Affinage

DIRAS3

GTP-binding protein Di-Ras3 · UniProt O95661

Length
229 aa
Mass
25.9 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 29 extracted findings
Cross-family judge faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DIRAS3 (ARHI/NOEY2) is a maternally imprinted, monoallelically paternally expressed small GTPase that acts as a tumor suppressor by re-routing multiple proliferative and motility signaling pathways and by initiating autophagy (PMID:9874798, PMID:12874023, PMID:19033662). It is a constitutively GTP-bound, 26 kDa GTPase with impaired hydrolysis, and its growth-suppressive activity depends both on a unique 34-residue N-terminal extension (NTE) and on C-terminal prenylation-mediated membrane association (PMID:12771940). The NTE is N-myristoylated and binds plasma-membrane phosphoinositides PI(3,4,5)P3 and PI(4,5)P2, forming a double membrane anchor that positions DIRAS3 to act on KRAS and PI3K at the membrane (PMID:37915607). At the membrane DIRAS3 directly heterodimerizes with K-RAS and H-RAS, disrupting RAS clusters, and forms a trimeric complex with H-RAS and C-RAF that suppresses C-RAF/B-RAF heterodimerization and C-RAF kinase activity, thereby blocking RAS/MEK/ERK signaling (PMID:22605333, PMID:23157514, PMID:31825828). DIRAS3 additionally restrains cell motility by sequestering STAT3 in the cytoplasm—competing with RanGTPase for importin binding to block its nuclear import—and by inhibiting FAK(Y397)/Src(Y416) phosphorylation, reducing GTP-RhoA, and dismantling actin stress fibers (PMID:19435463, PMID:21643014). A central function of DIRAS3 is initiation of autophagy: it nucleates the Autophagy Initiation Complex by binding BECN1, disrupting BECN1 homodimers, displacing BCL2, and recruiting PIK3C3, PIK3R4, and ATG14 (PMID:24879154), and it reinforces autophagy by enhancing EGFR internalization/degradation, lowering PI3K/AKT and RAS/ERK output, and releasing FOXo3a into the nucleus to induce ATG4, LC3-I, and Rab7 (PMID:24769729). Re-expression triggers autophagic cell death in culture but enables autophagy-dependent tumor dormancy in vivo (PMID:19033662). In KRAS-mutant cells DIRAS3 induces ROS-mediated apoptosis via NRF2 downregulation while engaging cytoprotective autophagy through the STK11/LKB1–AMPK pathway (PMID:38169324). DIRAS3 transcription is silenced by E2F1/E2F4–HDAC complexes, JMJD2A, EZH2-driven H3K27 trimethylation, acetyl-STAT3/DNMT1-mediated CpG methylation, and Sp1 loss, with reactivation possible through demethylating agents, HDAC inhibitors, or amino acid deprivation that downregulates mTOR and reduces E2F1/4 promoter binding (PMID:12874023, PMID:16158053, PMID:17230502, PMID:24886710, PMID:25077680, PMID:31052266).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1999 High

    Established DIRAS3/ARHI as a maternally imprinted tumor suppressor, framing the central question of how a small GTPase restrains cancer cell growth.

    Evidence Transfection re-expression with promoter-reporter assays and LOH analysis in breast/ovarian cancer cells

    PMID:9874798

    Open questions at the time
    • Molecular mechanism linking re-expression to cyclin D1 repression undefined
    • No biochemical characterization of the GTPase at this stage
  2. 2003 High

    Defined the protein-level requirements for tumor suppression, showing DIRAS3 is a constitutively GTP-bound GTPase whose unique NTE and membrane anchoring are both essential for activity.

    Evidence 32P labeling, site-directed mutagenesis/deletion constructs, clonogenic and membrane fractionation assays

    PMID:12771940

    Open questions at the time
    • Direct effectors at the membrane not yet identified
    • Structural basis of low GTPase activity not resolved
  3. 2003 High

    Identified the death modality and the epigenetic basis of silencing, linking ARHI re-expression to calpain-dependent apoptosis and promoter CpG-island methylation to its loss.

    Evidence Adenoviral re-expression with calpain/caspase inhibitors; methylation-specific PCR, bisulfite sequencing, methylated reporter constructs, hybrid-cell allelic analysis

    PMID:12499268 PMID:12874023

    Open questions at the time
    • Calpain substrates downstream of ARHI not defined
    • Trans-acting factors driving promoter methylation not yet identified
  4. 2003 High

    Connected histone modification state to ARHI transcription, showing acetylation/methylation marks at the locus are reversible drivers of expression.

    Evidence ChIP with 5-aza-dC and TSA treatment, Western blotting

    PMID:12874100

    Open questions at the time
    • Specific chromatin-modifying enzymes not yet assigned
  5. 2006 High

    Identified the transcriptional repressors, placing E2F1/E2F4–HDAC complexes directly at the ARHI promoter.

    Evidence EMSA supershift, ChIP, luciferase co-transfection, siRNA, TSA treatment

    PMID:16158053

    Open questions at the time
    • Upstream signals controlling E2F recruitment not yet linked
  6. 2007 High

    Resolved which HDACs enforce silencing, identifying HDAC1, 3, and 11 at the ARHI promoter.

    Evidence ChIP, individual HDAC siRNA, luciferase reporter, RT-PCR

    PMID:17230502

    Open questions at the time
    • Relative contribution of each HDAC in vivo not quantified
  7. 2008 High

    Reframed DIRAS3 as an autophagy regulator, showing it is required for autophagy and reconciling autophagic cell death in vitro with autophagy-dependent tumor dormancy in vivo.

    Evidence Doxycycline-inducible re-expression, EM, LC3 immunofluorescence/Western, PI3K/mTOR analysis, chloroquine, xenografts

    PMID:19033662

    Open questions at the time
    • Direct molecular partners in the autophagy machinery not yet identified
    • Determinants of death-versus-dormancy outcome unresolved
  8. 2009 High

    Provided a mechanism for nuclear-import inhibition, showing the NTE binds importins and competes with RanGTPase to block STAT3 nuclear entry.

    Evidence GST pulldown with purified importins, nuclear import assays, Ran competition, NTE deletion mutant

    PMID:19435463

    Open questions at the time
    • Full repertoire of blocked import cargoes beyond STAT3 not defined
  9. 2011 High

    Defined two parallel anti-motility pathways, showing DIRAS3 sequesters STAT3 and independently suppresses FAK/Src/RhoA signaling and stress fibers.

    Evidence Chemotaxis assays, Co-IP, fractionation, phospho-Western, JAK2 inhibitor, FAK/STAT3 siRNA, RhoA-GTP pulldown

    PMID:21643014

    Open questions at the time
    • Direct binding interface with FAK/RhoA components not mapped
  10. 2012 High

    Established the direct molecular basis for RAS/ERK inhibition, showing DIRAS3 binds C-RAF and forms a trimeric H-Ras/C-RAF complex that blocks RAF dimerization and kinase activity.

    Evidence Co-IP, in vitro direct binding, kinase assays, deletion mutants, siRNA, migration assays (two independent labs)

    PMID:22605333 PMID:23157514

    Open questions at the time
    • Stoichiometry of the trimeric complex in cells not fully resolved
  11. 2013 Medium

    Linked oncogenic signaling to DIRAS3 silencing, showing acetylated STAT3 recruits DNMT1 to the ARHI promoter to drive CpG methylation.

    Evidence ChIP for acetyl-STAT3, Co-IP with DNMT1, pyrosequencing, Western

    PMID:23604529

    Open questions at the time
    • Single lab; feedback loop with DIRAS3-mediated STAT3 sequestration not tested
  12. 2014 High

    Identified DIRAS3 as the nucleator of the Autophagy Initiation Complex, binding BECN1, disrupting its homodimers, and displacing BCL2 to assemble BECN1/PIK3C3/PIK3R4/ATG14.

    Evidence Co-IP in cells and dormant xenografts, siRNA, immunofluorescence colocalization, primary tumor correlation

    PMID:24879154

    Open questions at the time
    • Structural detail of the DIRAS3–BECN1 interface not defined here
  13. 2014 High

    Mapped the EGFR–FOXo3a–Rab7 arm of autophagy, showing DIRAS3 drives EGFR degradation and nuclear FOXo3a to induce autophagy genes and autophagosome-lysosome fusion.

    Evidence Inducible re-expression, EGFR internalization assay, phospho-Western, nuclear fractionation, siRNA, fluorescence microscopy

    PMID:24769729

    Open questions at the time
    • Mechanism of enhanced EGFR internalization not defined
  14. 2014 Medium

    Identified additional transcriptional regulators, placing JMJD2A (repressive, via E2F/HDAC) and Sp1 (activating) upstream of DIRAS3.

    Evidence ChIP, dual luciferase, Co-IP, knockdown/overexpression, migration/invasion, xenografts

    PMID:24886710 PMID:25193278

    Open questions at the time
    • Single labs; interplay between Sp1 activation and JMJD2A/E2F repression not integrated
  15. 2014 Low

    Computational modeling proposed a structural basis for low GTPase activity and STAT3 occlusion, but without experimental validation.

    Evidence Homology modeling, MD simulations, free-energy and docking analyses

    PMID:25499977

    Open questions at the time
    • Predicted N-terminal helix/switch II and STAT3 contacts not experimentally confirmed
  16. 2015 Medium

    Added EZH2-driven H3K27me3 as a histone-methylation route of silencing acting synergistically with DNA methylation.

    Evidence EZH2 shRNA, ChIP for H3K27me3 at the promoter, DZNep treatment, viability assays

    PMID:25077680

    Open questions at the time
    • Single lab; coordination with E2F/HDAC complexes not resolved
  17. 2016 Medium

    Refined the RAF-inhibition mechanism with KSR1 and extended DIRAS3's signaling reach to adipocyte differentiation.

    Evidence Co-IP and stoichiometry titrations for KSR1; overexpression/knockdown with Akt/mTOR/ERK phospho-Western and autophagy assays in primary human ASCs

    PMID:27211557 PMID:27368419

    Open questions at the time
    • Single labs; physiological role in adipose biology not established in vivo
  18. 2019 High

    Demonstrated direct RAS heterodimerization and cluster disruption as the structural basis for blocking RAS-driven transformation, and showed amino acid deprivation transcriptionally induces DIRAS3 via mTOR-dependent loss of E2F repression.

    Evidence Co-IP, super-resolution RAS cluster imaging, Raf kinase/transformation assays, NTE deletion, xenografts; ChIP for E2F1/4 under nutrient deprivation with mTOR Western

    PMID:31052266 PMID:31825828

    Open questions at the time
    • How NTE-mediated membrane targeting disrupts RAS nanoclusters mechanistically not fully resolved
    • Nutrient-sensing arm characterized in single lab
  19. 2019 Medium

    Mapped the autophagy-active region to switch II, showing a residue 93–107 peptide binds Beclin1 and inhibits DIRAS3-mediated autophagy.

    Evidence Tat-peptide uptake, Beclin1 binding/Co-IP, autophagy inhibition assays

    PMID:31003488

    Open questions at the time
    • Single lab; structural detail of the peptide–Beclin1 interface not resolved
  20. 2023 High

    Provided the membrane-targeting and biophysical basis of DIRAS3, identifying N-myristoylation and phosphoinositide-binding NTE that form a double membrane anchor, and characterizing nucleotide binding and oligomerization of the recombinant protein.

    Evidence Lipid-binding assays, mass spectrometry for N-myristoylation, all-atom MD; recombinant expression, SEC, 1H-15N HSQC NMR, truncation analysis

    PMID:37652393 PMID:37915607

    Open questions at the time
    • Functional consequence of monomer-dimer equilibrium in cells not established
    • Direct membrane structure not solved experimentally
  21. 2023 Medium

    Extended DIRAS3's anti-migratory function to E3-ligase-mediated control, showing it promotes RNF19B-dependent RAC1 ubiquitination and degradation in NSCLC.

    Evidence Co-IP of DIRAS3-RNF19B-RAC1, ubiquitination assay, proteasome inhibition, migration assays

    PMID:37485351

    Open questions at the time
    • Single lab; whether this is direct or scaffolded recruitment not fully resolved
  22. 2024 High

    Defined a KRAS-mutant-selective dual outcome, showing DIRAS3 induces ROS/NRF2-driven apoptosis while engaging cytoprotective autophagy via STK11/LKB1-AMPK and lysosomal p27.

    Evidence Inducible re-expression, ROS measurement, NRF2 Western/qPCR, isogenic KRAS comparison, AMPK Western, p27 localization, xenografts with autophagy inhibitors

    PMID:38169324

    Open questions at the time
    • Mechanism connecting KRAS inhibition to NRF2 downregulation not fully defined
    • Balance between pro-death and pro-survival arms context-dependence unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DIRAS3's membrane-anchored conformation simultaneously coordinates RAS-cluster disruption, importin competition, and BECN1-dependent autophagy initiation at the structural level remains unresolved.
  • No experimental structure of DIRAS3 bound to RAS, importin, or BECN1
  • Quantitative rules governing which effector pathway dominates in a given cell context unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0003924 GTPase activity 2 GO:0060090 molecular adaptor activity 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-9612973 Autophagy 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9609507 Protein localization 1
Partners
BECN1HRASKPNB1KRASKSR1RAF1RNF19BSTAT3
Complex memberships
Autophagy Initiation Complex (BECN1/PIK3C3/PIK3R4/ATG14/DIRAS3)DIRAS3/H-RAS/C-RAF trimeric complexE2F1/E2F4-HDAC repressor complex (at DIRAS3 promoter)

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Re-expression of NOEY2/ARHI in breast and ovarian cancer cells suppresses clonogenic growth, associated with downregulation of cyclin D1 promoter activity and induction of p21(WAF1/CIP1). The gene is maternally imprinted and expressed monoallelically from the paternal allele. Transfection-based re-expression, promoter-reporter assays, LOH analysis Proceedings of the National Academy of Sciences of the United States of America High 9874798
2003 ARHI encodes a 26 kDa GTP-binding protein constitutively maintained in a GTP-bound state due to impaired GTPase activity. Its unique 34-amino-acid N-terminal extension (NTE) is required for growth inhibition; deletion of NTE nearly abolishes inhibitory activity. Membrane association via C-terminal CAAX prenylation is required for full growth-inhibitory function. Mutation S51N reduces GTP binding and biological activity; mutation A46V increases growth inhibition correlating with further reduced GTPase activity. 32P-phosphorus labeling, site-directed mutagenesis, deletion constructs, clonogenic growth assays, membrane fractionation Oncogene High 12771940
2003 Re-expression of ARHI in breast and ovarian cancer cells induces apoptosis through a caspase-independent, calpain-dependent pathway. Calpain protein is upregulated 2–3-fold after ARHI re-expression, calpain cleavage is detected, and calpain inhibitors (but not caspase inhibitors) partially prevent ARHI-induced apoptosis. Adenoviral re-expression, TUNEL, Annexin V/flow cytometry, Western blotting, cDNA array, calpain inhibitor treatment Cancer research High 12499268
2003 ARHI is maternally imprinted with methylation of three CpG islands on the maternal allele. The paternal allele lacks methylation and is expressed. Hypermethylation of CpG island II in the promoter region completely abolishes ARHI expression in breast cancer cells, as confirmed by methylated construct transfection into luciferase reporter assays and by allele-specific methylation analysis in hybrid A9 cells. Methylation-specific PCR, bisulfite sequencing, luciferase reporter assays with methylated constructs, hybrid cell (A9) allele analysis, 5-aza-dC treatment Cancer research High 12874023
2003 Reactivation of ARHI expression by CpG demethylating agents and/or HDAC inhibitors is accompanied by increased histone H3 lysine 9/18 acetylation and decreased histone H3 lysine 9 methylation at the ARHI locus, demonstrating that histone modifications directly regulate ARHI transcription. Chromatin immunoprecipitation (ChIP), 5-aza-dC and TSA treatment, Western blotting Human molecular genetics High 12874100
2006 E2F1 and E2F4 bind to the ARHI promoter in vivo and repress its activity. E2F1/4 in complex with HDACs suppress the ARHI promoter; this repression is reversed by the HDAC inhibitor TSA or by siRNA knockdown of E2F1/4. pRB enhances repression by E2F1 but not E2F4. EMSA supershift assays, ChIP, luciferase reporter co-transfection, siRNA knockdown, TSA treatment Oncogene High 16158053
2007 Multiple HDACs (particularly HDAC1, 3, and 11) repress ARHI transcription. HDAC1 and HDAC3 are bound to the ARHI promoter in breast cancer cells (ChIP); depletion of HDAC1, 3, or 11 increases ARHI promoter activity and endogenous ARHI expression; HDAC inhibition increases E2F acetylation. ChIP, siRNA knockdown of individual HDACs, luciferase reporter co-transfection, RT-PCR International journal of cancer High 17230502
2008 Re-expression of ARHI in ovarian cancer cells induces autophagy by blocking PI3K signaling and inhibiting mTOR, upregulating ATG4, and colocalizing with cleaved LC3 in autophagosomes. ARHI is required for spontaneous and rapamycin-induced autophagy. In cell culture, ARHI causes autophagic cell death, but in xenografts ARHI enables tumor dormancy. Inhibition of autophagy with chloroquine reduces regrowth of dormant xenografts after ARHI knockdown. Doxycycline-inducible re-expression, immunofluorescence, LC3 cleavage Western blot, electron microscopy, PI3K/mTOR pathway analysis, chloroquine treatment, xenograft model The Journal of clinical investigation High 19033662
2009 ARHI binds to importins (including importin α1, α3, α5, α6, α7, β1, and importins 7, 8, 13) via its N-terminal extension, competes with RanGTPase for importin binding, and thereby blocks nuclear import of cargo proteins including phosphorylated STAT3. Deletion of the N-terminal extension greatly reduces importin binding. GST pulldown with purified GST-importin fusion proteins, nuclear import assays, competition assays with Ran, N-terminal deletion mutant Bioscience reports High 19435463
2011 Re-expression of ARHI decreases motility of IL-6- and EGF-stimulated ovarian cancer cells through two distinct signaling pathways: (1) ARHI binds to and sequesters STAT3 in the cytoplasm, preventing its nuclear translocation and localization in focal adhesion complexes; (2) ARHI inhibits FAK(Y397) and Src(Y416) phosphorylation, disrupts focal adhesions, blocks FAK-mediated RhoA signaling (reducing GTP-RhoA), and disrupts actin stress fiber formation in a FAK- and RhoA-dependent manner. Chemotaxis/haptotaxis assays, Co-immunoprecipitation, subcellular fractionation, phospho-antibody Western blot, JAK2 inhibitor AG490, FAK siRNA, Stat3 siRNA, RhoA-GTP pull-down Oncogene High 21643014
2012 DiRas3 (DIRAS3) directly binds C-RAF in vitro and associates with C-RAF in vivo in a nucleotide-independent manner (not requiring the N-terminal extension alone). DiRas3 forms a trimeric complex with H-Ras and C-RAF; this complex is more stable than binary complexes. DiRas3 expression inhibits activating phosphorylations of MEK and ERK, suppresses C-RAF/B-RAF heterodimerization, anchors C-RAF to membrane skeleton components, and inhibits C-RAF kinase activity. Knockdown of DiRas3 causes a persistent increase in MEK and ERK phosphorylation and increased MEK-dependent cell migration. Co-immunoprecipitation, in vitro direct binding assay, kinase activity assay, deletion mutants, siRNA knockdown, migration assays The Journal of biological chemistry High 22605333 23157514
2014 DIRAS3 forms the Autophagy Initiation Complex (AIC) containing BECN1, PIK3C3, PIK3R4, ATG14, and DIRAS3. DIRAS3 binds BECN1, disrupts BECN1 homodimers, and displaces BCL2 from BECN1, thereby increasing BECN1 association with PIK3C3 and ATG14 and activating the AIC. Amino acid starvation induces DIRAS3 expression and promotes autophagy; DIRAS3 depletion blocks starvation-induced autophagy. Co-immunoprecipitation, Co-IP in dormant xenograft cells, siRNA knockdown, immunofluorescence colocalization, correlation in primary ovarian cancer specimens Autophagy High 24879154
2014 ARHI enhances internalization and degradation of EGFR, thereby blocking PI3K/AKT and Ras/ERK signaling. Reduced phosphorylation of FOXo3a by these pathways sequesters FOXo3a in the nucleus, where it induces ATG4 and MAP-LC3-I expression and increases Rab7 expression (required for autophagosome-lysosome fusion). Knockdown of FOXo3a or Rab7 markedly inhibits autophagolysosome formation, producing enlarged autophagosomes. Doxycycline-inducible re-expression, EGFR internalization assay, phospho-Western blotting, nuclear fractionation, siRNA knockdown, fluorescence microscopy of autophagosome formation Cell death and differentiation High 24769729
2014 JMJD2A promotes breast cancer progression by transcriptionally repressing ARHI. Knockdown of JMJD2A increases ARHI expression; overexpression decreases it. E2Fs and HDACs are involved in JMJD2A-mediated ARHI repression. Re-expression of ARHI reverses the aggressive behavior induced by JMJD2A in vitro and in vivo. Co-immunoprecipitation, dual luciferase reporter assay, ChIP, siRNA/shRNA knockdown, overexpression, xenograft models Breast cancer research : BCR High 24886710
2014 Computational structural modeling reveals that ARHI's N-terminal helix engages hydrophobic interactions with switch II, accounting for its low intrinsic GTPase activity. The N-terminal helix and effector domain interact with the NTD of STAT3, making STAT3 inaccessible to Ran-importinβ-mediated nuclear translocation. ARHI also competes with RanGTPase for importinβ binding via basic-acidic patch interactions. Homology modeling, MD simulations, free energy landscape analysis, protein-protein docking Cellular signalling Low 25499977
2015 EZH2 promotes H3K27me3 at the ARHI promoter in ovarian cancer cells, and EZH2 knockdown restores ARHI expression. ARHI is synergistically silenced by DNA methylation and EZH2-mediated histone modification. shRNA knockdown of EZH2, ChIP for H3K27me3 at ARHI promoter, Western blot, DZNep (EZH2 inhibitor) treatment with cell viability assay Cell biochemistry and biophysics Medium 25077680
2016 DiRas3 binds KSR1 independently of activated Ras. Depending on stoichiometry of DiRas3 and oncogenic Ras, DiRas3 can enhance KSR1 homodimerization or recruit KSR1 to the Ras:C-RAF complex, reducing availability of C-RAF for B-RAF dimerization. This mechanism is shared by A-RAF and C-RAF. Co-immunoprecipitation, protein–protein interaction assays, stoichiometry titration experiments Cellular signalling Medium 27368419
2019 DIRAS3 directly interacts with RAS (both K-RAS and H-RAS) to form heteromers, disrupts RAS clustering at the plasma membrane, inhibits Raf kinase activation, and blocks transformation and cancer cell growth. Disruption of K-RAS clusters requires the DIRAS3 N-terminal extension and requires both DIRAS3 and K-RAS to be membrane-associated. Co-immunoprecipitation, fluorescence imaging of RAS clusters (super-resolution), Raf kinase assay, transformation assay, N-terminal deletion mutants, xenograft models Cell reports High 31825828
2019 Amino acid deprivation upregulates DIRAS3 by reducing E2F1/4 transcriptional repression at the DIRAS3 promoter (via mTOR downregulation), leading to autophagy induction. Acute amino acid withdrawal does not affect epigenetic regulation or miRNA levels that regulate DIRAS3; the effect is transcriptional. ChIP for E2F1/4 at DIRAS3 promoter under nutrient deprivation, mTOR pathway Western blot, siRNA knockdown, qRT-PCR Cancers Medium 31052266
2019 DIRAS3-derived peptide based on switch II region (residues 93–107) linked to Tat directly binds Beclin1 and inhibits starvation-induced DIRAS3-mediated autophagy in ovarian cancer cells. Peptide uptake assay, Beclin1 binding assay (Co-IP/pulldown), autophagy inhibition assay Cancers Medium 31003488
2023 The N-terminal extension (NTE) of DIRAS3 binds phosphoinositides PI(3,4,5)P3 and PI(4,5)P2 with rapid kinetics and strong affinity; lipid binding induces structural transition from disordered to amphipathic helix. Mass spectrometry identified N-myristoylation of DIRAS3. MD simulations predict double membrane anchoring (via NTE and prenylated C-terminus), stabilizing DIRAS3 at the plasma membrane where it can target PI3K and KRAS. Lipid-binding biochemical assays, mass spectrometry (N-myristoylation identification), all-atom molecular dynamics simulations, biochemical functional assays iScience High 37915607
2023 Recombinant DiRAS3 (C75S/C80S variant) exists in a monomer-dimer equilibrium in solution, with N- and C-terminal extensions contributing to dimerization. The GTPase domain (ΔNC) is monomeric and binds both GDP and GTP, confirming nucleotide-switching capacity despite G-box substitutions. The N-terminal extension contributes to aggregation and multimerization. Recombinant protein expression and purification, size exclusion chromatography, 1H-15N HSQC NMR spectroscopy, truncation analysis Protein expression and purification High 37652393
2024 DIRAS3-mediated inhibition of KRAS induces ROS-mediated apoptosis in PDAC and LGSOC cells with KRAS mutations (but not wild-type KRAS) by downregulating NRF2 transcription, reducing antioxidants, and inducing oxidative stress. DIRAS3 also induces cytoprotective autophagy in mutant KRAS cells by activating the STK11/LKB1-PRKAA/AMPK pathway, increasing lysosomal CDKN1B/p27, and inducing autophagic gene expression. Doxycycline-inducible DIRAS3 re-expression, ROS measurement (DCFDA), NRF2 Western/qPCR, KRAS-mutant vs wild-type cell comparison, AMPK pathway Western blot, p27 lysosomal localization, in vitro and xenograft models with chloroquine/DC661 treatment Autophagy High 38169324
2013 STAT3 acetylation in ovarian cancer cells promotes binding of acetylated STAT3 to the ARHI promoter and recruits DNA methyltransferase 1 (DNMT1), resulting in CpG island methylation and loss of ARHI expression. ChIP for acetylated STAT3 at ARHI promoter, Co-IP of acetylated STAT3 with DNMT1, pyrosequencing of CpG methylation, Western blotting Oncology reports Medium 23604529
2014 Sp1 transcriptionally activates DIRAS3, and JMJD2A suppresses Sp1 autoregulation in advanced breast cancer, leading to reduced Sp1 and consequently reduced DIRAS3 expression. Knockdown of DIRAS3 attenuates the anti-migratory/invasive effect of Sp1 overexpression. ChIP, dual luciferase reporter assay, Co-IP, deletion mutagenesis, siRNA knockdown, migration/invasion assays Breast cancer research and treatment Medium 25193278
2023 In NSCLC cells, DIRAS3 promotes polyubiquitination and proteasomal degradation of RAC1 by facilitating the binding of RAC1 to the E3 ubiquitin ligase RNF19B, thereby suppressing cancer cell migration. Co-immunoprecipitation (DIRAS3-RNF19B-RAC1 complex), ubiquitination assay, proteasome inhibitor experiment, migration assays, siRNA/overexpression iScience Medium 37485351
2000 Transgenic overexpression of ARHI in mice produces small stature, impairs mammary gland development and lactation (associated with decreased serum prolactin and progesterone, and lower estrogen and progesterone receptors in mammary glands/ovaries), causes ovarian folliculogenesis failure, loss of cerebellar cortex neurons, and impaired thymic development. Transgenic mouse model, immunohistochemistry for prolactin and hormone receptors, serum hormone measurements Cancer research Medium 10987306
2016 In human white adipose stromal/progenitor cells, DIRAS3 negatively regulates Akt, mTOR, and ERK1/2 signaling during adipogenesis and activates autophagy. Overexpression of DIRAS3 in weight-loss-donor ASCs completely inhibits Akt phosphorylation even in the presence of IGF-1. Overexpression and knockdown in primary human ASCs, phospho-Western blotting for Akt/mTOR/ERK/S6K1, adipogenesis assay, autophagy assay EBioMedicine Medium 27211557
2021 The N-terminal domain of NOEY2/DIRAS3 (NOEY2-N) directly binds VEGFR-2, inhibiting PI3K/PDK-1/TSC-2/p70S6K signaling downstream of VEGFR-2 and suppressing angiogenesis. Key interacting residues Lys15 and Arg16 in the N-terminal domain were identified by structural modeling. Xenograft tumor model (tumor growth and vascularity), Western blot of PI3K pathway, homology modeling and molecular dynamics to identify binding residues; direct binding assay with VEGFR-2 Biomolecules & therapeutics Low 34462379

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. The Journal of clinical investigation 385 19033662
1999 NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Proceedings of the National Academy of Sciences of the United States of America 256 9874798
2008 Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation. Cancer 132 18286529
2010 MicroRNAs 221/222 and genistein-mediated regulation of ARHI tumor suppressor gene in prostate cancer. Cancer prevention research (Philadelphia, Pa.) 121 21071579
2017 Long Noncoding RNA GAS5 Suppresses Cell Growth and Epithelial-Mesenchymal Transition in Osteosarcoma by Regulating the miR-221/ARHI Pathway. Journal of cellular biochemistry 119 28519068
2017 LncRNA H19 inhibits autophagy by epigenetically silencing of DIRAS3 in diabetic cardiomyopathy. Oncotarget 114 27903964
2003 ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers. Oncogene 86 12771940
2003 Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers. Cancer research 78 12874023
2011 The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways. Oncogene 77 21643014
2014 ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7. Cell death and differentiation 68 24769729
2002 Reexpression of the tumor suppressor gene ARHI induces apoptosis in ovarian and breast cancer cells through a caspase-independent calpain-dependent pathway. Cancer research 68 12499268
2011 Re-expression of ARHI (DIRAS3) induces autophagy in breast cancer cells and enhances the inhibitory effect of paclitaxel. BMC cancer 66 21244707
2014 DIRAS3 regulates the autophagosome initiation complex in dormant ovarian cancer cells. Autophagy 65 24879154
2019 Epigenetic inhibition of the tumor suppressor ARHI by light at night-induced circadian melatonin disruption mediates STAT3-driven paclitaxel resistance in breast cancer. Journal of pineal research 64 31077613
2003 Epigenetic regulation of ARHI in breast and ovarian cancer cells. Annals of the New York Academy of Sciences 61 12724231
2003 Reactivation of the silenced and imprinted alleles of ARHI is associated with increased histone H3 acetylation and decreased histone H3 lysine 9 methylation. Human molecular genetics 56 12874100
2006 E2F-HDAC complexes negatively regulate the tumor suppressor gene ARHI in breast cancer. Oncogene 55 16158053
2014 JMJD2A contributes to breast cancer progression through transcriptional repression of the tumor suppressor ARHI. Breast cancer research : BCR 54 24886710
2019 DIRAS3 (ARHI) Blocks RAS/MAPK Signaling by Binding Directly to RAS and Disrupting RAS Clusters. Cell reports 53 31825828
2007 Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer. International journal of cancer 52 17230502
2006 Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers. Methods in enzymology 52 16757345
2003 Loss of the expression of the tumor suppressor gene ARHI is associated with progression of breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 52 14506155
2015 ARHI (DIRAS3)-mediated autophagy-associated cell death enhances chemosensitivity to cisplatin in ovarian cancer cell lines and xenografts. Cell death & disease 51 26247722
2000 ARHI is the center of allelic deletion on chromosome 1p31 in ovarian and breast cancers. International journal of cancer 47 10797292
2006 Transcriptional and posttranscriptional down-regulation of the imprinted tumor suppressor gene ARHI (DRAS3) in ovarian cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 44 16638845
2004 Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular thyroid carcinogenesis. The Journal of clinical endocrinology and metabolism 43 15546898
2016 Weight Loss Upregulates the Small GTPase DIRAS3 in Human White Adipose Progenitor Cells, Which Negatively Regulates Adipogenesis and Activates Autophagy via Akt-mTOR Inhibition. EBioMedicine 40 27211557
2021 DIRAS3: An Imprinted Tumor Suppressor Gene that Regulates RAS and PI3K-driven Cancer Growth, Motility, Autophagy, and Tumor Dormancy. Molecular cancer therapeutics 39 34667114
2022 Resveratrol Contrasts IL-6 Pro-Growth Effects and Promotes Autophagy-Mediated Cancer Cell Dormancy in 3D Ovarian Cancer: Role of miR-1305 and of Its Target ARH-I. Cancers 37 35565270
2014 JMJD2A-dependent silencing of Sp1 in advanced breast cancer promotes metastasis by downregulation of DIRAS3. Breast cancer research and treatment 35 25193278
2013 Imprinted chromatin around DIRAS3 regulates alternative splicing of GNG12-AS1, a long noncoding RNA. American journal of human genetics 34 23871723
2001 Genomic structure and promoter characterization of an imprinted tumor suppressor gene ARHI. Biochimica et biophysica acta 34 11418188
2015 EZH2-induced H3K27me3 is associated with epigenetic repression of the ARHI tumor-suppressor gene in ovarian cancer. Cell biochemistry and biophysics 32 25077680
2011 The expression and clinical significance of GTP-binding RAS-like 3 (ARHI) and microRNA 221 and 222 in prostate cancer. The Journal of international medical research 32 22117988
2008 Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss. International journal of cancer 31 18302158
2009 ARHI, as a novel suppressor of cell growth and downregulated in human hepatocellular carcinoma, could contribute to hepatocarcinogenesis. Molecular carcinogenesis 30 18612997
2000 The human ARHI tumor suppressor gene inhibits lactation and growth in transgenic mice. Cancer research 30 10987306
2013 The tumor suppressor gene ARHI (DIRAS3) inhibits ovarian cancer cell migration through multiple mechanisms. Cell adhesion & migration 28 23357870
2019 The role of vascular endothelial growth factor, interleukin 8, and insulinlike growth factor in sustaining autophagic DIRAS3-induced dormant ovarian cancer xenografts. Cancer 27 30620384
2017 Silencing of the small GTPase DIRAS3 induces cellular senescence in human white adipose stromal/progenitor cells. Aging 27 28316325
2002 ARHI/NOEY2 inactivation may be important in breast tumor pathogenesis. Oncology 26 11914599
2016 Induction of autophagy by ARHI (DIRAS3) alters fundamental metabolic pathways in ovarian cancer models. BMC cancer 25 27784287
2010 Reexpression of ARHI inhibits tumor growth and angiogenesis and impairs the mTOR/VEGF pathway in hepatocellular carcinoma. Biochemical and biophysical research communications 25 21093415
2013 STAT3 acetylation-induced promoter methylation is associated with downregulation of the ARHI tumor-suppressor gene in ovarian cancer. Oncology reports 24 23604529
2009 Expression of the tumor suppressor ARHI inhibits the growth of pancreatic cancer cells by inducing G1 cell cycle arrest. Oncology reports 24 19639215
2023 Differential effects of the LncRNA RNF157-AS1 on epithelial ovarian cancer cells through suppression of DIRAS3- and ULK1-mediated autophagy. Cell death & disease 23 36805591
2019 Amino Acid Deprivation-Induced Autophagy Requires Upregulation of DIRAS3 through Reduction of E2F1 and E2F4 Transcriptional Repression. Cancers 23 31052266
2009 LOH at 1p31 (ARHI) and proliferation in lymph node-negative breast cancer. Cellular oncology : the official journal of the International Society for Cellular Oncology 23 19759414
2014 Structural perspective of ARHI mediated inhibition of STAT3 signaling: an insight into the inactive to active transition of ARHI and its interaction with STAT3 and importinβ. Cellular signalling 21 25499977
2014 ARHI overexpression induces epithelial ovarian cancer cell apoptosis and excessive autophagy. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 20 24476894
2019 DIRAS3-Derived Peptide Inhibits Autophagy in Ovarian Cancer Cells by Binding to Beclin1. Cancers 19 31003488
2012 Effect of ARHI on lung cancer cell proliferation, apoptosis and invasion in vitro. Molecular biology reports 19 23247805
2009 ARHI (DIRAS3), an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins. Bioscience reports 19 19435463
2007 NNAT and DIRAS3 genes are paternally expressed in pigs. Genetics, selection, evolution : GSE 19 17897599
2018 Correlation of ARHI upregulation with growth suppression and STAT3 inactivation in resveratrol-treated ovarian cancer cells. Cancer biomarkers : section A of Disease markers 18 29504523
2012 The tumour suppressor DiRas3 interacts with C-RAF and downregulates MEK activity to restrict cell migration. Biology of the cell 18 23157514
2016 Zebularine enhances apoptosis of human osteosarcoma cells by suppressing methylation of ARHI. Cancer science 17 27685841
2008 ARHI: A new target of galactose toxicity in Classic Galactosemia. Bioscience hypotheses 17 19122833
2019 Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma. BMC cancer 16 31088402
2013 Effects of ARHI on breast cancer cell biological behavior regulated by microRNA-221. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 16 23801152
2012 Effects of ARHI on cell cycle progression and apoptosis levels of breast cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 22528939
2012 The tumor suppressor DiRas3 forms a complex with H-Ras and C-RAF proteins and regulates localization, dimerization, and kinase activity of C-RAF. The Journal of biological chemistry 13 22605333
2024 Schizophyllum commune fruiting body polysaccharides inhibit glioma by mediating ARHI regulation of PI3K/AKT signalling pathway. International journal of biological macromolecules 12 39236963
2018 Distinct subgroup of the Ras family member 3 (DIRAS3) expression impairs metastasis and induces autophagy of gastric cancer cells in mice. Journal of cancer research and clinical oncology 12 30043279
2014 Over-expression of ARHI decreases tumor growth, migration, and invasion in human glioma. Medical oncology (Northwood, London, England) 12 24458808
2013 Inhibitory effect of ARHI on pancreatic cancer cells and NF-κB activity. Molecular medicine reports 12 23447002
2010 Imprinted tumor suppressor gene ARHI induces apoptosis correlated with changes in DNA methylation in pancreatic cancer cells. Molecular medicine reports 12 21472283
2024 DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas. Autophagy 11 38169324
2020 Re-expression of DIRAS3 and p53 induces apoptosis and impaired autophagy in head and neck squamous cell carcinoma. Military Medical Research 11 33038921
2022 DIRAS3, GPR171 and RAC2 were identified as the key molecular patterns associated with brain metastasis of breast cancer. Frontiers in oncology 10 36212434
2017 DNA methyltransferase inhibitors influence on the DIRAS3 and STAT3 expression and in vitro migration of ovarian and breast cancer cells. Ginekologia polska 10 29192415
2013 Expression of JMJD2A in infiltrating duct carcinoma was markedly higher than fibroadenoma, and associated with expression of ARHI, p53 and ER in infiltrating duct carcinoma. Indian journal of experimental biology 9 23678541
2021 Shensu IV prevents glomerular podocyte injury in nephrotic rats via promoting lncRNA H19/DIRAS3-mediated autophagy. Bioscience reports 8 33881140
2014 Breast cancer cells are arrested at different phases of the cell cycle following the re-expression of ARHI. Oncology reports 7 24676336
2018 Oncogenic DIRAS3 promotes malignant phenotypes of glioma by activating EGFR-AKT signaling. Biochemical and biophysical research communications 6 30266404
2016 Stabilization of C-RAF:KSR1 complex by DiRas3 reduces availability of C-RAF for dimerization with B-RAF. Cellular signalling 6 27368419
2009 NOEY2 mutations in primary breast cancers and breast hyperplasia. Breast (Edinburgh, Scotland) 6 19482475
2023 DIRAS3 regulates autophagy in an endometriosis epithelial cell line. Reproductive biomedicine online 5 37598541
2021 Genomic Imprinting at the Porcine DIRAS3 Locus. Animals : an open access journal from MDPI 5 34063661
2021 Overexpression of ARHI increases the sensitivity of cervical cancer cells to paclitaxel through inducing apoptosis and autophagy. Drug development research 5 34189759
2021 Novel Anti-Angiogenic and Anti-Tumour Activities of the N-Terminal Domain of NOEY2 via Binding to VEGFR-2 in Ovarian Cancer. Biomolecules & therapeutics 5 34462379
2017 The expression of aplysia ras homolog I (ARHI) and its inhibitory effect on cell biological behavior in esophageal squamous cell carcinoma. OncoTargets and therapy 5 28280356
2013 Effect of histone deacetylase inhibitors on cell apoptosis and expression of the tumor suppressor genes RUNX3 and ARHI in ovarian tumors. Molecular medicine reports 5 23504001
2012 The expression of ARHI in pT2a and pT2b stage gastric cancer and its clinical significance. Oncology reports 5 22427032
2024 Intrinsically Disordered Membrane Anchors of Rheb, RhoA, and DiRas3 Small GTPases: Molecular Dynamics, Membrane Organization, and Interactions. The journal of physical chemistry. B 4 38942776
2023 Membrane anchoring of the DIRAS3 N-terminal extension permits tumor suppressor function. iScience 4 37915607
2020 The Role of Methylation in the CpG Island of the ARHI Promoter Region in Cancers. Advances in experimental medicine and biology 4 32949395
2019 A Comparative Study of ARHI Imprinted Gene Detection and Fine-Needle Aspiration Cytology in the Differential Diagnosis of Benign and Malignant Thyroid Nodules. Genetic testing and molecular biomarkers 4 31411490
2017 ARHI is a novel epigenetic silenced tumor suppressor in sporadic pheochromocytoma. Oncotarget 4 29156798
2011 [Differential expression of the anti-oncogene ARHI between patients with and without endometriosis]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 4 21602127
2025 BST2 and DIRAS3 Drive Immune Evasion and Tumor Progression in High-Grade Glioma. International journal of molecular sciences 3 40649981
2025 DIRAS3 Inhibits Ovarian Cancer Cell Growth by Blocking the Fibronectin-Mediated Integrin β1/FAK/AKT Signaling Pathway. Cells 3 40862729
2023 DIRAS3 enhances RNF19B-mediated RAC1 ubiquitination and degradation in non-small-cell lung cancer cells. iScience 3 37485351
2022 GTP-binding protein Di-RAS3 diminishes the migration and invasion of non-small cell lung cancer by inhibiting the RAS/extracellular-regulated kinase pathway. Bioengineered 3 35170376
2019 EGFRvIII epigenetically regulates ARHI to promote glioma cell proliferation and migration. Experimental and molecular pathology 3 31751560
2014 Age-Related Hearing Impairment (ARHI) associated with GJB2 single mutation IVS1+1G>A in the Yakut population isolate in Eastern Siberia. PloS one 3 24959830
2014 Loss of ARHI expression in colon cancer and its clinical significance. Contemporary oncology (Poznan, Poland) 3 25477755
2002 [NOEY2 gene mRNA expression in breast cancer tissue and its relation to clinicopathological parameters]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 3 12485503
2023 Biochemical and biophysical characterization of the RAS family small GTPase protein DiRAS3. Protein expression and purification 2 37652393
2024 Intrinsically disordered membrane anchors of Rheb, RhoA and DiRas3 small GTPases: Molecular dynamics, membrane organization, and interactions. bioRxiv : the preprint server for biology 1 38712287

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