Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101793


Historical Background

RhoA was identified as a homolog of small GTPase Ras in a study using a cDNA library from mollusk Aplysia, hence its first name Aplysia Ras-related Homolog (ARH) 12 (Madaule and Axel 1985). RhoA, along with very related RhoB and RhoC, constitute the Rho subfamily of GTPases within the superfamily of Ras-related small GTPases and are found in all eukaryotic cells (Jaffe and Hall 2005). RhoA gene is located on chromosome 1 3p21.3 and, given that it is longer and contains more exons and introns, has been suggested to be the ancestor of both RhoC and RhoB (Wheeler and Ridley 2004), which evolved as duplication (RhoC) or reverse transcription (RhoB) from RhoA (Boureux et al. 2007; Wheeler and Ridley 2004). In line with this hypothesis, orthologs of RhoA, but not RhoC or RhoB, are found in nonvertebrates (Boureux et al. 2007). At the protein level, RhoA and RhoC are around 90% identical, with most divergence located in the hypervariable region at the C-terminus (Fig. 1). RhoA and most of the other GTPases are molecular switches cycling between an inactive guanine nucleotide diphosphate (GDP)-bound state and an active guanine nucleotide triphosphate (GTP)-bound state (Schaefer et al. 2014) (Fig. 2). Although early studies involved RhoA in controlling actin cytoskeleton organization, cell morphology, and migration (Ridley and Hall 1992), research in the last 20 years has highlighted the broader roles that RhoA displays in many fundamental biological processes in physiology and disease (Thumkeo et al. 2013; Wheeler and Ridley 2004), as we discuss below.
RhoA, Fig. 1

RhoA domain structure. Schematic of RhoA protein showing the different domains and key residues essential for its activity. Residues that can be used to generate dominant negative and constitutively active mutations are shown. Residues that are target of bacterial toxins and subject to posttranslational modifications (phosphorylation, ubiquitination, prenylation) are also depicted

RhoA, Fig. 2

Regulation of RhoA activity. Schematic summarizing the regulation of RhoA activity by GEFs, GAPs, GDIs and posttranslational modifications. Regulation of gene expression by transcription factors and by miRNAs is also depicted


RhoA is a monomeric protein comprised of 193 amino acids and a molecular mass of 21.7 kDa. The N-terminal part of the protein contains the G domain, a hallmark of Rho GTPases and other Ras-like GTPase proteins, which mediates guanine nucleotide binding (Schaefer et al. 2014). Most of the residues involved in GTP binding, stabilization, or regulation of hydrolysis are located here, such as Gly14, Thr19, Phe30, and Gln63 (Fig. 1). Switch 1(“effector region”) and 2 regions regulate the change in conformation between GTP- and GDP-bound states, known as “loading-spring” mechanism (Jaffe and Hall 2005; Schaefer et al. 2014), and the binding to effectors (Wheeler and Ridley 2004). Switch 1 also contains key residues needed for Rho GTPase regulation and that are target for bacterial toxins such as Clostridium botulinum exoenzyme C3 transferase (Asn41) or Clostridium difficile Toxin B (Thr37) (Kaibuchi et al. 1999) (Fig. 1). The insert domain of RhoA is involved in effector binding (ROCK, mDia) and in protein stability and transforming ability (Schaefer et al. 2014), showing also some sequence divergence between RhoA, RhoB, and RhoC (Wheeler and Ridley 2004). The C-terminus of GTPases directs the correct localization of Rho GTPases, and it is the region where there is most divergence between them, hinting at differential regulation (Wheeler and Ridley 2004). Prenylation of Cys190 in RhoA CAAX-box with a 20-carbon geranylgeranyl group confers stability and anchors RhoA into membranes (Figs. 1 and 2). This prenylation is essential for RhoA biological functions in the cytoplasm and plasma membrane (Bustelo et al. 2007; Wheeler and Ridley 2004).

Regulation of RhoA Activity

Upon activation, RhoA interacts with specific effector proteins to direct different biological processes (Schaefer et al. 2014; Wheeler and Ridley 2004) (Fig. 3). RhoA activation is promoted by guanine nucleotide exchange factors (GEFs), which exchange GDP for GTP, and negatively regulated by GTPase activating proteins (GAPs) that stimulate its intrinsic GTPase activity through hydrolysis of the gamma phosphate of GTP (Wheeler and Ridley 2004) (Fig. 2).
RhoA, Fig. 3

RhoA functions. Schematic that summarizes main cellular functions of RhoA through its effectors

There are over 80 GEFs and 70 GAPs that can regulate Rho GTPase activity. Rho GEFs bind to both switch regions of the GTPase, therefore overlapping with GAPs and effectors (Cherfils and Zeghouf 2013). Many GEFs show limited binding specificity. For example, Dbl and Vav1-3 can activate RhoA and also Rac1 and Cdc42; leukemia-associated RhoGEF (LARG) and p190RhoGEF activate RhoA/B/C but not Rac1 or Cdc42; and epithelial cell transforming sequence 2 (Ect2) activates RhoA but not Rac1 and Cdc42 (Cherfils and Zeghouf 2013; Schaefer et al. 2014).

Rho GEFs that can differentiate between RhoA and related RhoB/C are relatively rare. For example, XPLN (ARHGEF3, Dbl family) activates RhoA and RhoB but not RhoC, and atypical GEF SmgGDS activates RhoA and RhoC but not RhoB (Cherfils and Zeghouf 2013; Schaefer et al. 2014).

GAPs are not very specific either, and GAPs able to distinguish among RhoA/B/C are yet to be found. P190RhoGAP inactivates RhoA, RhoB, and RhoC but not Rac1 and Cdc42; while ARHGAP21 (ARHGAP10) inactivates RhoA and RhoC but not Cdc42 (Schaefer et al. 2014).

Guanidine nucleotide dissociation inhibitors (RhoGDIs) remove Rho proteins from the membrane by binding to the prenyl group, thus preventing interaction with effectors and also protecting them from proteolytic degradation (Fig. 2). Only three RhoGDIs have been found in mammals, among them RhoGDI1 and, to a lesser extent, RhoGDI2 both can bind RhoA (Cherfils and Zeghouf 2013; Schaefer et al. 2014).

RhoA activity can be also regulated by modulating its gene expression level (Fig. 2). RhoA is expressed in most tissues at varying levels (Wheeler and Ridley 2004) (http://www.genecards.org/cgi-bin/carddisp.pl?gene=RHOA). Several transcription factors have been shown to control RhoA expression. Myc cooperates with Skp2 to induce RhoA transcription by recruiting Miz1 and p300 to RhoA promoter (Chan et al. 2010). Nitric oxide and cGMP-dependent kinase (PKG)-mediated phosphorylation of transcription factor ATF-1 enhances its binding to cAMP-response element in RhoA promoter, increasing RhoA gene transcription and eventually RhoA protein stability (Croft and Olson 2011). Mutant p53 can increase RhoA activity indirectly via transcriptional upregulation of expression of RhoA GEF GEF-H1 (Mizuarai et al. 2006). Another level of gene regulation is exerted through noncoding microRNAs (Fig. 2), since RhoA expression can be suppressed by miR-31 (Valastyan et al. 2009) and miR-155 (Kong et al. 2008). Furthermore, miR-151 suppresses RhoGDI1, resulting in basal activation of RhoA (Croft and Olson 2011).

In addition to prenylation controlling correct localization (Figs. 1 and 2), other posttranslational modifications can determine specificity of Rho signaling (Hodge and Ridley 2016; Schaefer et al. 2014). Ser188 in RhoA C-terminus (Fig. 1) can be phosphorylated by protein kinase A (PKA) and cGMP-dependent protein kinase/protein kinase G (PKG), which inactivates RhoA by promoting binding to GDIs, membrane dissociation, and interfering with RhoA binding to ROCK. Phosphorylation on Ser188 also protects RhoA from ubiquitin-mediated proteasomal degradation by promoting its interaction with RhoGDI. Phosphorylation of Thr127 and Ser188 by protein kinase C (PKC) epsilon also contributes to the membrane localization of RhoA (Hodge and Ridley 2016; Schaefer et al. 2014).

Furthermore, RhoA can be ubiquitinated and targeted for proteosomal degradation by three different E3 ligase complexes (Fig. 1): SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) on Lys6and Lys7 and Lys51; SKP1–CUL1–F-box (SCF) FBXL19 complex on Lys135; and by the BTB/POZ domain-containing adaptor for CUL3-mediated RhoA degradation (BACURD)–CUL3–RING ubiquitin ligase complex (Hodge and Ridley 2016). SMURF1 targets activated RhoA, while Cullin targets GDP-bound RhoA and SCF/FBXL19 targets both active and inactive forms of RhoA for ubiquitination (Hodge and Ridley 2016).

RhoA Effectors

RhoA exerts its broad functions by binding to different downstream effectors (Fig. 3). The most common mechanism of effector activation by Rho GTPases involves disruption of intramolecular autoinhibitory interactions that expose functional domains within the effector protein (Jaffe and Hall 2005). Effectors bind through their Rho-binding domains (RBD) to the Switch 1 and 2 regions of RhoA, although differences in amino acid sequences may determine the affinity of these interactions (Wheeler and Ridley 2004). Table 1 and Fig. 3 summarize identified RhoA effectors and their functions (Bustelo et al. 2007; Kaibuchi et al. 1999; Wheeler and Ridley 2004).
RhoA, Table 1

RhoA effectors and their functions

Gene symbol

Protein name

Function/biological process


Citron kinase



Connector enhancer of kinase suppressor of Ras 1

Interacts with RhoA (Rhophilin) and Ras effectors (RalGDS)


Diacylglycerol kinase θ

Diacylglycerol depletion


Diaphanous-related formin 1,2

Cytoskeletal regulation, migration


Family with sequence similarity 65 member A

Golgi reorientation during cell migration


Filamin A

Cytoskeletal regulation, actin filament crosslinking


3-hydroxyacyl-coA dehydratase 3

Regulation of kinase cascades and gene expression


Inositol 1,4,5-trisphosphate receptor type 1

Calcium entry


Potasium channel subunit

Potasium entry



Kinesin binding, vesicular trafficking through microtubules


Phosphoinositide kinase lipid kinase

Modulation of phosphatidylinositol biphosphate levels


Protein kinase N, also known as PRKs

Vesicle recycling, cell cycle regulation, Pld1 activation


Phospholipase C epsilon 1

Lipid metabolism


Phospholipase, C type (PLC- γ1) Phospholipase C gamma 1

Lipid metabolism


Phospholipase, D type

Production of phosphatidic acid and choline (second messengers)


Protein phosphatase 1 regulatory subunit 12A

Myosin light chain inactivation, cytoskeletal regulation


Protein kinase C alpha

Signal transduction


Rhophilin Rho GTPase binding protein 1

Cytoskeletal regulation


Rho associated coiled-coil containing protein kinase 1,2

Cytoskeleton, migration, cytokinesis, blockage of cell contact inhibition, proliferation



Interaction with PDZ proteins, NF-кB activation

RhoA Functions

Mutated versions of RhoA on some conserved amino acids (Fig. 1) have proven to be useful tools to identify specific interaction partners and its biological activities. For example, dominant negative (T19N) or constitutively active (G14V or Q63L) forms of RhoA (Wheeler and Ridley 2004), along with the aforementioned Rho inhibitor C3 exoenzyme (Fig. 1).

Seminal studies showed that RhoA regulates formation of actin stress fibers and focal adhesion complexes in fibroblasts in response to growth factors (Ridley and Hall 1992). This cytoskeletal reorganization drives cell motility and invasion. During migration through 2D environments, RhoA controls both actin polymerization via mDia and force generation via ROCK and actomyosin contractility (Narumiya et al. 2009). RhoA activates ROCK, which phosphorylates (and thus inactivates) the myosin light chain phosphatase (MYPT or PPP1R12A) leading to the activation of myosin II and actomyosin contraction; ROCK can also directly phosphorylate the regulatory light chain MLC2 (Vicente-Manzanares et al. 2009). The classic model of cell migration in 2D suggested that Rac and Cdc42 are active at the leading edge to promote actin-rich protrusion formation, while Rho would be active only in the cell body and at the rear, to provide the actomyosin-mediated force needed for rear retraction and forward movement (Sadok and Marshall 2014). However, by using FRET-based Rho GTPase activity biosensors (Schaefer et al. 2014) it was shown that Rho is also active at the leading edge and activated before Rac and Cdc42 (Pertz et al. 2006). In addition, RhoA also controls membrane blebbing, another type of protrusions featured in amoeboid-like motility, which can only be seen in 3D environments (Pandya et al. 2017; Sadok and Marshall 2014).

During migration in 3D environments, Rho GTPases can coordinate different modes of movement (Pandya et al. 2017). In collagen-rich connective tissue with variable physical and chemical properties, single cells can either adopt a rounded/amoeboid, highly contractile, RhoA-driven mode of movement or an elongated/mesenchymal, lower contractility Rac-dependent mode of migration (Sanz-Moreno et al. 2008). Both types of movement rely on actomyosin contractility to generate the force needed for migration but differ in the levels of contractility required (Pandya et al. 2017).

RhoA signaling is also involved during collective invasion, since RhoA contributes to junction stabilization via promotion of formin-mediated actin nucleation and maintenance of leader-follower hierarchy, mechanocouping, and supracellular actomyosin contractility (Zegers and Friedl 2014).

Despite its widely studied role on cell migration, RhoA is involved in most of the fundamental cellular processes, some of them also relying on cytoskeletal organization by RhoA (Fig. 3). These include cytokinesis (Kishi et al. 1993), cell cycle progression (Olson et al. 1995), Golgi function and location (Mardakheh et al. 2016), vesicular trafficking (Ridley 2006), cell–cell adhesion (Nusrat et al. 1995), cell polarization (Fukata et al. 2003), and chemotaxis (Thumkeo et al. 2013). RhoA function is also essential in more specialized contexts. RhoA contributes to angiogenesis, phagocytosis, neutrophil recruitment, leukocyte transendothelial migration, and axonogenesis and axon branching (Jaffe and Hall 2005; Thumkeo et al. 2013). In addition, RhoA signaling contributes to maintenance of human embryonic stem cells through YAP/TAZ activity (Ohgushi et al. 2015).

Importantly, RhoA signaling can also regulate gene transcription in order to sustain biological responses through actin-dependent and actin-independent pathways. The former involves regulation of serum-response factor (SRF)-mediated transcription through SRF coactivator MKL1, also known as MAL and myocardin-related transcription factor-A (MRTF-A) (Croft and Olson 2011). RhoA-induced actin polymerization (high F-actin, low G-actin) through ROCK, LIMK, or mDia reduces the interaction between G-actin and MKL1 (which inhibits actin-dependent nuclear export of MKL1) and consequently results in its nuclear accumulation and enhanced SRF-mediated transcription of cytoskeletal proteins like actin or myosin light chain (Miralles et al. 2003). RhoA signaling can also affect gene transcription through actin-independent signal transduction pathways, such as regulation of MAP kinase, NF-KB, and STAT3 (Jaffe and Hall 2005). Intriguingly, some RhoA effectors such as ROCK and mDia have been found in the cell nucleus and linked to gene expression processes (Rajakyla and Vartiainen 2014).

In the last years, gene-targeting approaches have shed light into the important role of RhoA in vivo, even though it should be noted that functional compensation by other isoforms (i.e., RhoC) could obscure biological functions. RhoA null knockout mice are embryonic lethal at an early developmental stage (Thumkeo et al. 2013), imposing the need for conditional depletion strategies to elucidate biological roles at later stages. By using RhoA conditional knockout mice, it has been shown that RhoA is involved in many processes during development, such as regulation of cell-cell adhesion and contractility in some epithelial cell types (lens epithelium, neuroepithelium), the control of migration of excitatory neural progenitor cells, and in neural crest and cerebral cortex development (Thumkeo et al. 2013). In the hematopoietic lineage, RhoA contributes to the correct development of T and B cells and platelets. In vivo studies have also shown that RhoA exerts a protective role of cardiomyocyte function under pathological conditions (Thumkeo et al. 2013).

RhoA function is dysregulated in a number of pathological processes such as tumorigenesis (Pandya et al. 2017), immune-mediated diseases (Peckham et al. 2017), and atheroschlerosis (Cai et al. 2015). During bacterial infection, disruption of host epithelial and endothelial barriers and corruption of immune cell functions is driven by Rho-targeting toxins (Aktories 2011).

RhoA Function in Tumorigenesis

Given its involvement in most cellular processes, it is not surprising that RhoA signaling has been implicated in virtually all stages of cancer progression (Orgaz et al. 2014a; Sahai and Marshall 2002). Unlike related Ras-family of GTPases that are mutated in 30% of human tumors, mutation rates of Rho GTPases and, in particular RhoA, are relatively low in cancer (Orgaz et al. 2014a). However, aberrant overexpression of RhoA is found in a number of cancers, including breast, lung, colorectal, liver, and head and neck carcinomas (Orgaz et al. 2014a). Cancer cells hijack RhoA signaling during transformation and cancer progression, since RhoA is required for oncogenic transformation by Ras and other oncoproteins (Orgaz et al. 2014a). RhoA promotes cell proliferation by regulation of the cell cycle through induction of cyclin D1 and repression of p21 and p27 (Orgaz et al. 2014a; Sahai and Marshall 2002). RhoA has also been implicated in tumor senescence bypass in immortalized cells (Orgaz et al. 2014a; Sahai and Marshall 2002). Furthermore, RhoA signaling cooperates with JAK/STAT3 (Jaffe and Hall 2005; Sanz-Moreno et al. 2011) and NF-KB (Jaffe and Hall 2005) to sustain and propagate protumorigenic signals via enhanced proliferation and survival and evasion of apoptosis (Orgaz et al. 2014a).

A key role of RhoA in cancer arises from its control of migration and invasion, which underlie metastatic dissemination, one of the major problems in cancer (Pandya et al. 2017). Tumor cells exhibit a striking variety of invasion strategies. Importantly, cancer cells can switch between invasion modes in order to cope with challenging environments during metastatic dissemination (Sanz-Moreno et al. 2008). For example, highly contractile, RhoA/ROCK-driven amoeboid migration is favored in the invasive fronts of melanoma (Sanz-Moreno et al. 2011) and breast cancers (Pandya et al. 2017). This rounded-amoeboid migration can be sustained at the transcriptional levels through cooperation of Rho/ROCK with STAT3 (Sanz-Moreno et al. 2011) and TFG-beta/SMAD2-CITED signaling (Cantelli et al. 2015) in melanoma. High STAT3 signaling induces secretion of MMPs such as MMP-9 that promotes actomyosin contractile force and bleb-driven invasion through a positive feedback loop via CD44 and MLC2 phosphorylation to sustain amoeboid invasion (Orgaz et al. 2014b).

RhoA also plays an important role in integrating intracellular signals downstream of mechanosensors, which promotes cytoskeletal remodeling. Migration in constricted environments requires myosin II-driven contractility that is further increased by the inhibition of Rac activity, suggesting a switch from Rac-driven protrusive movement in an unconfined environment to Rho/ROCK-mediated, high actomyosin contractility-driven movement in constricted environments (Sadok and Marshall 2014). In response to increased matrix stiffness, Src activity and Rho/ROCK-driven actomyosin contractility are required for the activation of YAP and later actomyosin contractility, which promote and maintain the highly contractile cancer-associated fibroblast phenotype (Calvo et al. 2013). High Rho/ROCK-driven contractility in stromal fibroblasts also contributes to extracellular matrix remodeling that aids squamous cell carcinoma invasion (Gaggioli et al. 2007).

RhoA also participates in the process of intravasation, one of the first steps in the metastatic cascade. RhoA promotes formation of invadopodia that drive matrix barrier degradation, allowing tumor intravasation (Rodriguez-Hernandez et al. 2016). RhoA also contributes to adhesion to the endothelium and later transendothelial migration of cancer cells. Therefore, high RhoA/ROCK-driven actomyosin contractility favors intravasation and efficient transendothelial migration of rounded-amoeboid cancer cells in vivo (Sahai 2007).

Furthermore, higher levels of RhoA (also RhoC) and phosphorylated MLC2 contribute to more efficient lung colonization of the highly metastatic A375M2 melanoma cells when compared to low metastatic A375P melanoma cells (Orgaz et al. 2014a; Sanz-Moreno et al. 2008). Conversely, blockade of Rac with the Rac GAP FilGAP activates RhoA signaling, eventually facilitating in vivo extravasation of breast cancer cells. On the other hand, the RhoA GAP ARHGAP7 inhibits transendothelial migration of thymic lymphomas (Rodriguez-Hernandez et al. 2016).

Despite the aforementioned oncogenic potential of RhoA in several human cancers (Orgaz et al. 2014a), recent studies have unexpectedly identified a loss-of-function mutation on RhoA (G17V) in 60% of angioimmunoblastic T cell lymphomas (Palomero et al. 2014; Sakata-Yanagimoto et al. 2014; Yoo et al. 2014). However, in most cases RhoA mutation is found along with mutations in epigenetic regulators TET2 and DNMT3A – which supposedly occur earlier in transformation (Cortes and Palomero 2016) – suggesting that RhoA G17V mutation is a secondary event probably modulating T-cell lineage commitment. Furthermore, mutations on Tyr42 (Y42C) in the effector domain have been found in 20% diffuse-type gastric carcinomas (Kakiuchi et al. 2014; Wang et al. 2014). This RhoA Y42C mutant is still able to bind to ROCK efficiently but not to PKN (Sahai et al. 1998). RhoA Y42C could direct RhoA signals to specific protumorigenic ROCK-driven functions in these cancers. Further studies are warranted in order to elucidate the biological roles of such mutations in these two specific cancers.

Therapeutic Inhibition of RhoA Signaling

RhoA is an attractive therapeutic target in cancer due to its contribution to most steps in cancer progression. Several approaches have been explored to target Rho proteins by pharmacological agents (Mardilovich et al. 2012; Sahai and Marshall 2002). These include targeting lipid modification of the carboxyl terminus of Rho by using statins (already used in the clinic to limit cholesterol levels) or dual targeting farnesyl transferase and geranylgeranyl transferase inhibitors. However, if there is a clinical benefit in cancer with this approach is still not clear (Mardilovich et al. 2012). Another way would entail direct inhibition of RhoA function with bacterial enzymes such as a C3 exoenzyme. A modified version of C3 showed promising effects in preclinical models of spinal cord injury and entered trials for clinical evaluation (Mardilovich et al. 2012). Indirect inhibition of Rho by targeting activators RhoGEF was previously thought to be challenging, since GEF activation of GTPases is mediated by protein-protein interactions, usually regarded as undruggable. However, antagonists for GEFs Trio and leukemia-associated RhoGEF LARG have been identified (Mardilovich et al. 2012), even though these GEFs also activate Rac1 (Trio) and RhoB (LARG) which can have opposing effects to RhoA.

Due to the druggability of kinase targets, potent inhibitors of RhoA effectors such as ROCK have been developed and are more promising therapeutic tools. Due to its involvement in tumor initiation (Kumper et al. 2016) and metastasis (Sadok et al. 2015), inhibition of ROCK would be an ideal candidate to target different steps in cancer progression at once. A ROCK inhibitor is currently in clinical trials for solid tumors (ClinicalTrials.gov Identifier: NCT01585701). Other ROCK inhibitors are safe in humans since they have been used to treat subarachnoid hemorrhage in Japan since 1995 and are being clinically evaluated for hypertension and glaucoma (Feng et al. 2016). Furthermore, LIMK downstream of Rho/ROCK could also be a potential therapeutic target in cancer (Mardilovich et al. 2012).


RhoA belongs to the small family of Rho GTPases along with related RhoC and RhoC. RhoA has pleiotropic functions during physiological processes. It is best known for controlling the actin cytoskeleton and regulation of cell migration and invasion. In addition, RhoA in involved in control of cell cycle, mitosis, and cytokinesis; vesicular trafficking; Golgi function; cell-cell adhesion and polarization; axonogenesis, phagocytosis, and maintenance of stem cell status, among others. Therefore, it is not unexpected that RhoA function is dysregulated in pathological processes such as cancer. Cancer cells hijack RhoA signaling to acquire a more aggressive and metastatic status. This makes RhoA or its effectors potential therapeutic targets in cancer, among which ROCK is being clinically evaluated for solid tumors.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Randall Division of Cell and Molecular BiophysicsKing’s College LondonLondonUK