ARHGAP21 is a RhoGAP for RhoA and RhoC with a role in proliferation and migration of prostate adenocarcinoma cells

Lazarini, Mariana; Traina, Fabı́ola; Machado-Neto, João Agostinho; Barcellos, Karin Spät Albino; Moreira, Yuri B; Brandão, Marcelo Mendes; Verjovski-Almeida, Sérgio; Ridley, Anne J.; Saad, Sara Teresinha Olalla

doi:10.1016/j.bbadis.2012.11.010

Cited by 54 publications

(77 citation statements)

References 57 publications

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“…Cellular Context, How the RHOGAPs Determine and Regulate Specificity-Several cell-based studies have shown that there is specificity between RHOGAP and RHO proteins as follows: ARHGAP15, BCR, ␤-chimaerin, 3BP1, p68RACGAP, and FILGAP are specific for RAC1 (29, 50 -54); RALBP1 and MGCRACGAP1 are specific for both CDC42 and RAC1 (55-57); RICH1 and CDGAP are specific for CDC42 (58, 59); ARHGAP6, DLC1, DLC3, myosin IXb, OPHN1, p190A, and RA-RHOGAP are specific for RHOA (34, 47, 60 -68); ARHGAP18, ARHGAP21, and DLC1 are specific for RHOC (64,66,69); TCGAP is specific for TC10 (70); PARG1 is specific for RHOA (71), and ARHGAP30 is specific for WRCH1 (72).…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins

Amin

Jaiswal

Derewenda

et al. 2016

Journal of Biological Chemistry

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RHO GTPase-activating proteins (RHOGAPs) are one of the major classes of regulators of the RHO-related protein family that are crucial in many cellular processes, motility, contractility, growth, differentiation, and development. Using database searches, we extracted 66 distinct human RHOGAPs, from which 57 have a common catalytic domain capable of terminating RHO protein signaling by stimulating the slow intrinsic GTP hydrolysis (GTPase) reaction. The specificity of the majority of the members of RHOGAP family is largely uncharacterized. Here, we comprehensively investigated the sequence-structurefunction relationship between RHOGAPs and RHO proteins by combining our in vitro data with in silico data. The activity of 14 representatives of the RHOGAP family toward 12 RHO family proteins was determined in real time. We identified and structurally verified hot spots in the interface between RHOGAPs and RHO proteins as critical determinants for binding and catalysis. We have found that the RHOGAP domain itself is nonselective and in some cases rather inefficient under cell-free conditions. Thus, we propose that other domains of RHOGAPs confer substrate specificity and fine-tune their catalytic efficiency in cells.

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Section: Discussionmentioning

confidence: 99%

Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins

Amin

Jaiswal

Derewenda

et al. 2016

Journal of Biological Chemistry

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“…Thus, ARHGAP21 was identified as a potential tumor suppressor, being able to control the progression of the disease. ARHGAP21 depletion was also found to increase cell migration and decrease proliferation in prostate adenocarcinoma cell line (PC3) (Lazarini et al, ). The increase in migration was attributed to its RhoGAP action over RhoC, as the lack of ARHGAP21 resulted in increased RhoC activity, which in turn led to increased migration (Lazarini et al, ).…”

Section: Arhgap As a Regulator Of Cytoskeletal Processes In Cancer Cellsmentioning

confidence: 99%

ARHGAP21 as a master regulator of multiple cellular processes

Rosa

Soares

Silveira

et al. 2018

Journal Cellular Physiology

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The cellular cytoskeleton is involved with multiple biological processes and is tightly regulated by multiple proteins and effectors. Among these, the RhoGTPases family is one of the most important players. RhoGTPAses are, in turn, regulated by many other elements. In the past decade, one of those regulators, the RhoGAP Rho GTPase Activating Protein 21 (ARHGAP21), has been overlooked, despite being implied as having an important role on many of those processes. In this paper, we aimed to review the available literature regarding ARHGAP21 to highlight its importance and the mechanisms of action that have been found so far for this still unknown protein involved with cell adhesion, migration, Golgi regulation, cell trafficking, and even insulin secretion.

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“…They play a role in the migration, invasion and proliferation of tumor cells by affectting cell movement and adhesion in the cell-cell or cell-matrix, and the reconstruction of the extracellular matrix (5,6). Rho subfamily members play an important role in the migration, invasion and proliferation of tumor cells, while the behavior of the embryo implanted in the endometrium is similar with the behavior of tumor cells (7).…”

Section: Introductionmentioning

confidence: 99%

The PI3K/Akt signaling pathway exerts effects on the implantation of mouse embryos by regulating the expression of RhoA

Liu

Wang

2014

International Journal of Molecular Medicine

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The aim of this study was to investigate whether the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway affects the implantation of mouse embryos by regulating the expression of RhoA. The expression of PI3K, Akt, phosphorylated (p-)Akt, phosphatase and tensin homolog (PTEN) and RhoA in the uterus of mice on day 5 of pregnancy (D5) and in pseudopregnant mice was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry and western blot analysis. A functional analysis of these genes was also performed by the intrauterine injection with the PI3K inhibitor, LY294002, on day 2 of pregnancy (D2). The expression levels of PI3K, p-Akt, RhoA at the implantation site were higher than those at the inter-implantation site in the endometrium; however, opposite effects were observed for PTEN expression. The expression levels of the above genes in the pseudopregnant group and in the group injected with the PI3K/Akt inhibitor, LY294002, were markedly lower than those in the pregnant group. Functional experiments revealed that the number of implantation sites had been significantly decreased (P<0.05) following the intrauterine injection of the PI3K inhibitor, LY294002, on day 2 of gestation compared with the contralateral injection of phosphate-buffered saline (PBS). These results suggest that the PI3K/Akt signaling pathway affects embryo implantation by regulating the expression of RhoA.

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ARHGAP21 is a RhoGAP for RhoA and RhoC with a role in proliferation and migration of prostate adenocarcinoma cells

Abstract: Our results reveal new functions and signaling pathways regulated by ARHGAP21, and indicate that it could contribute to prostate cancer progression.

Cited by 54 publications

References 57 publications

Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins

Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins

ARHGAP21 as a master regulator of multiple cellular processes

The PI3K/Akt signaling pathway exerts effects on the implantation of mouse embryos by regulating the expression of RhoA

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