scholarly journals Rho Family GTPases in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1271
Author(s):  
Suranganie Dharmawardhane
Keyword(s):  
Cancer Therapy ◽  
Rho Gtpases ◽  
Therapeutic Strategies ◽  
Current Understanding ◽  
Special Issue ◽  
Central Importance ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
International Experts

This Special Issue containing seminal contributions from international experts highlights the current understanding of Rho GTPases in cancer, with an emphasis on recognizing their central importance as critical targets for cancer therapy and for chemosensitization of current therapeutic strategies [...]

Rho family GTPases

2012 ◽  
Vol 40 (6) ◽  
pp. 1378-1382 ◽  
Author(s):  
Alan Hall
Keyword(s):  
Actin Cytoskeleton ◽  
Rho Gtpases ◽  
Cellular Response ◽  
Molecular Switches ◽  
Effector Proteins ◽  
Eukaryotic Cells ◽  
Cell Behaviour ◽  
Wide Range ◽  
Rho Family Gtpases ◽  
Rho Family

Rho GTPases comprise a family of molecular switches that control signal transduction pathways in eukaryotic cells. A conformational change induced upon binding GTP promotes an interaction with target (effector) proteins to generate a cellular response. A highly conserved function of Rho GTPases from yeast to humans is to control the actin cytoskeleton, although, in addition, they promote a wide range of other cellular activities. Changes in the actin cytoskeleton drive many dynamic aspects of cell behaviour, including morphogenesis, migration, phagocytosis and cytokinesis, and the dysregulation of Rho GTPases is associated with numerous human diseases and disorders.

scholarly journals Differential activation and function of Rho GTPases during Salmonella–host cell interactions

2006 ◽  
Vol 175 (3) ◽  
pp. 453-463 ◽  
Author(s):  
Jayesh C. Patel ◽  
Jorge E. Galán
Keyword(s):  
Rho Gtpases ◽  
Food Poisoning ◽  
Bacterial Pathogen ◽  
Cellular Responses ◽  
Host Cells ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
And Function

Salmonella enterica, the cause of food poisoning and typhoid fever, has evolved sophisticated mechanisms to modulate Rho family guanosine triphosphatases (GTPases) to mediate specific cellular responses such as actin remodeling, macropinocytosis, and nuclear responses. These responses are largely the result of the activity of a set of bacterial proteins (SopE, SopE2, and SopB) that, upon delivery into host cells via a type III secretion system, activate specific Rho family GTPases either directly (SopE and SopE2) or indirectly (SopB) through the stimulation of an endogenous exchange factor. We show that different Rho family GTPases play a distinct role in Salmonella-induced cellular responses. In addition, we report that SopB stimulates cellular responses by activating SH3-containing guanine nucleotide exchange factor (SGEF), an exchange factor for RhoG, which we found plays a central role in the actin cytoskeleton remodeling stimulated by Salmonella. These results reveal a remarkable level of complexity in the manipulation of Rho family GTPases by a bacterial pathogen.

scholarly journals Rho-family GTPases modulate Ca2+-dependent ATP release from astrocytes

2008 ◽  
Vol 295 (1) ◽  
pp. C231-C241 ◽  
Author(s):  
Andrew E. Blum ◽  
Sheldon M. Joseph ◽  
Ronald J. Przybylski ◽  
George R. Dubyak
Keyword(s):  
Rho Gtpases ◽  
Atp Release ◽  
Rho Kinase ◽  
Astrocytoma Cells ◽  
Gap Junction Channel ◽  
Rho Family Gtpases ◽  
Clostridium Difficile Toxin ◽  
Protease Activated Receptor 1 ◽  
Rho Family ◽  
Clostridium Difficile Toxin B

Previously, we reported that activation of G protein-coupled receptors (GPCR) in 1321N1 human astrocytoma cells elicits a rapid release of ATP that is partially dependent on a Gq/phophospholipase C (PLC)/Ca2+ mobilization signaling cascade. In this study we assessed the role of Rho-family GTPase signaling as an additional pathway for the regulation of ATP release in response to activation of protease-activated receptor-1 (PAR1), lysophosphatidic acid receptor (LPAR), and M3-muscarinic (M3R) GPCRs. Thrombin (or other PAR1 peptide agonists), LPA, and carbachol triggered quantitatively similar Ca2+ mobilization responses, but only thrombin and LPA caused rapid accumulation of active GTP-bound Rho. The ability to elicit Rho activation correlated with the markedly higher efficacy of thrombin and LPA, relative to carbachol, as ATP secretagogues. Clostridium difficile toxin B and Clostridium botulinum C3 exoenzyme, which inhibit Rho-GTPases, attenuated the thrombin- and LPA-stimulated ATP release but did not decrease carbachol-stimulated release. Thus the ability of certain Gq-coupled receptors to additionally stimulate Rho-GTPases acts to strongly potentiate a Ca2+-activated ATP release pathway. However, pharmacological inhibition of Rho kinase I/II or myosin light chain kinase did not attenuate ATP release. PAR1-induced ATP release was also reduced twofold by brefeldin treatment suggesting the possible mobilization of Golgi-derived, ATP-containing secretory vesicles. ATP release was also markedly repressed by the gap junction channel inhibitor carbenoxolone in the absence of any obvious thrombin-induced change in membrane permeability indicative of hemichannel gating.

scholarly journals The Large GTPase, GBP-2, Regulates Rho Family GTPases to Inhibit Migration and Invadosome Formation in Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5632
Author(s):  
Geoffrey O. Nyabuto ◽  
John P. Wilson ◽  
Samantha A. Heilman ◽  
Ryan C. Kalb ◽  
Jonathan P. Kopacz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Rho Gtpases ◽  
Breast Cancer Cells ◽  
Primary Site ◽  
Common Cancer ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
4T1 Cells ◽  
Guanylate Binding Protein

Breast cancer is the most common cancer in women. Despite advances in early detection and treatment, it is predicted that over 43,000 women will die of breast cancer in 2021. To lower this number, more information about the molecular players in breast cancer are needed. Guanylate-Binding Protein-2 has been correlated with better prognosis in breast cancer. In this study, we asked if the expression of GBP-2 in breast cancer merely provided a biomarker for improved prognosis or whether it actually contributed to improving outcome. To answer this, the 4T1 model of murine breast cancer was used. 4T1 cells themselves are highly aggressive and highly metastatic, while 67NR cells, isolated from the same tumor, do not leave the primary site. The expression of GBP-2 was examined in the two cell lines and found to be inversely correlated with aggressiveness/metastasis. Proliferation, migration, and invadosome formation were analyzed after altering the expression levels of GBP-2. Our experiments show that GBP-2 does not alter the proliferation of these cells but inhibits migration and invadosome formation downstream of regulation of Rho GTPases. Together these data demonstrate that GBP-2 is responsible for cell autonomous activities that make breast cancer cells less aggressive.

scholarly journals Proximity-dependent proteomics reveals extensive interactions of Protocadherin-19 with regulators of Rho GTPases and the microtubule cytoskeleton

2020 ◽  
Author(s):  
Michelle R. Emond ◽  
Sayantanee Biswas ◽  
Matthew L. Morrow ◽  
James D. Jontes
Keyword(s):  
Nervous System ◽  
Behavioral Problems ◽  
Rho Gtpases ◽  
Protein Complexes ◽  
Epileptic Seizures ◽  
Centrosomal Protein ◽  
Surface Receptors ◽  
Rho Family Gtpases ◽  
Rho Family

AbstractProtocadherin-19 belongs to the cadherin family of cell surface receptors and has been shown to play essential roles in the development of the vertebrate nervous system. Mutations in human Protocadherin-19 (PCDH19) lead to PCDH19 Female-limited epilepsy (PCDH19 FLE) in humans, characterized by the early onset of epileptic seizures in children and a range of cognitive and behavioral problems in adults. Despite being considered the second most prevalent gene in epilepsy, very little is known about the intercellular pathways in which it participates. In order to characterize the protein complexes within which Pcdh19 functions, we generated Pcdh19-BioID fusion proteins and utilized proximity-dependent biotinylation to identify neighboring proteins. Proteomic identification and analysis revealed that the Pcdh19 interactome is enriched in proteins that regulate Rho family GTPases, microtubule binding proteins and proteins that regulate cell divisions. We cloned the centrosomal protein Nedd1 and the RacGEF Dock7 and verified their interactions with Pcdh19 in vitro. Our findings provide the first comprehensive insights into the interactome of Pcdh19, and provide a platform for future investigations into the cellular and molecular biology of this protein critical to the proper development of the nervous system.

scholarly journals RHO Family GTPases in the Biology of Lymphoma

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 646 ◽  
Author(s):  
Voena ◽  
Chiarle
Keyword(s):  
Rho Gtpases ◽  
Intracellular Signaling ◽  
Human Cancer ◽  
Loss Of Function ◽  
Cellular Processes ◽  
Ras Gtpase ◽  
Rho Family Gtpases ◽  
Ras Family ◽  
Human Lymphoma ◽  
Rho Family

RHO GTPases are a class of small molecules involved in the regulation of several cellular processes that belong to the RAS GTPase superfamily. The RHO family of GTPases includes several members that are further divided into two different groups: typical and atypical. Both typical and atypical RHO GTPases are critical transducers of intracellular signaling and have been linked to human cancer. Significantly, both gain-of-function and loss-of-function mutations have been described in human tumors with contradicting roles depending on the cell context. The RAS family of GTPases that also belong to the RAS GTPase superfamily like the RHO GTPases, includes arguably the most frequently mutated genes in human cancers (K-RAS, N-RAS, and H-RAS) but has been extensively described elsewhere. This review focuses on the role of RHO family GTPases in human lymphoma initiation and progression.

scholarly journals Cytotoxic Necrotizing Factor Type 1 Production by Uropathogenic Escherichia coli Modulates Polymorphonuclear Leukocyte Function

2005 ◽  
Vol 73 (9) ◽  
pp. 5301-5310 ◽  
Author(s):  
Jon M. Davis ◽  
Susan B. Rasmussen ◽  
Alison D. O'Brien
Keyword(s):  
Escherichia Coli ◽  
Rho Gtpases ◽  
Polymorphonuclear Leukocytes ◽  
Human Neutrophils ◽  
Cytotoxic Necrotizing Factor ◽  
Leukocyte Function ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
Factor Type

ABSTRACT Many strains of uropathogenic Escherichia coli (UPEC) produce cytotoxic necrotizing factor type 1 (CNF1), a toxin that constitutively activates the Rho GTPases RhoA, Rac1, and Cdc42. We previously showed that CNF1 contributes to the virulence of UPEC in a mouse model of ascending urinary tract infection and a rat model of acute prostatitis and that a striking feature of the histopathology of the mouse bladders and rat prostates infected with CNF1-positive strains is an elevation in levels of polymorphonuclear leukocytes (PMNs). We also found that CNF1 synthesis leads to prolonged survival of UPEC in association with human neutrophils. Here, we tested the hypothesis that CNF1 production by UPEC diminishes the antimicrobial capacity of mouse PMNs by affecting phagocyte function through targeting Rho family GTPases that are critical to phagocytosis and the generation of reactive oxygen species. We found that, as with human neutrophils, CNF1 synthesis provided a survival advantage to UPEC incubated with mouse PMNs. We also observed that CNF1-positive UPEC down-regulated phagocytosis, altered the distribution of the complement receptor CR3 (CD11b/CD18), enhanced the intracellular respiratory burst, and increased levels of Rac2 activation in PMNs. From these results, we conclude that modulation of PMN function by CNF1 facilitates UPEC survival during the acute inflammatory response.

scholarly journals Coupling of Rho family GTPases during mesenchymal-to-epithelial-like transitions

2018 ◽  
Author(s):  
Christopher P. Toret ◽  
Pruthvi C. Shivakumar ◽  
Pierre-françois Lenne ◽  
Andre Le Bivic
Keyword(s):  
Rho Gtpases ◽  
Rho Gtpase ◽  
Leading Edge ◽  
Dorsal Closure ◽  
Developmental Processes ◽  
Rho Family Gtpases ◽  
Rho Protein ◽  
Cellular Context ◽  
Rho Family

ABSTRACTMany metazoan developmental processes require cells to transition between migratory mesenchymal- and adherent epithelial-like states. These transitions require Rho GTPase-mediated actin rearrangements downstream of integrin and cadherin pathways. A regulatory toolbox of GEF and GAP proteins precisely coordinates Rho protein activities, yet defining the involvement of specific regulators within a cellular context remains a challenge due to overlapping and coupled activities. Here we demonstrate that Drosophila dorsal closure is a simple, powerful model for Rho GTPase regulation during leading edge to cadherin contact transitions. During these transitions a Rac GEF elmo-dock complex regulates both lamellipodia and Rho1-dependent, actomyosin-mediated tension at initial cadherin contacts. Moreover, the Drosophila Rho GAP arhgap21 ortholog controls Rac and Rho GTPases during the same processes and genetically regulates the elmo-dock complex. This study presents a fresh framework to understand the inter-relationship between GEF and GAP proteins that tether Rac and Rho cycles during developmental processes.

scholarly journals Autophosphorylation-dependent degradation of Pak1, triggered by the Rho-family GTPase, Chp

2007 ◽  
Vol 404 (3) ◽  
pp. 487-497 ◽  
Author(s):  
Monika Weisz Hubsman ◽  
Natalia Volinsky ◽  
Edward Manser ◽  
Deborah Yablonski ◽  
Ami Aronheim
Keyword(s):  
Rho Gtpases ◽  
Cellular Functions ◽  
Kinase Activation ◽  
Homologous Protein ◽  
T Cell Migration ◽  
Rho Family Gtpases ◽  
Small Rho Gtpases ◽  
Rho Family ◽  
First Time ◽  
Pak1 Activation

The Paks (p21-activated kinases) Pak1, Pak2 and Pak3 are among the most studied effectors of the Rho-family GTPases, Rac, Cdc42 (cell division cycle 42) and Chp (Cdc42 homologous protein). Pak kinases influence a variety of cellular functions, but the process of Pak down-regulation, following activation, is poorly understood. In the present study, we describe for the first time a negative-inhibitory loop generated by the small Rho-GTPases Cdc42 and Chp, resulting in Pak1 inhibition. Upon overexpression of Chp, we unexpectedly observed a T-cell migration phenotype consistent with Paks inhibition. In line with this observation, overexpression of either Chp or Cdc42 caused a marked reduction in the level of Pak1 protein in a number of different cell lines. Chp-induced degradation was accompanied by ubiquitination of Pak1, and was dependent on the proteasome. The susceptibility of Pak1 to Chp-induced degradation depended on its p21-binding domain, kinase activity and a number of Pak1 autophosphorylation sites, whereas the PIX- (Pak-interacting exchange factor) and Nck-binding sites were not required. Together, these results implicate Chp-induced kinase autophosphorylation in the degradation of Pak1. The N-terminal domain of Chp was found to be required for Chp-induced degradation, although not for Pak1 activation, suggesting that Chp provides a second function, distinct from kinase activation, to trigger Pak degradation. Collectively, our results demonstrate a novel mechanism of signal termination mediated by the Rho-family GTPases Chp and Cdc42, which results in ubiquitin-mediated degradation of one of their direct effectors, Pak1.

scholarly journals Involvement of Rho Family GTPases in p19Arf- and p53-Mediated Proliferation of Primary Mouse Embryonic Fibroblasts

2004 ◽  
Vol 24 (3) ◽  
pp. 1426-1438 ◽  
Author(s):  
Fukun Guo ◽  
Yi Zheng
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Rho Gtpases ◽  
Growth Regulation ◽  
Cell Transformation ◽  
Rho Kinase ◽  
Intracellular Signals ◽  
Primary Mouse ◽  
Rho Family Gtpases ◽  
Rho Family

ABSTRACT The Rho family GTPases Rac1, RhoA, and Cdc42 function as molecular switches that transduce intracellular signals regulating gene expression and cell proliferation as well as cell migration. p19Arf and p53, on the other hand, are tumor suppressors that act both independently and sequentially to regulate cell proliferation. To investigate the functional interaction and cooperativeness of Rho GTPases with the p19Arf-p53 pathway, we examined the contribution of Rho GTPases to the gene transcription and cell proliferation unleashed by deletion of p19Arf or p53 in primary mouse embryo fibroblasts. We found that (i) p19Arf or p53 deficiency led to a significant increase in PI 3-kinase activity, which in turn upregulated RhoA and Rac1 activities; (ii) deletion of p19Arf or p53 led to an increase in cell growth rate that was in part dependent on RhoA, Rac1, and Cdc42 activities; (iii) p19Arf or p53 deficiency caused an enhancement of the growth-related transcription factor NF-κB and cyclin D1 activities that are partly dependent on RhoA or Cdc42 but not on Rac1; (iv) forced expression of the activating mutants of Rac1, RhoA, or Cdc42 caused a hyperproliferative phenotype of the p19Arf −/− and p53 −/− cells and promoted transformation of both cells; (v) RhoA appeared to contribute to p53-regulated cell proliferation by modulating cell cycle machinery, while hyperactivation of RhoA further suppressed a p53-independent apoptotic signal; and (vi) multiple pathways regulated by RhoA, including that of Rho-kinase, were required for RhoA to fully promote the transformation of p53 −/− cells. Taken together, these results provide strong evidence indicating that signals through the Rho family GTPases can both contribute to cell growth regulation by p19Arf and p53 and cooperate with p19Arf or p53 deficiency to promote primary cell transformation.

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