The RND1 Small GTPase: Main Functions and Emerging Role in Oncogenesis

Mouly, Laetitia; Gilhodes, Julia; Lemarié, Anthony; Moyal, Elizabeth Cohen-Jonathan; Toulas, Christine; Favre, Gilles; Sordet, Olivier; Monferran, Sylvie

doi:10.3390/ijms20153612

Cited by 14 publications

(12 citation statements)

References 63 publications

(140 reference statements)

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“…For example, the Rnd (Rnd1-3) and RhoBTB (RhoBTB1-3) subfamilies have amino acid substitutions in their GTPase domain that are not recognized by RhoGAPs, and thus, their GTP hydrolysis rate cannot be accelerated by these proteins. These subfamily members are thus constitutively active and GTP-bound, although they have intact GDP/GTP nucleotide exchange activity [14,15]. Similarly, RhoH has defective GTPase activity and is unable to hydrolyze GTP, and therefore is presumed to be constitutively active [16].…”

Section: Regulation Of Rho Gtpases By Ptmsmentioning

confidence: 99%

Dysregulation of Rho GTPases in Human Cancers

Jung

Yoon

Lim

et al. 2020

Cancers

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Rho GTPases play central roles in numerous cellular processes, including cell motility, cell polarity, and cell cycle progression, by regulating actin cytoskeletal dynamics and cell adhesion. Dysregulation of Rho GTPase signaling is observed in a broad range of human cancers, and is associated with cancer development and malignant phenotypes, including metastasis and chemoresistance. Rho GTPase activity is precisely controlled by guanine nucleotide exchange factors, GTPase-activating proteins, and guanine nucleotide dissociation inhibitors. Recent evidence demonstrates that it is also regulated by post-translational modifications, such as phosphorylation, ubiquitination, and sumoylation. Here, we review the current knowledge on the role of Rho GTPases, and the precise mechanisms controlling their activity in the regulation of cancer progression. In addition, we discuss targeting strategies for the development of new drugs to improve cancer therapy.

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Section: Regulation Of Rho Gtpases By Ptmsmentioning

confidence: 99%

Dysregulation of Rho GTPases in Human Cancers

Jung

Yoon

Lim

et al. 2020

Cancers

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“…RND1 is a small GTPase that belongs to RND subfamily. RND1 protein's function depends on epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms rather than GDP/GTP exchange [ 12 ]. Under normal circumstances, RND1 is also involved in biological angiogenesis, neural connections and embryonic development [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…RND1 protein's function depends on epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms rather than GDP/GTP exchange [ 12 ]. Under normal circumstances, RND1 is also involved in biological angiogenesis, neural connections and embryonic development [ 12 ]. Researchers investigated the tumor suppressor effect of RND1 in several tumors, and the influence of RND1 on EMT was discovered.…”

Section: Discussionmentioning

confidence: 99%

“…Rho family GTPase 1 (RND1), an atypical member of the Rho GTPase family, is predominantly in an active GTP-bound conformation that lacks GTP hydrolysis activity [ 10 ]. The essential function of RND family, including RND1, is to regulate the morphology and cytoskeleton [ 11 ], while RND1 also participates in angiogenesis, nerve connections and embryonic development [ 12 ]. The current research indicated that RND1 displays the characteristics of a tumor suppressor gene.…”

Section: Introductionmentioning

confidence: 99%

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Rho family GTPase 1 (RND1), a novel regulator of p53, enhances ferroptosis in glioblastoma

Sun

Yuan

et al. 2022

Cell Biosci

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Background Ferroptosis is an iron dependent cell death closely associated with p53 signaling pathway and is aberrantly regulated in glioblastoma (GBM), yet the underlying mechanism needs more exploration. Identifying new factors which regulate p53 and ferroptosis in GBM is essential for treatment. Methods Glioma cell growth was evaluated by cell viability assays and colony formation assays. Lipid reactive oxygen species (ROS) assays, lipid peroxidation assays, glutathione assays, and transmission electron microscopy were used to assess the degree of cellular lipid peroxidation of GBM. The mechanisms of RND1 in regulation of p53 signaling were analyzed by RT-PCR, western blot, immunostaining, co-immunoprecipitation, ubiquitination assays and luciferase reporter assays. The GBM‐xenografted animal model was constructed and the tumor was captured by an In Vivo Imaging System (IVIS). Results From the The Cancer Genome Atlas (TCGA) database, we summarized that Rho family GTPase 1 (RND1) expression was downregulated in GBM and predicted a better prognosis of patients with GBM. We observed that RND1 influenced the glioma cell growth in a ferroptosis-dependent manner when GBM cell lines U87 and A172 were treated with Ferrostatin-1 or Erastin. Mechanistically, we found that RND1 interacted with p53 and led to the de-ubiquitination of p53 protein. Furthermore, the overexpression of RND1 promoted the activity of p53-SLC7A11 signaling pathway, therefore inducing the lipid peroxidation and ferroptosis of GBM. Conclusions We found that RND1, a novel controller of p53 protein and a positive regulator of p53 signaling pathway, enhanced the ferroptosis in GBM. This study may shed light on the understanding of ferroptosis in GBM cells and provide new therapeutic ideas for GBM.

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“…14 (Lee et al, 2007;Luo et al, 2017;Rodriguez-Gabin et al, 2004). 15 (Mouly et al, 2019;Okada et al, 2015;Riou et al, 2010). 16 (Heng et al, 2008;Riou et al, 2010).…”

Section: Western Blotting and Antibodiesmentioning

confidence: 99%

Regulation of GTPase function by autophosphorylation

Johnson

et al. 2021

Preprint

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A unifying feature of the RAS superfamily is a functionally conserved GTPase cycle that proteins use to transition between active and inactive states. Here, we demonstrate that active site autophosphorylation of some small GTPases is an intrinsic regulatory mechanism that reduces nucleotide hydrolysis and enhances nucleotide exchange, thus altering the on/off switch that forms the basis for their signaling functions. Using x-ray crystallography, nuclear magnetic resonance spectroscopy, biolayer interferometry binding assays, and molecular dynamics on autophosphorylated mutants of H-RAS and K-RAS, we show that phosphoryl transfer from GTP requires dynamic movement of the switch II domain and that autophosphorylation promotes nucleotide exchange by opening of the active site and extraction of the stabilizing Mg. Finally, we demonstrate that autophosphorylated K-RAS exhibits altered effector interactions, including a reduced affinity for RAF proteins. Thus, autophosphorylation leads to altered active site dynamics and effector interaction properties, creating a pool of GTPases that are functionally distinct from the non-phosphorylated counterpart.

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The RND1 Small GTPase: Main Functions and Emerging Role in Oncogenesis

Cited by 14 publications

References 63 publications

Dysregulation of Rho GTPases in Human Cancers

Dysregulation of Rho GTPases in Human Cancers

Rho family GTPase 1 (RND1), a novel regulator of p53, enhances ferroptosis in glioblastoma

Regulation of GTPase function by autophosphorylation

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