Affinage

RAC3

Ras-related C3 botulinum toxin substrate 3 · UniProt P60763

Length
192 aa
Mass
21.4 kDa
Annotated
2026-06-10
78 papers in source corpus 39 papers cited in narrative 40 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

The RAC3 symbol denotes two molecularly distinct proteins documented in this corpus: a Rho-family small GTPase and an unrelated p160 nuclear receptor coactivator. The small GTPase Rac3 cycles between GDP- and GTP-bound states—regulated by GEFs such as Vav2 and the GAP Bcr—and engages multiple effector pathways including PAK1, JNK, p38 MAPK, ERK2, and phospholipase Cβ2/SRF to control actin remodeling, transformation, and cell adhesion (PMID:9252344, PMID:10618392, PMID:16267012). Membrane targeting and transforming activity require C-terminal geranylgeranylation, and its distinct polybasic C-terminus drives perinuclear localization and functions non-redundant with Rac1 (PMID:14633727, PMID:17244648). In cancer, Rac3 promotes invasion through invadopodial maturation via a phospho-cortactin→Vav2→Rac3 axis and through Rac3/ERK2/NF-κB and p38 MAPK signaling that drives MMP-9 secretion and EMT, while opposing Rac1-driven cell-matrix adhesion by modulating GIT1 and Arf6 (PMID:16027728, PMID:17244648, PMID:19494130, PMID:23388133, PMID:28356423, PMID:28900489). Rac3 abundance is controlled by FBXL19-mediated polyubiquitination at K166 targeting it for proteasomal degradation (PMID:24684802). In the nervous system Rac3 is enriched in axons and growth cones and drives Neurabin I-dependent neuritogenesis, and de novo missense variants in conserved residues cause a neurodevelopmental disorder; switch-region gain-of-function alleles disrupt cortical neuron migration and axonogenesis through hyperactivation of PAK1, established by dominant-negative PAK1 rescue (PMID:14622142, PMID:16525025, PMID:30293988, PMID:35851598, PMID:35595279). Signaling-deficient alleles (T17R) and GAP-resistant alleles (N92K) demonstrate that both loss and gain of Rac3 signaling perturb neuronal migration and morphology (PMID:41090727, PMID:40015633). Separately, the p160 coactivator RAC3/SRC-3 is imported to the nucleus via a bHLH-domain bipartite NLS and importin α3, where it potentiates transcription by nuclear receptors, NF-κB, and Nrf2 (binding the Neh4/Neh5 domains and ARE enhancers), with in vivo roles in growth and reproduction shown by knockout mice (PMID:9238002, PMID:11094166, PMID:10823921, PMID:16875678, PMID:22370642).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    Established that the RAC3 symbol covers two unrelated proteins: a p160 nuclear receptor coactivator and a Rho-family GTPase, each with a defined molecular activity.

    Evidence Cloning, co-IP, and reporter assays identifying the coactivator; parallel cloning and GTPase/JNK assays identifying the GTPase regulated by Bcr

    PMID:9238002 PMID:9252344

    Open questions at the time
    • Shared symbol creates persistent ambiguity in downstream literature
    • Effectors and regulators initially defined only for individual pathways
  2. 2000 High

    Defined how each protein engages downstream machinery—the GTPase driving proliferation through PAK versus JNK in breast cancer, and the coactivator bridging NF-κB and glucocorticoid receptor transcription.

    Evidence GTPase pull-down with dominant-negative epistasis and kinase/DNA-synthesis assays; co-IP and reporter assays for NF-κB; knockout mouse phenotyping for the coactivator

    PMID:10618392 PMID:10823921 PMID:11094166

    Open questions at the time
    • Mechanism of Rac3 membrane mislocalization in cancer cells not resolved at structural level
    • NF-κB coactivation supported by single-lab co-IP/reporter
  3. 2001 High

    Identified that the GTPase's divergent C-terminus mediates isoform-specific partner binding (CIB) and integrin-coupled adhesion, distinguishing Rac3 from Rac1/Rac2.

    Evidence Reciprocal co-IP, co-localization, fractionation, adhesion/spreading assay, and endogenous GTPase pull-down

    PMID:11756406

    Open questions at the time
    • Functional consequence of CIB binding beyond αIIbβ3 adhesion not explored
    • Whether CIB acts as effector or regulator unclear
  4. 2003 High

    Dissected the GTPase effector repertoire (PLCβ2, SRF, poor MLK binding) and the membrane-targeting requirement (geranylgeranylation), and mapped neuronal axonal localization.

    Evidence Effector-domain mutagenesis, GST pull-downs, focus/soft-agar assays, isoprenoid-switching mutagenesis with GGTI, and Rac3-specific immunofluorescence in developing brain

    PMID:14605486 PMID:14622142 PMID:14633727 PMID:16267012

    Open questions at the time
    • In vivo PLCβ2/SRF contribution to transformation not separated from PAK
    • Prenylation studies in cancer cell lines only
  5. 2005 High

    Genetic knockouts revealed in vivo, isoform-specific roles for the GTPase in leukemia progression and in nervous-system function not compensated by Rac1.

    Evidence rac3-null mice with GTPase pull-down from primary lymphoma and survival analysis; rotarod behavioral testing

    PMID:15964829 PMID:15964830

    Open questions at the time
    • Molecular basis of the motor/learning phenotype without histological change unexplained
    • Cell-of-origin for Rac3 activation in leukemia not pinpointed
  6. 2006 High

    Determined that the coactivator's transcriptional function requires importin-α3-dependent nuclear import via a bHLH bipartite NLS, and extended coactivation to Nrf2; identified Neurabin I as the effector for GTPase-driven neuritogenesis.

    Evidence NLS mutagenesis, importin-α3 co-IP, nuclear import and reporter assays; Gal4-Nrf2 reporter with dominant-negative; yeast two-hybrid and domain-specific rescue for Neurabin I

    PMID:16525025 PMID:16756760 PMID:16875678

    Open questions at the time
    • Nrf2 coactivation by reporter only at this stage
    • Neurabin I link to specific in vivo neuronal phenotypes not yet shown
  7. 2007 High

    Showed the GTPase opposes Rac1 in neuronal adhesion/morphology and that the coactivator assembles a cytoplasmic anti-apoptotic complex, defining distinct cytoplasmic roles for the two proteins.

    Evidence Isoform-specific siRNA with domain-swap mutagenesis and RhoA epistasis; co-IP of coactivator with AIF/Hsp90/dynein plus kinase/apoptosis assays

    PMID:17244648 PMID:17968310

    Open questions at the time
    • GTPase target reducing integrin adhesion not molecularly identified here
    • AIF/Hsp90/dynein complex stoichiometry and direct contacts undefined
  8. 2009 High

    Provided the molecular basis for the GTPase's anti-adhesive function through βPix-independent GIT1 binding and suppression of Arf6 activity.

    Evidence Reciprocal co-IP, Arf6 GTPase activity assay, and Arf6/ARNO rescue of spreading

    PMID:19494130

    Open questions at the time
    • Structural determinant of βPix-independent GIT1 binding not defined
    • Single-cell-system mechanism
  9. 2012 Medium

    Connected both proteins to autophagy regulation—the GTPase as an isoform-specific suppressor and the coactivator as a nuclear/cytoplasmic inhibitor of starvation-induced autophagy.

    Evidence Isoform-specific siRNA plus ectopic rescue under Icmt inhibition; coactivator overexpression/knockdown with LC3 markers and nuclear fractionation

    PMID:21852230 PMID:22957814

    Open questions at the time
    • Direct autophagy machinery target of either protein not identified
    • Coactivator autophagy work single-lab
  10. 2012 High

    Mapped the coactivator–Nrf2 interaction at domain resolution and at the chromatin level, defining how it potentiates ARE-driven antioxidant transcription.

    Evidence GST pull-down domain mapping (PasB/R3B3 to Neh4/Neh5), FRET, co-IP, and ChIP at the HO-1 ARE

    PMID:22370642

    Open questions at the time
    • Physiological antioxidant output in vivo not assessed
    • Competition with other co-regulators at ARE unresolved
  11. 2017 High

    Established a defined invasion-promoting signaling axis for the GTPase: phospho-cortactin recruits Vav2, which activates Rac3 at invadopodia to drive matrix degradation.

    Evidence SH2-domain screen, co-IP, Rac3 FRET biosensor, isoform-specific knockdown and constitutively active rescue, matrix degradation assay

    PMID:28356423 PMID:28900489

    Open questions at the time
    • Downstream effector at invadopodia (PAK vs other) not fully resolved
    • p38 axis in lung cancer relies on pharmacological epistasis
  12. 2014 High

    Identified the ubiquitin-ligase machinery controlling GTPase abundance: FBXL19 polyubiquitinates Rac3 at K166 for proteasomal degradation, linking turnover to EMT control.

    Evidence Co-IP, in-cell ubiquitination assay, K166 site-directed mutagenesis, FBXL19 truncation, and E-cadherin functional readout

    PMID:24684802

    Open questions at the time
    • Signals controlling FBXL19–Rac3 engagement unknown
    • Whether nucleotide state affects degradation not tested
  13. 2022 High

    Demonstrated that de novo RAC3 GTPase variants cause neurodevelopmental disease through PAK1 hyperactivation, with dominant-negative PAK1 rescuing migration defects in vivo.

    Evidence In vitro effector-binding biochemistry, in utero electroporation of cortical neurons, dominant-negative PAK1 rescue across multiple switch-region variants including F28S

    PMID:30293988 PMID:35595279 PMID:35851598

    Open questions at the time
    • Variant-specific effector preferences not fully mapped to phenotype severity
    • MLK2 contribution excluded only for some alleles
  14. 2025 High

    Revealed that the disorder spectrum includes signaling-deficient and GAP-resistant alleles, showing both loss and gain of Rac3 signaling disrupt neuronal migration and axonogenesis.

    Evidence GDP/GTP exchange and hydrolysis assays, effector pull-downs (PAK1/MLK2/N-WASP/ROCK1), SRF/NF-κB/AP1 reporters, and in utero electroporation for R66W, T17R, and N92K

    PMID:39682779 PMID:40015633 PMID:41090727

    Open questions at the time
    • Mechanism by which a signaling-deficient allele impairs neurons not resolved
    • Effector engaged by GAP-resistant N92K in neurons in vivo not pinpointed
  15. 2025 Medium

    Connected the GTPase to regulated cell death by showing it modulates ferroptosis in cancer and prion-affected neurons.

    Evidence SETD8/YBX1 transcriptional axis and KLF1-driven fatty-acid synthesis in cancer; RAC3 depletion in CJD cortex with ferroptosis assays

    PMID:38987564 PMID:39376007 PMID:40562790

    Open questions at the time
    • Direct molecular link between Rac3 and ferroptotic machinery undefined
    • Opposing pro- and anti-ferroptotic roles across contexts unreconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the divergent C-terminal/polybasic region of the Rac3 GTPase encodes its perinuclear localization and non-redundant effector selection at structural resolution, and how nucleotide state intersects with FBXL19-mediated turnover, remain unresolved.
  • No high-resolution structure linking C-terminus to localization
  • Integration of turnover, prenylation, and nucleotide cycling unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 6 GO:0140110 transcription regulator activity 5 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-9612973 Autophagy 2 R-HSA-392499 Metabolism of proteins 1
Partners
BCRCIBFBXL19GIT1MLK2NEURABIN IPAK1VAV2
Complex memberships
AIF/Hsp90/dynein cytoplasmic complex (coactivator)SCF(FBXL19) E3 ubiquitin ligase (substrate)

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 RAC3 (receptor-associated coactivator 3) was identified as a transcriptional coactivator for steroid/nuclear receptors. It interacts with several ligand-bound receptors through their ligand-dependent activation domains (AF-2), can activate transcription when tethered to a heterologous DNA-binding domain, and overexpression enhances ligand-dependent transcriptional activation in mammalian cells. RAC3 is related to SRC-1 and TIF2, placing it in the p160 coactivator family. Cloning, co-immunoprecipitation, mammalian cell transfection/reporter assays, sequence analysis Proceedings of the National Academy of Sciences of the United States of America High 9238002
1997 Rac3 (the small GTPase, distinct from the coactivator RAC3) is a novel Rho family member with GTPase activity regulated by Bcr. Constitutively activated Rac3 efficiently stimulates the c-Jun N-terminal kinase (JNK) signaling pathway. Rac3 protein levels are serum-inducible. Rac3 differs from Rac1/2 at its carboxyl-terminal end, a domain associated with subcellular localization and binding to cellular regulators. Molecular cloning, GTPase activity assay, Bcr-GAP assay, JNK reporter assay, serum stimulation experiments, chromosomal mapping The Journal of biological chemistry High 9252344
2000 Endogenous, hyperactive Rac3 (small GTPase) is present in highly proliferative human breast cancer cell lines due to its distinct membrane localization and altered regulatory factors affecting guanine nucleotide state. Active Rac3 drives persistent kinase activity of PAK (p21-activated kinase) isoforms and JNK via two separate pathways. Only the Rac3-PAK pathway—not the Rac3-JNK pathway—is critical for DNA synthesis in breast cancer cells. GTPase activity assay (pull-down), dominant-negative mutant transfection, kinase assays, subcellular fractionation, DNA synthesis assay Proceedings of the National Academy of Sciences of the United States of America High 10618392
2000 The nuclear receptor coactivator RAC3 functions as a coactivator of NF-κB by binding to the active form of NF-κB. Overexpression of RAC3 restores GR-dependent transcription and negates GR/NF-κB transrepression. Competition between GR and NF-κB for RAC3 binding is proposed as a mechanism for mutual transcriptional antagonism. Co-immunoprecipitation, reporter gene assays, overexpression experiments in mammalian cells FEBS letters Medium 11094166
2000 Genetic disruption of SRC-3/RAC3 (p160 coactivator) in mice results in dwarfism, delayed puberty, reduced female reproductive function, and blunted mammary gland development, demonstrating in vivo roles in growth hormone regulation and estrogen production pathways. Gene knockout in mice, hormonal analysis, phenotypic characterization Proceedings of the National Academy of Sciences of the United States of America High 10823921
2001 Activated Rac3 (V12Rac3) specifically interacts with CIB, a protein that binds the α(IIb)β(3) fibrinogen receptor, but not with Rac1 or Rac2. This interaction requires the C-terminal end of Rac3 and Rac3 membrane localization. Co-expression of V12Rac3 and CIB stimulates α(IIb)β(3)-mediated adhesion and spreading on fibrinogen; adhesion through α(IIb)β(3) specifically activates endogenous GTP-bound Rac3. Co-immunoprecipitation, co-localization by immunofluorescence, Triton-insoluble fractionation, cell adhesion/spreading assay, GTPase pull-down The Journal of biological chemistry High 11756406
2002 Activated Rac3 interacts with NRBP (a protein containing a kinase-homology domain with associated kinase activity) in a GTP-dependent manner. NRBP and activated Rac3 co-localize at endomembranes and at the cell periphery in lamellipodia. Overexpression of NRBP causes redistribution of the Golgi marker p58, consistent with impairment of ER-to-Golgi transport, but does not activate JNK, p38, or actin rearrangements. Yeast two-hybrid, co-immunoprecipitation in COS cells, immunocytochemistry/co-localization, kinase activity assay International journal of molecular medicine Medium 11956649
2003 Rac3 (small GTPase) induces transformation (focus formation and anchorage-independent growth) and membrane ruffling. Effector domain mutant analysis shows that multiple effector pathways are required for anchorage-independent growth by Rac3. Rac3 activates phospholipase Cβ2 and signals to the serum response factor (SRF). Rac3 binds poorly to MLK2 and MLK3, which distinguishes it from Rac1. Transcription of cyclin D1 correlated with anchorage-independent growth. Effector domain mutagenesis, luciferase reporter assays, GST pull-down assays, focus formation and soft agar assays Cancer research High 16267012
2003 Constitutively active V12Rac3 expression in mammary epithelium (MMTV-V12Rac3 transgenic mice) leads to elevated PAK1 phosphorylation, impaired lactational differentiation, defective postlactational involution (persistent epithelial islands), increased p38 MAPK phosphorylation after weaning, and lymphocyte infiltration—demonstrating that sustained Rac3-PAK1 and Rac3-p38 MAPK signaling disrupts mammary gland physiology in vivo. Transgenic mouse model (MMTV promoter), immunoblotting for PAK1 phosphorylation and p38 MAPK activation, histological analysis Cells, tissues, organs Medium 14605486
2003 Rac3 (small GTPase) co-localizes with actin filaments in developing brain, specifically with the terminal portions of calbindin-positive Purkinje cell axons in the deep cerebellar nuclei, implicating Rac3 in actin-mediated remodeling of Purkinje cell neuritic terminals during synaptogenesis. Rac3 and Rac1 show distinct subcellular distributions in the developing brain. Rac3-specific antibodies, immunofluorescence/co-localization with actin, pre- and post-synaptic markers, GFAP, calbindin; western blotting The European journal of neuroscience Medium 14622142
2003 Posttranslational geranylgeranylation of Rac1 and Rac3 (small GTPases) is required for their membrane-ruffling and transforming activities. C-terminal farnesylated versions of both activated and wild-type Rac1 and Rac3 are resistant to GGTI inhibition, identifying these proteins as physiological targets of geranylgeranyltransferase I inhibitors. C-terminal isoprenoid-switching mutagenesis, GGTI treatment, focus formation, membrane ruffling assay, c-Jun transcriptional reporter Cancer research Medium 14633727
2005 In Rac3 knockout mice, Bcr/Abl-induced lymphoblastic leukemia showed specifically activated Rac3 (not Rac1 or Rac2) in malignant precursor B-lineage lymphoblasts. Female P190 BCR/ABL transgenic mice lacking rac3 had longer average survival, directly demonstrating a stimulatory in vivo role for Rac3 in leukemia. Gene targeting (rac3 null mice), GTPase activation pull-down from primary lymphoma lysates, survival analysis of transgenic leukemia model Molecular and cellular biology High 15964830
2005 Rac3 knockout mice are viable and fertile with no obvious developmental defects but show superior motor coordination and learning on rotarod compared to wild-type littermates, revealing a specific behavioral function of Rac3 in the nervous system that is not compensated by Rac1. Gene targeting, rotarod behavioral test, histological and immunohistological analysis Molecular and cellular biology High 15964829
2005 siRNA-mediated depletion of Rac3 (small GTPase) strongly inhibits invasion of SNB19 glioblastoma and BT549 breast carcinoma cells without affecting lamellipodia formation or substantially affecting cell migration. Rac1 depletion strongly inhibits lamellipodia formation and migration, revealing non-overlapping roles for these GTPases in invasion. siRNA knockdown, invasion assay, migration assay, lamellipodia quantification Oncogene High 16027728
2006 Rac3-induced neuritogenesis requires binding to Neurabin I (a neuronal F-actin binding protein). Neurabin I co-partitions and co-localizes with Rac3 at growth cones, inducing Neurabin I association to the cytoskeleton. Antisense knockdown of Neurabin I abolishes Rac3-induced neuritogenesis, which is rescued by exogenous Neurabin I but not by a Neurabin I mutant lacking the Rac3-binding domain. Yeast two-hybrid, co-localization, biochemical fractionation, antisense oligonucleotide knockdown, rescue with deletion mutant Molecular biology of the cell High 16525025
2006 Nuclear localization of the coactivator RAC3 is mediated by a bipartite NLS located within the conserved bHLH domain, and nuclear import requires importin α3. Mutation of basic amino acids in the NLS abolishes nuclear localization. Cytoplasmic-restricted RAC3 loses transcriptional coactivator function, demonstrating that nuclear localization is essential for coactivator activity. NLS mutagenesis, EGFP-fusion nuclear import assay, co-immunoprecipitation with importin α3, transcriptional reporter assay Biochemical and biophysical research communications High 16875678
2006 RAC3 (p160 coactivator) up-regulates the transactivation activity of the Nrf2 transactivation domain in a dose-dependent manner. Dominant-negative RAC3 mutants dampen this effect. Other co-regulators (CBP/p300, CARM1, PRMT1, p/CAF) also activate Nrf2 TAD, and show synergistic effects in combination with RAC3. Gal4-Nrf2-luciferase reporter system, dominant-negative mutagenesis, overexpression in HepG2 cells Journal of biochemistry and molecular biology Medium 16756760
2007 Rac3 (small GTPase) and Rac1 have opposing functions in neuronal N1E-115 cells: Rac1 depletion decreases cell-matrix adhesions and causes cell rounding, whereas Rac3 depletion induces stronger adhesions and increases neurite-like protrusion outgrowth. Residues 185–187 in the polybasic C-terminal region determine the functional difference and the distinct intracellular localization (Rac1 at plasma membrane, Rac3 predominantly perinuclear). Rac3's opposing function on cell adhesion is not mediated by RhoA signaling but acts through negatively affecting integrin-mediated cell-matrix adhesions. siRNA knockdown, C-terminal chimera/mutant analysis, immunofluorescence localization, adhesion and morphology assays, RhoA epistasis experiments Journal of cell science High 17244648
2007 Overexpression of the coactivator RAC3 inhibits hydrogen-peroxide-induced apoptosis via enhanced NF-κB activity, inhibition of caspase-9 activation, diminished nuclear AIF localization, increased AKT and p38 kinase activities, and inhibition of ERK2. RAC3 was found in a cytoplasmic protein complex containing AIF, Hsp90, and dynein, suggesting a role in cytoplasmic-to-nuclear transport of these proteins. Overexpression, co-immunoprecipitation (RAC3 with AIF/Hsp90/dynein), kinase activity assays, apoptosis assays, immunofluorescence for AIF localization Oncogene Medium 17968310
2009 Rac3 (small GTPase) interacts with GIT1 (a multifunctional Arf-GAP protein), but unlike Rac1-GIT1, the Rac3-GIT1 interaction is not mediated by βPix. Rac3 expression severely attenuates GIT1-paxillin interaction, causing defective paxillin distribution and focal adhesion formation. Rac3 also reduces Arf6 activity; wild-type Arf6 or the Arf6-GEF ARNO rescues cell spreading in Rac3-expressing cells. Thus Rac3 opposes Rac1-induced adhesion by differently modulating GIT1 signaling. Co-immunoprecipitation, Arf6 GTPase activity assay, immunofluorescence, rescue experiments with Arf6/ARNO Journal of cell science High 19494130
2011 siRNA knockdown of Rac3 (small GTPase, not coactivator), but not of Rac1 or Rac2, induces autophagy. Ectopic expression of Rac3 significantly rescues cells from autophagy and cell death induced by isoprenylcysteine carboxylmethyltransferase (Icmt) inhibition, identifying Rac3 as an isoform-specific negative regulator of autophagy. siRNA knockdown (Rac1, Rac2, Rac3), Icmt inhibition, autophagy assays, ectopic expression rescue experiments The Journal of biological chemistry High 21852230
2011 RAC3 (small GTPase) acts as a ligand-specific co-activator of ERα, existing in a GTP-bound state in the nucleus. RAC3 overexpression induces pro-growth and pro-migratory gene expression and increases ERα-positive breast cancer cell migration. Chemical inhibition and genetic knockdown of RAC3 antagonize E2-induced cell proliferation, migration, and ERα-mediated gene expression. T7 phage display screen against full-length ERα, genome-wide exon array, cell-based co-activator assays, GTP-binding assay, siRNA knockdown, migration assay Oncogene Medium 21217774
2012 RAC3 (nuclear receptor coactivator) overexpression inhibits autophagy induced by starvation or rapamycin through both nuclear translocation-dependent and -independent mechanisms. Hypoxia suppresses RAC3 gene expression, leading to autophagy activation in tumor cells. Overexpression and knockdown experiments, autophagy markers (LC3, etc.), rapamycin/starvation induction, nuclear fractionation Cancer science Medium 22957814
2012 RAC3 (nuclear coactivator) directly binds Nrf2 protein in the nucleus. GST pull-down identified that both RAC3-PasB (N-terminal) and RAC3-R3B3 (C-terminal) domains bind to Neh4 and Neh5 transactivation domains of Nrf2. Chromatin immunoprecipitation showed RAC3 binds to the ARE enhancer region of the HO-1 promoter via Nrf2. Co-immunoprecipitation, FRET analysis, GST pull-down with domain mapping, chromatin immunoprecipitation (ChIP), HO-1 reporter assay Oncogene High 22370642
2013 Rac3 (small GTPase) depletion in invasive MDA-MB-231 breast cancer cells (but not non-invasive MCF-7 cells) reduces invasion, cell adhesion to collagen, and increases TNF-induced apoptosis. The mechanism involves a Rac3/ERK-2/NF-κB signaling pathway responsible for MMP-9 secretion and cytokine (IL-6, IL-8, GRO) production and resistance to apoptosis. siRNA knockdown, invasion assay, adhesion assay, apoptosis assay, cytokine secretion profiling, western blotting for NF-κB and ERK BMC cancer Medium 23388133
2014 FBXL19 (an F-box protein within the SCF E3 ubiquitin ligase complex) interacts with Rac3 (small GTPase), polyubiquitinates it, and targets it for proteasomal degradation. Lysine 166 in Rac3 was identified as the ubiquitination acceptor site. C-terminal truncation of FBXL19 abolishes its interaction with and ubiquitination of Rac3. Rac3 degradation by FBXL19 attenuates TGFβ1-induced E-cadherin downregulation in esophageal cancer cells. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K166), FBXL19 truncation mutants, immunoblotting, immunostaining Molecular cancer High 24684802
2017 Phosphorylated cortactin (pY421/pY466) recruits the Vav2 guanine nucleotide exchange factor via Vav2's SH2 domain to invadopodia. Vav2 activates Rac3 at invadopodia (shown by a Rac3 biosensor). Rac3 knockdown reduces matrix degradation by invadopodia; constitutively active Rac3 rescues invadopodium function in Vav2-knockdown cells. Thus phospho-cortactin→Vav2→Rac3 is a defined signaling axis promoting invadopodial maturation and invasion. SH2 domain screen (comprehensive human SH2 binding assay), co-immunoprecipitation, Rac3 FRET biosensor, siRNA knockdown, rescue with constitutively active Rac3, matrix degradation assay Molecular biology of the cell High 28356423
2017 Rac3 (small GTPase) regulates cell invasion, migration, and EMT in lung adenocarcinoma via the p38 MAPK pathway. Rac3 knockdown decreases p38 MAPK activity, E-cadherin expression increases, and vimentin decreases. A p38 MAPK inhibitor (LY2228820) phenocopies Rac3 silencing for invasion, migration, and EMT markers. Lentiviral shRNA knockdown, PathScan intracellular signaling array, western blotting, pharmacological inhibition (LY2228820), invasion/migration assay Journal of Cancer Medium 28900489
2018 De novo missense variants in RAC3 (small GTPase) at conserved residues cause a novel neurodevelopmental syndrome with severe intellectual disability and brain malformations. In silico modeling and comparison to somatic cancer-associated variants support a gain-of-function (constitutive activation) mechanism. Genome sequencing, international data-sharing for variant identification, in silico protein modeling Genetics in medicine Medium 30293988
2021 Rac3 protein in hippocampal neurons is distributed mainly in the cytoplasm but is also found in axons and dendrites with partial synaptic localization, as confirmed by biochemical fractionation. In cerebral cortex, Rac3 is distributed strongly in axons and moderately in cytoplasm at postnatal days 2 and 18. Immunoblotting with tissue-specific expression profiling, biochemical fractionation, immunofluorescence of brain slices and cultured neurons Developmental neuroscience Medium 34839287
2022 Multiple de novo RAC3 variants cause neurodevelopmental disorder. In vitro analyses showed all tested variants are biochemically and biologically active with variable affinity for downstream effectors including PAK1. Switch II region variants (Q61L, E62del, D63N, Y64C) in embryonic mouse brain (in utero electroporation) cause cortical neuron migration and morphology defects; defective migration by E62del, D63N, and Y64C was rescued by dominant-negative PAK1, establishing PAK1 as the key effector downstream of these variants. In vitro GTPase/effector binding biochemical assays, in utero electroporation, cortical neuron migration analysis, dominant-negative PAK1 rescue Brain High 35851598
2022 The p.F28S variant of RAC3 (small GTPase) has increased intrinsic GTP/GDP-exchange activity (spontaneously activated) and binds downstream effectors PAK1 and MLK2. In hippocampal neurons it suppresses differentiation and causes cell rounding with lamellipodia. In utero electroporation shows migration defects of excitatory neurons and axon growth delay; migration defects were rescued by dominant-negative PAK1 but not MLK2, implicating PAK1 as the critical downstream effector. In vitro GDP/GTP exchange assay, effector pull-down (PAK1, MLK2), primary hippocampal neuron culture, in utero electroporation, dominant-negative rescue Journal of medical genetics High 35595279
2023 METTL3 in NSCLC cells mediates CAF-promoted migration/invasion by increasing m6A modification of RAC3 mRNA, resulting in increased RAC3 mRNA stability and translation. Elevated RAC3 promotes cell migration via the AKT/NF-κB pathway. m6A methylation assay, METTL3 knockdown, mRNA stability assay, western blotting, transwell migration/invasion, in vivo xenograft International journal of biological sciences Medium 37056933
2024 The RAC3 p.R66W variant exhibits modestly enhanced intrinsic GDP/GTP exchange and impaired GTP hydrolysis. It interacts with downstream effectors PAK1, MLK2, and N-WASP but fails to activate SRF-, AP1-, and NFκB-mediated transcription. In vivo (in utero electroporation), RAC3-R66W impairs cortical neuron migration and axonal elongation. GDP/GTP exchange assay, GTP hydrolysis assay, effector pull-down (PAK1, MLK2, N-WASP), luciferase reporter assay, primary hippocampal neuron differentiation, in utero electroporation Cells High 39682779
2024 SETD8 facilitates nuclear translocation of YBX1 (through post-transcriptional mechanisms), which then transcriptionally upregulates RAC3 in Ewing's sarcoma cells, thereby inhibiting apoptosis and ferroptosis. Knockdown of SETD8 reduces RAC3 expression and promotes apoptosis and ferroptosis. RNA-seq, mass spectrometry proteomics, RNA interference, in vivo xenograft, SETD8 inhibitor (UNC0379) Cell death & disease Medium 38987564
2024 KLF1 acts as an upstream transcriptional activator of RAC3 in bladder cancer cisplatin-resistant cells (confirmed by dual-luciferase and ChIP assays). RAC3 overexpression increases fatty acid synthesis (via FASN and DGAT2) and promotes cisplatin resistance; FASN inhibitor Orlistat mitigates RAC3-mediated cisplatin resistance. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA/overexpression, FASN inhibitor treatment, cisplatin resistance assay American journal of men's health Medium 39376007
2025 RAC3 (small GTPase) facilitates prion-induced ferroptosis in neuronal cells. Depletion of RAC3 was observed in pathologically afflicted cortices of CJD patients. In experimental settings, RAC3 enhances ferroptotic susceptibility downstream of PrPC signaling. Analysis of CJD patient cortex samples, RAC3 depletion experiments, ferroptosis marker assays Nature communications Medium 40562790
2025 The RAC3 p.T17R variant shows markedly increased GDP/GTP exchange, preference for GDP binding, undetectable GTP hydrolysis, and minimal binding to canonical RAC effectors (PAK1, MLK2, N-WASP), failing to activate SRF-, NFκB-, or AP1-dependent transcription. Neuronal overexpression impairs axon formation, delays cortical neuron migration, and reduces dendritic arborization in vivo. This represents a signaling-deficient allele distinct from canonical gain-of-function variants. GDP/GTP exchange assay, GTP hydrolysis assay, effector pull-down, luciferase reporter assay, primary hippocampal neuron morphology, in utero electroporation Cells High 41090727
2025 The RAC3 p.N92K variant (located outside core functional P-loop/switch regions) is resistant to GAP-mediated inactivation, responsive to GEF activation, and binds PAK1, MLK2, and Rho-kinase 1. It activates SRF, NFκB, and AP1 gene expression. In vivo (in utero electroporation), it causes cortical neuron migration defects and periventricular clustering, and impairs axon elongation. Biochemical GAP assay, GEF activation assay, effector pull-down, luciferase reporter assay, structural modeling, in utero electroporation The Journal of biological chemistry High 40015633
2025 CCR7, a chemokine receptor, localizes to invadopodia in breast cancer cells. Tyrosine phosphorylation of CCR7 directs recruitment of Vav2 to invadopodia, which activates Rac3 and promotes cancer cell invasion across lymphatic endothelium. This CCR7→Vav2→Rac3 axis mediates lymphatic metastatic dissemination. Immunofluorescence co-localization, phospho-CCR7 assay, Vav2 recruitment assay, Rac3 activation assay, invasion across lymphatic endothelium assay bioRxivpreprint Medium

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proceedings of the National Academy of Sciences of the United States of America 495 9238002
2000 The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proceedings of the National Academy of Sciences of the United States of America 434 10823921
1997 Characterization of RAC3, a novel member of the Rho family. The Journal of biological chemistry 211 9252344
2000 Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway. Proceedings of the National Academy of Sciences of the United States of America 204 10618392
2005 Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Oncogene 202 16027728
2005 Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells. Breast cancer research : BCR 106 16280046
2000 RAC-3 is a NF-kappa B coactivator. FEBS letters 106 11094166
2005 Generation and characterization of Rac3 knockout mice. Molecular and cellular biology 99 15964829
2013 Rac3 induces a molecular pathway triggering breast cancer cell aggressiveness: differences in MDA-MB-231 and MCF-7 breast cancer cell lines. BMC cancer 94 23388133
2012 The nuclear cofactor RAC3/AIB1/SRC-3 enhances Nrf2 signaling by interacting with transactivation domains. Oncogene 94 22370642
2003 The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription. Oncogene 73 12569362
2003 Differential distribution of Rac1 and Rac3 GTPases in the developing mouse brain: implications for a role of Rac3 in Purkinje cell differentiation. The European journal of neuroscience 72 14622142
2001 The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading. The Journal of biological chemistry 58 11756406
2014 F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation. Molecular cancer 56 24684802
2003 Rac1 and Rac3 are targets for geranylgeranyltransferase I inhibitor-mediated inhibition of signaling, transformation, and membrane ruffling. Cancer research 52 14633727
2007 The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action. Oncogene 49 17968310
2022 Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes. Brain : a journal of neurology 47 35851598
2020 RAC3 Promotes Proliferation, Migration and Invasion via PYCR1/JAK/STAT Signaling in Bladder Cancer. Frontiers in molecular biosciences 47 33062641
2005 Generation of rac3 null mutant mice: role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia. Molecular and cellular biology 46 15964830
2007 Rac1 and Rac3 have opposing functions in cell adhesion and differentiation of neuronal cells. Journal of cell science 42 17244648
2018 De novo missense variants in RAC3 cause a novel neurodevelopmental syndrome. Genetics in medicine : official journal of the American College of Medical Genetics 41 30293988
2017 Phosphorylated cortactin recruits Vav2 guanine nucleotide exchange factor to activate Rac3 and promote invadopodial function in invasive breast cancer cells. Molecular biology of the cell 40 28356423
2017 Rac3 Regulates Cell Invasion, Migration and EMT in Lung Adenocarcinoma through p38 MAPK Pathway. Journal of Cancer 37 28900489
2019 The Rac3 GTPase in Neuronal Development, Neurodevelopmental Disorders, and Cancer. Cells 36 31514269
2006 Regulation of Nrf2 transactivation domain activity by p160 RAC3/SRC3 and other nuclear co-regulators. Journal of biochemistry and molecular biology 36 16756760
2023 Cancer-associated fibroblasts promote migration and invasion of non-small cell lung cancer cells via METTL3-mediated RAC3 m6A modification. International journal of biological sciences 34 37056933
2011 A role for Rac3 GTPase in the regulation of autophagy. The Journal of biological chemistry 33 21852230
2011 RAC3 is a pro-migratory co-activator of ERα. Oncogene 32 21217774
2007 RAC3 down-regulation sensitizes human chronic myeloid leukemia cells to TRAIL-induced apoptosis. FEBS letters 30 17927986
2022 Gain-of-function p.F28S variant in RAC3 disrupts neuronal differentiation, migration and axonogenesis during cortical development, leading to neurodevelopmental disorder. Journal of medical genetics 28 35595279
2022 RAC3 Inhibition Induces Autophagy to Impair Metastasis in Bladder Cancer Cells via the PI3K/AKT/mTOR Pathway. Frontiers in oncology 28 35847878
2015 Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks. Cerebral cortex (New York, N.Y. : 1991) 28 26582364
2017 RAC3 influences the chemoresistance of colon cancer cells through autophagy and apoptosis inhibition. Cancer cell international 26 29209153
2002 Interaction of the small GTPase Rac3 with NRBP, a protein with a kinase-homology domain. International journal of molecular medicine 26 11956649
2009 Rac3 inhibits adhesion and differentiation of neuronal cells by modifying GIT1 downstream signaling. Journal of cell science 24 19494130
2007 Hyperactivity and novelty-induced hyperreactivity in mice lacking Rac3. Behavioural brain research 24 17889944
2003 Targeted expression of activated Rac3 in mammary epithelium leads to defective postlactational involution and benign mammary gland lesions. Cells, tissues, organs 22 14605486
1997 Structure and chromosomal assignment to 22q12 and 17qter of the ras-related Rac2 and Rac3 human genes. Genomics 21 9299243
2019 Rac1 and Rac3 GTPases differently influence the morphological maturation of dendritic spines in hippocampal neurons. PloS one 20 31369617
2005 Expression of Rac3 in human brain tumors. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 20 15993075
2000 The small GTPase RAC3 gene is located within chromosome band 17q25.3 outside and telomeric of a region commonly deleted in breast and ovarian tumours. Cytogenetics and cell genetics 20 10894930
2015 Silencing of Rac3 inhibits proliferation and induces apoptosis of human lung cancer cells. Asian Pacific journal of cancer prevention : APJCP 19 25854406
2011 Rac1 and Rac3 GTPases regulate the development of hilar mossy cells by affecting the migration of their precursors to the hilus. PloS one 19 21949760
2019 Rac3, but not Rac1, promotes ox-LDL induced endothelial dysfunction by downregulating autophagy. Journal of cellular physiology 18 31332791
2006 Rac3-induced neuritogenesis requires binding to Neurabin I. Molecular biology of the cell 16 16525025
2021 Expression Analyses of Rac3, a Rho Family Small GTPase, during Mouse Brain Development. Developmental neuroscience 14 34839287
2015 RAC3 more than a nuclear receptor coactivator: a key inhibitor of senescence that is downregulated in aging. Cell death & disease 14 26469953
2021 Rac3 Expression and its Clinicopathological Significance in Patients With Bladder Cancer. Pathology oncology research : POR 13 34257551
2005 Rac3-mediated transformation requires multiple effector pathways. Cancer research 13 16267012
2014 The levels of RAC3 expression are up regulated by TNF in the inflammatory response. FEBS open bio 12 24918060
2012 Nuclear receptor coactivator RAC3 inhibits autophagy. Cancer science 12 22957814
2022 Hypomethylated gene RAC3 induces cell proliferation and invasion by increasing FASN expression in endometrial cancer. The international journal of biochemistry & cell biology 11 35917927
1998 Identification of a novel Rac3-interacting protein C1D. International journal of molecular medicine 11 9852280
2006 Nuclear localization of coactivator RAC3 is mediated by a bipartite NLS and importin alpha3. Biochemical and biophysical research communications 10 16875678
2024 Pulsatilla saponin D regulates ras-related C3 botulinum toxin substrate 3 (RAC3) to overcome resistance to paclitaxel in lung adenocarcinoma cells. BMC cancer 7 38200409
2024 An unusual presentation of de novo RAC3 variation in prenatal diagnosis. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 7 38214746
2021 Rac1 and Rac3 have opposite functions in Schwann cells during developmental myelination. Neuroscience letters 7 33812927
2021 Functional relationship between CFTR and RAC3 expression for maintaining cancer cell stemness in human colorectal cancer. Cellular oncology (Dordrecht, Netherlands) 6 33616840
2018 Role of RAC3 coactivator in the adipocyte differentiation. Cell death discovery 6 30062065
2024 Unveiling the role of RAC3 in the growth and invasion of cisplatin-resistant bladder cancer cells. Journal of cellular and molecular medicine 5 38847477
2024 Revealing the mechanisms of RAC3 in tumor aggressiveness, the immunotherapy response, and drug resistance in bladder cancer. Frontiers in oncology 5 39351351
2024 The p.R66W Variant in RAC3 Causes Severe Fetopathy Through Variant-Specific Mechanisms. Cells 5 39682779
2023 Rac1 and Rac3 GTPases and TPC2 are required for axonal outgrowth and migration of cortical interneurons. Journal of cell science 5 36744839
2020 Upregulation of RAC3 in bladder cancer predicts adverse clinical outcome and increased tumor immune response. International journal of clinical and experimental pathology 5 33425095
2024 SETD8 inhibits apoptosis and ferroptosis of Ewing's sarcoma through YBX1/RAC3 axis. Cell death & disease 4 38987564
2018 The inflammatory cytokine TNF contributes with RAC3-induced malignant transformation. EXCLI journal 4 30585274
2017 Study on the molecular mechanism of Rac3 on regulating autophagy in human lung cancer cells. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 4 28534368
2024 KLF1 Activates RAC3 to Mediate Fatty Acid Synthesis and Enhance Cisplatin Resistance in Bladder Cancer Cells. American journal of men's health 3 39376007
2007 [RAC3 nuclear receptor co-activator has a protective role in the apoptosis induced by different stimuli]. Medicina 3 18051230
2025 A p.N92K variant of the GTPase RAC3 disrupts cortical neuron migration and axon elongation. The Journal of biological chemistry 2 40015633
2025 Prion-induced ferroptosis is facilitated by RAC3. Nature communications 2 40562790
2011 [RAC3 overexpression is a transforming and proliferative signal that contributes to tumoral development]. Medicina 2 21296718
2011 Absence of Rac1 and Rac3 GTPases in the nervous system hinders thymic, splenic and immune-competence development. European journal of immunology 2 21469092
2025 Prenatal diagnosis of a de novo 17q25.3 microdeletion encompassing RAC3 and CSNK1D in a fetus associated with partial agenesis of the corpus callosum, small brain volume, micrognathia and total anomalous pulmonary venous return. Taiwanese journal of obstetrics & gynecology 1 40049823
2025 A Pleiotropic and Functionally Divergent RAC3 Variant Disrupts Neurodevelopment and Impacts Organogenesis. Cells 0 41090727
2025 Rac3 promotes proliferation and invasion of endometrial cancer through the AKT/mTOR signalling pathway. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology 0 41123453
2025 Recurrent RAC3 related neuro-rachopathy in a pair of Indian siblings with novel findings: expanding the spectrum of brain anomalies. Clinical dysmorphology 0 41198064
2023 Dispensable role of Rac1 and Rac3 after cochlear hair cell specification. Journal of molecular medicine (Berlin, Germany) 0 37204479

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