* 602048
RAS-RELATED C3 BOTULINUM TOXIN SUBSTRATE 1; RAC1
Alternative titles; symbols
RHO FAMILY, SMALL GTP-BINDING PROTEIN RAC1
CED10, C. ELEGANS, HOMOLOG OF
HGNC Approved Gene Symbol: RAC1
Cytogenetic location: 7p22.1 Genomic coordinates (GRCh38) : 7:6,374,527-6,403,967 (from NCBI)
Gene-Phenotype Relationships
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p22.1 | Intellectual developmental disorder, autosomal dominant 48 | 617751 | Autosomal dominant | 3 |
TEXT
Description
The RAC1 gene encodes a RHO GTPase involved in modulation of the cytoskeleton which plays a role in multiple cellular functions, including phagocytosis, mesenchymal-like migration, neuronal polarization, axonal growth, and differentiation of multiple cell types. RAC1 is also involved in cellular growth and cell-cycle regulation (summary by Reijnders et al., 2017).
Gene Family
Members of the RAS superfamily of small GTP-binding proteins (see 190020) appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases.
Cloning and Expression
Didsbury et al. (1989) identified 2 human cDNAs, called RAC1 and RAC2 (602049) by them, that are 92% identical and share 58% and 26 to 30% amino acid identity with human RHOS and RAS, respectively. The 2 genes encode the C-terminal consensus sequence (CXXX-COOH), which localizes RAS to the inner plasma membrane, and the residues gly12 and ala59, at which sites mutations elicit transforming potential to RAS. The authors detected RAC1 mRNA in brain and liver tissue and in HL-60 cells differentiating to neutrophil-like morphology. Using transfection experiments, Didsbury et al. (1989) showed that RAC1 and RAC2 are substrates for ADP-ribosylation by the C3 component of botulinum toxin. Drivas et al. (1990) cloned 4 RAS-like sequences, 1 of which, TC25, appears to be identical to RAC1. See also RAC3 (602050).
Matos et al. (2000) isolated the RAC1 gene from genomic DNA. Northern blot analysis demonstrated expression of 1.2- and 2.5-kb transcripts in all 12 tissues studied, with the strongest expression in heart, placenta, and kidney. The 2 transcripts were expressed in tissue-specific ratios, and multiple polyadenylation sites were found. By RT-PCR, Matos et al. (2000) found alternative splicing within the coding region of RAC1; a second gene product with an additional 57 nucleotides, which corresponded to RAC1B, a splice variant previously described by Jordan et al. (1999). Matos et al. (2000) showed that RAC1B is a constitutively active mutant which induces the formation of lamellipodia in fibroblasts.
Gene Structure
Matos et al. (2000) demonstrated that the RAC1 gene is 29 kb long and contains 7 exons. The RAC1 promoter lacks both a TATA box and CCAAT box, contains a CpG island surrounding the transcription initiation sites, and is GC rich, all characteristics of a housekeeping gene.
Mapping
By FISH and inclusion within a mapped clone, Matos et al. (2000) mapped the RAC1 gene to 7p22 near PMS2 (600259). They also found a processed RAC1 pseudogene at Xq26.2-q27.2.
Gene Function
By screening rat brain cytosol for proteins that interacted with Ras (HRAS; 190020)-related GTPases, or p21 proteins, of the Rho (RHOA; 165390) subfamily, Manser et al. (1994) identified 3 proteins, designated PAKs (see PAK1; 602590) that interacted with the GTP-bound forms of human CDC42 and RAC1, but not RHOA.
To identify the effector pathways that mediate the activities induced by RAC, Joneson et al. (1996) isolated mutant RAC proteins that could discriminate among the RAC targets PAK and POR1 (601638) in the yeast 2-hybrid system. PAK proteins are a family of highly conserved serine/threonine kinases that are activated by interaction with RAC1 (Manser et al., 1994). POR1 interacts with RAC1 and appears to function in RAC-induced membrane ruffling which is apparently induced by actin polymerization (Van Aelst et al., 1996). Joneson et al. (1996) reported that 1 mutant of activated human RAC protein was defective in its binding to PAK3 (300142) and failed to stimulate PAK and JNK (see 601158) activity. This mutant did bind to POR1 and it induced membrane ruffling and transformation. A second RAC mutant, which bound PAK but not POR1, induced JNK activation but was defective in inducing membrane ruffling and transformation. The authors concluded that the effects of RAC on the JNK cascade and on actin polymerization and cell proliferation are mediated by distinct effector functions that diverge at the level of RAC itself. No RAC mutants were isolated that separated the ability of RAC to induce membrane ruffling and to stimulate cell proliferation. These results led Joneson et al. (1996) to conclude that RAC-mediated pathways leading to actin polymerization and proliferation are interdependent.
RAC1 appears to function in the regulation of actin filaments at the plasma membrane, resulting in the production of lamellipodia and ruffles, the generation of reactive oxygen species in phagocytic and nonphagocytic cells, and activation of the family of stress-activated protein kinases (JNKs/SAPKs). Moore et al. (1997) transiently expressed a dominant-negative form of RAC1 in rat fibroblasts and found that it resulted in cytostatic growth arrest. Cell cycle analysis demonstrated that cells expressing the transgene accumulated in G2/M. The results suggested that RAC1 is required for cell proliferation and provided the first demonstration in mammalian cells of a role for small GTP-binding proteins in the G2/M transition.
Integrin-mediated reorganization of cell shape leads to an altered cellular phenotype. Kheradmand et al. (1998) found that disruption of the actin cytoskeleton, initiated by binding of soluble antibody to alpha-5 (135620)/beta-1 (135630) integrin, led to increased expression of the collagenase-1 gene (120355) in rabbit synovial fibroblasts. Activation of RAC1, which is downstream of the integrin, was necessary for this process, and expression of activated RAC1 was sufficient to increase expression of collagenase-1. RAC1 activation generated reactive oxygen species that were essential for nuclear factor kappa-B (164011)-dependent transcriptional regulation of interleukin-1-alpha (147760), which, in an autocrine manner, induced collagenase-1 gene expression. Remodeling of the extracellular matrix and consequent alterations of integrin-mediated adhesion and cytoarchitecture are central to development, wound healing, inflammation, and malignant disease. Kheradmand et al. (1998) stated that the resulting activation of RAC1 may lead to altered gene regulation and alterations in cellular morphogenesis, migration, and invasion.
The signal transducers and activators of transcription (STAT) transcription factors become phosphorylated on tyrosine and translocate to the nucleus after stimulation of cells with growth factors or cytokines. Simon et al. (2000) showed that the RAC1 guanosine triphosphatase can bind to and regulate STAT3 (102582) activity. Dominant-negative RAC1 inhibited STAT3 activation by growth factors, whereas activated RAC1 stimulated STAT3 phosphorylation on both tyrosine and serine residues. Moreover, activated RAC1 formed a complex with STAT3 in mammalian cells. Yeast 2-hybrid analysis indicated that STAT3 binds directly to active but not inactive RAC1 and that the interaction occurs via the effector domain. Simon et al. (2000) concluded that RAC1 may serve as an alternative mechanism for targeting STAT3 to tyrosine kinase signaling complexes.
Epidermal growth factor receptor (EGFR; 131550) signaling involves small GTPases of the Rho family, and EGFR trafficking involves small GTPases of the Rab family. Lanzetti et al. (2000) reported that the EPS8 (600206) protein connects these signaling pathways. EPS8 is a substrate of EGFR that is held in a complex with SOS1 (182530) by the adaptor protein E3B1 (SSH3BP1; 603050), thereby mediating activation of RAC. Through its SH3 domain, EPS8 interacts with RNTRE (605405). Lanzetti et al. (2000) showed that RNTRE is a RAB5 (179512) GTPase-activating protein whose activity is regulated by EGFR. By entering in a complex with EPS8, RNTRE acts on RAB5 and inhibits internalization of the EGFR. Furthermore, RNTRE diverts EPS8 from its RAC-activating function, resulting in the attenuation of RAC signaling. Thus, depending on its state of association with E3B1 or RNTRE, EPS8 participates in both EGFR signaling through RAC and EGFR trafficking through RAB5.
Neural Wiskott-Aldrich syndrome protein (N-WASP; 605056) functions in several intracellular events including filopodium formation, vesicle transport, and movement of viruses, by stimulating rapid actin polymerization through the ARP2/3 complex. N-WASP is regulated by the direct binding of CDC42 (116952), which exposes the domain in N-WASP that activates the ARP2/3 complex. A WASP-related protein, WAVE/SCAR (see 605875), functions in RAC-induced membrane ruffling; however, RAC does not bind directly to WAVE, raising the question of how WAVE is regulated by RAC. Miki et al. (2000) demonstrated that IRSP53 (605475), a substrate for insulin receptor with unknown function, is the 'missing link' between RAC and WAVE2. Activated RAC binds to the N terminus of IRSP53, and the C-terminal SH3 domain of IRSP53 binds to WAVE2 to form a trimolecular complex. From studies of ectopic expression, Miki et al. (2000) found that IRSP53 is essential for RAC to induce membrane ruffling, probably because it recruits WAVE2, which stimulates actin polymerization mediated by the ARP2/3 complex.
Rhodopsin (RHO; 180380) is essential for photoreceptor morphogenesis; photoreceptors lacking rhodopsin degenerate in humans, mice, and Drosophila. Chang and Ready (2000) reported that transgenic expression of a dominant-active Drosophila Rho guanosine triphosphatase, Rac1, rescued photoreceptor morphogenesis in rhodopsin null mutants. Expression of dominant-negative Rac1 resulted in a phenotype similar to that seen in rhodopsin null mutants. Rac1 was localized in a specialization of the photoreceptor cortical actin cytoskeleton, which was lost in rhodopsin null mutants. Thus, rhodopsin appears to organize the actin cytoskeleton through RAC1, contributing a structural support essential for photoreceptor morphogenesis.
Studying rat hippocampal neurons in culture, Hernandez-Deviez et al. (2002) determined that dendritic arbor development is regulated by complex interactions of ARNO (602488), ARF6 (600464), and RAC1. Activation of ARNO and ARF6 resulted in signaling through RAC1 that suppressed dendritic branching.
Eden et al. (2002) reported a mechanism by which RAC1 and the adaptor protein NCK (600508) activate actin nucleation through WAVE1 (605035). WAVE1 exists in a heterotetrameric complex that includes orthologs of human PIR121 (606323), NAP125 (NCKAP1; 604891), and HSPC300 (611183). Whereas recombinant WAVE1 is constitutively active, the WAVE1 complex is inactive. Eden et al. (2002) proposed that Rac1 and Nck cause dissociation of the WAVE1 complex, which releases active WAVE1-HSPC300 and leads to actin nucleation. Eden et al. (2002) also determined that ABI2 (606442) interacts with WAVE1 and appears to remain associated with the NAP125-PIR121 subcomplex upon dissociation of the WAVE1 complex.
Sin et al. (2002) used in vivo time-lapse imaging of optic tectal cells in Xenopus laevis tadpoles to demonstrate that enhanced visual activity driven by a light stimulus promotes dendritic arbor growth. The stimulus-induced dendritic arbor growth requires glutamate receptor (see 138249)-mediated synaptic transmission, decreased RhoA (165390) activity, and increased RAC and CDC42 (116952) activity. Sin et al. (2002) concluded that their results delineated a role for Rho GTPases in the structural plasticity driven by visual stimulation in vivo.
Katoh and Negishi (2003) demonstrated that RHO G (179505) interacts directly with ELMO2 (606421) in a GTP-dependent manner and forms a ternary complex with DOCK180 (601403) to induce activation of RAC1. The RHO G-ELMO2-DOCK180 pathway is required for activation of RAC1 and cell spreading mediated by integrin, as well as for neurite outgrowth induced by nerve growth factor. Katoh and Negishi (2003) concluded that RHO G activates RAC1 through ELMO and DOCK180 to control cell morphology.
RAC phosphorylates merlin (NF2; 607379) via PAK activation (Xiao et al., 2002; Kissil et al., 2002). Kaempchen et al. (2003) hypothesized that merlin deficiency might cause an activation of RAC and its dependent signaling pathways, in particular the protumorigenic JNK (601158) pathway. The authors documented enhanced activation of RAC1 in primary human schwannoma cells, found both RAC and its effector PAK1 (602590) at the membrane where they colocalized, and described increased levels of phosphorylated JNK in the nucleus of these cells. The authors concluded that merlin regulates RAC activation, and suggested that this may important for human schwannoma cell dedifferentiation.
In human coronary artery vascular smooth muscle cells, UPA (PLAU; 191840) stimulates cell migration via a UPA receptor (UPAR, or PLAUR; 173391) signaling complex containing TYK2 (176941) and phosphatidylinositol 3-kinase (PI3K; see 601232). Kiian et al. (2003) showed that association of TYK2 and PI3K with active GTP-bound forms of both RHOA and RAC1, but not CDC42, as well as phosphorylation of myosin light chain (see 160781), are downstream events required for UPA/UPAR-directed migration.
Faucherre et al. (2003) demonstrated interaction of the RhoGAP domain of OCRL1 (300535), the phosphatidylinositol 4,5-bisphosphate-5-phosphatase mutant in Lowe oculocerebrorenal syndrome (309000), with the Rho GTPase Rac. Activated Rac GTPase associated with the OCRL1 RhoGAP domain in vitro and coimmunoprecipitated with endogenous OCRL1. OCRL1 RhoGAP exhibited a significant interaction with GDP-bound Rac in vitro. Immunofluorescence studies and Golgi perturbation assays demonstrated that a fraction of endogenous Rac colocalized with OCRL1 and gamma-adaptin (603533) in the trans-Golgi network. The authors concluded that OCRL1 is a bifunctional protein which, in addition to its PIP2 5-phosphatase activity, binds to Rac GTPase.
By yeast 2-hybrid analysis of a mouse T-cell cDNA library, Uhlik et al. (2003) showed that a C-terminal fragment of mouse Osm (CCM2; 607929) interacted with Mekk3 (MAP3K3; 602539), a p38 (MAPK14; 600289) activator that responds to sorbitol-induced hyperosmotic conditions. Mekk3 and Osm colocalized in the cytoplasmic compartment of cotransfected cells, and the Mekk3-Osm complex was recruited to Rac1- and cytoskeletal actin-containing membrane ruffles in response to sorbitol treatment. Protein interaction assays showed that Osm interacted directly with the Mekk3 substrate Mkk3 (MAP2K3; 602315), with actin, and with both GDP- and GTP-loaded Rac1. Uhlik et al. (2003) concluded that the RAC1-OSM-MEKK3-MKK3 complex is required for regulation of p38 activity in response to osmotic shock.
By electroporating genes into chicken presomitic mesenchymal cells, Nakaya et al. (2004) demonstrated that Cdc42 and Rac1 play different roles in mesenchymal-epithelial transition. Different levels of Cdc42 appeared to affect the binary decision between epithelial and mesenchymal states. Proper levels of Rac1 were also necessary for somitic epithelialization, since cells with either activated or inhibited Rac1 failed to undergo correct epithelialization.
By yeast 2-hybrid analysis and in vitro binding assays, Malecz et al. (2000) showed that a 56-amino acid domain in the C terminus of human SYNJ2 (609410) interacted with RAC1. Expression of constitutively active RAC1 caused the translocation of SYNJ2 from the cytoplasm to the plasma membrane. Both activated RAC1 and a membrane-targeted version of SYNJ2 inhibited endocytosis of EGFR and transferrin receptor (TFRC; 190010), a process that depends on polyphosphoinositides.
Chuang et al. (2004) found that small interfering RNA-mediated depletion of RAC1 or SYNJ2 in 2 human glioblastoma cell lines inhibited migration of the cells through 3-dimensional gel and rat brain slices, and it inhibited cell migration on glioma-derived extracellular matrix. Depletion of RAC1 or SYNJ2 inhibited formation of lamellipodia and invadopodia, specialized membrane structures involved in extracellular matrix degradation. Chuang et al. (2004) concluded that SYNJ2 and RAC1 contribute to cell invasion and migration by regulating the formation of invadopodia and lamellipodia.
RAC1 stimulates actin remodeling at the cell periphery, leading to lamellipodia formation. Steffen et al. (2004) found that Sra1 (CYFIP1; 606322) and Nap1 (NCKAP1) interacted with Wave2 and Abi1 (SSH3BP1) in resting mouse melanoma cells or following Rac1 activation. Microinjection of constitutively active RAC1 resulted in translocation of Sra1, Nap1, Wave2, and Abi1 to the tips of membrane protrusions. Moreover, removal of SRA1 or NAP1 by RNA interference in human or mouse cells abrogated formation of RAC1-dependent lamellipodia. Microinjection of active RAC1 failed to restore lamellipodia protrusion in cells lacking either SRA1 or NAP1. Steffen et al. (2004) concluded that SRA1 and NAP1 are essential components of a WAVE2- and ABI1-containing complex linking RAC1 to site-directed actin assembly.
Radisky et al. (2005) found that exposure of mouse mammary epithelial cells to MMP3 (185250) induces the expression of an alternatively spliced form of RAC1, which causes an increase in cellular reactive oxygen species. The reactive oxygen species stimulated the expression of the transcription factor Snail (see 604238) and epithelial-mesenchymal transition, and caused oxidative damage to DNA and genomic instability. Radisky et al. (2005) concluded that these findings identified a pathway in which a component of the breast tumor microenvironment alters cellular structure in culture and tissue structure in vivo, leading to malignant transformation.
Kinchen et al. (2005) showed that in C. elegans, CED1 (see 107770), CED6 (see 608165), and CED7 (see 601615) are required for actin reorganization around the apoptotic cell corpse, and that CED1 and CED6 colocalize with each other and with actin around the dead cell. Furthermore, Kinchen et al. (2005) found that the CED10(Rac) GTPase acts genetically downstream of these proteins to mediate corpse removal, functionally linking the 2 engulfment pathways and identifying the CED1, CED6, and CED7 signaling module as upstream regulators of Rac activation.
Yeung et al. (2006) devised genetically encoded probes to assess surface potential in intact cells. These probes revealed marked, localized alterations in the change of the inner surface of the plasma membrane of macrophages during the course of phagocytosis. Hydrolysis of phosphoinositides and displacement of phosphatidylserine accounted for the change in surface potential at the phagosomal cup. Signaling molecules such as KRAS (190070), RAC1, and c-SRC (190090) that are targeted to the membrane by electrostatic interactions were rapidly released from membrane subdomains where the surface charge was altered by lipid remodeling during phagocytosis.
Using a fluorescent probe that binds to Rac-GTP, Halet and Carroll (2007) found that Rac-GTP was polarized in the cortex overlying the meiotic spindle in mouse oocytes. Polarization of Rac activation occurred during spindle migration and was promoted by the proximity of chromatin to the cortex. Inhibition of Rac during oocyte maturation caused a permanent block at prometaphase I and spindle elongation. In metaphase II-arrested oocytes, Rac inhibition caused the spindle to detach from the cortex and prevented polar body emission after activation. Halet and Carroll (2007) concluded that RAC-GTP plays a major role in oocyte meiosis via the regulation of spindle stability and anchoring to the cortex.
Using human and other mammalian cells, Guo et al. (2007) showed that RAC used PAK to directly activate transmembrane guanylyl cyclases (e.g., GUCY2E; 601138), leading to increased cellular cGMP levels. This RAC-cGMP signaling pathway was involved in platelet-derived growth factor (PDGF; see 173430)-induced fibroblast cell migration and lamellipodium formation.
Harraz et al. (2008) demonstrated that SOD1 (147450) directly regulated cellular NOX2 (300481) production of reactive oxygen species by binding RAC1 and inhibiting RAC1 GTPase activity. Oxidation of RAC1 uncoupled SOD1 binding in a reversible fashion, suggesting a model of redox sensing.
Park et al. (2007) identified brain-specific angiogenesis inhibitor-1 (BAI1; 602682) as a receptor upstream of ELMO (606420) and as a receptor that can bind phosphatidylserine on apoptotic cells. BAI1 is a 7-transmembrane protein belonging to the adhesion-type G protein-coupled receptor family with an extended extracellular region. Park et al. (2007) showed that BAI1 functions as an engulfment receptor in both the recognition and subsequent internalization of apoptotic cells. Through multiple lines of investigation, Park et al. (2007) identified phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells, as a ligand for BAI1. The thrombospondin type 1 (188060) repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signaling, BAI1 forms a trimeric complex with ELMO and Dock180 (601403), and functional studies suggested that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells. Last, Park et al. (2007) found that decreased BAI1 expression or interference with BAI1 function inhibited the engulfment of apoptotic targets ex vivo and in vivo. Thus, Park et al. (2007) concluded that BAI1 is a phosphatidylserine recognition receptor that can directly recruit a Rac-GEF complex to mediate the uptake of apoptotic cells.
Shibata et al. (2008) showed that a constitutively active RAC1 mutant potentiated aldosterone-induced mineralocorticoid receptor (NR3C2; 600983) nuclear accumulation and transcriptional activity in HEK293 cells transfected with human constructs. In cultured rat podocytes, activated RAC1 facilitated mineralocorticoid receptor nuclear accumulation via PAK (see 602590) phosphorylation. Shibata et al. (2008) found that mice lacking Rho GDP-dissociation inhibitor-alpha (ARHGDIA; 601925) developed progressive renal disease characterized by heavy albuminuria and podocyte damage. These renal changes were associated with increased Rac1 and mineralocorticoid receptor signaling in the kidney without alteration in systemic aldosterone status. Pharmacologic intervention with a Rac-specific small molecule inhibitor diminished mineralocorticoid receptor overactivity and renal damage. Furthermore, mineralocorticoid receptor blockade suppressed albuminuria and histologic changes in Arhgdia -/- mice. Shibata et al. (2008) concluded that RAC1 modulates mineralocorticoid receptor activity, and that activation of the RAC1-mineralocorticoid receptor pathway has a major role in the pathogenesis of renal damage.
Machacek et al. (2009) examined GTPase coordination in mouse embryonic fibroblasts both through simultaneous visualization of 2 GTPase biosensors and using a 'computational multiplexing' approach capable of defining the relationships between multiple protein activities visualized in separate experiments. They found that RhoA (165390) is activated at the cell edge synchronous with edge advancement, whereas Cdc42 (116952) and Rac1 are activated 2 microns behind the edge with a delay of 40 seconds. This indicates that Rac1 and RhoA operate antagonistically through spatial separation and precise timing, and that RhoA has a role in the initial events of protrusion, whereas Rac1 and Cdc42 activate pathways implicated in reinforcement and stabilization of newly expanded protrusions.
Wu et al. (2009) developed an approach to produce genetically encoded photoactivatable derivatives of Rac1, a key GTPase regulating actin cytoskeletal dynamics in metazoan cells. Rac1 mutants were fused to the photoreactive LOV (light oxygen voltage) domain from phototropin, sterically blocking Rac1 interactions until irradiation unwound a helix linking LOV to Rac1. Photoactivatable Rac1 (PA-Rac1) could be reversibly and repeatedly activated using 458- or 473-nm light to generate precisely localized cell protrusions and ruffling. Localized Rac activation or inactivation was sufficient to produce cell motility and control the direction of cell movement. Myosin was involved in Rac control of directionality but not in Rac-induced protrusion, whereas PAK was required for Rac-induced protrusion. PA-Rac1 was used to elucidate Rac regulation of RhoA in cell motility. Rac and Rho coordinate cytoskeletal behaviors with seconds and submicrometer precision. Rac was shown to inhibit RhoA in mouse embryonic fibroblasts, with inhibition modulated at protrusions and ruffles. A PA-Rac crystal structure and modeling revealed LOV-Rac interactions that will facilitate extension of this photoactivation approach to other proteins.
Juncadella et al. (2013) showed that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete antiinflammatory cytokines, dependent upon intracellular signaling by the small GTPase RAC1. Inducible deletion of Rac1 expression specifically in airway epithelial cells in a mouse model resulted in defective engulfment by epithelial cells and aberrant antiinflammatory cytokine production. Intranasal priming and challenge of these mice with house dust mite extract or ovalbumin as allergens led to exacerbated inflammation, augmented Th2 cytokines and airway hyperresponsiveness, with decreased Il10 (124092) in bronchial lavages. Rac1-deficient epithelial cells produced much higher Il33 (608678) upon allergen or apoptotic cell encounter, with increased numbers of nuocyte-like cells. Administration of exogenous Il10 'rescued' the airway inflammation phenotype in Rac1-deficient mice, with decreased Il33. Collectively, these genetic and functional studies suggested a role for RAC1-dependent engulfment by airway epithelial cells and in establishing the antiinflammatory environment, and that defects in cell clearance in the airway could contribute to inflammatory responses towards common allergens.
Keestra et al. (2013) demonstrated that NOD1 (605980) senses cytosolic microbial products by monitoring the activation state of small Rho GTPases. Activation of RAC1 and CDC42 (116952) by bacterial delivery or ectopic expression of SopE, a virulence factor of the enteric pathogen Salmonella, triggered the NOD1 signaling pathway with consequent RIP2 (603455)-mediated induction of NF-kappa-B (see 164011)-dependent inflammatory responses. Similarly, activation of the NOD1 signaling pathway by peptidoglycan required RAC1 activity. Furthermore, Keestra et al. (2013) showed that constitutively active forms of RAC1, CDC42, and RHOA (165390) activated the NOD1 signaling pathway.
Sun et al. (2016) found that overexpression of Elmo2 in mouse adipocytes and rat skeletal muscle cells enhanced insulin-dependent Glut4 (SLC2A4; 138190) membrane translocation. In contrast, knockdown of Elmo2 suppressed Glut4 translocation. Elmo2 was required for insulin-induced Rac1 GTP loading and Akt (AKT1; 164730) membrane association, but not Akt activation, in rat skeletal muscle cells. Sun et al. (2016) concluded that ELMO2 regulates insulin-dependent GLUT4 membrane translocation by modulating RAC1 activity and AKT membrane compartmentalization.
Hedrick et al. (2016) described a 3-molecule model of structural long-term potentiation of murine dendritic spines, implicating the localized, coincident activation of Rac1, RhoA, and Cdc42 as a causal signal of structural long-term potentiation. This model posited that complete tripartite signal overlap in spines confers structural long-term potentiation, but that partial overlap primes spines for structural plasticity. By monitoring the spatiotemporal activation patterns of these GTPases during structural long-term potentiation, Hedrick et al. (2016) found that such spatiotemporal signal complementation simultaneously explains 3 integral features of plasticity: the facilitation of plasticity by BDNF, the postsynaptic source of which activates Cdc42 and Rac1, but not RhoA; heterosynaptic facilitation of structural long-term potentiation, which is conveyed by diffusive Rac1 and RhoA activity; and input specificity, which is afforded by spine-restricted Cdc42 activity.
Molecular Genetics
In 7 unrelated boys with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751), Reijnders et al. (2017) identified 7 different de novo heterozygous missense mutations in the RAC1 gene (see, e.g., 602048.0001-602048.0006). The mutations were found by whole-exome sequencing, and the patients were ascertained from several different research studies and the GeneMatcher database. In vitro functional expression studies of selected variants showed different effects: 2 mutations (C18Y, 602048.0001 and N39S, 602048.0002) had a dominant-negative effect on fibroblast spreading and caused reduced neuronal proliferation in a zebrafish model, whereas 1 mutation (Y64D; 602048.0004) resulted in constitutive activation of RAC1. The other mutations appeared to have lesser and unclear effects on RAC1 function. Reijnders et al. (2017) noted that the large phenotypic variability among patients may represent mutation-specific effects.
In 7 unrelated patients with MRD48, Banka et al. (2022) identified 5 heterozygous mutations in the RAC1 gene (602048.0004; 602048.0007-602048.0010). The mutations, which were identified as part of the Deciphering Developmental Disorders Study, were all located in the RAC1 switch II region. They were confirmed to be de novo in 4 of the patients. GTP pull-down assays in HEK293 cells expressing RAC1 with the Y64D (602048.0004), Y64C (602048.0008), or R68G (602048.0010) mutation demonstrated increased GTP binding compared to wildtype RAC1. Banka et al. (2022) concluded that all 3 mutations resulted in increased levels of the activated GTP-bound form of RAC1. Expression of RAC1 with each of the mutations in NIH3T3 fibroblasts resulted in increased signaling through the WAVE regulatory complex (WRC) and PAK family kinases.
Animal Model
Gu et al. (2003) generated mice with a conditional deficiency in Rac1 in order to avoid the embryonic lethality observed in homozygous Rac1-deficient mice. Rac1-deficient hemopoietic stem cells (HSCs), but not Rac2-deficient HSCs, failed to engraft in the marrow of irradiated recipient mice. Deletion of both Rac1 and Rac2 resulted in a massive egress of HSCs into the peripheral blood circulation. Rac2, but not Rac1, regulated superoxide production and directed migration in neutrophils. Gu et al. (2003) concluded that the 2 GTPases play distinct roles in actin organization, cell survival, and proliferation in neutrophils and HSCs, possibly due to the subcellular localization of each protein.
Walmsley et al. (2003) generated mice with a conditional Rac1 deficiency specifically in the B-cell lineage. In the absence of both Rac1 and Rac2, B-cell development was almost completely blocked. Both GTPases were required to transduce B-cell receptor (BCR) signals leading to proliferation, survival, and the upregulation of Baffr (TNFRSF13C; 606269), the B-cell-activating receptor for BAFF (TNFSF13B; 603969), which is required for B-cell development and maintenance.
Using 2-photon video microscopy and lymph node cells from Rac1- and Rac2-deficient mice, Benvenuti et al. (2004) showed that dendrites of mature dendritic cells, under the control of Rac1 and Rac2, but not Rho itself, contact and then entrap naive T cells.
Benitah et al. (2005) generated mice with a conditional deletion of Rac1 in adult epidermis. Deletion of Rac1 stimulated stem cells to divide and undergo terminal differentiation, leading to failure to maintain the interfollicular epidermis, hair follicles, and sebaceous glands. Rac1 exerts its effects in the epidermis by negatively regulating c-Myc (190080) through phosphorylation of p21-activated kinase-2 (PAK2; 605022). The dorsal skin of the conditionally deleted Rac1 mice showed 3 to 6 distinct phenotypes, designated early, middle, and late. After 3 to 5 days (early), there was thickening of the interfollicular epidermis (IFE) with increased numbers of living and cornified cell layers, and the infundibulum, at the junction between the IFE and hair follicle, was expanded. After 7 to 9 days (middle), there was disorganization and decreased cellularity of the IFE basal layer, together with cell enlargement. Sebaceous glands were also enlarged and disorganized. After 11 to 15 days, the late phenotype developed: partial or complete loss of viable IFE cell layers, diminution of the hair follicle bulb, and degeneration of the infundibulum into cysts. Benitah et al. (2005) concluded that a pleiotropic regulator of cell adhesion and the cytoskeleton plays a critical role in controlling exit from the stem cell niche and proposed that Rac and Myc represent a global stem cell regulatory axis.
Satoh et al. (2006) generated mice with a temporal and specific deletion of cardiomyocyte Rac1. Compared to wildtype or heterozygous mice, the hearts of homozygous mutant mice showed decreased gp91-phox (CYBB; 300481) and p67-phox (NCF2; 608515) interaction, NADPH oxidase activity, and myocardial oxidative stress in response to angiotensin II (see 106150) stimulation, which correlated with decreased myocardial hypertrophy. Satoh et al. (2006) concluded that RAC1 is critical for the hypertrophic response in the heart.
Corbetta et al. (2009) generated Rac1 and Rac3 double-knockout mice by conditionally deleting Rac1 in neurons of Rac3 -/- mice. Double-knockout mice were smaller than controls, but brain weight was normal. Double-knockout mice had neurologic abnormalities with spontaneous seizures and died around postnatal day-13. Brains of mutant mice showed specific defects in dorsal hippocampal hilus that were associated with alterations in the formation of hippocampal circuitry. Analysis with hippocampal cultures revealed that Rac1 and Rac3 played a synergistic role in the formation of dendritic spines, and as a result, spine formation was strongly hampered in neurons lacking Rac1 and Rac3.
By analyzing Rac1 and Rac3 double-knockout mice, Vaghi et al. (2014) demonstrated that Rac1 and Rac3 were required for development of cortical and hippocampal GABAergic interneurons, as the number of parvalbumin (PV)-positive cells was reduced in hippocampus and cortex of mutant mice. Deletion of the Rac1 and Rac3 also caused a defect in maturation of PV-positive interneurons, indicating that Rac1 and Rac3 were also required for development of hippocampal and cortical inhibitory circuits. The decreased number of cortical migrating interneurons and their altered morphology indicated a role for Rac1 and Rac3 in regulating motility of cortical interneurons, thus interfering with their final localization. In addition, while electrophysiologic passive and active properties of pyramidal neurons, including membrane capacity, resting potential, and spike amplitude and duration, were normal, these cells showed reduced spontaneous inhibitory currents and increased excitability in mutant mice.
Banka et al. (2022) expressed Rac1 with the Y64D mutation (602408.0008) in Drosophila embryo neurons and showed that the neurons had reduced axonal length and increased collateral branch precursors. The Drosophila embryos also demonstrated defects in axonal organization and abnormal morphology of class IV dendritic arborization neurons.
ALLELIC VARIANTS 10 Selected Examples):
.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
SNP: rs1554263326, ClinVar: RCV000513864, RCV003441902
In a 13-year-old boy (patient 1) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751) Reijnders et al. (2017) identified a de novo heterozygous c.53G-A transition (c.53G-A, NM_006908) in exon 2 of the RAC1 gene, resulting in a cys18-to-tyr (C18Y) substitution at a highly conserved residue within the GTP/GDP binding site. The mutation, which was found by whole-exome sequencing, was not found in the ExAC database or an in-house database. Transfection of the C18Y mutation into fibroblasts resulted in an increase in the proportion of cells rich in filopodia, a reduction in cells rich in lamellipodia/ruffles, and a decrease in the cell circularity index, indicating a change in fibroblast spreading and consistent with a dominant-negative effect. Expression of the C18Y mutation into zebrafish embryos resulted in significantly reduced neuronal proliferation and structural defects in the cerebellum compared to wildtype. Specifically, there was depletion of axons that crossed the midline. The patient had microcephaly (-2.5 SD) and pronounced cerebellar defects.
.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
SNP: rs1554263624, ClinVar: RCV000514438, RCV001255401, RCV002274050, RCV003317250
In a 9-year-old boy (patient 2) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751) Reijnders et al. (2017) identified a de novo heterozygous c.116A-G transition (c.116A-G, NM_006908) in exon 3 of the RAC1 gene, resulting in an asn39-to-ser (N39S) substitution at a highly conserved residue in the switch I motif. The mutation, which was found by whole-exome sequencing, was not found in the ExAC database or an in-house database. Transfection of the N39S mutation into fibroblasts resulted in an increase in the proportion of cells rich in filopodia, a reduction in cells rich in lamellipodia/ruffles, and a decrease in the cell circularity index, indicating a change in fibroblast spreading and consistent with a dominant-negative effect. Expression of the mutation into zebrafish embryos resulted in significantly reduced neuronal proliferation compared to wildtype. The patient had microcephaly (-3 SD).
.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
SNP: rs1554264268, ClinVar: RCV000515033, RCV000520996
In a 4.5-month-old boy (patient 4) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751) Reijnders et al. (2017) identified a de novo heterozygous c.470G-A transition (c.470G-A, NM_006908) in exon 7 of the RAC1 gene, resulting in a cys157-to-tyr (C157Y) substitution at a highly conserved residue adjacent to the GTP/GDP binding site. The mutation, which was found by whole-exome sequencing, was not found in the ExAC database or an in-house database. Transfection of the C157Y mutation into fibroblasts resulted in a tendency towards increased filopodia and reduced lamellipodia/ruffles, but did not result in a significant change in circularity index compared to controls, suggesting a modest impact on RAC1 function in these assays.
.0004 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
SNP: rs1554263626, ClinVar: RCV000514176, RCV001550793
In a 12-year-old boy (patient 5) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751) Reijnders et al. (2017) identified a de novo heterozygous c.190T-G transversion (c.190T-G, NM_006908) in exon 3 of the RAC1 gene, resulting in a tyr64-to-asp (Y64D) substitution at a highly conserved residue within the switch II motif. The mutation, which was found by whole-exome sequencing, was not found in the ExAC database or an in-house database. Fibroblasts transfected with mutant Y64D showed increased circularity index and a greater proportion of cells exhibiting lamellipodia or ruffles, suggesting constitutive activation of RAC1. The mutant Y64D protein localized strongly to the leading edge of ruffles and lamellipodia in fibroblasts.
In 3 unrelated patients (patients 3, 4, and 5) with MRD48, Banka et al. (2022) identified heterozygosity for the Y64D substitution in the switch II region of RAC1. The mutation was confirmed to be de novo in patients 4 and 5; the parents of patient 3 were not available for testing. Expression of RAC1 with the Y64D mutation in NIH3T3 fibroblasts resulted in increased signaling through the WAVE regulatory complex (WRC) and PAK family kinases.
.0005 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
SNP: rs1554263625, ClinVar: RCV000514583, RCV001821433
In a 33-month-old boy (patient 6) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751) Reijnders et al. (2017) identified a de novo heterozygous c.151G-A transition (c.151G-A, NM_006908) in exon 3 of the RAC1 gene, resulting in a val51-to-met (V51M) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing, was not found in the ExAC database or an in-house database. Transfection of the V51M mutation into fibroblasts resulted in a tendency towards increased filopodia and reduced lamellipodia/ruffles, but did not result in a significant change in circularity index compared to controls, suggesting a modest impact on RAC1 function in these assays. This patient had significant macrocephaly (+4.16 SD), as did an unrelated patient (patient 7) who had a different mutation affecting the same codon (V51L; 602048.0006).
.0006 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
SNP: rs1554263625, ClinVar: RCV000515028, RCV003150251
In a 4.5-year-old boy (patient 7) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751) Reijnders et al. (2017) identified a de novo heterozygous c.151G-C transversion (c.151G-C, NM_006908) in exon 3 of the RAC1 gene, resulting in a val51-to-leu (V51L) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing, was not found in the ExAC database or an in-house database. This patient had significant macrocephaly (+4.5 SD), as did an unrelated patient (patient 6) who had a different mutation affecting the same codon (V51M; 602048.0005).
.0007 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
SNP: rs2534029561, ClinVar: RCV003156716, RCV003332418
In a 2-year-old girl (patient 1) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751), Banka et al. (2022) identified heterozygosity for a c.181C-G transversion (c.181C-G, NM_006908.4) in the RAC1 gene, resulting in a gln61-to-glu (Q61E) substitution in the RAC1 switch II region. The mutation, which was identified as part of the Deciphering Developmental Disorders Study, was found to be de novo.
.0008 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
SNP: rs2115201389, ClinVar: RCV001808906
In a 3-year-old girl (patient 6) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751), Banka et al. (2022) identified heterozygosity for a c.191A-G transition (c.191A-G, NM_006908.4) in the RAC1 gene, resulting in a tyr64-to-cys (Y64C) substitution in the RAC1 switch II region. The mutation, which was identified as part of the Deciphering Developmental Disorders Study, was found to be de novo. Expression of RAC1 with the Y64C mutation in NIH3T3 fibroblasts resulted in increased signaling through the WAVE regulatory complex (WRC) and PAK family kinases.
.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
SNP: rs2115201406, ClinVar: RCV003156718
In a 5-year-old girl (patient 7) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751), Banka et al. (2022) identified heterozygosity for a c.202C-A transversion (c.202C-A, NM_006908.4) in the RAC1 gene, resulting in an arg68-to-ser (R68S) substitution in the RAC1 switch II region. Neither parent was available for testing. The mutation was identified as part of the Deciphering Developmental Disorders Study. Expression of RAC1 with the R68S mutation in NIH3T3 fibroblasts resulted in increased signaling through the WAVE regulatory complex (WRC) and PAK family kinases.
.0010 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 48
SNP: rs2115201406, ClinVar: RCV003156719
In a 15-year-old boy (patient 8) with autosomal dominant intellectual developmental disorder-48 (MRD48; 617751), Banka et al. (2022) identified heterozygosity for a c.202C-G transversion (c.202C-G, NM_006908.4) in the RAC1 gene, resulting in an arg68-to-gly (R68G) substitution in the RAC1 switch II region. The variant was not present in the mother, but the father was not available for testing. The mutation was identified as part of the Deciphering Developmental Disorders Study.
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Ada Hamosh - updated : 09/18/2019
Cassandra L. Kniffin - updated : 10/30/2017
Paul J. Converse - updated : 09/14/2016
Ada Hamosh - updated : 05/06/2013
Ada Hamosh - updated : 2/20/2013
Matthew B. Gross - updated : 5/10/2011
Matthew B. Gross - updated : 5/6/2010
Ada Hamosh - updated : 10/13/2009
Patricia A. Hartz - updated : 2/24/2009
Patricia A. Hartz - updated : 12/19/2008
Ada Hamosh - updated : 4/22/2008
Cassandra L. Kniffin - updated : 2/29/2008
Patricia A. Hartz - updated : 7/9/2007
Ada Hamosh - updated : 11/28/2006
Marla J. F. O'Neill - updated : 6/23/2006
Patricia A. Hartz - updated : 3/2/2006
Ada Hamosh - updated : 2/1/2006
George E. Tiller - updated : 9/12/2005
Ada Hamosh - updated : 8/15/2005
Ada Hamosh - updated : 8/3/2005
Patricia A. Hartz - updated : 6/13/2005
George E. Tiller - updated : 3/10/2005
Patricia A. Hartz - updated : 2/18/2005
Patricia A. Hartz - updated : 10/7/2004
Paul J. Converse - updated : 9/14/2004
Paul J. Converse - updated : 10/24/2003
Ada Hamosh - updated : 7/24/2003
Cassandra L. Kniffin - updated : 2/5/2003
Ada Hamosh - updated : 9/13/2002
Ada Hamosh - updated : 12/18/2000
Ada Hamosh - updated : 12/14/2000
Joanna S. Amberger - updated : 12/6/2000
Ada Hamosh - updated : 11/15/2000
Ada Hamosh - updated : 10/20/2000
Victor A. McKusick - updated : 5/5/1998
Victor A. McKusick - updated : 10/14/1997
carol : 03/29/2023
carol : 03/28/2023
mgross : 12/09/2022
alopez : 04/26/2022
alopez : 09/18/2019
carol : 11/01/2017
alopez : 10/31/2017
alopez : 10/31/2017
ckniffin : 10/30/2017
mgross : 09/14/2016
alopez : 05/06/2013
alopez : 2/22/2013
alopez : 2/22/2013
alopez : 2/22/2013
terry : 2/20/2013
alopez : 11/26/2012
alopez : 6/21/2011
terry : 6/10/2011
terry : 5/25/2011
mgross : 5/10/2011
wwang : 5/14/2010
mgross : 5/6/2010
alopez : 10/22/2009
terry : 10/13/2009
mgross : 2/24/2009
mgross : 1/5/2009
terry : 12/19/2008
alopez : 5/9/2008
terry : 4/22/2008
wwang : 3/19/2008
ckniffin : 2/29/2008
wwang : 9/21/2007
alopez : 9/18/2007
terry : 7/9/2007
alopez : 12/7/2006
terry : 11/28/2006
wwang : 6/26/2006
terry : 6/23/2006
mgross : 3/2/2006
alopez : 2/2/2006
terry : 2/1/2006
alopez : 10/20/2005
terry : 9/12/2005
alopez : 8/18/2005
terry : 8/15/2005
alopez : 8/4/2005
terry : 8/3/2005
mgross : 6/13/2005
alopez : 3/10/2005
mgross : 2/18/2005
terry : 2/2/2005
mgross : 10/7/2004
mgross : 9/14/2004
mgross : 10/24/2003
tkritzer : 7/25/2003
terry : 7/24/2003
carol : 2/14/2003
ckniffin : 2/5/2003
alopez : 11/19/2002
alopez : 11/19/2002
terry : 11/18/2002
alopez : 9/16/2002
alopez : 9/16/2002
tkritzer : 9/13/2002
tkritzer : 9/13/2002
joanna : 4/24/2001
alopez : 4/18/2001
mgross : 12/18/2000
carol : 12/14/2000
terry : 12/7/2000
joanna : 12/6/2000
joanna : 12/6/2000
mgross : 11/15/2000
alopez : 10/20/2000
dkim : 9/11/1998
alopez : 8/31/1998
alopez : 5/7/1998
terry : 5/5/1998
alopez : 5/4/1998
mark : 11/25/1997
dholmes : 11/5/1997
mark : 10/14/1997
mark : 10/14/1997
mark : 10/14/1997