase-activating (GAP) and Ral binding domains (GBD) of RLIP76 (RalBP1). Biomolecular NMR assignments 3 21915608

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