ARHGAP21 (Rho GTPase activating protein 21)
2016-12-01 Mariana Ferreira Pissarra , Sara Teresinha Olalla Saad , Mariana Lazarini AffiliationIdentity
HGNC
LOCATION
10p12.1 - 10p12.3
LOCUSID
ALIAS
ARHGAP10
FUSION GENES
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.
DNA/RNA
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.
Proteins
Figure 1. Schematic representation of ARHGAP21 protein. Domain positions were based on National Center for Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/gene/57584).
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
(Source: http://www.ncbi.nlm.nih.gov/homologene)
Table 1. Comparative identity of human ARHGAP21 with other species
| % Identity for: Homo sapiens ARHGAP21 | Symbol | Protein | DNA |
| vs. P. troglodytes | ARHGAP21 | 99.5 | 99.5 |
| vs. M. mulatta | ARHGAP21 | 98.2 | 98.0 |
| vs. C. lupus | ARHGAP21 | 87.1 | 85.6 |
| vs. B. taurus | ARHGAP21 | 87.3 | 85.0 |
| vs. M. musculus | Arhgap21 | 87.3 | 84.0 |
| vs. R. norvegicus | Arhgap21 | 86.9 | 83.3 |
| vs. G. gallus | ARHGAP21 | 74.9 | 75.1 |
| vs. X. tropicalis | arhgap21 | 65.1 | 67.4 |
| vs. D. rerio | arhgap21 | 57.9 | 59.5 |
(Source: http://www.ncbi.nlm.nih.gov/homologene)
Mutations
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 (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic).
Implicated in
Top 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 name
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 name
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 name
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 name
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).
Entity name
Breast cancer
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).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 21173159 | 2011 | β-Arrestin 1 inhibits the GTPase-activating protein function of ARHGAP21, promoting activation of RhoA following angiotensin II type 1A receptor stimulation. | Anthony DF et al |
| 23235160 | 2013 | ARHGAP21 protein, a new partner of α-tubulin involved in cell-cell adhesion formation and essential for epithelial-mesenchymal transition. | Barcellos KS et al |
| 12056806 | 2002 | ARHGAP10, a novel human gene coding for a potentially cytoskeletal Rho-GTPase activating protein. | Bassères DS et al |
| 19268501 | 2009 | ARHGAP21 modulates FAK activity and impairs glioblastoma cell migration. | Bigarella CL et al |
| 18662671 | 2008 | ARHGAP21 associates with FAK and PKCzeta and is redistributed after cardiac pressure overload. | Borges L et al |
| 16261155 | 2006 | Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display. | Carles A et al |
| 15793564 | 2005 | Golgi-localized GAP for Cdc42 functions downstream of ARF1 to control Arp2/3 complex and F-actin dynamics. | Dubois T et al |
| 25744409 | 2015 | ARHGAP21 prevents abnormal insulin release through actin rearrangement in pancreatic islets from neonatal mice. | Ferreira SM et al |
| 21763613 | 2011 | Planar cell polarity: coordinating morphogenetic cell behaviors with embryonic polarity. | Gray RS et al |
| 8072546 | 1994 | Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate. | Harlan JE et al |
| 23200924 | 2013 | ARHGAP21 is a RhoGAP for RhoA and RhoC with a role in proliferation and migration of prostate adenocarcinoma cells. | Lazarini M et al |
| 27010858 | 2016 | ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells. | Luo N et al |
| 11279148 | 2001 | Interaction between the Btk PH domain and phosphatidylinositol-3,4,5-trisphosphate directly regulates Btk. | Saito K et al |
| 16184169 | 2005 | ARHGAP10 is necessary for alpha-catenin recruitment at adherens junctions and for Listeria invasion. | Sousa S et al |
| 17222083 | 2007 | Current knowledge of the large RhoGAP family of proteins. | Tcherkezian J et al |
| 27226243 | 2016 | A lateral signalling pathway coordinates shape volatility during cell migration. | Zhang L et al |
Other Information
Locus ID:
NCBI: 57584
MIM: 609870
HGNC: 23725
Ensembl: ENSG00000107863
Variants:
dbSNP: 57584
ClinVar: 57584
TCGA: ENSG00000107863
COSMIC: ARHGAP21
RNA/Proteins
Expression (GTEx)
Pathways
| Pathway | Source | External ID |
|---|---|---|
| Signal Transduction | REACTOME | R-HSA-162582 |
| Signaling by Rho GTPases | REACTOME | R-HSA-194315 |
| Rho GTPase cycle | REACTOME | R-HSA-194840 |
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 36676763 | 2023 | ARHGAP21 Is Involved in the Carcinogenic Mechanism of Cholangiocarcinoma: A Study Based on Bioinformatic Analyses and Experimental Validation. | 1 |
| 36764390 | 2023 | Silencing of ARHGAP21, a Rho GTPase activating protein (RhoGAP), reduces the growth of prostate cancer xenografts in NOD/SCID mice. | 0 |
| 37712268 | 2023 | [ARHGAP21 inhibits epithelial-mesenchymal transition by inactivating the WNT signaling pathway in non-small cell lung cancer]. | 0 |
| 36676763 | 2023 | ARHGAP21 Is Involved in the Carcinogenic Mechanism of Cholangiocarcinoma: A Study Based on Bioinformatic Analyses and Experimental Validation. | 1 |
| 36764390 | 2023 | Silencing of ARHGAP21, a Rho GTPase activating protein (RhoGAP), reduces the growth of prostate cancer xenografts in NOD/SCID mice. | 0 |
| 37712268 | 2023 | [ARHGAP21 inhibits epithelial-mesenchymal transition by inactivating the WNT signaling pathway in non-small cell lung cancer]. | 0 |
| 33727037 | 2021 | Deficiency of ARHGAP21 alters megakaryocytic cell lineage responses and enhances platelet hemostatic function. | 2 |
| 33727037 | 2021 | Deficiency of ARHGAP21 alters megakaryocytic cell lineage responses and enhances platelet hemostatic function. | 2 |
| 29212046 | 2018 | Hematopoietic defects in response to reduced Arhgap21. | 11 |
| 29856495 | 2018 | ARHGAP21 as a master regulator of multiple cellular processes. | 12 |
| 29212046 | 2018 | Hematopoietic defects in response to reduced Arhgap21. | 11 |
| 29856495 | 2018 | ARHGAP21 as a master regulator of multiple cellular processes. | 12 |
| 28749339 | 2017 | PTEN controls glandular morphogenesis through a juxtamembrane β-Arrestin1/ARHGAP21 scaffolding complex. | 10 |
| 28749339 | 2017 | PTEN controls glandular morphogenesis through a juxtamembrane β-Arrestin1/ARHGAP21 scaffolding complex. | 10 |
| 25691070 | 2015 | Genetic association of ARHGAP21 gene variant with mandibular prognathism. | 13 |
Citation
Mariana Ferreira Pissarra ; Sara Teresinha Olalla Saad ; Mariana Lazarini
ARHGAP21 (Rho GTPase activating protein 21)
Atlas Genet Cytogenet Oncol Haematol. 2016-12-01
Online version: http://atlasgeneticsoncology.org/gene/43137/arhgap21
