Affinage

RAC2

Ras-related C3 botulinum toxin substrate 2 · UniProt P15153

Length
192 aa
Mass
21.4 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAC2 is a hematopoietic-restricted Rho-family GTPase that functions as a molecular switch to coordinate NADPH oxidase activation, actin cytoskeletal remodeling, granule exocytosis, and survival signaling in innate and adaptive immune cells. In the GTP-bound state, RAC2 translocates to the membrane cytoskeleton and directly binds p67phox with ~6-fold selectivity over RAC1, serving as an obligatory activating subunit of the phagocyte NADPH oxidase; it simultaneously drives ARP2/3- and cofilin-dependent actin free barbed end generation for chemotaxis and selectively triggers primary granule exocytosis in neutrophils (PMID:8550629, PMID:10072071, PMID:17954607, PMID:15073033). RAC2 is activated by multiple GEFs—P-Rex1 downstream of Gβγ/PI3K, PLD2 via lipase-independent CRIB-mediated exchange, DOCK2, and Vav1/2—and is stabilized by ALDH2-mediated protection from K48-linked ubiquitination at Lys123 (PMID:16243036, PMID:22106281, PMID:18662984, PMID:35354308). Human RAC2 mutations cause distinct primary immunodeficiency syndromes: the dominant-negative D57N allele cannot bind GTP and sequesters GEFs, while the gain-of-function E62K mutation is GAP-resistant and produces excessive superoxide with T/B lymphopenia (PMID:10758162, PMID:30723080).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1991 High

    Establishing RAC2's post-translational processing: the identity of the lipid modification was unknown for this newly cloned GTPase, and demonstration that Rac2 undergoes geranylgeranylation at the C-terminal CSLL motif established the membrane-targeting mechanism essential for its signaling function.

    Evidence In vitro translation with radiolabeled mevalonate/FPP, site-directed mutagenesis, and chemical analysis of the isoprenoid

    PMID:1903399

    Open questions at the time
    • Whether geranylgeranylation is sufficient for membrane targeting in intact cells
    • Identity of the prenyltransferase acting on Rac2
  2. 1994 High

    Placing RAC2 within the NADPH oxidase assembly pathway: subcellular fractionation showed that Rac2 co-translocates with p47phox and p67phox to the membrane actin cytoskeleton upon neutrophil activation, and that this translocation requires p47phox, establishing Rac2 as an integral component of oxidase assembly.

    Evidence Subcellular fractionation of activated neutrophils including p47phox-deficient CGD cells

    PMID:8120032

    Open questions at the time
    • Whether Rac2 membrane translocation is truly p47phox-dependent or indirect
    • Direct binding partner at the membrane
  3. 1996 High

    Identifying RAC2's direct effector in the oxidase: Rac2 binds p67phox (not p47phox) in a GTP-dependent manner with ~6-fold selectivity over Rac1, and effector-site mutations that abolish p67phox binding also abolish oxidase activity, defining the mechanistic basis for Rac2 selectivity in the respiratory burst.

    Evidence Yeast two-hybrid with Rac2 effector domain mutants; independent fractionation in CGD patient neutrophils showing Rac2 translocation is p67phox/p47phox-independent

    PMID:8550629 PMID:8670049

    Open questions at the time
    • Structural basis for Rac2 vs Rac1 selectivity for p67phox
    • Whether RhoGDI release is rate-limiting
  4. 1997 High

    Defining the GTPase cycle parameters: biochemical characterization showed that activating mutations G12V and Q61L are GAP-insensitive and hydrolyze GTP very slowly, while GEF-mediated exchange requires intact switch 1 and switch 2 regions, establishing the regulatory logic of the Rac2 GTP/GDP cycle.

    Evidence In vitro GTP hydrolysis, GAP, and GEF (smgGDS) exchange assays with purified recombinant Rac2 mutants

    PMID:9012677

    Open questions at the time
    • Physiological GEF identity in neutrophils unknown at this time
    • Structural basis for GAP resistance
  5. 1999 High

    Demonstrating non-redundant in vivo roles: Rac2 knockout neutrophils are defective in chemotaxis, F-actin generation, MAPK activation, and superoxide production, while parallel studies showed fMLP activates Rac2 via Gi-coupled PI3K signaling, establishing Rac2 as the rate-limiting GTPase for multiple specialized neutrophil functions.

    Evidence Rac2 knockout mouse with functional assays; PAK-PBD pulldown with pharmacological inhibitors in human neutrophils

    PMID:10072071 PMID:10364257

    Open questions at the time
    • Degree of overlap with Rac1 in neutrophils
    • Downstream effector specificity for chemotaxis vs oxidase
  6. 2000 High

    Linking RAC2 to human immunodeficiency and broader signaling: the D57N mutation was identified as a cause of neutrophil immunodeficiency through dominant-negative GEF sequestration; simultaneously, Rac2 was shown to activate Akt/BAD/Bcl-XL survival signaling in mast cells and NF-κB/p38 MAPK for TH1 IFN-γ expression, revealing functions beyond the oxidase.

    Evidence Biochemical GTP-binding assays and retroviral expression for D57N; Rac2 KO mast cells for survival pathway; transgenic/KO T cells for IFN-γ promoter studies

    PMID:10758162 PMID:10843388 PMID:10864872 PMID:10961859

    Open questions at the time
    • Whether D57N affects adaptive immunity in patients
    • Rac2-specific effectors in T cell signaling
  7. 2002 High

    Resolving isoform selectivity, C-terminal targeting requirements, and effector coupling: Rac2 is preferentially activated (~4-fold over Rac1) by fMLP; the C-terminal TRQQKRP motif is essential for geranylgeranylation and localization; activated Rac2 stimulates PLCβ2 membrane association via its PH domain; and DOCK2 activates Rac2 downstream of TCR to drive IL-2 transcription.

    Evidence Rac-GTP affinity precipitation with gene dosage; C-terminal deletion mutagenesis with rescue; FRAP of GFP-PLCβ2; co-IP of DOCK2-CD3ζ with Rac2 activation assay

    PMID:12176041 PMID:12176888 PMID:12391220 PMID:12509427

    Open questions at the time
    • Structural basis for preferential activation of Rac2 over Rac1
    • Whether DOCK2-Rac2 axis is the primary GEF pathway in neutrophils
  8. 2003 High

    Establishing isoform-specific roles in phagocytosis and hematopoiesis: conditional double-KO demonstrated that Rac2 uniquely controls superoxide and directed migration while both isoforms cooperate for HSC retention; live-cell FRAP showed GFP-Rac2 continuously exchanges on phagosomes requiring flavocytochrome b558; and Rac2-null macrophages have selective FcγR phagocytosis defects.

    Evidence Conditional Rac1/Rac2 double-KO mice; FRAP in PLB-985 and X-CGD cells during phagocytosis; Rac2-/- macrophage functional assays

    PMID:14564009 PMID:14623873 PMID:15528331

    Open questions at the time
    • Mechanism by which flavocytochrome b558 retains Rac2 at phagosomes
    • Whether HSC egress phenotype is Rac2-specific or requires both isoforms
  9. 2004 High

    Defining spatial activation dynamics and granule selectivity: FRET imaging revealed Rac2 activation is spatially restricted to actin-poor regions during phagosome closure (distinct from Rac1), and Rac2 selectively controls primary but not secondary/tertiary granule exocytosis.

    Evidence Quantitative FRET-based stoichiometry imaging in live macrophages; granule release assays in Rac2-/- neutrophils

    PMID:15073033 PMID:15169870

    Open questions at the time
    • Mechanism of primary granule selectivity
    • Identity of effector linking Rac2 to granule fusion machinery
  10. 2005 High

    Dissecting effector pathway specificity and identifying P-Rex1 as a selective GEF: systematic Rac2 effector domain mutagenesis showed chemotaxis and superoxide are controlled by separable effector interactions; P-Rex1 was identified as a Gβγ/PIP3-regulated GEF with higher affinity for Rac2 than Rac1.

    Evidence Rac2 effector mutant rescue in Rac2-/- neutrophils; P-Rex1-/- mouse with Rac activation assay and co-IP

    PMID:15814684 PMID:16243036

    Open questions at the time
    • Complete effector map for chemotaxis-specific signaling
    • Redundancy between P-Rex1 and other Rac2 GEFs in vivo
  11. 2007 High

    Resolving distinct actin assembly mechanisms: Rac2 drives de novo actin free barbed end generation through cofilin and ARP2/3, while Rac1 mediates barbed end uncapping, establishing isoform-specific control of cytoskeletal remodeling at the leading edge.

    Evidence Free barbed end assay in permeabilized Rac1-/- and Rac2-/- neutrophils maintaining receptor signaling

    PMID:17954607

    Open questions at the time
    • How Rac2 activates cofilin specifically
    • Whether this mechanism operates in non-neutrophil hematopoietic cells
  12. 2008 High

    Expanding RAC2's role to adaptive immunity and defining parallel activation pathways: Rac2 was shown to be specifically required for B cell adhesion and immunological synapse formation via Rap1-GTP downstream of BCR/Src/Vav/PI3K; neutrophil chemotaxis was found to use dual PI3K-dependent and Src-ELMO-DOCK2-dependent Rac2 activation pathways.

    Evidence Rac2-/- B cells with adhesion/synapse assays; pharmacological and genetic pathway dissection in neutrophils including triple Src-family KO mice

    PMID:18191593 PMID:18662984

    Open questions at the time
    • Relative contribution of each parallel pathway in vivo
    • Whether Vav1/2 activates Rac2 directly or indirectly in B cells
  13. 2011 High

    Identifying PLD2 as a lipase-independent Rac2 GEF and extending Rac2 biology to innate immune sensing and neutrophil retention: PLD2 directly catalyzes GDP/GTP exchange on Rac2 via two CRIB motifs with ~3 nM affinity; Rac2 was identified as a mediator of CNF1-triggered innate immunity via Rip1/Rip2; and zebrafish studies established Rac2's role in 3D neutrophil motility and CXCR4-dependent marrow retention.

    Evidence In vitro GEF assay with recombinant proteins, FRET, CRIB deletion mutants; genetic epistasis in mammalian cells and Drosophila; zebrafish live imaging with Rac2D57N and morphants

    PMID:21378159 PMID:22014524 PMID:22018470 PMID:22106281

    Open questions at the time
    • Whether PLD2 GEF activity operates on Rac2 in vivo in neutrophils
    • Structural basis of CRIB-mediated exchange
    • Mammalian validation of CXCR4-Rac2 retention axis
  14. 2014 Medium

    Linking RAC2 to post-transcriptional gene regulation: activated Rac2 interacts with Myosin IIA (Myh9) in monocytes, driving HuR nuclear-to-cytosolic translocation and VEGF-A mRNA stabilization to promote arteriogenesis.

    Evidence Proteomic identification, co-IP, Myh9-/- macrophages, HuR translocation assay, hindlimb ischemia model

    PMID:25180062

    Open questions at the time
    • Whether Rac2-Myh9 interaction is direct or scaffolded
    • Generalizability to other mRNA targets
    • Not independently replicated
  15. 2019 High

    Defining the biochemical basis of gain-of-function immunodeficiency: the E62K mutation retains intrinsic GTPase activity but is resistant to GAP-stimulated hydrolysis, producing constitutively active Rac2 with excessive superoxide, impaired chemotaxis, and T/B lymphopenia—mechanistically distinct from the dominant-negative D57N disease.

    Evidence Biochemical GTPase/GAP assays; Rac2+/E62K knock-in mouse phenotyping; patient neutrophil functional studies

    PMID:30723080

    Open questions at the time
    • How prolonged Rac2-GTP causes lymphopenia
    • Whether other GAP-resistant mutations produce similar phenotypes
  16. 2022 High

    Revealing a non-catalytic stabilization mechanism: ALDH2 directly binds Rac2 and prevents its K48-linked polyubiquitination at Lys123, and the common ALDH2 rs671 variant fails to protect Rac2, impairing macrophage efferocytosis.

    Evidence Co-IP, proteomics, ubiquitination assay, ALDH2-/- bone marrow transplant, Rac2 overexpression rescue

    PMID:35354308

    Open questions at the time
    • Identity of the E3 ligase targeting Rac2 K123
    • Whether ALDH2-Rac2 interaction is relevant in neutrophils
    • Structural basis of ALDH2-Rac2 binding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for Rac2 vs Rac1 selectivity by p67phox and GEFs; the effector(s) linking Rac2 specifically to primary granule fusion; the E3 ubiquitin ligase targeting Rac2 at K123; and how gain-of-function Rac2 mutations cause lymphopenia.
  • No high-resolution structure of Rac2-p67phox complex
  • Primary granule fusion effector unidentified
  • E3 ligase for Rac2 unknown
  • Mechanism of Rac2 GOF-induced lymphopenia unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 3 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5
Partners
ALDH2DOCK2MYH9NCF1NCF2PLCB2PLD2PREX1
Complex memberships
NADPH oxidase (phagocyte)

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Rac2-deficient neutrophils display significant defects in chemotaxis, F-actin generation, p38 and p42/p44 MAP kinase activation induced by chemoattractants, and superoxide production, establishing Rac2 as an essential regulator of multiple specialized neutrophil functions. Rac2 knockout mouse model with functional assays (chemotaxis, F-actin, MAPK activation, superoxide production) Immunity High 10072071
1994 Rac2 operates as a component of the neutrophil respiratory burst oxidase; upon neutrophil activation, Rac2 transfers from the cytosol to the submembranous actin cytoskeleton together with p47phox and p67phox, and this transfer requires p47phox. Subcellular fractionation of activated neutrophils, including p47phox-deficient CGD neutrophils The Journal of biological chemistry High 8120032
1996 Rac2 interacts directly with the NADPH oxidase component p67phox in a GTP-dependent manner (not p47phox), and p67phox binds Rac2 approximately 6-fold more strongly than Rac1; Rac2 effector site mutants inactive in NADPH oxidase lose interaction with p67phox. Yeast two-hybrid system with Rac effector mutants The Journal of biological chemistry High 8550629
2000 Human RAC2 D57N mutation (Asp57Asn) binds GDP but not GTP, inhibits NADPH oxidase activation and superoxide production in vitro, and acts as a dominant-negative by sequestering guanine nucleotide exchange factors; it causes neutrophil immunodeficiency with defects in chemotaxis, polarization, granule secretion, and superoxide production. Molecular cloning, in vitro biochemical assay (GTP binding, oxidase reconstitution), retroviral expression in bone marrow cells Proceedings of the National Academy of Sciences of the United States of America High 10758162 10961859
1991 Rac2 undergoes carboxyl-terminal isoprenylation (geranylgeranylation, 20-carbon) at the cysteine in the CAAX-like CSLL motif; the three-amino acid extension distal to the cysteine is required for this modification. In vitro translation with [3H]mevalonate or [3H]farnesyl pyrophosphate, site-directed mutagenesis, Raney nickel hydrolysis/gel permeation chromatography The Journal of biological chemistry High 1903399
1999 Stimulation of human neutrophils with fMLP and LTB4 (Gi-coupled receptors) leads to rapid, transient Rac2 activation via PI3K; PMA activates Rac2 in a PI3K-independent manner. Rac2 activation by fMLP/LTB4 is blocked by pertussis toxin, indicating Gi coupling. PAK-Rac-binding domain pulldown assay for GTP-bound Rac2; pharmacological inhibitors (wortmannin, LY294002, pertussis toxin) The Journal of biological chemistry High 10364257
2000 Rac2 stimulates Akt activation and regulates expression of BAD and Bcl-XL, mediating growth factor-dependent survival as well as actin-based functions (adhesion, migration, degranulation) in mast cells. Rac2 knockout mast cells, survival/proliferation assays, Western blot for Akt activation and Bcl-2 family members Immunity High 10843388
2000 Rac2 activates IFN-γ promoter through cooperative activation of NF-κB and p38 MAPK pathways, driving TH1 differentiation; constitutively active Rac2 transgenic T cells show enhanced IFN-γ production, and Rac2-/- T cells show decreased IFN-γ under TH1 conditions. Constitutively active Rac2 transgenic mice, Rac2 KO mice, dominant-negative Rac expression, IFN-γ promoter assays Science (New York, N.Y.) High 10864872
2003 Rac2 (but not Rac1) regulates superoxide production and directed migration in neutrophils; both Rac1 and Rac2 deletion causes massive egress of hematopoietic stem/progenitor cells from marrow; distinct non-redundant roles established for the two isoforms. Conditional double-knockout mouse model; functional assays for superoxide, migration, actin organization, HSC engraftment Science (New York, N.Y.) High 14564009
2004 Rac2 activation during FcγR-mediated phagocytosis is spatially and temporally distinct from Cdc42 and Rac1; Rac2 activation increases uniformly and transiently in the actin-poor region of phagosomal membrane during phagosome closure, distinct from Rac1 which is active throughout the phagocytic cup. FRET-based stoichiometry imaging in live macrophages using fluorescent chimeras of Rac2, PBD, and actin Molecular biology of the cell High 15169870
2004 Rac2 is selectively required for primary granule (myeloperoxidase, elastase, CD63) exocytosis in neutrophils in response to chemoattractants; secondary and tertiary granule release are normal in Rac2-null neutrophils. Rac2 knockout bone marrow neutrophils; granule release assays, confocal microscopy for CD63 mobilization Blood High 15073033
2005 P-Rex1 (a Gβγ- and PIP3-regulated GEF) preferentially activates Rac2 over Rac1 in mouse neutrophils downstream of fMLP; P-Rex1 shows higher affinity for Rac2 than Rac1 by co-immunoprecipitation with dominant-negative isoforms. P-Rex1 knockout mouse; Rac activation assay; co-immunoprecipitation with Rac2(S17N) vs Rac1(S17N) Current biology : CB High 16243036
2005 Rac2 controls chemotaxis and superoxide production via distinct effector pathways: Rac2 mutants V36A, F37A, N39A bind PAK1 and p67phox but cannot rescue either function; N43A (binds Por1/Arfaptin2, p67phox, PAK1) rescues superoxide but not chemotaxis; Y40C (no effector binding) rescues myeloid colony growth but not migration or superoxide. Rac2 effector domain mutagenesis, retroviral expression in Rac2-/- neutrophils, functional rescue assays Journal of immunology (Baltimore, Md. : 1950) High 15814684
2002 Chemoattractant fMLP preferentially activates Rac2 (~4-fold more Rac2-GTP than Rac1-GTP) in wild-type neutrophils; Rac2 is rate-limiting for fMLP-stimulated F-actin, chemotaxis, and superoxide production, as shown by gene dosage effects in heterozygous Rac2+/- neutrophils. Affinity precipitation assay for Rac-GTP in wild-type, Rac2-/-, and Rac2+/- neutrophils Journal of immunology (Baltimore, Md. : 1950) High 12391220
2007 Rac2 mediates cofilin- and ARP2/3-dependent free barbed end generation downstream of fMLP receptor, while Rac1 mediates uncapping of existing barbed ends; these two isoforms regulate distinct actin assembly mechanisms at the leading edge. Neutrophil permeabilization model maintaining receptor signaling; free barbed end assay in Rac1-/- and Rac2-/- neutrophils The Journal of cell biology High 17954607
2001 Rac2 D57N displays markedly enhanced GTP dissociation rate (~10% GTP binding vs wild-type), does not respond to guanine nucleotide exchange factors, and sequesters endogenous GEFs to dominantly suppress Rac1 and Rac2 activity in hematopoietic cells. In vitro GTP binding kinetics with recombinant Rac2 D57N; retroviral expression in primary murine bone marrow cells The Journal of biological chemistry High 11278678
2002 The TRQQKRP motif near the C-terminus of Rac2 is essential for efficient geranylgeranylation and correct intracellular localization; deletion of this motif reduces prenylation, delocalizes Rac2, and abolishes rescue of Rac2-deficient neutrophil functions. Deletion mutagenesis, retroviral expression in Rac2-/- cells, prenylation assays, confocal localization Blood High 12176888
2002 Activated Rac2 (constitutively active Rac2(12V)) stimulates PLCβ2 activity and enhances its membrane association via the PLCβ2 N-terminal PH domain; Rac2 dramatically increases the exchange component of PLCβ2 fluorescence recovery at the plasma membrane. FRAP of GFP-PLCβ2 chimeras in live cells with constitutively active Rac2(12V); PH domain deletion mutants The Journal of biological chemistry High 12509427
1997 Rac2 G12V and Q61L activating mutants hydrolyze GTP very slowly and are unresponsive to p190 Rac-GAP; guanine nucleotide exchange by smgGDS requires intact switch 1 and switch 2 regions of Rac2; G12V mutation functionally interacts with switch regions. In vitro GTP hydrolysis assays, GAP assays, GEF (smgGDS) exchange assays with purified recombinant Rac2 mutants Biochemistry High 9012677
2008 PKC phosphorylates gp91phox/NOX2, enhancing its diaphorase activity and its binding to Rac2, p67phox, and p47phox; PKC-mediated phosphorylation is a novel mechanism of NADPH oxidase complex assembly and activation. In vitro PKC phosphorylation of recombinant gp91phox cytosolic domain; 2D tryptic peptide mapping; binding assays FASEB journal High 19028840
2011 PLD2 functions as a guanine nucleotide exchange factor (GEF) for Rac2: PLD2 directly binds Rac2 via two CRIB motifs in its PH/PX domains, stimulates GDP dissociation and GTP association on Rac2, and this GEF function is catalysis-independent (lipase-dead PLD2-K758R retains GEF activity). In vitro GEF assay with purified recombinant proteins; co-immunoprecipitation; FRET in live cells; PLD2 CRIB deletion mutants Proceedings of the National Academy of Sciences of the United States of America High 22106281
2011 PLD2 contains two CRIB motifs (CRIB-1 and CRIB-2) in/around the PH domain that specifically bind Rac2; the PLD2-Rac2 interaction has an apparent Kd of ~3 nM, is preferential for Rac2-GTP over Rac2-GDP, and is required for PLD2-mediated Rac2 activation in cells. Co-immunoprecipitation, FRET with CFP-Rac2/YFP-PLD2, in vitro binding with recombinant proteins, CRIB deletion mutants The Journal of biological chemistry High 21378159
2008 Rac2 is activated downstream of Src-family kinases, Vav1/Vav2, and PI3K after BCR engagement; Rac2 (but not Rac1) is specifically required for B cell adhesion to ICAM-1 and immunological synapse formation, acting upstream of Rap1-GTP and actin polymerization. Rac2-/- B cells; constitutively active Rac2 expression; Rac2 activation assay; adhesion and synapse formation assays Immunity High 18191593
1996 In p67phox-deficient CGD neutrophils, Rac2 translocates to the membrane independently of p67phox; in p47phox-deficient neutrophils, Rac2 also translocates independently of p47phox, while p67phox translocation requires p47phox. Subcellular fractionation of stimulated neutrophils from CGD patients lacking p67phox or p47phox The Biochemical journal High 8670049
2003 GFP-Rac2 continuously exchanges between phagosomal membrane and cytosol during phagocytosis (high FRAP turnover); this exchange does not depend on actin cytoskeleton rearrangement and requires flavocytochrome b558. FRAP of GFP-Rac2 in PLB-985 cells and X-CGD PLB-985 cells during phagocytosis; cytochalasin B treatment The Journal of biological chemistry High 14623873
2005 S100A8 (but not S100A9) directly binds both p67phox and Rac2, and S100A8/A9 promotes NADPH oxidase activation by transferring arachidonic acid as a cofactor; S100A9-null neutrophils show impaired oxidase activity. Protein-protein interaction studies (pulldown/binding); cell-free oxidase assay; S100A9-/- bone marrow neutrophils; S100A8/A9 arachidonic acid-binding mutant FASEB journal High 15642721
2012 Rac2 GTPase alters mitochondrial membrane potential and electron flow through mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high ROS levels in CML leukemia stem cells; Rac2 genetic deletion or small-molecule inhibition reduces MRC-cIII-derived ROS and genomic instability. Genetic deletion and small-molecule inhibition of Rac2; mitochondrial membrane potential assays; ROS measurements; chromosomal aberration analysis Blood Medium 22411871
2011 NCF2-encoded p67phox with a rare missense variant shows reduced binding to RAC2, providing genetic evidence that the RAC2-p67phox interaction is functionally important in vivo for NADPH oxidase activity and IBD susceptibility. Direct sequencing; functional binding assay of variant p67phox with RAC2 Gut Medium 21900546
2008 CXCL8-mediated Rac2 activation and chemotaxis in neutrophils proceeds via two parallel pathways: PI3K-dependent and Src-ELMO-Dock2-dependent; combined inhibition of both pathways severely impairs Rac2 activation and chemotaxis. PI3K inhibitor (wortmannin), Src inhibitor (PP2), Dock2 shRNA knockdown; neutrophils from hck-/-fgr-/-lyn-/- mice; Rac2 activation assay The Journal of biological chemistry Medium 18662984
2002 DOCK2 associates with the CD3ζ subunit of the TCR complex and activates Rac2 in hematopoietic cells; DOCK2-activated Rac2 drives IL-2 promoter activity, and dominant-negative Rac2 suppresses DOCK2-induced IL-2 transcription. Co-immunoprecipitation of DOCK2 with CD3ζ; Rac2 activation assay in 293T and Jurkat cells; IL-2 promoter reporter assay Biochemical and biophysical research communications Medium 12176041
2013 iNOS forms a complex with Rac2 in the cytosol of resting neutrophils; after phagocytosis, the iNOS-Rac2 complex translocates to phagosomes, where it drives NO, superoxide, and ROS/RNS generation and microbial killing. Co-immunoprecipitation; subcellular fractionation; siRNA knockdown of Rac2 and iNOS; iNOS-/- mouse neutrophils Antioxidants & redox signaling Medium 23875749
2014 Activated Rac2 interacts with Myosin IIA heavy chain (Myh9) in monocytes downstream of CCR2 and β2 integrin co-engagement; Rac2-Myh9 interaction drives nuclear-to-cytosolic HuR translocation and VEGF-A mRNA stabilization, mediating arteriogenesis. Proteomic identification of Rac2 interactors; co-immunoprecipitation; Myh9-/- macrophages; HuR translocation assay; hindlimb ischemia model The Journal of experimental medicine Medium 25180062
2011 CNF1 (E. coli effector) modifies Rac2, which then interacts with the innate immune adaptor Rip1-Rip2 in mammalian cells to drive an immune response; this represents effector-triggered immunity via Rac2. Genetic and biochemical analysis in mammalian cells and Drosophila; pathway dissection with IMD/Rip kinase signaling Immunity Medium 22018470
2019 Dominant activating RAC2[E62K] mutation retains intrinsic GTP hydrolysis but renders RAC2 resistant to GAP-stimulated hydrolysis, resulting in prolonged GTP-bound RAC2, excessive superoxide production, impaired fMLF chemotaxis, and T/B cell lymphopenia. Biochemical GTPase assays with GAP; cell line transfection; neutrophil functional assays; Rac2+/E62K knock-in mouse Blood High 30723080
2003 In human monocytes (unlike neutrophils), Rac1 (not Rac2) is the predominant isoform, dissociates from RhoGDI upon activation, translocates to membrane, and interacts with p67phox and p47phox to form the active NADPH oxidase complex. Western blot for Rac isoforms; co-immunoprecipitation of Rac1 with p67phox and p47phox in activated monocytes The Journal of biological chemistry Medium 12912997
2006 AIF-1 interacts with Rac2 in vascular smooth muscle cells (VSMC); Rac2 colocalizes with AIF-1 in the cytoplasm and co-translocates to lamellipodia upon PDGF stimulation; AIF-1 expression leads to Rac2 activation, increased VSMC migration, NADPH oxidase activation, and PAK1/ERK1/2/p38 activation. Bacterial two-hybrid screen; pulldown and colocalization; retroviral Rac2 overexpression in VSMC; kinase activation assays American journal of physiology. Cell physiology Medium 16987989
2003 Rac2-null macrophages have selective defects in FcγR-mediated phagocytosis and NADPH oxidase activity, while CR3-mediated phagocytosis and actin polymerization are normal; peritoneal macrophage accumulation during inflammation is also reduced. Rac2-/- macrophage functional assays (phagocytosis, oxidase, actin polymerization, migration) Journal of immunology (Baltimore, Md. : 1950) High 15528331
2001 Rac2 mediates cross-talk between PI3K and the p21ras-Raf-Mek-ERK pathway in mast cells; Nf1+/- × Rac2-/- genetic intercross shows that Rac2-mediated ERK hyperactivation directly contributes to hyperproliferation of neurofibromin-deficient mast cells. Genetic intercross of Nf1+/- and Rac2-/- mice; in vitro and in vivo mast cell proliferation assays; ERK activation assays The Journal of experimental medicine High 11435472
2022 ALDH2 directly interacts with Rac2 and stabilizes it by attenuating K48-linked polyubiquitination at lysine 123; the ALDH2 rs671 mutant fails to protect Rac2 from degradation, impairing macrophage efferocytosis. Immunoprecipitation; proteomics; ubiquitination assay; ALDH2-/- mouse bone marrow transplant model; Rac2 overexpression rescue Arteriosclerosis, thrombosis, and vascular biology High 35354308
2011 In zebrafish, Rac2 is required for neutrophil 3D motility and polarization of F-actin dynamics and PI3K signaling in vivo; Rac2 also mediates CXCR4-dependent neutrophil retention in hematopoietic tissue, independent of cell motility. Zebrafish Rac2D57N expression and Rac2 morphants; live imaging with photoconversion tracking; epistasis with WHIM syndrome CXCR4 mutation Developmental cell High 22014524

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity 443 10072071
2003 Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science (New York, N.Y.) 398 14564009
2000 Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proceedings of the National Academy of Sciences of the United States of America 343 10758162
2004 Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Molecular biology of the cell 299 15169870
2000 Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood 270 10961859
2003 Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling. Science (New York, N.Y.) 209 14564011
2004 Requirement of Rac1 and Rac2 expression by mature dendritic cells for T cell priming. Science (New York, N.Y.) 196 15326354
1994 Cytosolic guanine nucleotide-binding protein Rac2 operates in vivo as a component of the neutrophil respiratory burst oxidase. Transfer of Rac2 and the cytosolic oxidase components p47phox and p67phox to the submembranous actin cytoskeleton during oxidase activation. The Journal of biological chemistry 167 8120032
2006 Rac1 and Rac2 regulate macrophage morphology but are not essential for migration. Journal of cell science 155 16772332
1999 Phosphoinositide 3-kinase-dependent and -independent activation of the small GTPase Rac2 in human neutrophils. The Journal of biological chemistry 150 10364257
2012 Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors. Blood 148 22411871
2011 NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut 147 21900546
2005 The arachidonic acid-binding protein S100A8/A9 promotes NADPH oxidase activation by interaction with p67phox and Rac-2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 145 15642721
2008 Regulation of the phagocyte NADPH oxidase activity: phosphorylation of gp91phox/NOX2 by protein kinase C enhances its diaphorase activity and binding to Rac2, p67phox, and p47phox. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 137 19028840
2000 Rac2 stimulates Akt activation affecting BAD/Bcl-XL expression while mediating survival and actin function in primary mast cells. Immunity 134 10843388
2000 Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science (New York, N.Y.) 134 10864872
1991 Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA. The Journal of biological chemistry 127 1903399
2008 Activation of the small GTPase Rac2 via the B cell receptor regulates B cell adhesion and immunological-synapse formation. Immunity 125 18191593
2004 Rac2 is critical for neutrophil primary granule exocytosis. Blood 124 15073033
2011 Dual roles for Rac2 in neutrophil motility and active retention in zebrafish hematopoietic tissue. Developmental cell 119 22014524
2008 Identifying the relative contributions of Rac1 and Rac2 to osteoclastogenesis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 115 17922611
2005 P-Rex1 is a primary Rac2 guanine nucleotide exchange factor in mouse neutrophils. Current biology : CB 109 16243036
2014 Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo. PloS one 108 24770346
2004 Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles. Journal of immunology (Baltimore, Md. : 1950) 107 15528331
2002 Chemoattractant-stimulated Rac activation in wild-type and Rac2-deficient murine neutrophils: preferential activation of Rac2 and Rac2 gene dosage effect on neutrophil functions. Journal of immunology (Baltimore, Md. : 1950) 107 12391220
1996 Mechanisms of NADPH oxidase activation: translocation of p40phox, Rac1 and Rac2 from the cytosol to the membranes in human neutrophils lacking p47phox or p67phox. The Biochemical journal 107 8670049
2016 Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production. Arteriosclerosis, thrombosis, and vascular biology 103 27834690
2001 Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. The Journal of experimental medicine 101 11435472
2001 Deficiency of small GTPase Rac2 affects T cell activation. The Journal of experimental medicine 96 11581314
2007 Rac1 and Rac2 differentially regulate actin free barbed end formation downstream of the fMLP receptor. The Journal of cell biology 95 17954607
2002 The Rac2 guanosine triphosphatase regulates B lymphocyte antigen receptor responses and chemotaxis and is required for establishment of B-1a and marginal zone B lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 95 11907095
2008 Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development. Blood 92 18579797
1996 The Rac target NADPH oxidase p67phox interacts preferentially with Rac2 rather than Rac1. The Journal of biological chemistry 92 8550629
1995 Function of wild-type or mutant Rac2 and Rap1a GTPases in differentiated HL60 cell NADPH oxidase activation. Blood 90 7833480
2014 RAC2 loss-of-function mutation in 2 siblings with characteristics of common variable immunodeficiency. The Journal of allergy and clinical immunology 84 25512081
2003 Human monocytes use Rac1, not Rac2, in the NADPH oxidase complex. The Journal of biological chemistry 83 12912997
2011 Pathogen-derived effectors trigger protective immunity via activation of the Rac2 enzyme and the IMD or Rip kinase signaling pathway. Immunity 82 22018470
2005 Drosophila melanogaster Rac2 is necessary for a proper cellular immune response. Genes to cells : devoted to molecular & cellular mechanisms 80 16098145
2002 Repression of rac2 mRNA expression by Anaplasma phagocytophila is essential to the inhibition of superoxide production and bacterial proliferation. Journal of immunology (Baltimore, Md. : 1950) 80 12471136
2001 Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency. The Journal of biological chemistry 77 11278678
2012 Zymosan induces NADPH oxidase activation in human neutrophils by inducing the phosphorylation of p47phox and the activation of Rac2: involvement of protein tyrosine kinases, PI3Kinase, PKC, ERK1/2 and p38MAPkinase. Biochemical pharmacology 66 23085266
2002 Rac2 regulation of phospholipase C-beta 2 activity and mode of membrane interactions in intact cells. The Journal of biological chemistry 65 12509427
2008 Parallel phosphatidylinositol 3-kinase (PI3K)-dependent and Src-dependent pathways lead to CXCL8-mediated Rac2 activation and chemotaxis. The Journal of biological chemistry 59 18662984
2019 Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood 58 30723080
2013 Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders. Experimental cell research 58 23850828
2013 Interaction of inducible nitric oxide synthase with rac2 regulates reactive oxygen and nitrogen species generation in the human neutrophil phagosomes: implication in microbial killing. Antioxidants & redox signaling 56 23875749
2003 Continuous translocation of Rac2 and the NADPH oxidase component p67(phox) during phagocytosis. The Journal of biological chemistry 56 14623873
1997 L-selectin regulates actin polymerisation via activation of the small G-protein Rac2. Biochemical and biophysical research communications 54 9070897
2010 Rac1 and Rac2 GTPases are necessary for early erythropoietic expansion in the bone marrow but not in the spleen. Haematologica 51 20065081
2010 Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo. Blood 49 20407032
2005 Rac2 regulates neutrophil chemotaxis, superoxide production, and myeloid colony formation through multiple distinct effector pathways. Journal of immunology (Baltimore, Md. : 1950) 49 15814684
2002 Rac2-deficient mice display perturbed T-cell distribution and chemotaxis, but only minor abnormalities in T(H)1 responses. Immunology and cell biology 49 12067410
2014 Chemokine-coupled β2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis. The Journal of experimental medicine 48 25180062
2011 RAC2, AEP, and ICAM1 expression are associated with CNS disease in a mouse model of pre-B childhood acute lymphoblastic leukemia. Blood 45 21606482
2010 RtxA1-induced expression of the small GTPase Rac2 plays a key role in the pathogenicity of Vibrio vulnificus. The Journal of infectious diseases 45 19919301
2016 Rac2 Functions in Both Neutrophils and Macrophages To Mediate Motility and Host Defense in Larval Zebrafish. Journal of immunology (Baltimore, Md. : 1950) 44 27837107
2007 Signaling requirements for translocation of P-Rex1, a key Rac2 exchange factor involved in chemoattractant-stimulated human neutrophil function. Journal of leukocyte biology 44 17227822
2005 Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure. Stem cells (Dayton, Ohio) 44 15749928
2016 The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein. The Journal of biological chemistry 43 27542411
2011 Phospholipase D2 (PLD2) is a guanine nucleotide exchange factor (GEF) for the GTPase Rac2. Proceedings of the National Academy of Sciences of the United States of America 42 22106281
2005 Impaired NADPH oxidase activity in Rac2-deficient murine neutrophils does not result from defective translocation of p47phox and p67phox and can be rescued by exogenous arachidonic acid. Journal of leukocyte biology 40 16275890
2003 Rac2 specificity in macrophage integrin signaling: potential role for Syk kinase. The Journal of biological chemistry 40 12917394
1998 Rac1, and not Rac2, is involved in the regulation of the intracellular hydrogen peroxide level in HepG2 cells. The Biochemical journal 40 9576845
2011 The mechanism of cell membrane ruffling relies on a phospholipase D2 (PLD2), Grb2 and Rac2 association. Cellular signalling 39 21419846
2001 Clinical features of a human Rac2 mutation: a complex neutrophil dysfunction disease. The Journal of pediatrics 37 11445809
1994 Synthesis of androst-5-en-7-ones and androsta-3,5-dien-7-ones and their related 7-deoxy analogs as conformational and catalytic probes for the active site of aromatase. Journal of medicinal chemistry 37 8035427
2022 Macrophage ALDH2 (Aldehyde Dehydrogenase 2) Stabilizing Rac2 Is Required for Efferocytosis Internalization and Reduction of Atherosclerosis Development. Arteriosclerosis, thrombosis, and vascular biology 36 35354308
2020 RAC2 and primary human immune deficiencies. Journal of leukocyte biology 35 32542921
2010 Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis. Blood 35 21084708
2002 The TRQQKRP motif located near the C-terminus of Rac2 is essential for Rac2 biologic functions and intracellular localization. Blood 34 12176888
2017 Rac2 deficiency attenuates CCl4-induced liver injury through suppressing inflammation and oxidative stress. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 32 28759751
2005 CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism. Blood 32 15802529
2011 The exquisite regulation of PLD2 by a wealth of interacting proteins: S6K, Grb2, Sos, WASp and Rac2 (and a surprise discovery: PLD2 is a GEF). Cellular signalling 31 21740967
2020 The Impression of a Nonexisting Catalytic Effect: The Role of CotB2 in Guiding the Complex Biosynthesis of Cyclooctat-9-en-7-ol. Journal of the American Chemical Society 30 33289561
2016 Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells. Nature communications 30 27425374
2014 Rac2 is involved in bleomycin-induced lung inflammation leading to pulmonary fibrosis. Respiratory research 30 24970330
2019 Heterozygous activating mutation in RAC2 causes infantile-onset combined immunodeficiency with susceptibility to viral infections. Clinical immunology (Orlando, Fla.) 28 31071452
2009 Regulation of inflammation by Rac2 in immune complex-mediated acute lung injury. American journal of physiology. Lung cellular and molecular physiology 28 19801448
2007 Genetic and pharmacologic evidence implicating the p85 alpha, but not p85 beta, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis. Blood 28 17483298
1997 Guanine nucleotide binding properties of Rac2 mutant proteins and analysis of the responsiveness to guanine nucleotide dissociation stimulator. Biochemistry 28 9012677
2017 Rac2 is required for alternative macrophage activation and bleomycin induced pulmonary fibrosis; a macrophage autonomous phenotype. PloS one 27 28817691
2009 Suppressed hindlimb perfusion in Rac2-/- and Nox2-/- mice does not result from impaired collateral growth. American journal of physiology. Heart and circulatory physiology 27 19151256
2023 Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells. Nature biomedical engineering 26 37749310
2020 Additive effects of simulated microgravity and ionizing radiation in cell death, induction of ROS and expression of RAC2 in human bronchial epithelial cells. NPJ microgravity 26 33298974
2019 Nonconserved miR-608 suppresses prostate cancer progression through RAC2/PAK4/LIMK1 and BCL2L1/caspase-3 pathways by targeting the 3'-UTRs of RAC2/BCL2L1 and the coding region of PAK4. Cancer medicine 26 31389670
2017 (22β,25R)-3β-Hydroxy-spirost-5-en-7-iminoxy-heptanoic acid exhibits anti-prostate cancer activity through caspase pathway. Steroids 26 28143704
2009 Differential regulation of phospholipase C-beta2 activity and membrane interaction by Galphaq, Gbeta1gamma2, and Rac2. The Journal of biological chemistry 26 20007712
2006 Cytokine expression and AIF-1-mediated activation of Rac2 in vascular smooth muscle cells: a role for Rac2 in VSMC activation. American journal of physiology. Cell physiology 26 16987989
2002 Activation of Rac-1, Rac-2, and Cdc42 by hemopoietic growth factors or cross-linking of the B-lymphocyte receptor for antigen. Blood 26 12384416
2000 Differential expression and regulation of GTPases (RhoA and Rac2) and GDIs (LyGDI and RhoGDI) in neutrophils from patients with severe congenital neutropenia. Blood 26 10779444
2003 Activation of Rac2 and Cdc42 on Fc and complement receptor ligation in human neutrophils. Journal of leukocyte biology 25 12960248
2002 DOCK2 mediates T cell receptor-induced activation of Rac2 and IL-2 transcription. Biochemical and biophysical research communications 25 12176041
2017 Overexpression of microRNA-722 fine-tunes neutrophilic inflammation by inhibiting Rac2 in zebrafish. Disease models & mechanisms 24 28954734
2011 Evidence for two CRIB domains in phospholipase D2 (PLD2) that the enzyme uses to specifically bind to the small GTPase Rac2. The Journal of biological chemistry 24 21378159
2005 Neutrophil primary granule release and maximal superoxide generation depend on Rac2 in a common signalling pathway. Canadian journal of physiology and pharmacology 24 15759052
2011 Agonist activation of f-actin-mediated eosinophil shape change and mediator release is dependent on Rac2. International archives of allergy and immunology 23 21576984
1999 Expression and translocation of Rac2 in eosinophils during superoxide generation. Immunology 23 10540223
2002 RAC2 GTPase deficiency and myeloid cell dysfunction in human and mouse. Journal of pediatric hematology/oncology 22 12468931
2018 RAC2 promotes abnormal proliferation of quiescent cells by enhanced JUNB expression via the MAL-SRF pathway. Cell cycle (Georgetown, Tex.) 21 29895215
2005 Rac2 expression and mutation in human brain tumors. Acta neurochirurgica 21 15812594