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ARHGAP21 (Rho GTPase activating protein 21)

Written2016-12Mariana Ferreira Pissarra, Sara Teresinha Olalla Saad, Mariana Lazarini
Hematology and Blood Transfusion Center-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas (MFP, STOS, ML); Department of Biological Sciences, Federal University of São Paulo, Diadema (ML), Brazil.;

Abstract ARHGAP21 is a Rho GTPase-activating protein (RhoGAP). Like other members of the RhoGAP family, ARHGAP21 enhances the intrinsic GTPase activity of small Rho GTPases, leading to their inactivation. ARHGAP21 participates in cellular proliferation, adhesion, migration and vesicle traffic. This review comprises information on DNA/RNA, the encoded protein and protein functions.

Keywords ARHGAP21; Rho GTPase-activating protein; RhoGAP; cellular proliferation; adhesion; migration; vesicle traffic; glioblastoma multiforme; prostate adenocarcinoma; ovarian cancer; breast cancer; head and neck squamous cell carcinoma.

(Note : for Links provided by Atlas : click)


Alias (NCBI)Rho GTPase activating protein 21
formerly: ARHGAP10
HGNC Alias symbKIAA1424
LocusID (NCBI) 57584
Atlas_Id 43137
Location 10p12.1 - 10p12.3  [Link to chromosome band 10p12]
Location_base_pair Starts at 24583614 and ends at 24723887 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ARHGAP21.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ARHGAP21 (10p12.1)::ASPHD2 (22q12.1)ARHGAP21 (10p12.1)::ENKUR (10p12.1)ARHGAP21 (10p12.1)::GPR158 (10p12.1)
ARHGAP21 (10p12.1)::PDCD11 (10q24.33)CTNNA3 (10q21.3)::ARHGAP21 (10p12.1)


Description The entire ARHGAP21 gene has approximately 141,813 base pairs (bp) (Start: 24,583,609 and End: 24,725,421; on the reverse strand) and is composed of 26 exons. The cDNA contains 5877 bp.


  Figure 1. Schematic representation of ARHGAP21 protein. Domain positions were based on National Center for Biotechnology Information (NCBI) (
Description RhoGAPs are usually large proteins with additional domains other than the RhoGAP domain (Tcherkezian and Lamarche-Vane 2007). ARHGAP21 is composed of 1958 amino acids and has a predicted molecular weight of 217 kDa. In addition to the RhoGAP domain, ARHGAP21 comprises a PH (pleckstrin homology) and a PDZ domain (Figure 1). Although PH domains can bind to phosphatidylinositol lipids within biological membranes (Harlan et al. 1994; Saito et al. 2001), the ARHGAP21 PH domain has been demonstrated to not bind to lipids (Dubois et al. 2005). ARHGAP21 has been described to be SUMOylated in lysine K1443 by SUMO2/3. This post-translational modification may possibly explain the higher weight found by mass spectrometry (250 kDa) in contrast with the predicted weight (Bigarella et al. 2009).
Expression ARHGAP21 gene was widely expressed in a panel of different human tissues. Higher ARHGAP21 gene expression was observed in brain, heart, skeletal muscle, and placenta (Basseres et al. 2002). Results from FANTOM5 project also showed an increased ARHGAP21 gene expression in tissues of the human nervous system, such as cerebellum, diencephalon and hippocampus (Expression Atlas data bank).
Localisation ARHGAP21 has been shown to localize in the nuclei and cytoplasm of different cell types, such as adenocarcinoma PC3 and LNCAP cells and in glioblastoma T98G cells (Bigarella et al. 2009; Lazarini et al. 2013). In epithelial Caco-2 and JEG-3 cells, ARHGAP21 was detected at the cell-cell junctions and at the nucleus and perinuclear region (Sousa et al. 2005). Breast adenocarcinoma MCF-7 cells and HeLa cells presented ARHGAP21 localization in Golgi complex and in vesicular cytoplasmic structures (Dubois et al. 2005). In cardiomyocytes, ARHGAP21 was relocated from the nucleus to Z-lines and costameres after pressure overload (Borges et al. 2008).
Function ARHGAP21 acts as a RhoGAP for RHOA, RHOC andCDC42, but not for RAC1 (Dubois et al. 2005; Sousa et al. 2005; Lazarini et al. 2013). Such as occurs with other RhoGAP proteins, the ARHGAP21 RhoGAP activity has not been tested for most Rho GTPases. However, several ARHGAP21 partners have been described, suggesting that ARHGAP21 functions as a scaffold, linking Rho GTPases to other signaling pathways. ARHGAP21 has been shown to interact with ARF1, ARF6 (Dubois et al. 2005), catenin alpha (Sousa et al. 2005), PTK2 (FAK), PRKCZ (PKC zeta) (Borges et al. 2008), arrestin beta (Anthony et al. 2011), tubulin alpha (Barcellos et al. 2013), PRICKLE1 (Zhang et al. 2016). The functions of ARHGAP21 have been investigated in several types of cells. ARHGAP21 plays a role in cell proliferation (Lazarini et al. 2013; Luo et al. 2016), migration (Bigarella et al. 2009; Lazarini et al. 2013), vesicle traffic (Dubois et al. 2005), cell adhesions (Sousa et al. 2005; Barcellos et al. 2013; Zhang et al. 2016) and insulin secretion (Ferreira et al. 2015).
Homology ARHGAP21 shares homology with other members of the RhoGAP protein family (Tcherkezian and Lamarche-Vane 2007). ARHGAP21 also presents high homology among different species (Table 1).
Table 1. Comparative identity of human ARHGAP21 with other species
% Identity for: Homo sapiens ARHGAP21SymbolProteinDNA
vs. P. troglodytesARHGAP2199.599.5
vs. M. mulattaARHGAP2198.298.0
vs. C. lupusARHGAP2187.185.6
vs. B. taurusARHGAP2187.385.0
vs. M. musculusArhgap2187.384.0
vs. R. norvegicusArhgap2186.983.3
vs. G. gallusARHGAP2174.975.1
vs. X. tropicalis arhgap2165.167.4
vs. D. rerioarhgap2157.959.5



Somatic COSMIC (Catalogue of somatic mutations in cancer) reported 70 synonymous substitutions, 194 missense substitution, 24 nonsense substitution, 4 insertion frameshift, 1 deletion inframe, 8 deletion frameshift (

Implicated in

Note The role of ARHGAP21 has been evaluated in different types of human cancers, mostly using knockdown or overexpression assays in cancer cell lines.
Entity Head and neck squamous cell carcinoma (HNSCC)
Note ARHGAP21 was identified as a differentially expressed gene in hypopharyngeal carcinoma, using Differential Display analysis. The increased ARHGAP21 expression in tumor tissues compared to normal matched tissues was further confirmed with additional techniques, such as reverse Northern hybridization. Immunohistochemistry analysis revealed a weak cytoplasmic ARHGAP21 staining in neoplastic cells of (HNSCC), whereas no staining was detected in normal uvula epithelium (Carles et al. 2006). However, studies on ARHGAP21 functions in HNSCC have not been published to date.
Entity Glioblastoma multiforme
Note ARHGAP21 functions were investigated in glioblastoma cell lines. In T98G and U138MG cells, both N-terminal and C-terminal portions of ARHGAP21 interacted with Focal Adhesion Kinase (FAK). Confocal micrographs showed that this interaction possibly occurs in the perinuclear region. FAK phosphorylation in Tyr397 and in Tyr925 was higher in T98G cells silenced for ARHGAP21, in comparison with control cells. Phosphorylation of Scr and p130CAS, two downstream FAK effectors, was also increased. T98G cells silenced for ARHGAP21 displayed morphological changes, which resembled epithelial mesenchymal transition. These cells also presented higher Cdc42 activity and increased rate of migration and MMP-2 secretion, indicating a possible tumor suppressor role in glioblastoma cells (Bigarella et al. 2009).
Entity Prostate adenocarcinoma
Note ARHGAP21 function was investigated in prostate adenocarcinoma cells (Barcellos et al. 2013; Lazarini et al. 2013). However, ARHGAP21 expression in primary cells and impact in patient prognosis remains unknown. ARHGAP21 has been shown to inactivate RhoA and RhoC, though not Cdc42, in PC3 cells (human prostate adenocarcinoma cell line). PC3 cells with ARHGAP21 overexpression presented a round morphology, with increased protrusions and decreased adhesion in the tissue culture plastic plate. A similar phenotype was observed after p190 RhoGAP overexpression. ARHGAP21 silencing decreased PC3 cell proliferation, whereas increased random migration speed in fibronectin coated plates. In addition, microarray assays revealed a number of genes with altered expression in PC3 cells silenced for ARHGAP21, such as genes involved in the endothelin-1 signaling pathway (Lazarini et al. 2013). In DU145 cells, another model of prostate adenocarcinoma, ARHGAP21 interacted with tubulin alpha and was relocated from the perinuclear region to the front of the polarized cells after initiation of migration. DU145 cells silenced for ARHGAP21 also presented increased migration rate. However, stimulation with HGF had no effect upon the migration and scattering of the cells silenced for ARHGAP21. A decreased effect of HGF treatment was also observed in epithelial-mesenchymal transition (EMT) markers of DU145 cells silenced for ARHGAP21, in comparison to control cells (Barcellos et al. 2013).
Entity Ovarian Cancer
Note ARHGAP21 expression was reported to be reduced in cancer ovarian tissues compared to adjacent non-tumorous tissue, using quantitative PCR analysis. Reduced ARHGAP21 expression correlated with poor survival of patients. In contrast, lentiviral overexpression ARHGAP21 in A2780 and HO-8910 ovarian cancer cell lines led to decreased proliferation. When A2780 cells overexpressing ARHGAP21 were subcutaneously injected into Nude mice, a decreased tumor volume was observed. ARHGAP21 overexpression also induced G0/G1 phase cell cycle arrest and apoptosis, whereas decreased the adhesion on fibronectin, migration and invasiveness of A2780 and HO-8910 cells (Luo et al. 2016).
Note ARHGAP21 has shown a role in lateral signaling of MDA-MB-231 breast cancer cell line. Prickle (Pk) is a core planar cell polarity (PCP) component (Gray et al. 2011) and Pk1 has been demonstrated to interact with ARHGAP21, using affinity purification and mass spectrometry assay in MDA-MB-231 cells. The RhoGAP ARHGAP23 was identified as another Pk1 interactor. Separate knockdown of ARHGAP21 or ARHGAP23 induced no significant effect on the migration of MDA-MB-231 stimulated with active conditioned media (ACM) derived from fibroblast L cells. However, combinatorial silencing of both ARHGAPs inhibited ACM-induced migration. Pk1, ARHGAP21 and ARHGAP23 localized at non-protrusive membranes that are lateral to active protrusions. Concomitant ARHGAP21/23 silencing also induced a round morphology and diffuse protrusive activity. In addition, MDA-MB-231 silenced for ARHGAP21/23 presented increased RhoA activity and subsequent increase of myosin light chain 2 and focal adhesion activities, as well as alteration in mechanical properties of cell membrane. According to this study, the Pk1-ARHGAP21/23 complex confines protrusive activity of MDA-MB-231 cells through the regulation of RhoA activity (Zhang et al. 2016).


β-Arrestin 1 inhibits the GTPase-activating protein function of ARHGAP21, promoting activation of RhoA following angiotensin II type 1A receptor stimulation
Anthony DF, Sin YY, Vadrevu S, Advant N, Day JP, Byrne AM, Lynch MJ, Milligan G, Houslay MD, Baillie GS
Mol Cell Biol 2011 Mar;31(5):1066-75
PMID 21173159
ARHGAP21 protein, a new partner of α-tubulin involved in cell-cell adhesion formation and essential for epithelial-mesenchymal transition
Barcellos KS, Bigarella CL, Wagner MV, Vieira KP, Lazarini M, Langford PR, Machado-Neto JA, Call SG, Staley DM, Chung JY, Hansen MD, Saad ST
J Biol Chem 2013 Jan 25;288(4):2179-89
PMID 23235160
ARHGAP10, a novel human gene coding for a potentially cytoskeletal Rho-GTPase activating protein
Bassères DS, Tizzei EV, Duarte AA, Costa FF, Saad ST
Biochem Biophys Res Commun 2002 Jun 14;294(3):579-85
PMID 12056806
ARHGAP21 modulates FAK activity and impairs glioblastoma cell migration
Bigarella CL, Borges L, Costa FF, Saad ST
Biochim Biophys Acta 2009 May;1793(5):806-16
PMID 19268501
ARHGAP21 associates with FAK and PKCzeta and is redistributed after cardiac pressure overload
Borges L, Bigarella CL, Baratti MO, Crosara-Alberto DP, Joazeiro PP, Franchini KG, Costa FF, Saad ST
Biochem Biophys Res Commun 2008 Oct 3;374(4):641-6
PMID 18662671
Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display
Carles A, Millon R, Cromer A, Ganguli G, Lemaire F, Young J, Wasylyk C, Muller D, Schultz I, Rabouel Y, Dembélé D, Zhao C, Marchal P, Ducray C, Bracco L, Abecassis J, Poch O, Wasylyk B
Oncogene 2006 Mar 16;25(12):1821-31
PMID 16261155
Golgi-localized GAP for Cdc42 functions downstream of ARF1 to control Arp2/3 complex and F-actin dynamics
Dubois T, Paléotti O, Mironov AA, Fraisier V, Stradal TE, De Matteis MA, Franco M, Chavrier P
Nat Cell Biol 2005 Apr;7(4):353-64
PMID 15793564
ARHGAP21 prevents abnormal insulin release through actin rearrangement in pancreatic islets from neonatal mice
Ferreira SM, Santos GJ, Rezende LF, Gonçalves LM, Santos-Silva JC, Bigarella CL, Carneiro EM, Saad ST, Boschero AC, Barbosa-Sampaio HC
Life Sci 2015 Apr 15;127:53-8
PMID 25744409
Planar cell polarity: coordinating morphogenetic cell behaviors with embryonic polarity
Gray RS, Roszko I, Solnica-Krezel L
Dev Cell 2011 Jul 19;21(1):120-33
PMID 21763613
Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate
Harlan JE, Hajduk PJ, Yoon HS, Fesik SW
Nature 1994 Sep 8;371(6493):168-70
PMID 8072546
ARHGAP21 is a RhoGAP for RhoA and RhoC with a role in proliferation and migration of prostate adenocarcinoma cells
Lazarini M, Traina F, Machado-Neto JA, Barcellos KS, Moreira YB, Brandão MM, Verjovski-Almeida S, Ridley AJ, Saad ST
Biochim Biophys Acta 2013 Feb;1832(2):365-74
PMID 23200924
ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells
Luo N, Guo J, Chen L, Yang W, Qu X, Cheng Z
Cell Death Dis 2016 Mar 24;7:e2157
PMID 27010858
Interaction between the Btk PH domain and phosphatidylinositol-3,4,5-trisphosphate directly regulates Btk
Saito K, Scharenberg AM, Kinet JP
J Biol Chem 2001 May 11;276(19):16201-6
PMID 11279148
ARHGAP10 is necessary for alpha-catenin recruitment at adherens junctions and for Listeria invasion
Sousa S, Cabanes D, Archambaud C, Colland F, Lemichez E, Popoff M, Boisson-Dupuis S, Gouin E, Lecuit M, Legrain P, Cossart P
Nat Cell Biol 2005 Oct;7(10):954-60
PMID 16184169
Current knowledge of the large RhoGAP family of proteins
Tcherkezian J, Lamarche-Vane N
Biol Cell 2007 Feb;99(2):67-86
PMID 17222083
A lateral signalling pathway coordinates shape volatility during cell migration
Zhang L, Luga V, Armitage SK, Musiol M, Won A, Yip CM, Plotnikov SV, Wrana JL
Nat Commun 2016 May 26;7:11714
PMID 27226243


This paper should be referenced as such :
Mariana Ferreira Pissarra, Sara Teresinha Olalla Saad, Mariana Lazarini
ARHGAP21 (Rho GTPase activating protein 21)
Atlas Genet Cytogenet Oncol Haematol. 2017;21(9):313-316.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(10;10)(p12;q21) CTNNA3::ARHGAP21

External links


HGNC (Hugo)ARHGAP21   23725
Entrez_Gene (NCBI)ARHGAP21    Rho GTPase activating protein 21
GeneCards (Weizmann)ARHGAP21
Ensembl hg19 (Hinxton)ENSG00000107863 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000107863 [Gene_View]  ENSG00000107863 [Sequence]  chr10:24583614-24723887 [Contig_View]  ARHGAP21 [Vega]
ICGC DataPortalENSG00000107863
Genatlas (Paris)ARHGAP21
SOURCE (Princeton)ARHGAP21
Genetics Home Reference (NIH)ARHGAP21
Genomic and cartography
GoldenPath hg38 (UCSC)ARHGAP21  -     chr10:24583614-24723887 -  10p12.1|10p12.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ARHGAP21  -     10p12.1|10p12.3   [Description]    (hg19-Feb_2009)
GoldenPathARHGAP21 - 10p12.1|10p12.3 [CytoView hg19]  ARHGAP21 - 10p12.1|10p12.3 [CytoView hg38]
Genome Data Viewer NCBIARHGAP21 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB037845 AF480466 AK074589 AK090642 AK295649
RefSeq transcript (Entrez)NM_001367447 NM_001367448 NM_001367449 NM_001367450 NM_001367451 NM_001367452 NM_001367453 NM_001367454 NM_001367455 NM_020824
Consensus coding sequences : CCDS (NCBI)ARHGAP21
Gene ExpressionARHGAP21 [ NCBI-GEO ]   ARHGAP21 [ EBI - ARRAY_EXPRESS ]   ARHGAP21 [ SEEK ]   ARHGAP21 [ MEM ]
Gene Expression Viewer (FireBrowse)ARHGAP21 [ Firebrowse - Broad ]
GenevisibleExpression of ARHGAP21 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)57584
GTEX Portal (Tissue expression)ARHGAP21
Human Protein AtlasENSG00000107863-ARHGAP21 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ5T5U3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ5T5U3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ5T5U3
Domaine pattern : Prosite (Expaxy)PDZ (PS50106)    PH_DOMAIN (PS50003)    RHOGAP (PS50238)   
Domains : Interpro (EBI)PDZ    PDZ_6    PDZ_sf    PH-like_dom_sf    PH_domain    Rho_GTPase_activation_prot    RhoGAP_dom   
Domain families : Pfam (Sanger)PDZ_6 (PF17820)    PH (PF00169)    RhoGAP (PF00620)   
Domain families : Pfam (NCBI)pfam17820    pfam00169    pfam00620   
Domain families : Smart (EMBL)PDZ (SM00228)  PH (SM00233)  RhoGAP (SM00324)  
Conserved Domain (NCBI)ARHGAP21
PDB (RSDB)2DHJ    2J59    2YUY   
PDB Europe2DHJ    2J59    2YUY   
PDB (PDBSum)2DHJ    2J59    2YUY   
PDB (IMB)2DHJ    2J59    2YUY   
Structural Biology KnowledgeBase2DHJ    2J59    2YUY   
SCOP (Structural Classification of Proteins)2DHJ    2J59    2YUY   
CATH (Classification of proteins structures)2DHJ    2J59    2YUY   
AlphaFold pdb e-kbQ5T5U3   
Human Protein Atlas [tissue]ENSG00000107863-ARHGAP21 [tissue]
Protein Interaction databases
IntAct (EBI)Q5T5U3
Ontologies - Pathways
Ontology : AmiGOGolgi membrane  GTPase activator activity  protein binding  Golgi apparatus  cytosol  plasma membrane  Golgi organization  signal transduction  actin cytoskeleton  cell junction  cytoplasmic vesicle membrane  regulation of catalytic activity  regulation of small GTPase mediated signal transduction  Golgi localization  establishment of Golgi localization  maintenance of Golgi location  organelle transport along microtubule  
Ontology : EGO-EBIGolgi membrane  GTPase activator activity  protein binding  Golgi apparatus  cytosol  plasma membrane  Golgi organization  signal transduction  actin cytoskeleton  cell junction  cytoplasmic vesicle membrane  regulation of catalytic activity  regulation of small GTPase mediated signal transduction  Golgi localization  establishment of Golgi localization  maintenance of Golgi location  organelle transport along microtubule  
REACTOMEQ5T5U3 [protein]
REACTOME PathwaysR-HSA-194840 [pathway]   
NDEx NetworkARHGAP21
Atlas of Cancer Signalling NetworkARHGAP21
Wikipedia pathwaysARHGAP21
Orthology - Evolution
GeneTree (enSembl)ENSG00000107863
Phylogenetic Trees/Animal Genes : TreeFamARHGAP21
Homologs : HomoloGeneARHGAP21
Homology/Alignments : Family Browser (UCSC)ARHGAP21
Gene fusions - Rearrangements
Fusion : MitelmanARHGAP21::ASPHD2 [10p12.1/22q12.1]  
Fusion : MitelmanARHGAP21::ENKUR [10p12.1/10p12.1]  
Fusion : MitelmanARHGAP21::PDCD11 [10p12.1/10q24.33]  
Fusion : MitelmanCTNNA3::ARHGAP21 [10q21.3/10p12.1]  
Fusion : QuiverARHGAP21
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerARHGAP21 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ARHGAP21
Exome Variant ServerARHGAP21
GNOMAD BrowserENSG00000107863
Varsome BrowserARHGAP21
ACMGARHGAP21 variants
Genomic Variants (DGV)ARHGAP21 [DGVbeta]
DECIPHERARHGAP21 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisARHGAP21 
ICGC Data PortalARHGAP21 
TCGA Data PortalARHGAP21 
Broad Tumor PortalARHGAP21
OASIS PortalARHGAP21 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICARHGAP21  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DARHGAP21
Mutations and Diseases : HGMDARHGAP21
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)ARHGAP21
DoCM (Curated mutations)ARHGAP21
CIViC (Clinical Interpretations of Variants in Cancer)ARHGAP21
NCG (London)ARHGAP21
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry ARHGAP21
NextProtQ5T5U3 [Medical]
Target ValidationARHGAP21
Huge Navigator ARHGAP21 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDARHGAP21
Pharm GKB GenePA134973559
Clinical trialARHGAP21
DataMed IndexARHGAP21
PubMed44 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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