Alternative titles; symbols
HGNC Approved Gene Symbol: RHOA
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:49,359,145-49,411,976 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic | 618727 | 3 |
Madaule and Axel (1985) identified a new family of Ras genes, the Rho genes, related to a gene originally identified in Aplysia. Human cDNAs encoding 3 Rho, or ARH (Aplysia Ras-related homolog), proteins were isolated and designated H6 (RHOB; 165370), H9 (RHOC; 165380), and H12 (RHOA). RHOA encodes a 191-amino acid protein that shares 85% homology with RHOB and 35% homology with HRAS (190020) (Yeramian et al., 1987).
Cannizzaro et al. (1990) mapped 1 member of the ARH family, the H12 (RHOA) gene, to chromosome 3p21 by in situ hybridization. Kiss et al. (1997) assigned the RHOA gene to chromosome 3p21.3 by fluorescence in situ hybridization and by PCR study of somatic cell hybrids.
Maesaki et al. (1999) reported the 2.2-angstrom crystal structure of RhoA bound to an effector domain of protein kinase PRKCL1 (601302). The structure revealed the antiparallel coiled-coil finger (ACC finger) fold of the effector domain that binds to the Rho specificity-determining regions containing switch I, beta strands B2 and B3, and the C-terminal alpha helix A5, predominantly by specific hydrogen bonds. The ACC finger fold is distinct from those for other small G proteins and provides evidence for the diverse ways of effector recognition. Sequence analysis based on the structure suggested that the ACC finger fold is widespread in Rho effector proteins.
Lutz et al. (2007) determined the crystal structure of the G-alpha-q (600998)-p63RhoGEF (610215)-RhoA complex, detailing the interactions of G-alpha-q with the Dbl and pleckstrin homology (DH and PH) domains of p63RhoGEF. These interactions involved the effector-binding site and the C-terminal region of G-alpha-q and appeared to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio (601893), Duet (604605), and p63RhoGEF were shown to constitute a family of G-alpha-q effectors that appear to activate RhoA both in vitro and in intact cells. Lutz et al. (2007) proposed that this structure represents the crux of an ancient signal transduction pathway that is expected to be important in an array of physiologic processes.
The small guanosine triphosphatase (GTP) Rho regulates remodeling of the actin cytoskeleton during cell morphogenesis and motility. In their Figure 3C, Maekawa et al. (1999) diagrammed proposed signaling pathways for Rho-induced remodeling of the actin cytoskeleton. They demonstrated that active Rho signals to its downstream effector ROCK1 (601702), which phosphorylates and activates LIM kinase (see 601329). LIM kinase, in turn, phosphorylates cofilin (601442), inhibiting its actin-depolymerizing activity.
Nakamura et al. (2001) studied the role of Rho in the migration of corneal epithelial cells in rabbit. They detected both ROCK1 and ROCK2 (604002) in the corneal epithelium at protein and mRNA levels. They found that exoenzyme C3, a Rho inhibitor, inhibits corneal epithelial migration in a dose-dependent manner and prevents the stimulatory effect of the Rho activator lysophosphatidic acid (LPA). Both cytochalasin B, an inhibitor of actin filament assembly, and ML7, an inhibitor of myosin light chain kinase, also prevent LPA stimulation of epithelial migration. The authors suggested that Rho mediates corneal epithelial migration in response to external stimuli by regulating the organization of the actin cytoskeleton.
Rao et al. (2001) investigated the role of Rho kinase in the modulation of aqueous humor outflow facility. The treatment of human trabecular meshwork and canal of Schlemm cells with a Rho kinase-specific inhibitor led to significant but reversible changes in cell shape and decreased actin stress fibers, focal adhesions, and protein phosphotyrosine staining. Based on the Rho kinase inhibitor-induced changes in myosin light chain phosphorylation and actomyosin organization, the authors suggested that cellular relaxation and loss of cell-substratum adhesions in the human trabecular meshwork and canal of Schlemm cells could result in either increased paracellular fluid flow across the canal of Schlemm or altered flow pathway through the juxtacanalicular tissue, thereby lowering resistance to outflow. They suggested Rho kinase as a potential target for the development of drugs to modulate intraocular pressure in glaucoma patients.
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 activity, and increased RAC (see 602048) 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.
Zhou et al. (2003) found that Rho and its effector Rock1 preferentially regulated the amount of A-beta(42), a highly amyloidogenic, 42-residue amyloid beta (104760) peptide, produced in vitro and that only those NSAIDs (nonsteroidal antiinflammatory drugs) effective as Rho inhibitors lowered A-beta(42). Administration of a selective Rock inhibitor also preferentially lowered brain levels of A-beta(42) in a transgenic mouse model of Alzheimer disease (104300). Thus, Zhou et al. (2003) concluded that the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce A-beta(42) through inhibition of Rho activity.
Wang et al. (2003) found that atypical protein kinase C-zeta (PKC2; 176982), an effector of the Cdc42/Rac1-PAR6 (607484) polarity complex, recruited Smurf1 (605568) to cellular protrusions, where it controlled the local level of RhoA. Smurf1 thus links the polarity complex to degradation of RhoA in lamellipodia and filopodia to prevent RhoA signaling during dynamic membrane movements.
Using mouse brain endothelial cells, Crose et al. (2009) showed that Ccm2 (607929) interacted with the RhoA ubiquitin ligase Smurf1. Ccm2 directed Smurf1 to the cell periphery, which led to local degradation of RhoA. Knockdown of Ccm2 resulted in RhoA stability and cytoskeletal changes leading to monolayer permeability, decreased tubule formation, and reduced cell migration. Crose et al. (2009) concluded that CCM2 contributes to endothelial cell integrity by regulating SMURF1-directed RHOA degradation.
Borikova et al. (2010) showed that knockdown of Ccm1 (KRIT1; 604214), Ccm2, or Ccm3 (603285) in mouse embryonic endothelial cells induced RhoA overexpression and persistent RhoA activity at the cell edge, as well as in the cytoplasm and nucleus. RhoA activation was especially pronounced following Ccm1 knockdown. Knockdown of Ccm1, Ccm2, or Ccm3 inhibited formation of vessel-like tubes and invasion of extracellular matrix. Knockdown or inhibition of Rock2 countered these effects and was associated with inhibition of RhoA-stimulated phosphorylation of myosin light chain-2 (MLC2; see 160781). Borikova et al. (2010) concluded that the protein complex made up of CCM1, CCM2, and CCM3 regulates RhoA activation and cytoskeletal dynamics.
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.
Wu et al. (2005) showed that transcripts for RhoA, a small GTPase that regulates the actin cytoskeleton, are localized in developing axons and growth cones, and that this localization is mediated by an axonal targeting element located in the RhoA 3-prime untranslated region. Sema3A (603961) induces intraaxonal translation of RhoA mRNA, and this local translation of RhoA is necessary and sufficient for Sema3A-mediated growth cone collapse. Wu et al. (2005) concluded that their studies indicate that local RhoA translation regulates the neuronal cytoskeleton and identify a new mechanism for the regulation of RhoA signaling.
RhoA signaling plays a critical role in many cellular processes, including cell migration. Valderrama et al. (2006) showed that the vaccinia F11L protein interacts directly with RhoA, inhibiting its signaling by blocking the interaction with its downstream effectors ROCK (601702) and mammalian Dia (300108). RNA interference-mediated depletion of F11L during infection resulted in the absence of vaccinia-induced cell motility and inhibition of viral morphogenesis. Disruption of the RhoA binding site in F11L, which resembles that of ROCK, led to an identical phenotype. Thus, Valderrama et al. (2006) concluded that inhibition of RhoA signaling is required for both vaccinia morphogenesis and virus-induced cell motility.
Pertz et al. (2006) used a fluorescent biosensor, based on a novel design preserving reversible membrane interactions, to visualize the spatiotemporal dynamics of RhoA activity during cell migration. In randomly migrating cells, RhoA activity is concentrated in a sharp band directly at the edge of protrusions. It is observed sporadically in retracting tails, and is low in the cell body. RhoA activity is also associated with peripheral ruffles and pinocytic vesicles, but not with dorsal ruffles induced by platelet-derived growth factor (PDGF; see 173430). In contrast to randomly migrating cells, PDGF-induced membrane protrusions have low RhoA activity, potentially because PDGF strongly activates Rac, which had been shown to antagonize RhoA activity. Pertz et al. (2006) concluded that different extracellular cues induce distinct patterns of RhoA signaling during membrane protrusion.
Yoshida et al. (2006) found that in S. cerevisiae the small GTP-binding protein RhoA stimulates type 2 myosin contractility and formin (FMN1; 136535)-dependent assembly of the cytokinetic actin contractile ring. Yoshida et al. (2006) found that budding yeast Polo-like kinase Cdc5 (see 602868) controls the targeting and activation of RhoA at the division site via Rho1 guanine nucleotide exchange factors. Yoshida et al. (2006) concluded that this role of Cdc5 (Polo-like kinase) in regulating Rho1 is likely to be relevant to cytokinesis and asymmetric cell division in other organisms.
Canman et al. (2008) noted that, during cytokinesis, RhoA orchestrates contractile ring assembly and constriction. RhoA signaling is controlled by the central spindle, a set of microtubule bundles that forms between the separating chromosomes. Centralspindlin is a protein complex consisting of kinesin-6 ZEN4 (KIF23; 605064) and the Rho GTPase-activating protein CYK4 (RACGAP1; 604980) and is required for central spindle assembly and cytokinesis in C. elegans. Canman et al. (2008) found that 2 separation-of-function mutations in the GAP domain of CYK4 lead to cytokinesis defects that mimic centralspindlin loss of function. These defects could be rescued by depletion of RAC or its effectors, but not by depletion of RhoA. Canman et al. (2008) concluded that inactivation of RAC by CYK4 functions in parallel with RhoA activation to drive contractile ring constriction during cytokinesis.
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 is activated at the cell edge synchronous with edge advancement, whereas Cdc42 (116952) and Rac1 (602048) 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.
In studies in vascular smooth muscle cells (VSMC), Guilluy et al. (2010) demonstrated that ARHGEF1 (601855) is specifically responsible for angiotensin receptor-1 (AGTR1; 106165)-mediated RHOA activation through a mechanism involving the phosphorylation of tyr738 in ARHGEF1 by JAK2 (147796). Guilluy et al. (2010) generated mice lacking Arhgef1 in VSMCs and found that the mutant mice were protected against angiotensin II (see 106150)-dependent hypertension without alteration in baseline blood pressure or the response to other vasoactive factors. Guilluy et al. (2010) concluded that control of RHOA signaling through ARHGEF1 is central to the development of angiotensin II-dependent hypertension.
Murakoshi et al. (2011) used 2-photon fluorescence lifetime imaging microscopy to monitor the activity of 2 Rho GTPases, RhoA and Cdc42, in single dendritic spines undergoing structural plasticity associated with long-term potentiation in CA1 pyramidal neurons in cultured slices of rat hippocampus. When long-term volume increase was induced in a single spine using 2-photon glutamate uncaging, RhoA and Cdc42 were rapidly activated in the stimulated spine. These activities decayed over about 5 minutes, and were then followed by a phase of persistent activation lasting more than half an hour. Although active RhoA and Cdc42 were similarly mobile, their activity patterns were different. RhoA activation diffused out of the stimulated spine and spread over about 5 microns along the dendrite. In contrast, Cdc42 activation was restricted to the stimulated spine, and exhibited a steep gradient at the spine necks. Inhibition of the Rho-Rock pathway preferentially inhibited the initial spine growth, whereas the inhibition of the Cdc42-Pak pathway blocked the maintenance of sustained structural plasticity. RhoA and Cdc42 activation depended on calcium ion/calmodulin-dependent kinase (CaMKII). Thus, Murakoshi et al. (2011) concluded that RhoA and Cdc42 relay transient CaMKII activation to synapse-specific, long-term signaling required for spine structural plasticity.
Borras et al. (2015) demonstrated that inhibiting the trabecular meshwork RhoA pathway by delivering a mutated, dominant-negative RhoA gene (scAAV2.dnRhoA) inside a long-expressing recombinant virus reduced nocturnal elevation of intraocular pressure (IOP) in rats. By visual inspection, human trabecular meshwork cells infected with scAAV2.dnRhoA showed diminished stress fiber formation. A single-dose injection of scAAV2.dnRhoA into rat eyes prevented elevation of IOP during the nocturnal cycle for at least 4 weeks.
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 (113505), 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.
In 6 of 7 unrelated patients with ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (EDFAOB; 618727), Vabres et al. (2019) identified somatic mosaic missense mutations in the RHOA gene: E47K (165390.0001) in 5 patients and P71S (165390.0002) in 1. The seventh patient could not be analyzed due to failed quality controls. The mutations were absent from blood samples of the patients, but in skin-derived DNA samples, mutant allele fractions ranged from 1.9% to 33.5%. Neither variant was found in in-house exome data from approximately 1,500 individuals or in public variant databases.
Bivalacqua et al. (2004) studied the contribution of RhoA/Rho kinase signaling to erectile dysfunction in streptozotocin (STZ) diabetic rats. Rho kinase and eNOS (163729) colocalized in the endothelium of corpus cavernosum, and RhoA and Rho kinase abundance and Mypt1 (602021) phosphorylation were elevated in STZ diabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive NOS activity, and cGMP levels were reduced in STZ diabetic rat penis. Bivalacqua et al. (2004) introduced a dominant-negative RhoA mutant and found that erectile responses in the STZ diabetic rats improved to values similar to controls.
In 5 unrelated patients (S1, S2, S4, S5, and S7) with ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (EDFAOB; 618727), Vabres et al. (2019) identified somatic mosaicism for a c.139G-A transition (c.139G-A, NM_001664.3) in the RHOA gene, resulting in a glu47-to-lys (E47K) substitution at a highly conserved residue. The mutation was absent from blood samples of the patients, but in skin-derived DNA samples, mutant allele fractions ranged from 1.9% to 33.5%. The variant was not found in in-house WES data from approximately 1,500 individuals, or in the dbSNP (build 147), COSMIC, ExAC, or gnomAD databases. Immunocytochemical analysis of transfected NIH/3T3 cells displayed reduced cell spreading and a decreased number of stress fibers, as well as microtubule disorganization, indicating a dominant-negative or otherwise inactivating effect with the E47K variant. In addition, immunoblot analysis revealed reduced levels of MYPT1 (PPP1R12A; 602021) and MLC2 (MYL2; 160781) phosphorylation at sites targeted by a major downstream effector of activated RHOA.
In a 14-year-girl (patient S3) with ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (EDFAOB; 618727), Vabres et al. (2019) identified somatic mosaicism for a c.211C-T transition (c.211C-T, NM_001664.3) in the RHOA gene, resulting in a pro71-to-ser (P71S) substitution at a highly conserved residue. The mutation was absent from patient blood samples, but in fresh skin-derived DNA samples, mutant allele fractions ranged from 24.3% to 29%. The variant was not found in in-house WES data from approximately 1,500 individuals, or in the dbSNP (build 147), COSMIC, ExAC, or gnomAD databases. Immunocytochemical analysis of transfected NIH/3T3 cells displayed reduced cell spreading and a decreased number of stress fibers, as well as microtubule disorganization, indicating a dominant-negative or otherwise inactivating effect with the variant. In addition, immunoblot analysis revealed reduced levels of MYPT1 (PPP1R12A; 602021) and MLC2 (MYL2; 160781) phosphorylation at sites targeted by a major downstream effector of activated RHOA.
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