Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

RhoC (RHOC)

  • Francisco M. Vega
  • Nicolas Reymond
  • Anne J. Ridley
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_59

Synonyms

Historical Background

RhoC was originally identified, together with its close homologs RhoA and RhoB, as a ras-related small GTPase (Madaule and Axel 1985). They together comprise the Rho subfamily of small GTPases characterized by their high homology within the group of Rho GTPases in vertebrates. The human RhoC gene maps to chromosome 1p13.1-p21. Human RhoA and RhoC are 93% similar at the protein level; divergence between the two proteins is mainly concentrated in the so-called variable region of the proteins, at the C-terminus. Orthologs of RhoC are present in all vertebrates and some invertebrate chordates including Ciona intestinalis, but only one Rho gene is present in the model organisms Drosophila melanogaster and Caenorhabditis elegans (Boureux et al. 2007). Following the discovery of RhoC, it was initially described to induce reorganization of the actin cytoskeleton and regulation of cell shape, attachment, and motility when overexpressed in mammalian cells, similar to the effects of RhoA (Chardin et al. 1989; Paterson et al. 1990). Most subsequent studies focused on RhoA and relatively little attention was paid to RhoC. The focus of attention shifted when it was discovered that RhoC had specific roles during cancer metastasis not shared with RhoA (Clark et al. 2000). Since then, multiple studies have investigated functional differences between RhoA, RhoB, and RhoC.
RhoC (RHOC), Fig. 1

RhoC domain structure and features. Schematic of the human RhoC protein showing the different domains and residues important for its activity and used for dominant-negative and constitutively active mutations as described in the text. The C-terminal 14 amino acids including the CAAX box sequence and a comparison with RhoA is shown. Red amino acids indicate nonconserved residues. GG depicts the prenylation site

Regulation of RhoC Activity

RhoC is a GTPase that acts as a molecular switch, cycling between a GDP-bound inactive state and a GTP-bound active state; when bound to GTP, it interacts with a variety of effector proteins to regulate different cellular processes (Wheeler and Ridley 2004). It is activated by guanine nucleotide exchange factors (GEFs), which stimulate the exchange of GDP for GTP on the protein, and negatively regulated by GTPase activating proteins (GAPs), which stimulate its intrinsic GTPase activity. Like several other Rho GTPases, it can also associate with Rho GTPase dissociation inhibitor proteins (RhoGDIs) which further regulate its activity, in part by sequestering the protein in the cytoplasm (Griner et al. 2015). RhoC is posttranslationally modified at the C-terminus by addition of a geranylgeranyl lipid group (Fig. 1). This modification allows it to anchor into membranes and is believed to be essential for its biological function. These modes of regulation are shared with the other Rho subfamily proteins, RhoA and RhoB. The distinct functions of RhoC compared to RhoA and RhoB could reflect a different localization, which would in turn enable it to be regulated by specific GEFs and GAPs and bind to specific effector proteins (Schaefer et al. 2014).

Most GEFs, GAPs, and GDIs have only been tested on RhoA, but would be expected to act on RhoC as well, based on the high sequence similarity between the two proteins. A few have been tested specifically on RhoC, including the GEFs ARHGEF5 (also known as TIM) and ARHGEF40 (previously known as Scambio); the GAPs p190RhoGAP, ARHGAP26 (also known as GRAF), p50RhoGAP (ARHGAP1), and MYO9B (also known as Myr5); and the three RhoGDI proteins (Bos et al. 2007). Few regulators have been compared for their activity on RhoA versus RhoC. One of the few examples is the GEF ARHGEF3 (also known as XPLN), which acts on RhoA and RhoB but not RhoC, but no RhoC-specific GEFs or GAPs have been described so far (Arthur et al. 2002; Schmidt and Hall 2002). The protein ARHGAP18 acts on RhoC and not RhoA in endothelial cells, although this might reflect cell-type-specific regulation (Chang et al. 2014). A report described enhanced RhoC activity over RhoA in pancreatic carcinoma cells which correlated with an increase in RhoC membrane localization, indicating that differential localization can play a major role in Rho protein specificity (Dietrich et al. 2009).

RhoC is widely expressed, but its levels vary between different human tissues (GTEx Analysis Release V6p). Overexpression of RhoC has been reported in some pathological conditions compared to normal tissues, and this indicates that its expression is regulated in response to external stimuli. One way in which RhoC expression is regulated in cells is by the action of noncoding microRNAs. In recent years, many of these polynucleotides have been described to target RhoC. For example, in breast and other cancers, the overexpression of the microRNA miRNA-10b induces the upregulation of RhoC by inhibiting the translation of the messenger RNA encoding HOXD10, and this in turn promotes invasion and metastasis (Ma et al. 2007; Liao et al. 2014; Wang et al. 2016). In squamous cell carcinoma, the downregulation of microRNA-138 induces metastasis by reducing direct RhoC mRNA degradation (Jiang et al. 2010). Other miRNAs regulating RhoC include miRNA-372 (Liu et al. 2016), miRNA106b (Chen et al. 2015a), miR-509 (Xing et al. 2015), and miR-93-5P (Chen et al. 2015b).

Posttranslational modifications of some Rho GTPases regulate their expression and/or activity (Hodge and Ridley 2016). Notably, RhoA activity is inhibited by protein kinase A-mediated phosphorylation on Ser188, but this residue is not conserved in RhoC; instead, the equivalent residue in RhoC is Arg188 (Fig. 1), which contributes to membrane binding (Ellerbroek et al. 2003; Patel et al. 2016). RhoA is also ubiquitinated and subsequently targeted for proteasomal degradation by a cullin3-based ubiquitin ligase, but this does not appear to be the case for RhoC (Chen et al. 2009). RhoC phosphorylation at Ser73 by Akt has been shown to be required for downstream signaling in breast cancer cells (Lehman et al. 2012). Although other posttranslational modifications on RhoC have not yet been characterized, several phosphorylation and ubiquitination sites have been identified in high-throughput mass spectrometry-based screens (www.phosphosite.org).

RhoC Effectors

Because RhoA, RhoB, and RhoC possess a high level of sequence identity at the protein level, they share many common downstream effectors (Wheeler and Ridley 2004; Ridley 2013). The affinity of these different interactions might vary due to amino acid sequence differences. Interactions with effectors were all mapped between their Rho switch I and II regions and mostly the unique Rho-binding domain (RBD) of their effectors (Fig. 1): Rhotekin, Rhophilin-1, Rho-associated kinase (ROCK-1 and-2), protein kinases N1 and N3 (Pkn1/Prk1; Pkn3/Prk3) (Hutchinson et al. 2013; Unsal-Kacmaz et al. 2012), mDia1, and citron kinase. RhoC and RhoA also interact with phospholipase C-ε (PLC-ε) via its catalytic core. The MAP3K protein ZAK (also known as MRK) directly binds to the GTP-bound forms of both RhoA and RhoC in vitro (Korkina et al. 2013).

RhoC also binds to specific downstream effectors including some members of the formin-like family of proteins (Fig. 2): RhoC interacts with FMNL2 and FMNL3 (Kitzing et al. 2010; Vega et al. 2011). RhoC also binds to IQGAP1 (Wu et al. 2011; Jacquemet and Humphries 2013). RhoC binds RhoGDI2 (ARHGDIB), a guanine nucleotide dissociation inhibitor (GDI), more efficiently than RhoA but less than Rac1 (Griner et al. 2015).

RhoC Functions in Tumorigenesis

Formation of Metastases

RhoC expression and activity is often increased in many cancers and correlates with progression, metastasis formation and poor prognosis for patients (Vega and Ridley 2008) (Fig. 2). A role for RhoC in cancer was first identified in a screen for genes upregulated in melanoma metastases, and expression of constitutively active or dominant-negative forms of RhoC correlated with the formation or the inhibition of lung metastases, respectively (Clark et al. 2000). RhoC was subsequently also detected to be upregulated in prostate cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, hepatocellular cancer, pancreatic ductal adenocarcinoma, non-small cell lung carcinoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and skin squamous cell carcinoma (Karlsson et al. 2009). RhoC is now proposed to be a prognostic marker in many different cancers. Studies with RhoC knockout mice indicated that RhoC is dispensable for breast cancer initiation but is critical for cancer cell metastasis formation in the lung (Hakem et al. 2005). The inhibition of RhoC has subsequently been described to reduce cancer cell invasion, tumor growth, and metastasis in several in vitro and in vivo models (Fig. 2). For example, RhoC regulates cancer cell interaction with endothelial cells during cancer cell extravasation both in vitro and in vivo (Reymond et al. 2015). RhoC can also contribute to the metastatic potential and abundance of cancer stem cells (Islam et al. 2014; Rosenthal et al. 2012).

Mutations of RhoC in cancer are very rare: the COSMIC database reports only 29 missense mutations and 5 deletions leading to frameshifts (accessed 26/06/2016). These mutations are scattered across the RhoC protein, indicating they are likely to be mostly passenger mutations. Some of its downstream effectors such as ROCK1 have been reported to be oncogenic in cancers (Lochhead et al. 2010).

Migration and Invasion

RhoC has a unique role in cell migration, distinct from RhoA, which could underlie its specific contribution to cancer cell invasion and metastasis (Fig. 2). For example, RhoC expression is increased during colon carcinoma cell epithelial-mesenchymal transition (EMT) and regulates EMT-induced migration (Bellovin et al. 2006), as well as TGFβ-induced cervical cancer EMT (He et al. 2015). RhoC mediates EGF-induced E-cadherin downregulation (a marker of EMT) in head and neck cancer (Tumur et al. 2015). Since EMT often occurs during epithelial cancer invasion, these results imply a causal role for RhoC in promoting cancer progression.

RhoC promotes polarized cell migration and invasion by controlling cell spreading and Rac1 activation around the cell periphery hence restricting lamellipodial broadening (Vega et al. 2011). RhoC regulates breast cancer cell adhesion with the extracellular matrix and motility and invasion by modulating the expression and co-localization of α2 and β1 integrins on collagen I (Wu et al. 2011). RhoC is also implicated in the degradation of extracellular matrix as it is involved in the formation of matrix-degrading invadopodia: an active ring of RhoC restricts cofilin activity and focuses on invadopodial protrusion and degradation (Bravo-Cordero et al. 2011). In addition, RhoC coordinates prostate cancer cell invasion in vitro by activating Pyk2, FAK, MAPK, and AKT, which results in activation of the matrix metalloproteinases 2 and 9 (MMP2 and MMP9) (Iiizumi et al. 2008) (Fig. 2). RhoC is also involved in the transcriptional program that controls TGFβ1-induced switch between cohesive and single cell motility of breast cancer cells (Giampieri et al. 2009).

Angiogenesis

RhoC can stimulate the production of pro-angiogenic factors by breast cancer cells (Merajver and Usmani 2005). RhoC is a downstream effector of vascular endothelial growth factor (VEGF) in endothelial cells and cancer cells. RhoC is thus essential for hepatocellular carcinoma VEGF-induced angiogenesis (Wang et al. 2008). RhoC is rapidly activated by VEGF and mediates VEGF-induced proliferation of human endothelial cells in vitro, although RhoC depletion inhibited migration (Hoeppner et al. 2015). These pro-tumoral functions could potentiate the vascularization of tumors that express RhoC and also may facilitate cancer cell intravasation and extravasation during tumor metastasis.

Proliferation and Apoptosis Resistance

As well as inducing cancer cell invasion, RhoC often affects cancer cell proliferation. For example, RhoC depletion in human gastric carcinoma inhibits proliferation and increases apoptosis in vitro (Sun et al. 2007), and RhoC promotes human esophageal squamous cell carcinoma and breast cancer cell proliferation in mice in vivo (Faried et al. 2006). RhoC seems to regulate the proliferation of gastric cancer cells through interaction with IQGAP1 (Wu et al. 2012). On the other hand, RNAi-mediated suppression of RhoC in hepatocellular carcinoma cells showed that RhoC does not regulate cancer cell proliferation in mice and that depletion of RhoC in endothelial cells does not affect their apoptosis (Wang et al. 2008).

A recent comprehensive proteomic study on etoposide-resistant lung cancer cell lines to explore the mechanism of chemoresistance showed that elevated RhoC expression is associated with chemotherapeutic resistance (Paul et al. 2016). RhoC expression was also increased in human breast cancer samples following chemotherapy and was induced by etoposide in MCF7 breast cancer cells in vitro (Kawata et al. 2014).

RhoC Regulates Transcription Factors

RhoC is induced in melanoma cells by the transcriptional regulator ETS-1. This indirectly stabilizes the AP-1 family transcription factor c-Jun through the actin cytoskeleton (Spangler et al. 2012). C-Jun is an oncogene which is a critical mediator of tumor development.

RhoC is involved in STAT3 phosphorylation in head and neck squamous cell carcinoma (HNSCC) and therefore in promoting the activation of core cancer stem cell transcription factors in HNSCC (Islam et al. 2014). STAT3 signaling pathways are well known to promote cancer progression via a role in tumor cell proliferation, survival, invasion, and immunosuppression, as well as through inflammation, obesity, stem cells, and the pre-metastatic niche (Yu et al. 2014) (Fig. 2).
RhoC (RHOC), Fig. 2

RhoC functions in cancer. Schematic of the RhoC protein showing the different functions of RhoC and its downstream effectors in cancer. Noncolored functions and interactors are shared with RhoA, while orange-colored functions and interactors are RhoC specific. Note the arrow between migration/invasion and metastasis formation is a dotted line because not all the RhoC effectors have been tested in vivo

Tools for the Study of RhoC Function

Classic tools for the study of Rho GTPases, including RhoC, took advantage of some conserved amino acids essential for catalytic function to make single mutations that produce dominant-negative (T19N substitution) or constitutively active (G14V or Q63L substitutions) forms of the protein (Wheeler and Ridley 2004) (Fig. 1). However, these mutations have the disadvantage that they do not discriminate between closely related Rho GTPases like RhoA and RhoC. Bacterial toxins, like Clostridium botulinum exoenzyme C3 transferase or toxin B, efficiently inhibit Rho activity by covalently modifying the protein on key residues, but again they target RhoA, RhoB, and RhoC proteins, and, although they were essential to establish the role of these proteins in regulating the actin cytoskeleton (Chardin et al. 1989; Paterson et al. 1990), they cannot be used to study RhoC-specific functions. RNA interference technology has revealed specific biological functions for RhoC in cells and shown that RhoA and RhoC regulate cytoskeletal dynamics, cell morphology, migration, and invasion in different complementary ways (Vega et al. 2011; Bellovin et al. 2006; Bravo-Cordero et al. 2011; Wu et al. 2010).

Spatiotemporal regulation of Rho GTPase activity is crucial to understand the complex integration of players involved in cell motility. The combined use of live-cell imaging and fluorescence resonance energy transfer (FRET) biosensors is helping to decipher how the activity of RhoC and other Rho GTPases is tightly regulated in space and time within cells. Using a RhoC-specific FRET biosensor in cancer cells, RhoC has been shown to be active in invadopodia and proposed to stimulate cofilin phosphorylation to promote matrix degradation in invadopodia (Bravo-Cordero et al. 2014). Biosensors for RhoA and RhoC showed that they are active in different regions of protruding lamellipodia (Zawistowski et al. 2013).

Summary

RhoC is a member of the small family of Rho GTPases that is very closely related to RhoA. It is best known for its roles in cell migration and controlling actin cytoskeletal dynamics. Several studies in cultured cells now clearly indicate that RhoC has some different functions to RhoA, involving specific interacting partners. This is also reflected by studies in mouse models, where the unique contributions of RhoC to cancer progression and metastasis formation have been described. RhoC is upregulated in many types of human cancer, particularly in aggressive metastatic cancers, and therefore has the potential to be a biomarker for cancer progression. RhoC signaling could also be a possible target in cancer therapy. Biosensors are being used to decipher where and when RhoC is activated in cells and should in the future allow us to identify specific activators of RhoC. They could also be used in vivo to increase our understanding of the contributions of RhoC to cancer.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Francisco M. Vega
    • 1
  • Nicolas Reymond
    • 1
  • Anne J. Ridley
    • 1
  1. 1.Department of Medical Physiology and Biophysics, Instituto de Biomedicina de SevillaUniversidad de SevillaSevilleSpain