RND3 (Rho family GTPase 3)

2013-01-01   Xia Hongwei , Zhang Yucheng , Bi Feng 

The Laboratory of Signal Transduction, Molecular Targeting Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China

Identity

HGNC
LOCATION
2q23.3
LOCUSID
ALIAS
ARHE,Rho8,RhoE,memB
FUSION GENES

DNA/RNA

Description

According to Entrez-Gene, RND3 gene maps to NC_000002.11 in the region between 151324709 and 151344180. According to Spidey (mRNA to genomic sequence alignment tool, http://www.ncbi.nlm.nih.gov/spidey), RND3 has 6 exons, the sizes being 100, 190, 88, 110, 135, 2047.

Proteins

Expression

RND3 expression is highly regulated in response to multiple different stimulies and conditions.
At transcriptionally, RND3 could be directly regulated by many transcriptional factors, including P53, HIF-1a, Foxd3, NF-KB, etc. RND3 mRNA and protein levels was up-regulated upon DNA damage-inducing stimuli including chemotherapeutic agents and ultraviolet (UV) irradiation. The response to genetoxic agents is mediated by p53, which binds specifically to the RND3 promoter and regulates RND3 expression while UV-induced RND3 up-regulation in keratinocytes does not depend on p53 status. So there must be other DNA damage-induced transcription factors to stimulate RND3 transcription. For example, NF-kB could induce RND3 expression in prostate cancer cells. Hypoxia-inducible factor (HIF)-1 can increase RND3 protein levels, thereby promotes epithelial to mesenchymal transition in gastric cancer cells under hypoxic conditions. The induced RND3 expression represents a pivotal cellular adaptive response to hypoxia with implications in gastric cancer cell EMT and invasion. In addition, mutant B-Raf promotes migration and invasion through inducing RND3 expression in melanoma cells. FOXD3 was proved to be recruited to the RND3 promoter and downregulated RND3 expression at the mRNA and protein levels, thus downregulates migration and invasion in melanoma cells. The mTOR pathway is responsible for the increased expression of RND3 in subependymal giant cell astrocytomas and rare brain tumours where the mTOR inhibitors TSC1 or TSC2 are mutated. The TGF-b pathway is also involved in the RND3 expression since the TGF-b family member MIC-1/GDF15 could reduce the RND3 expression in prostate cancer cells.
At post-transcriptionally, RND3 mRNA could also be a target of the miRNAs. Mir-200b directly downregulated the expression of RND3 at the mRNA and protein levels, promoted expression of the downstream protein cyclin D1 and increased S-phase entry in HeLa cells. There is also study showing that RND3 mRNA may be a target of the miR-200c in breast cancer cells. MiR-17 targets RND3 tumor suppressor gene, promotes cell proliferation, tumor growth, cell cycle progression in colorectal carcinoma.

Localisation

Located in the membranes, Golgi.

Function

RND3 is an atypical member of the Rho family, and the study about this molecule is relatively fewer than other members of the Rho family. However the recent study shows that RND3 could regulate a diverse set of biological activities including actin organization, cell motility, cell-cycle progression, apoptosis and development.

Role in actin organization
Many studies on the functions of RND3 have been carried out in several cultured cell lines, most of these studies have shown that RND3 could regulate the actin cytoskeleton by inducing loss of stress fibres and cell rounding.
Previous studies have shown that RND3 interacts with p190 RhoGAP and might increase the intrinsic GAP activity of p190 RhoGAP for RhoA, thereby reducing RhoA-GTP levels. Recent reports have shown that a KERRA (Lys-Glu-Arg-Arg-Ala) sequence in their N-terminus of RND3 could mediate the lipid raft targeting of p190 RhoGAP correlated with its activation. RND3 could also negatively regulates Syx (a RhoA-GEF) through interacting with Syx Raf1-like ubiquitin-related domain thus act as an antagonists of RhoA signaling.
RhoA directly stimulates stress fibres through activation of the serine/threonine kinases ROCK1 and ROCK2. RND3 could interact with the amino-terminal region of ROCK1 comprising the kinase domain, so RND3 competited with other ROCK1 substrates, such as myosin light chain phosphatase, and hence prevent stress fibre formation.

Role in cell cycle regulation
Many studies have been indicated that RND3 could inhibit cell proliferation and these data show that RND3 is able to block cell-cycle progression at different phases.
Most studies about cell-cycle shown that RND3 could block cell-cycle progression at the G1 phase. The mechanism may be that RND3 could decrease the level of cyclin D1, reduce Rb phosphorylation and transcription of E2F-regulated genes. RND3 blocks the phosphorylation of the translational repressor 4E-BP1 in response to extracellular stimuli and also inhibits the expression and transcriptional activity of the eIF4E target c-Myc. Recent studies show that elevation of RND3 expression markedly increased the expression level of PTEN and p27 and decreased pAkt level, thus inhibit cell-cycle progression.
RND3 could also block cell-cycle progression at the G2/M phase. The study in a prostate cancer cell line shows that forced RND3 overexpression inhibits the expression of CDC2 and cyclin B1 which are essential for G2/M transition and induction of G2/M arrest.

Role in cell apoptosis and survival
The fuction of RND3 is complex, RND3 can modulate cell survival and apoptosis. RND3 can induce apoptosis in prostate cancer, esophageal squamous cell carcinoma and glioblastoma cell lines. However, in some cancer cell lines, high levels of RND3 can decrease apoptosis and ShRNA mediated RND3 depletion resulted in an increase in apoptosis in response to genotoxic agents or UVB. RND3 could increase survival in osteosarcoma cells through down-regulate the activity of ROCK1 which itself can mediate membrane blebbing and apoptosis in these cells. RND3 may promote the multidrug resistance phenotype of gastric cancer cells by decreasing the expression of pro-apoptotic protein Bax at post-transcriptional level.

Role in development
RND3 plays an important role in the normal development, RND3 null mice (RND3 gt/gt) show an abnormal body position with profound motor impairment and impaired performance in most neurobehavioral tests, they are smaller at birth, display growth retardation and early postnatal death. There is a delay of neuromuscular maturation, a reduction in the number of spinal motor neurons, a decrease in the number and the total length of the neurites in the RND3 gt/gt mice.
Over-expression of RND3 induces neurite-like formation through inhibition of the RhoA/ROCK-I signalling and also involves in NGF-induced neurite extension.

Implicated in

Entity name
Lung tumors
Oncogenesis
RND3 expression was dramatically increased in the cytoplasm of lung cancer cells compared with undetectable expression of RND3 in the adjacent nontumoral cells. The cancer-related survival of RND3-negative patients are longer than that of RND3-positive ones. RND3 overexpression may serve as an independent marker for cancer-related survival in patients with non-small cell lung cancer. Overexpression of RND3 was also significantly associated with the patients smoking history and DNA copy number changes.
Entity name
Prostate cancer
Oncogenesis
RND3 mRNA and protein expression were significantly reduced in malignant tissue compared to benign samples. Forced RND3 overexpression in a prostate cancer cell line inhibits the expression of CDC2 and cyclin B1, which induce G2/M arrest, and also increases apoptotic cell death. Genetic profiling of human prostate cancer cell lines shows that RND3 may serve as a potential new molecular marker for assessing the metastatic potential of PCa.
Entity name
Mammary epithelial tumor
Oncogenesis
The expression level of RND3 in cancerous tissues was decreased or absent compared with adjacent normal tissues and RND3 could also serve as a negative marker in the development and progression of breast carcinoma. Exogenously expressed RND3/RND3 induces the formation of highly sealed tight junctions, co-localizes with actin at the cell periphery and induces beta-catenin and ZO-1 to sites of cell-cell contact in mammary epithelial tumor cells.
Entity name
Human glioblastoma
Oncogenesis
Overexpression of RND3 disrupts actin cytoskeleton organization, inhibits cell proliferation and induces apoptosis in U87 glioblastoma cell line. RND3 reduces Rb phosphorylation, cyclin D1 expression and also inhibits ERK activation following serum stimulation of quiescent U87 cells.
Entity name
Esophageal squamous cell carcinoma
Oncogenesis
The mRNA and protein expression levels of RND3 was significantly downregulated in ESCC (esophageal squamous cell carcinoma) tissues and cell lines, RND3 expression was tightly correlated with differentiation degree, clinical staging, and lymph node metastasis of the patients with ESCC, but there is no significant association between RND3 expression and gender or age of the patients with ESCC. Foced downregulation of RND3 expression in ESCC cells promoted cell proliferation, cell cycle progression, as well as cell invasion in vitro, and inhibited cell apoptosis, while upregulation of RND3 expression in ESCC cells inhibited cell proliferation, arrested cell cycle at G0/G1 phase, reduced cell invasion, and promoted cell apoptosis. RND3 may play an important role in the development and progression of ESCC.
Entity name
Melanoma
Oncogenesis
Many studies have revealed that RND3 overexpressed in melanoma cells. B-Raf-mediated up-regulation of RND3 appears to participate in the promoting melanoma cell invasion by reorganizating the actin cytoskeleton and focal adhesions. Upregulation of FOXD3 expression inhibits the migration, invasion, and spheroid outgrowth of mutant B-RAF melanoma cells through downregulating RND3 expression at the transcriptional level.
Entity name
Mesenchymal tumor
Oncogenesis
Reduced expression of RND3 increases invasiveness and metastatic potential in mesenchymal tumor cells while ectopic RND3 expression reduced their invasive ability in vitro and their metastatic potential in vivo.
Entity name
Pancreatic cancer
Oncogenesis
A pancreatic cancer-specific expression profiling shows that RND3 is overexpressed in pancreatic cancer cells.
Entity name
Liver cancer
Oncogenesis
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. According to previous study, RND3 was down-regulated in HCC cell lines, as compared to nontumor liver cells. Whats more, the patients with low expression of RND3 had a shorter survival than those with high expression. Therefore, RND3 expression could act as a significant prognostic predictor for HCC patients. The SiRNA-mediated down-regulation of Rnd3 expression induced a loss of E-cadherin and epithelial-mesenchymal transition through the up-regulation of the zinc finger E-box binding homeobox protein, ZEB2, and the down-regulation of miR-200b and miR-200c.
Entity name
Gastric cancer
Oncogenesis
RND3 expression is down-regulated in gastric cancer cells and its expression is regulated by histone deacetylation, but not DNA methylation at the epigenetic levels in gastric cancer cells. However, RND3 expression is up-regulated in gastric cancer cells under hypoxic conditions. And HIF-1a could up-regulate RND3 expression through binding a hypoxia-responsive element (HRE) on the RND3 promoter at the transcriptional level. Besides, RND3 is overexpressed in the SGC7901 cell line and enhanced the resistance of SGC7901 cells to several kinds of antitumor drugs by decreasing the expression of Bax at post-transcriptional level.
Entity name
Colorectal cancer
Oncogenesis
RND3 is downregulated in colorectal carcinoma (CRC) and RND3 expression was significantly lower in CRC tissues than in normal tissues and adenomas. Forced expression of RND3 can decrease the size of colorectal tumor and reduce the CD44 expression and further study shows that RND3 could inhibite the transcriptional activity of cd44 promoter. MiR-17 also plays an important role in CRC carcinogenesis by targeting RND3, thus promotes cell proliferation, tumour growth and cell cycle progression. However, recent study show RND3 could also promote invasion and metastasis in human colorectal cancer and it could also serve as an independent prognostic marker in addition to the tumor, node, metastasis staging system. So the function of RND3 is complex.

Bibliography

Pubmed IDLast YearTitleAuthors
110938082000Growth-suppressive effect of non-steroidal anti-inflammatory drugs on 11 colon-cancer cell lines and fluorescence differential display of genes whose expression is influenced by sulindac.Akashi H et al
178507882007Taking Rho GTPases to the next level: the cellular functions of atypical Rho GTPases.Aspenström P et al
195893692009RhoE is spatiotemporally regulated in the postnatal mouse CNS.Ballester-Lurbe B et al
157543462005Small G-protein RhoE is underexpressed in prostate cancer and induces cell cycle arrest and apoptosis.Bektic J et al
146678072004Identification of genes involved in estrogenic action in the human prostate using microarray analysis.Bektic J et al
212097962010Reduced expression of the ROCK inhibitor Rnd3 is associated with increased invasiveness and metastatic potential in mesenchymal tumor cells.Belgiovine C et al
182988932008Rho GTPases of the RhoBTB subfamily and tumorigenesis.Berthold J et al
171701052007The protective role of a small GTPase RhoE against UVB-induced DNA damage in keratinocytes.Boswell SA et al
170353532007Evolution of the Rho family of ras-like GTPases in eukaryotes.Boureux A et al
191536532009The role of microRNAs in metastasis and epithelial-mesenchymal transition.Bracken CP et al
145618242003Modulation of RhoA-Rho kinase-mediated Ca2+ sensitization of rabbit myometrium during pregnancy - role of Rnd3.Cario-Toumaniantz C et al
164934132006Function and regulation of Rnd proteins.Chardin P et al
211099742011Epigenetic modification of RhoE expression in gastric cancer cells.Chen J et al
187080312008Anoikis: a necessary death program for anchorage-dependent cells.Chiarugi P et al
211893602011In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes.Chun KH et al
112836062001Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I.Coleman ML et al
222723522012RhoE is regulated by cyclic AMP and promotes fusion of human BeWo choriocarcinoma cells.Collett GP et al
166845412006The amino acid sensitive TOR pathway from yeast to mammals.Dann SG et al
160834252005RhoGDI: multiple functions in the regulation of Rho family GTPase activities.Dovas A et al
183693722008RhoE controls myoblast alignment prior fusion through RhoA and ROCK.Fortier M et al
86493761996Identification of a novel human Rho protein with unusual properties: GTPase deficiency and in vivo farnesylation.Foster R et al
199518992010Plasticity of cell migration: a multiscale tuning model.Friedl P et al
122440612002Rapostlin is a novel effector of Rnd2 GTPase inducing neurite branching.Fujita H et al
176068642007Loss of p53 promotes RhoA-ROCK-dependent cell migration and invasion in 3D matrices.Gadea G et al
169367382006Cell cycle control and beyond: emerging roles for the retinoblastoma gene family.Genovese C et al
192436912009Cytokinesis: GAP gap.Glotzer M et al
197955162009Xenopus Rnd1 and Rnd3 GTP-binding proteins are expressed under the control of segmentation clock and required for somite formation.Goda T et al
208116432010The RhoA GEF Syx is a target of Rnd3 and regulated via a Raf1-like ubiquitin-related domain.Goh LL et al
222349322012Rnd3/RhoE Is down-regulated in hepatocellular carcinoma and controls cellular invasion.Grise F et al
173607142007Protein kinase C-mediated down-regulation of cyclin D1 involves activation of the translational repressor 4E-BP1 via a phosphoinositide 3-kinase/Akt-independent, protein phosphatase 2A-dependent mechanism in intestinal epithelial cells.Guan L et al
96714861998RhoE regulates actin cytoskeleton organization and cell migration.Guasch RM et al
110940872000Induced expression of Rnd3 is associated with transformation of polarized epithelial cells by the Raf-MEK-extracellular signal-regulated kinase pathway.Hansen SH et al
157380002005Direct interaction of Rnd1 with FRS2 beta regulates Rnd1-induced down-regulation of RhoA activity and is involved in fibroblast growth factor-induced neurite outgrowth in PC12 cells.Harada A et al
187197082008Mammalian Rho GTPases: new insights into their functions from in vivo studies.Heasman SJ et al
186902132008Neurogenin 2 controls cortical neuron migration through regulation of Rnd2.Heng JI et al
169291622006Potential mRNA degradation targets of hsa-miR-200c, identified using informatics and qRT-PCR.Hurteau GJ et al
146571632003A role of Rnd1 GTPase in dendritic spine formation in hippocampal neurons.Ishikawa Y et al
162124952005Rho GTPases: biochemistry and biology.Jaffe AB et al
214782672011FOXD3 regulates migration properties and Rnd3 expression in melanoma cells.Katiyar P et al
119406532002Socius is a novel Rnd GTPase-interacting protein involved in disassembly of actin stress fibers.Katoh H et al
192441132009Rnd3 regulation of the actin cytoskeleton promotes melanoma migration and invasive outgrowth in three dimensions.Klein RM et al
219171482011A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition.Klein RM et al
180459872008B-RAF regulation of Rnd3 participates in actin cytoskeletal and focal adhesion organization.Klein RM et al
189464882008Mechanism of multi-site phosphorylation from a ROCK-I:RhoE complex structure.Komander D et al
165544142006Expression of RND proteins in human myometrium.Lartey J et al
214977512011Rnd-ing up RhoA activity to link neurogenesis with steps in neuronal migration.Li J et al
191015102009RhoE enhances multidrug resistance of gastric cancer cells by suppressing Bax.Li K et al
189968432009Rnd1 regulates axon extension by enhancing the microtubule destabilizing activity of SCG10.Li YH et al
189231512009RhoE Is required for keratinocyte differentiation and stratification.Liebig T et al
129418312003Macrophage inhibitory cytokine 1 reduces cell adhesion and induces apoptosis in prostate cancer cells.Liu T et al
102004281999The Rho-related protein Rnd1 inhibits Ca2+ sensitization of rat smooth muscle.Loirand G et al
222131232012Down-regulation of RhoE is associated with progression and poor prognosis in hepatocellular carcinoma.Luo H et al
221328202012Up-regulated miR-17 promotes cell proliferation, tumour growth and cell cycle progression by targeting the RND3 tumour suppressor gene in colorectal carcinoma.Luo H et al
197230222009Regulation of Rnd3 localization and function by protein kinase C alpha-mediated phosphorylation.Madigan JP et al
171961872007Rnd family genes are differentially regulated by 3,4-methylenedioxymethamphetamine and cocaine acute treatment in mice brain.Marie-Claire C et al
215525372011RhoE deficiency produces postnatal lethality, profound motor deficits and neurodevelopmental delay in mice.Mocholí E et al
191036062009Rho-kinase contributes to sustained RhoA activation through phosphorylation of p190A RhoGAP.Mori K et al
198270502010Microarray analysis reveals potential target genes of NF-kappaB2/p52 in LNCaP prostate cancer cells.Nadiminty N et al
125906512003Rho family GTPase Rnd2 interacts and co-localizes with MgcRacGAP in male germ cells.Naud N et al
95315581998A new member of the Rho family, Rnd1, promotes disassembly of actin filament structures and loss of cell adhesion.Nobes CD et al
176390852007TGF-beta signaling-mediated morphogenesis: modulation of cell adhesion via cadherin endocytosis.Ogata S et al
152976732004The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras.Oinuma I et al
223576152012Rnd1 and Rnd3 targeting to lipid raft is required for p190 RhoGAP activation.Oinuma I et al
171749232006RhoE is a pro-survival p53 target gene that inhibits ROCK I-mediated apoptosis in response to genotoxic stress.Ongusaha PP et al
214355542011Proneural transcription factors regulate different steps of cortical neuron migration through Rnd-mediated inhibition of RhoA signaling.Pacary E et al
224285612012Neuronal polarization is impaired in mice lacking RhoE expression.Peris B et al
182044402008PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE.Pinner S et al
171820352007RhoE interferes with Rb inactivation and regulates the proliferation and survival of the U87 human glioblastoma cell line.Poch E et al
176079432007GTPases in semaphorin signaling.Püschel AW et al
157759722005RhoE function is regulated by ROCK I-mediated phosphorylation.Riento K et al
160425652005Function and regulation of RhoE.Riento K et al
208360902010Rnd proteins: multifunctional regulators of the cytoskeleton and cell cycle progression.Riou P et al
186145392008Rho Family GTPase modification and dependence on CAAX motif-signaled posttranslational modification.Roberts PJ et al
157777892005Rnd3/RhoE induces tight junction formation in mammary epithelial tumor cells.Rubenstein NM et al
224545242012Plakoglobin-dependent regulation of keratinocyte apoptosis by Rnd3.Ryan KR et al
20046026200917Beta-estradiol induces gastrointestinal motility disorder by decreasing CPI-17 phosphorylation via changes in rho-family G-protein Rnd expression in small intestine.Shimomura A et al
196659782009Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells.Shimono Y et al
184635352008Low-dose chemotherapeutic agents regulate small Rho GTPase activity in dendritic cells.Shurin GV et al
199687602010RhoE stimulates neurite-like outgrowth in PC12 cells through inhibition of the RhoA/ROCK-I signalling.Talens-Visconti R et al
119316392002Vps4-A (vacuolar protein sorting 4-A) is a binding partner for a novel Rho family GTPase, Rnd2.Tanaka H et al
164813212006Pragmin, a novel effector of Rnd2 GTPase, stimulates RhoA activity.Tanaka H et al
201338202010Novel proteins regulated by mTOR in subependymal giant cell astrocytomas of patients with tuberous sclerosis complex and new therapeutic implications.Tyburczy ME et al
191365562009Different requirement for Rnd GTPases of R-Ras GAP activity of Plexin-C1 and Plexin-D1.Uesugi K et al
198509232009RhoE inhibits 4E-BP1 phosphorylation and eIF4E function impairing cap-dependent translation.Villalonga P et al
199463292010The role of COX-2 in intestinal inflammation and colorectal cancer.Wang D et al
128420092003Rnd proteins function as RhoA antagonists by activating p190 RhoGAP.Wennerberg K et al
206836432010MicroRNA-200b regulates cyclin D1 expression and promotes S-phase entry by targeting RND3 in HeLa cells.Xia W et al
195238142009Dendritic spine formation and stabilization.Yoshihara Y et al
117847922002Antagonistic effects of Rnd1 and RhoD GTPases regulate receptor activity in Semaphorin 3A-induced cytoskeletal collapse.Zanata SM et al
220074782011[The effect of RhoE on CD44 promoter and the malignant behaviors of colorectal cancer cell].Zhou HJ et al
220374642011Transcriptional up-regulation of RhoE by hypoxia-inducible factor (HIF)-1 promotes epithelial to mesenchymal transition of gastric cancer cells during hypoxia.Zhou J et al
229411562013RhoE is associated with relapse and prognosis of patients with colorectal cancer.Zhou J et al

Other Information

Locus ID:

NCBI: 390
MIM: 602924
HGNC: 671
Ensembl: ENSG00000115963

Variants:

dbSNP: 390
ClinVar: 390
TCGA: ENSG00000115963
COSMIC: RND3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000115963ENST00000263895P61587
ENSG00000115963ENST00000375734P61587
ENSG00000115963ENST00000409557E9PFH1
ENSG00000115963ENST00000439275Q53RZ3
ENSG00000115963ENST00000454202Q53RZ3

Expression (GTEx)

0
50
100
150

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
182044402008PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE.94
23622247201314-3-3 proteins interact with a hybrid prenyl-phosphorylation motif to inhibit G proteins.47
192441132009Rnd3 regulation of the actin cytoskeleton promotes melanoma migration and invasive outgrowth in three dimensions.35
119406532002Socius is a novel Rnd GTPase-interacting protein involved in disassembly of actin stress fibers.31
189464882008Mechanism of multi-site phosphorylation from a ROCK-I:RhoE complex structure.31
206836432010MicroRNA-200b regulates cyclin D1 expression and promotes S-phase entry by targeting RND3 in HeLa cells.30
180459872008B-RAF regulation of Rnd3 participates in actin cytoskeletal and focal adhesion organization.29
157543462005Small G-protein RhoE is underexpressed in prostate cancer and induces cell cycle arrest and apoptosis.25
171820352007RhoE interferes with Rb inactivation and regulates the proliferation and survival of the U87 human glioblastoma cell line.25
290229202017The lncRNA TUG1 modulates proliferation in trophoblast cells via epigenetic suppression of RND3.25

Citation

Xia Hongwei ; Zhang Yucheng ; Bi Feng

RND3 (Rho family GTPase 3)

Atlas Genet Cytogenet Oncol Haematol. 2013-01-01

Online version: http://atlasgeneticsoncology.org/gene/46247/rnd3