RHOA (ras homolog gene family, member A)

2014-09-01   Rebeca Manso 

Identity

HGNC
LOCATION
3p21.31
LOCUSID
ALIAS
ARH12,ARHA,EDFAOB,RHO12,RHOH12
FUSION GENES

Abstract

Review on RHOA, with data on DNA\/RNA, on the protein encoded and where the gene is implicated.

DNA/RNA

Description

The RhoA gene can be found on chromosome 3 at location: 49371585-49424530. This gene includes 5 exons.

Transcription

This gene has 6 transcripts (splice variants): 2031 bp (variant a); 961 bp (variant b); 889 bp (variant c); 633 bp (variant d); 539 bp (variant e); 388 bp (variant f).

Proteins

Atlas Image
Schematic representation of the domains of RhoA. The available functional and structural data show that RHO-GTP-binding proteins are made-up of an effector domain, four separate guanosine phosphate binding regions that span the length of the core structure, a hypervariable region and a CAAX box motif (Lartey and López Bernal, 2009).

Description

The RhoA protein encodes five alternative isoforms: variant a (193 amino acids), variant b (187 amino acids), variant c (90 amino acids), variant d (129 amino acids) and variant e (86 amino acids).
- RhoA structure:
The available functional and structural data show that RHO-GTP-binding proteins are made-up of an effector domain, four separate guanosine phosphate binding regions that span the length of the core structure, a hypervariable region and a CAAX box motif (C: Cys; A: aliphatic residue; X: any residue). The effector domain (residues 26-45) changes conformation between the GTP bound and GDP bound states. All RHO proteins have conserved residues at Gly14, Thr19, Phe30 and Gln93 which are involved in binding, stabilization or regulation of GTP hydrolysis. The N-terminus region also contains switch 1 (residues 27-40) and switch 2 (residues 59-78) regions which change conformation between GTP- and GDP-bound states and may facilitate changes in effector region required for binding to downstream targets. RhoA protein is target for several bacterial toxins, which modify key conserved amino acids involved in their regulation. These include Clostridium botulinum exoenzyme C3 transferase, which modifies Asn41, and Toxin B, which acts on Thr37. The hypervariable region made-up of residues 173-189 is the region of most diversity between individual RHO family members. It may contain sites for palmitoylation and a polybasic region which can determine membrane association. The C-terminus of RhoA is essential for correct localization of the protein. RhoA is post-translationally modified by prenylation of a conserved C-terminal cysteine followed by methylation and proteolytic removal of the last three amino acids. The prenyl group (geranylgeranyl) anchors the GTPase into membranes and this modification is essential for its stability, cell growth, transformation, and cytoskeletal organization.
- RhoA activity regulation:
Rho GTPases can be activated by intrinsic or extrinsic cues, setting off a signaling cascade (Etienne-Manneville and Hall, 2002). Rho GTPases behave as molecular switches that fluctuate between inactive and active states, two conformations that depend on the binding of either GDP or GTP to the GTPases, respectively (Bustelo et al., 2007). Two types of regulatory proteins control this cycling: guanine nucleotide-exchange factors (GEFs), which activate Rho GTPases by catalyzing the exchange of GDP for GTP (Rossman et al., 2005), and GTPase-activating proteins (GAPs), which inactivate the GTPases by enhancing intrinsic GTP hydrolysis activity (Bos et al., 2007). There are over 80 GEFs and 70 GAPs for Rho GTPases, whose activity is tightly regulated and can be highly specific. RhoA can be sequestered in the cytoplasm by guanine nucleotide-dissociation inhibitors (GDIs), which bind prenylated GDP-bound Rho proteins (Garcia-Mata et al., 2011), allowing translocation of Rho GTPases between membranes and cytosol.
- RhoA effectors binding:
To date, at least 21 proteins have been identified which directly interact with RhoA (ROCK1, ROCK2, PRKcA, PKN1, PKN2, RTKN1, RTKN2, RHPN1, RHPN2, KTN1, CIT, DIAPH1, KCNA2, ITRP1, PLD, MYBPH, PIP5K, FAK, BORG, MBS, GDIA). Some of these have been shown to contribute to specific responses downstream of RhoA. Similarly to GEFs and GAPs, effectors bind to Rho both through the Switch 1 and 2 regions, but the amino acids involved in interaction with each target differ.
Atlas Image
RhoA activity regulation. Rho GTPase activity is controlled by guanine nucleotide exchange factor (GEF), GTPase-activating protein (GAP) and guanine nucleotide dissociation inhibitor (GDI). GEF activates Rho GTPases by facilitating the release of GDP and the binding of GTP. GAP inactivates Rho GTPases by promoting hydrolysis of the bound GTP molecules, resulting in their quick change from the GTP-bound form to the GDP-bound form. GDI binds to C-terminal prenyl groups on some Rho proteins, maintaining them in the inactive state. Active Rho GTPases act on their downstream effector proteins, stimulating a variety of cellular processes (Chi et al., 2013).

Expression

RhoA protein is expressed in all tissues tested. RhoA expression in normal human tissues, embryonic tissues and stem cells.

Localisation

RhoA localizes predominantly in the plasmatic membrane and cytoplasm. Also, it localizes to cell-cell contacts and cell projections.

Function

RhoA is a protein involved in multiple cellular processes.
- Role in actin organization:
RhoA protein plays a central role in regulating cell shape, polarity and locomotion through their effects on actin polymerization, actomyosin contractility, cell adhesion, and microtubule dynamics. RhoA is believed to act primarily at the rear of migrating cells to promote detachment.
RhoA directly stimulates actin polymerization through activiation of diaphanous-related formins (DRFs, also known as Dia proteins). These stimulate addition of actin monomers to the fast-growing end of actin filaments. DRFs act together with ROCKs to mediate Rho-induced stress fiber formation. ROCK-mediated phosphorylation of LIMK and consequent inhibition of cofilin also contributes to the increase in actin filaments in response to Rho. In addition, ROCKs induce actomyosin-based contractility and phosphorylate several proteins involved in regulating myosins and other actin-binding proteins. Actomyosin contractility is important in migrating cells for detachment of the rear. Microtubules are essential for determining cell polarity as well as for vesicular locomotion and intracellular transport. The concerted action of ROCK and Dia is essential for the regulation of cell polarity and organization of microtubules. ROCK phosphorylates TAU and MAP2, proteins that regulate microtubule stability.
RhoA plays a key role in regulating the integrity of cell-extracellular matrix and cell-cell adhesions, the latter including both adherens junctions and tight junctions. Loss of cell-cell junctions is required form the migration of epithelial cells and may be regulated reciprocally by ROCKs and DRFs. Also, RhoA is localized to developing axons and growth cones, and this localization is mediated by an axonal targeting element located in the RhoA 3 untranslated region (UTR). Local RhoA translations regulates the neuronal cytoskeleton and identify a new mechanism for the regulation of RhoA signaling (Wu et al., 2005). On the other hand, increasing expression of the transcription repressor, GCF2, can silence RhoA expression, leading to actin cytoskeleton disorganization (Shen et al., 2012).
- Role in cell migration:
The inhibition of RhoA signaling by blocking the interaction with its downstream effectors Rho-associated kinase (ROCK) and mDia is required for both vaccinia morphogenesis and virus-induced cell motility (Valderrama et al., 2006).
- Role in cell protrusion:
RhoA activates focal adhesion kinase (FAK) signaling. 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 (Machacek et al., 2009).
- Role in exocytosis:
RhoA is involved in Ca2+-dependent exocytosis at least partly through the reorganization of actin filaments (Komuro et al., 1996). This type of exocytosis is regulated by G12/G13 alpha through a Rho/Rho-associated kinase-dependent pathway (Yamaguchi et al., 2000).
- Role in endocytosis:
RhoA helps direct endocytosis in a variety of cell types (Lamaze et al., 1996; Khandelwal et al., 2010; Yu et al., 2010). RhoA is essential for clathrin- and caveolar- independent endocytosis (Sabharanjak et al., 2002). Treatment with the PI3K inhibitor (LY294002) or the FAK inhibitor (PF573228) suppresses compensatory endocytosis by inhibiting the activation of RhoA and then reducing the recruitment of ROCK (Khandelwal et al., 2010).
- Role in cytokinesis:
Cytokinesis requires actomyosin-based contraction. Inhibition of ROCK or citron kinase causes defects in cytokinesis resulting in multinucleate cells. Diaphanous-related formins (DRFs) are also implicated in this process, the DRF mDia1 localizes to the cleavage furrow during cytokinesis. DRFs could contribute to cytokinesis by stimulating local actin polymerization and/or by coordinating microtubules with actin filaments at the site of the contractile ring. RhoA signaling is controlled by the central spindle, a set of microtubule bundles that forms between the separating chromosomes. Thus, inactivation of Rac by centralspindlin functions in parallel with RhoA activation to drive contractile ring constriction during cytokinesis (Canman et al., 2008).
- Role in cell cycle regulation:
RhoA plays a pivotal role in G1 cell cycle progression, primarily through regulation of both cyclin D1 expression, and the levels of the cyclin-dependent kinase inhibitors p21 and p27. Multiple pathways seem to link Rho proteins to the control of cyclin D1 levels. Many of these involve the activation of protein kinases, leading to the subsequent modulation of transcription factor activity. RhoA suppresses p21 levels in multiple normal and transformed cell lines. This effect appears to occur through a transcriptional mechanism but is independent of p53, a major transcriptional regulator of p21. RhoA plays an important role in determining the levels of p27 through a pathway involving its effector, the Rho-associated kinases. RhoA facilitates entry into S phase by degradation of the cyclin-dependent kinase inhibitor p27kip1 (Hirai et al., 1997).
- Role in development:
RhoA protein is required for processes involving cell migration in development including: neurite outgrowth, dorsal closure, bone formation, and myogenesis. Rho-loss of function is embryonically lethal in mouse development by E7. This is attributed to failure in gastrulation and an inability of cells to migrate.
- Role in transcriptional control:
The relationship between many of the cellular functions mediated by RhoA with transcriptional regulation has been described. RhoA modulates the activity of SRF, NF-kappaB, c/EBPb, Stat3, Stat5, FHL-2, PAX6, GATA-4, E2F, estrogen receptor alpha, estrogen receptor beta, CREB, and transcription factors that depend on the JNK and p38 MAP kinase pathways. Substrates to these kinases include c-Jun, ELK, PEA3, ATF2, MEF2A, Max and CHOP/GADD153.
- Role in cell proliferation:
RhoA plays cell type-specific roles in the regulation of cell proliferation. RhoA plays critical roles in both early and late stages of B-cell development (Zhang et al., 2012).

Mutations

Note

48 mutations have been described in the RhoA gene, according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database.
De novo mutations have been described in patients with Burkitt lymphoma: R5Q and I23R (Richter et al., 2012; Rohde et al., 2014); peripheral T-cell lymphoma: G17V, affecting the GTP-binding domain (Manso et al., 2014; Palomero et al., 2014; Sakata-Yanagimoto et al., 2014; Yoo et al., 2014); head and neck carcinoma: E40Q and Y42I, affecting the effector domain (Lawrence et al., 2014); diffuse-type gastric carcinoma: R5Q, Y42I and G17V (Kakiuchi et al., 2014).

Implicated in

Entity name
Breast carcinoma
Oncogenesis
RhoA protein levels were significantly increased in breast cancer compared with the corresponding normal tissue. Of particular note, protein levels of RhoA were barely detectable in normal mammary tissue, but were highly expressed in all breast tumors tested. Interestingly, RhoA protein levels correlated with increasing breast tumor grade. Moreover, decreased metastasis-free survival was predicted by RhoA and ROCK1 co-overexpression in breast cell lines and cancer tissues (Gilkes et al., 2014). On the other hand, blocking RhoA activity with the RhoA pathway specific inhibitor H-1152, or a RhoA specific siRNA, resulted in inhibition of invasive behavior in a triple-negative breast cancer cell line (Fagan-Solis et al., 2013).
Entity name
Ovarian carcinoma
Oncogenesis
Expression of RhoA is significantly increased in advanced ovarian carcinomas and also in the peritoneal disseminated lesions (Horiuchi et al., 2008). The expression of the protein is further upregulated in tumors of stages III/IV when compared to those of stages I/II. Analysis of matched pairs of primary and metastatic lesions showed that expression of both RhoA mRNA was significantly higher in metastatic lesions of peritoneal dissemination than in the respective primary tumors.
Entity name
Testicular cancer
Oncogenesis
RhoA is involved in testicular germinal epithelial carcinogenesis and progression in testicular germ cell tumors (GCT) (Kamai et al., 2001). Protein expression of RhoA and its two major downstream effectors ROCK1 and ROCK2, was significantly higher in tumor tissue than in nontumor tissue from 57 patients with GCT. The expression was greater in tumors of higher stages than lower stages, thus RhoA correlates with tumor stage and aggressiveness.
Entity name
Pelvic/ureteric cancer
Oncogenesis
Both mRNA and protein level of RhoA are elevated in pelvic/ureteric cancer with an increase in lymph node metastasis. The expression levels of RhoA were related to poorly differentiated grade and muscle invasion and associated with a shorter disease-free and overall survival. These findings suggest that RhoA is involved in the invasion and metastasis of upper urinary tract cancer, indicating that RhoA may be a useful prognostic factor in this disease.
Entity name
Bladder cancer
Oncogenesis
A similar deregulation of RhoA is observed in bladder cancer. In this sense, RhoA and ROCK protein levels are elevated in tumors, again with higher expression in less differentiated tumors and metastatic lymph nodes compared to normal bladder. Interestingly, the levels of expression of RhoA and ROCK correlated positively with one another suggesting that the GTPase and its effector synergize to promote tumor progression.
Entity name
Lung tumors
Oncogenesis
Of the two major forms of lung cancer, small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), the former has a greater metastatic potential. The expression and activation of RhoA is greater in SCLC than NSCLC cell lines. It has been observed that RhoA repress the expression of nitric oxide synthase-2 (NOS-2) in a lung cancer-derived cell line. Since NOS-2 activity is related to reduced proliferation, RhoA could be eliminating this antiproliferative signal in lung carcinogenesis. In addition, inhibition of RhoA by C3 exoenzyme or through ADP-ribosylation leads to an increase in cadherin-based adhesion and loss of motility of SCLC. RhoA overexpression and delta-catenin positive expression are consistently found in NSCLC, but not in normal lung tissue (Zhang et al., 2014).
Entity name
Oesophageal squamous cell carcinoma (ESCC)
Oncogenesis
RhoA and RhoC proteins promote both cell proliferation and cell invasion of human ESCC cell lines in vitro and in vivo (Faried et al., 2006). There were significant correlations among RhoA overexpression and tumor-node-metastasis (TNM) clinical classification, lymphatic invasion, and blood-vessel invasion. The five-year survival rates for ESCC patients with RhoA overexpression were significantly lower than those in patients with RhoA under-expression. The expression of RhoA protein appeared to be correlated with tumour progression of ESCC. Patients with RhoA overexpression tended to have poor prognosis compared with patients with RhoA under-expression.
Entity name
Gastric cancer
Oncogenesis
RhoA was found frequently overexpressed in gastric cancer tissues compared with normal tissues, suggesting that RhoA may play a critical role in the carcinogenesis of this type of cancer. The interference of RhoA expression and/or activity could significantly inhibit the proliferation and tumorigenicity of gastric cancer cells and enhance the chemosensitivity to therapeutic agents such as Adriamycin and 5-fluorouracil. Inhibition of RhoA/ROCK signaling pathway promotes the apoptosis of gastric cancer cells (Xu et al., 2012). Recently, recurrent gain-of-function mutations of RhoA have been described in diffuse-type gastric carcinoma (Kakiuchi et al., 2014).
Entity name
Hepatocellular carcinoma (HCC)
Oncogenesis
Invasiveness of HCC is facilitated by the Rho/Rho-kinase pathway and likely to be relevant to tumor progression. The Rho/Rho-kinase may be useful as a prognostic indicator and in the development of novel therapeutic strategies. The high expression of RhoA protein in HCC plays an important role in intrahepatic recurrence of patients who underwent a hepatectomy for HCC, and RhoA is a useful marker for predicting early recurrence in an early-stage HCC (Fukui et al., 2006). Overexpression of RhoA is associated with poor prognosis in HCC (Li et al., 2006; Hu et al., 2013).
Entity name
Pancreatic tumor
Oncogenesis
Although overexpression of RhoA has not been detected in any pancreatic tumor tissue to date, it might nevertheless also be involved in pancreatic tumors. The progression of pancreatic tumors is partially controlled by the balance between Tiam1-Rac1 and RhoA (Guo et al., 2013). Use of two 3-hydroxy 3methylgultaryl coenzyme A (HMG-CoA) reductase inhibitors, fluvastatin and lovastatin inhibit human pancreatic cancer cell invasion and metastasis in a Rho-dependent manner. These inhibitors prevent the synthesis of cholesterol precursors necessary for proper membrane translocation of Rho protein. Also, BART plays a role in inhibiting cell invasion by regulating the activity of RhoA in pancreatic cancer cells (Taniuchi et al., 2011).
Entity name
Colorectal cancer
Oncogenesis
A high proportion of colon cancers overexpress RhoA and several aspects of colon tumor biology have been related to Rho GTPases. Leptin receptor and leptin-induced migration of colonic epithelial cancer cells is dependent on RhoA, since inhibition of the activity of the GTPase through introduction of dominant negative mutants completely abolishes the invasive capacity of the tumor cells. On the other hand, GCF2 plays an important role in colorectal cancer metastasis by regulating RhoA-induced cell adhesion, migration, and invasion (Ariake et al., 2012).
Entity name
Head and neck squamous cell carcinoma
Oncogenesis
RhoA, Rac2, and other proteins involved in initiating cell motility are promising clinical molecular markers for head and neck squamous cell cancer (Abraham et al., 2001). Mutations have affecting the effector domain (ED) have been described: these include five E40Q mutations and a single Y42I mutation, which alter the seventh and ninth amino acids, respectively, of the ED (Lawrence et al., 2014).
Entity name
Oncogenesis
New studies identify recurrent dominant-negative mutation of the RhoA GTPase gene in these lymphomas. In T-cell lines, expression of the G17V mutant reduced the formation of stress fibers in fibroblast, increased cell proliferation and cell migration. It has an important role in the pathogenesis of angioimmunoblastic t-cell lymphoma (AITL) and other subtypes of PTCL (Manso et al., 2014; Palomero et al., 2014; Sakata-Yanagimoto et al., 2014; Yoo et al., 2014).
Oncogenesis
RhoA modulates functional and physical interaction between ROCK1 and Erk1/Erk2 in selenite-induced apoptosis of human leukaemia cells (Li et al., 2013).
Entity name
Oncogenesis
The mutation R5Q is detection in patients with pediatric Burkitt lymphoma. RhoA mutant induced inactivate the RhoA protein. Thus, deregulation of RhoA by mutation is a recurrent event in Burkitt lymphomagenesis in children (Rohde et al., 2014).
Entity name
Oncogenesis
Higher expression of RhoA in CML could be responsible for increased proliferation of polymorphonuclear leukocytes (PMNL) cells (Molli et al., 2012).
Entity name
Prostate cancer
Oncogenesis
LPA stimulates RhoA and increased PC-3 prostate cancer cell invasion activity through an NF-kappaB-dependent pathway (Hwang et al., 2006). Inhibition of RhoA activity induced senescence-like arrest in a human prostate carcinoma cell line (Park et al., 2007).
Entity name
Oncogenesis
Lipophilic statins induced membrane RhoA relocalization to the cytosol and inhibited RhoA activity, which resulted in decreased phospho-p42/p44- mitogen-activated protein kinases (MAPKs) and Bcl-2 levels. Constitutively active RhoA rescued phospho-p42/p44-MAPKs and Bcl-2 and abolished statin-induced apoptosis (Fromigué et al., 2006).
Entity name
Glioblastoma
Oncogenesis
Decreased RhoA activity occurred in correlation with increased glioma cell migration (Fortin Ensign et al., 2013).
Entity name
Cervical cancer
Oncogenesis
Overexpression of RhoA promotes the proliferation and migration of cervical cancer cells (Liu et al., 2014).
Entity name
Squamous cell carcinoma of tongue (TSCC)
Oncogenesis
RhoA plays a significant role in TSCC progression by regulating cell migration and invasion through Wnt/β-catenin signaling pathway and cell proliferation through cell cycle regulation, respectively (Yan et al., 2014).
Entity name
Neurological disorders
Oncogenesis
RhoA protein was lower in the Alzheimers disease (AD) brain hippocampus, reflecting loss of the membrane bound. Altered subcellular targeting of RhoA is related to neurodegeneration (Huesa et al., 2010). In addition, an upregulation of RhoA immunoreactivity occurs in the brains of patients with intractable epilepsy (Yuan et al., 2010). Also, the Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase (Berto et al., 2007).
Entity name
Diabetic nephropathy
Oncogenesis
High glucose activates RhoA/Rho-kinase in mesangial cells (MC), leading to downstream AP-1 activation and fibronectin induction. Inhibition of this pathway in vivo prevents the pathologic changes of diabetic nephropathy, supporting a potential role for inhibitors of RhoA/Rho in the treatment of diabetic renal disease (Peng et al., 2008).
Entity name
Pregnancy
Oncogenesis
In the early stage pregnancy, up-regulation of RhoA induced by low oxygen conditions may play an important role in regulation of HIF-1α expression in trophoblast cells (Hayashi et al., 2005).
Entity name
Pulmonary hypertension (PH)
Oncogenesis
RhoA and Rho kinase activities are increased in PH (Guilluy et al., 2009). Inhibition of this pathway is involved in the beneficial effect of sildenafil on PH (Guilluy et al., 2005).
Entity name
Hypertension
Oncogenesis
RhoA signaling through Arhgef1 is central to the development of angiotensin II-dependent hypertension and identify Arhgef1 as a potential target for the treatment of hypertension (Guilluy et al., 2010).

Bibliography

Pubmed IDLast YearTitleAuthors
115685562001Motility-related proteins as markers for head and neck squamous cell cancer.Abraham MT et al
227500952012GCF2/LRRFIP1 promotes colorectal cancer metastasis and liver invasion through integrin-dependent RhoA activation.Ariake K et al
110532552000Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3-kinase-, rho-, and rac-dependent signaling pathways.Attoub S et al
155887662004Rho GTPases in human cancer: an unresolved link to upstream and downstream transcriptional regulation.Benitah SA et al
174887802007The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase.Berto G et al
108164162000Rho GTPases and their effector proteins.Bishop AL et al
175401682007GEFs and GAPs: critical elements in the control of small G proteins.Bos JL et al
173736582007GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo.Bustelo XR et al
190569852008Inhibition of Rac by the GAP activity of centralspindlin is essential for cytokinesis.Canman JC et al
235388402013Roles of rho GTPases in intracellular transport and cellular transformation.Chi X et al
116417772001Ras and RhoA suppress whereas RhoB enhances cytokine-induced transcription of nitric oxide synthase-2 in human normal liver AKN-1 cells and lung cancer A-549 cells.Delarue FL et al
124782842002Rho GTPases in cell biology.Etienne-Manneville S et al
232554052013The RhoA pathway mediates MMP-2 and MMP-9-independent invasive behavior in a triple-negative breast cancer cell line.Fagan-Solis KD et al
167506232006RhoA and RhoC proteins promote both cell proliferation and cell invasion of human oesophageal squamous cell carcinoma cell lines in vitro and in vivo.Faried A et al
158370492005Correlation between RhoA overexpression and tumour progression in esophageal squamous cell carcinoma.Faried A et al
241095882013Implications of Rho GTPase Signaling in Glioma Cell Invasion and Tumor Progression.Fortin Ensign SP et al
122377742002Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parameters.Fritz G et al
103282161999Rho GTPases are over-expressed in human tumors.Fritz G et al
164702222006RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation.Fromigué O et al
168105022006Expression and prognostic role of RhoA GTPases in hepatocellular carcinoma.Fukui K et al
217790262011The 'invisible hand': regulation of RHO GTPases by RHOGDIs.Garcia-Mata R et al
104986561999Cell motility mediated by rho and Rho-associated protein kinase plays a critical role in intrahepatic metastasis of human hepatocellular carcinoma.Genda T et al
243241332014Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells.Gilkes DM et al
158921192005Rho GTPase expression in tumourigenesis: evidence for a significant link.Gómez del Pulgar T et al
200984302010The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure.Guilluy C et al
192995012009RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling.Guilluy C et al
162057232005Inhibition of RhoA/Rho kinase pathway is involved in the beneficial effect of sildenafil on pulmonary hypertension.Guilluy C et al
233227322013Balanced Tiam1-rac1 and RhoA drives proliferation and invasion of pancreatic cancer cells.Guo X et al
155986822005Hypoxia up-regulates hypoxia-inducible factor-1alpha expression through RhoA activation in trophoblast cells.Hayashi M et al
89952161997Geranylgeranylated rho small GTPase(s) are essential for the degradation of p27Kip1 and facilitate the progression from G1 to S phase in growth-stimulated rat FRTL-5 cells.Hirai A et al
190380092008Overexpression of RhoA enhances peritoneal dissemination: RhoA suppression with Lovastatin may be useful for ovarian cancer.Horiuchi A et al
238429482013Loss of p57 expression and RhoA overexpression are associated with poor survival of patients with hepatocellular carcinoma.Hu T et al
200616252010Altered distribution of RhoA in Alzheimer's disease and AbetaPP overexpressing mice.Huesa G et al
164023872006Lysophosphatidic acid stimulates PC-3 prostate cancer cell Matrigel invasion through activation of RhoA and NF-kappaB activity.Hwang YS et al
248162552014Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma.Kakiuchi M et al
111676472001Overexpression of RhoA mRNA is associated with advanced stage in testicular germ cell tumour.Kamai T et al
125810112003RhoA is associated with invasion and lymph node metastasis in upper urinary tract cancer.Kamai T et al
152691552004Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer.Kamai T et al
204610562010Compensatory endocytosis in bladder umbrella cells occurs through an integrin-regulated and RhoA- and dynamin-dependent pathway.Khandelwal P et al
128837062003Rho regulates the hepatocyte growth factor/scatter factor-stimulated cell motility of human oral squamous cell carcinoma cells.Kitajo H et al
90774521996Involvement of Rho and Rac small G proteins and Rho GDI in Ca2+-dependent exocytosis from PC12 cells.Komuro R et al
1183244620023-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis.Kusama T et al
87002101996Regulation of receptor-mediated endocytosis by Rho and Rac.Lamaze C et al
195898552009RHO protein regulation of contraction in the human uterus.Lartey J et al
243903502014Discovery and saturation analysis of cancer genes across 21 tumour types.Lawrence MS et al
238285712013RhoA modulates functional and physical interaction between ROCK1 and Erk1/2 in selenite-induced apoptosis of leukaemia cells.Li F et al
168067922006Overexpression of RhoA is associated with poor prognosis in hepatocellular carcinoma.Li XR et al
251042222014Overexpression of RhoA promotes the proliferation and migration of cervical cancer cells.Liu X et al
196930132009Coordination of Rho GTPase activities during cell protrusion.Machacek M et al
247864572014The RHOA G17V gene mutation occurs frequently in peripheral T-cell lymphoma and is associated with a characteristic molecular signature.Manso R et al
224434732012RhoA: a therapeutic target for chronic myeloid leukemia.Molli PR et al
244137342014Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas.Palomero T et al
176585172007Inhibitory role of RhoA on senescence-like growth arrest by a mechanism involving modulation of phosphatase activity.Park C et al
183564102008RhoA/Rho-kinase contribute to the pathogenesis of diabetic renal disease.Peng F et al
231435952012Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing.Richter J et al
146574862003Cell migration: integrating signals from front to back.Ridley AJ et al
250444152014Recurrent RHOA mutations in pediatric Burkitt lymphoma treated according to the NHL-BFM protocols.Rohde M et al
156880022005GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors.Rossman KL et al
119708922002GPI-anchored proteins are delivered to recycling endosomes via a distinct cdc42-regulated, clathrin-independent pinocytic pathway.Sabharanjak S et al
244137372014Somatic RHOA mutation in angioimmunoblastic T cell lymphoma.Sakata-Yanagimoto M et al
225714632012The transcription factor GCF2 is an upstream repressor of the small GTPAse RhoA, regulating membrane protein trafficking, sensitivity to doxorubicin, and resistance to cisplatin.Shen DW et al
218334732011BART inhibits pancreatic cancer cell invasion by inhibiting ARL2-mediated RhoA inactivation.Taniuchi K et al
164243402006Vaccinia virus-induced cell motility requires F11L-mediated inhibition of RhoA signaling.Valderrama F et al
125793232003The small GTPase RhoA has greater expression in small cell lung carcinoma than in non-small cell lung carcinoma and contributes to their unique morphologies.Varker KA et al
150206702004Rho-family GTPases: it's not only Rac and Rho (and I like it).Wennerberg K et al
161078492005Local translation of RhoA regulates growth cone collapse.Wu KY et al
225845062012Inhibition of RhoA/ROCK signaling pathway promotes the apoptosis of gastric cancer cells.Xu XT et al
108999462000Galpha(12) and galpha(13) inhibit Ca(2+)-dependent exocytosis through Rho/Rho-associated kinase-dependent pathway.Yamaguchi Y et al
250014802014Silencing RhoA inhibits migration and invasion through Wnt/β-catenin pathway and growth through cell cycle regulation in human tongue cancer.Yan G et al
245840702014A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma.Yoo HY et al
204780622010Endocytic pathways mediating oligomeric Abeta42 neurotoxicity.Yu C et al
201405372010Altered expression of the small guanosine triphosphatase RhoA in human temporal lobe epilepsy.Yuan J et al
251207482014Co-expression of delta-catenin and RhoA is significantly associated with a malignant lung cancer phenotype.Zhang D et al
224389962012RhoA of the Rho family small GTPases is essential for B lymphocyte development.Zhang S et al

Other Information

Locus ID:

NCBI: 387
MIM: 165390
HGNC: 667
Ensembl: ENSG00000067560

Variants:

dbSNP: 387
ClinVar: 387
TCGA: ENSG00000067560
COSMIC: RHOA

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000067560ENST00000418115P61586
ENSG00000067560ENST00000418115A0A024R324
ENSG00000067560ENST00000422781C9JX21
ENSG00000067560ENST00000445425C9JNR4
ENSG00000067560ENST00000454011C9JRM1

Expression (GTEx)

0
100
200
300
400
500
600
700
800
900
1000

Pathways

PathwaySourceExternal ID
mTOR signaling pathwayKEGGko04150
Wnt signaling pathwayKEGGko04310
TGF-beta signaling pathwayKEGGko04350
Axon guidanceKEGGko04360
Focal adhesionKEGGko04510
Adherens junctionKEGGko04520
Tight junctionKEGGko04530
T cell receptor signaling pathwayKEGGko04660
Leukocyte transendothelial migrationKEGGko04670
Regulation of actin cytoskeletonKEGGko04810
Pathogenic Escherichia coli infectionKEGGko05130
Colorectal cancerKEGGko05210
mTOR signaling pathwayKEGGhsa04150
Wnt signaling pathwayKEGGhsa04310
TGF-beta signaling pathwayKEGGhsa04350
Axon guidanceKEGGhsa04360
Focal adhesionKEGGhsa04510
Adherens junctionKEGGhsa04520
Tight junctionKEGGhsa04530
T cell receptor signaling pathwayKEGGhsa04660
Leukocyte transendothelial migrationKEGGhsa04670
Regulation of actin cytoskeletonKEGGhsa04810
Pathogenic Escherichia coli infectionKEGGhsa05130
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Vascular smooth muscle contractionKEGGhsa04270
Chemokine signaling pathwayKEGGko04062
Vascular smooth muscle contractionKEGGko04270
Chemokine signaling pathwayKEGGhsa04062
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Bacterial invasion of epithelial cellsKEGGko05100
Bacterial invasion of epithelial cellsKEGGhsa05100
Pancreatic secretionKEGGko04972
Pancreatic secretionKEGGhsa04972
TuberculosisKEGGko05152
TuberculosisKEGGhsa05152
PertussisKEGGko05133
PertussisKEGGhsa05133
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Platelet activationKEGGhsa04611
Oxytocin signaling pathwayKEGGhsa04921
Oxytocin signaling pathwayKEGGko04921
cGMP-PKG signaling pathwayKEGGhsa04022
cGMP-PKG signaling pathwayKEGGko04022
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
HemostasisREACTOMER-HSA-109582
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GPVI-mediated activation cascadeREACTOMER-HSA-114604
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
p75 NTR receptor-mediated signallingREACTOMER-HSA-193704
p75NTR regulates axonogenesisREACTOMER-HSA-193697
Axonal growth stimulationREACTOMER-HSA-209563
Axonal growth inhibition (RHOA activation)REACTOMER-HSA-193634
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
Signaling by ERBB2REACTOMER-HSA-1227986
Signaling by Rho GTPasesREACTOMER-HSA-194315
Rho GTPase cycleREACTOMER-HSA-194840
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases Activate ROCKsREACTOMER-HSA-5627117
RHO GTPases activate PKNsREACTOMER-HSA-5625740
RHO GTPases activate CITREACTOMER-HSA-5625900
RHO GTPases activate KTN1REACTOMER-HSA-5625970
RHO GTPases Activate ForminsREACTOMER-HSA-5663220
RHO GTPases Activate Rhotekin and RhophilinsREACTOMER-HSA-5666185
Signaling by TGF-beta Receptor ComplexREACTOMER-HSA-170834
TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)REACTOMER-HSA-2173791
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (12/13) signalling eventsREACTOMER-HSA-416482
G-protein beta:gamma signallingREACTOMER-HSA-397795
G beta:gamma signalling through PI3KgammaREACTOMER-HSA-392451
Signaling by WntREACTOMER-HSA-195721
Beta-catenin independent WNT signalingREACTOMER-HSA-3858494
PCP/CE pathwayREACTOMER-HSA-4086400
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Semaphorin interactionsREACTOMER-HSA-373755
Sema4D in semaphorin signalingREACTOMER-HSA-400685
Sema4D mediated inhibition of cell attachment and migrationREACTOMER-HSA-416550
Sema4D induced cell migration and growth-cone collapseREACTOMER-HSA-416572
EPH-Ephrin signalingREACTOMER-HSA-2682334
EPHA-mediated growth cone collapseREACTOMER-HSA-3928663
EPHB-mediated forward signalingREACTOMER-HSA-3928662
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
ERBB2 Regulates Cell MotilityREACTOMER-HSA-6785631
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinasesREACTOMER-HSA-8849471
DeubiquitinationREACTOMER-HSA-5688426
Ovarian tumor domain proteasesREACTOMER-HSA-5689896
Neutrophil degranulationREACTOMER-HSA-6798695
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA444516HypercholesterolemiaDiseaseClinicalAnnotationassociatedPD23166513
PA451089pravastatinChemicalClinicalAnnotationassociatedPD23166513
PA451363simvastatinChemicalClinicalAnnotationassociatedPD23166513

References

Pubmed IDYearTitleCitations
150687892004Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment.1127
146575012003Regulation of cell polarity and protrusion formation by targeting RhoA for degradation.210
157935692005Regulation of PTEN by Rho small GTPases.193
161032262005An ECT2-centralspindlin complex regulates the localization and function of RhoA.186
166224182006Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling.163
244137342014Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas.156
248162552014Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma.149
244137372014Somatic RHOA mutation in angioimmunoblastic T cell lymphoma.143
185417052008The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of Cdc42 and RhoA.133
182875192008GEF-H1 couples nocodazole-induced microtubule disassembly to cell contractility via RhoA.132

Citation

Rebeca Manso

RHOA (ras homolog gene family, member A)

Atlas Genet Cytogenet Oncol Haematol. 2014-09-01

Online version: http://atlasgeneticsoncology.org/gene/42107/rhoa

Historical Card

2007-01-01 RHOA (ras homolog gene family, member A) by  Teresa Gómez del Pulgar,Juan Carlos Lacal 

Translational Oncology Unit, CSIC-UAM-La Paz, Madrid, Spain