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1
Mosaddeghzadeh, Niloufar, i Mohammad Reza Ahmadian. "The RHO Family GTPases: Mechanisms of Regulation and Signaling". Cells 10, nr 7 (20.07.2021): 1831. http://dx.doi.org/10.3390/cells10071831.
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Much progress has been made toward deciphering Rho GTPase functions, and many studies have convincingly demonstrated that altered signal transduction through Rho GTPases is a recurring theme in the progression of human malignancies. It seems that 20 canonical RHO GTPases are likely regulated by three GDIs, 85 GEFs, and 66 GAPs, and eventually interact with >70 downstream effectors. A recurring theme is the challenge in understanding the molecular determinants of the specificity of these four classes of interacting proteins that, irrespective of their functions, bind to common sites on the surface of RHO GTPases. Identified and structurally verified hotspots as functional determinants specific to RHO GTPase regulation by GDIs, GEFs, and GAPs as well as signaling through effectors are presented, and challenges and future perspectives are discussed.
2
Mulloy, James C., Jose A. Cancelas, Marie-Dominique Filippi, Theodosia A. Kalfa, Fukun Guo i Yi Zheng. "Rho GTPases in hematopoiesis and hemopathies". Blood 115, nr 5 (4.02.2010): 936–47. http://dx.doi.org/10.1182/blood-2009-09-198127.
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AbstractRho family GTPases are intracellular signaling proteins regulating multiple pathways involved in cell actomyosin organization, adhesion, and proliferation. Our knowledge of their cellular functions comes mostly from previous biochemical studies that used mutant overexpression approaches in various clonal cell lines. Recent progress in understanding Rho GTPase functions in blood cell development and regulation by gene targeting of individual Rho GTPases in mice has allowed a genetic understanding of their physiologic roles in hematopoietic progenitors and mature lineages. In particular, mouse gene–targeting studies have provided convincing evidence that individual members of the Rho GTPase family are essential regulators of cell type–specific functions and stimuli-specific pathways in regulating hematopoietic stem cell interaction with bone marrow niche, erythropoiesis, and red blood cell actin dynamics, phagocyte migration and killing, and T- and B-cell maturation. In addition, deregulation of Rho GTPase family members has been associated with multiple human hematologic diseases such as neutrophil dysfunction, leukemia, and Fanconi anemia, raising the possibility that Rho GTPases and downstream signaling pathways are of therapeutic value. In this review we discuss recent genetic studies of Rho GTPases in hematopoiesis and several blood lineages and the implications of Rho GTPase signaling in hematologic malignancies, immune pathology. and anemia.
3
Olayioye, Monilola A., Bettina Noll i Angelika Hausser. "Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases". Cells 8, nr 12 (21.11.2019): 1478. http://dx.doi.org/10.3390/cells8121478.
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As membrane-associated master regulators of cytoskeletal remodeling, Rho GTPases coordinate a wide range of biological processes such as cell adhesion, motility, and polarity. In the last years, Rho GTPases have also been recognized to control intracellular membrane sorting and trafficking steps directly; however, how Rho GTPase signaling is regulated at endomembranes is still poorly understood. In this review, we will specifically address the local Rho GTPase pools coordinating intracellular membrane trafficking with a focus on the endo- and exocytic pathways. We will further highlight the spatiotemporal molecular regulation of Rho signaling at endomembrane sites through Rho regulatory proteins, the GEFs and GAPs. Finally, we will discuss the contribution of dysregulated Rho signaling emanating from endomembranes to the development and progression of cancer.
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Kjøller, Lars, i Alan Hall. "Signaling to Rho GTPases". Experimental Cell Research 253, nr 1 (listopad 1999): 166–79. http://dx.doi.org/10.1006/excr.1999.4674.
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Voena i Chiarle. "RHO Family GTPases in the Biology of Lymphoma". Cells 8, nr 7 (26.06.2019): 646. http://dx.doi.org/10.3390/cells8070646.
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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.
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Fritz, Rafael Dominik, i Olivier Pertz. "The dynamics of spatio-temporal Rho GTPase signaling: formation of signaling patterns". F1000Research 5 (26.04.2016): 749. http://dx.doi.org/10.12688/f1000research.7370.1.
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Rho GTPases are crucial signaling molecules that regulate a plethora of biological functions. Traditional biochemical, cell biological, and genetic approaches have founded the basis of Rho GTPase biology. The development of biosensors then allowed measuring Rho GTPase activity with unprecedented spatio-temporal resolution. This revealed that Rho GTPase activity fluctuates on time and length scales of tens of seconds and micrometers, respectively. In this review, we describe Rho GTPase activity patterns observed in different cell systems. We then discuss the growing body of evidence that upstream regulators such as guanine nucleotide exchange factors and GTPase-activating proteins shape these patterns by precisely controlling the spatio-temporal flux of Rho GTPase activity. Finally, we comment on additional mechanisms that might feed into the regulation of these signaling patterns and on novel technologies required to dissect this spatio-temporal complexity.
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Zubor, Pavol, Zuzana Dankova, Zuzana Kolkova, Veronika Holubekova, Dusan Brany, Sandra Mersakova, Marek Samec i in. "Rho GTPases in Gynecologic Cancers: In-Depth Analysis toward the Paradigm Change from Reactive to Predictive, Preventive, and Personalized Medical Approach Benefiting the Patient and Healthcare". Cancers 12, nr 5 (20.05.2020): 1292. http://dx.doi.org/10.3390/cancers12051292.
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Rho guanosine triphospatases (GTPases) resemble a conserved family of GTP-binding proteins regulating actin cytoskeleton dynamics and several signaling pathways central for the cell. Rho GTPases create a so-called Ras-superfamily of GTPases subdivided into subgroups comprising at least 20 members. Rho GTPases play a key regulatory role in gene expression, cell cycle control and proliferation, epithelial cell polarity, cell migration, survival, and apoptosis, among others. They also have tissue-related functions including angiogenesis being involved in inflammatory and wound healing processes. Contextually, any abnormality in the Rho GTPase function may result in severe consequences at molecular, cellular, and tissue levels. Rho GTPases also play a key role in tumorigenesis and metastatic disease. Corresponding mechanisms include a number of targets such as kinases and scaffold/adaptor-like proteins initiating GTPases-related signaling cascades. The accumulated evidence demonstrates the oncogenic relevance of Rho GTPases for several solid malignancies including breast, liver, bladder, melanoma, testicular, lung, central nervous system (CNS), head and neck, cervical, and ovarian cancers. Furthermore, Rho GTPases play a crucial role in the development of radio- and chemoresistance e.g. under cisplatin-based cancer treatment. This article provides an in-depth overview on the role of Rho GTPases in gynecological cancers, highlights relevant signaling pathways and pathomechanisms, and sheds light on their involvement in tumor progression, metastatic spread, and radio/chemo resistance. In addition, insights into a spectrum of novel biomarkers and innovative approaches based on the paradigm shift from reactive to predictive, preventive, and personalized medicine are provided.
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Barlow, Haley Rose, i Ondine Cleaver. "Building Blood Vessels—One Rho GTPase at a Time". Cells 8, nr 6 (6.06.2019): 545. http://dx.doi.org/10.3390/cells8060545.
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Blood vessels are required for the survival of any organism larger than the oxygen diffusion limit. Blood vessel formation is a tightly regulated event and vessel growth or changes in permeability are linked to a number of diseases. Elucidating the cell biology of endothelial cells (ECs), which are the building blocks of blood vessels, is thus critical to our understanding of vascular biology and to the development of vascular-targeted disease treatments. Small GTPases of the Rho GTPase family are known to regulate several processes critical for EC growth and maintenance. In fact, many of the 21 Rho GTPases in mammals are known to regulate EC junctional remodeling, cell shape changes, and other processes. Rho GTPases are thus an attractive target for disease treatments, as they often have unique functions in specific vascular cell types. In fact, some Rho GTPases are even expressed with relative specificity in diseased vessels. Interestingly, many Rho GTPases are understudied in ECs, despite their known expression in either developing or mature vessels, suggesting an even greater wealth of knowledge yet to be gleaned from these complex signaling pathways. This review aims to provide an overview of Rho GTPase signaling contributions to EC vasculogenesis, angiogenesis, and mature vessel barrier function. A particular emphasis is placed on so-called “alternative” Rho GTPases, as they are largely understudied despite their likely important contributions to EC biology.
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Zhang, Zheng, Ming Liu i Yi Zheng. "Role of Rho GTPases in stem cell regulation". Biochemical Society Transactions 49, nr 6 (2.12.2021): 2941–55. http://dx.doi.org/10.1042/bst20211071.
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The future of regenerative medicine relies on our understanding of stem cells which are essential for tissue/organ generation and regeneration to maintain and/or restore tissue homeostasis. Rho family GTPases are known regulators of a wide variety of cellular processes related to cytoskeletal dynamics, polarity and gene transcription. In the last decade, major new advances have been made in understanding the regulatory role and mechanism of Rho GTPases in self-renewal, differentiation, migration, and lineage specification in tissue-specific signaling mechanisms in various stem cell types to regulate embryonic development, adult tissue homeostasis, and tissue regeneration upon stress or damage. Importantly, implication of Rho GTPases and their upstream regulators or downstream effectors in the transformation, migration, invasion and tumorigenesis of diverse cancer stem cells highlights the potential of Rho GTPase targeting in cancer therapy. In this review, we discuss recent evidence of Rho GTPase signaling in the regulation of embryonic stem cells, multiple somatic stem cells, and cancer stem cells. We propose promising areas where Rho GTPase pathways may serve as useful targets for stem cell manipulation and related future therapies.
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Guo, Daji, Xiaoman Yang i Lei Shi. "Rho GTPase Regulators and Effectors in Autism Spectrum Disorders: Animal Models and Insights for Therapeutics". Cells 9, nr 4 (31.03.2020): 835. http://dx.doi.org/10.3390/cells9040835.
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The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. Recent evidence suggests that dysfunction of Rho GTPase signaling contributes substantially to the pathogenesis of autism spectrum disorder (ASD). It has been found that 20 genes encoding Rho GTPase regulators and effectors are listed as ASD risk genes by Simons foundation autism research initiative (SFARI). This review summarizes the clinical evidence, protein structure, and protein expression pattern of these 20 genes. Moreover, ASD-related behavioral phenotypes in animal models of these genes are reviewed, and the therapeutic approaches that show successful treatment effects in these animal models are discussed.
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Dandamudi, Akhila, Huzoor Akbar, Jose Cancelas i Yi Zheng. "Rho GTPase Signaling in Platelet Regulation and Implication for Antiplatelet Therapies". International Journal of Molecular Sciences 24, nr 3 (28.01.2023): 2519. http://dx.doi.org/10.3390/ijms24032519.
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Platelets play a vital role in regulating hemostasis and thrombosis. Rho GTPases are well known as molecular switches that control various cellular functions via a balanced GTP-binding/GTP-hydrolysis cycle and signaling cascade through downstream effectors. In platelets, Rho GTPases function as critical regulators by mediating signal transduction that drives platelet activation and aggregation. Mostly by gene targeting and pharmacological inhibition approaches, Rho GTPase family members RhoA, Rac1, and Cdc42 have been shown to be indispensable in regulating the actin cytoskeleton dynamics in platelets, affecting platelet shape change, spreading, secretion, and aggregation, leading to thrombus formation. Additionally, studies of Rho GTPase function using platelets as a non-transformed model due to their anucleated nature have revealed valuable information on cell signaling principles. This review provides an updated summary of recent advances in Rho GTPase signaling in platelet regulation. We also highlight pharmacological approaches that effectively inhibited platelet activation to explore their possible development into future antiplatelet therapies.
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Bai, Yanyang, Xiaoliang Xiang, Chunmei Liang i Lei Shi. "Regulating Rac in the Nervous System: Molecular Function and Disease Implication of Rac GEFs and GAPs". BioMed Research International 2015 (2015): 1–17. http://dx.doi.org/10.1155/2015/632450.
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Rho family GTPases, including RhoA, Rac1, and Cdc42 as the most studied members, are master regulators of actin cytoskeletal organization. Rho GTPases control various aspects of the nervous system and are associated with a number of neuropsychiatric and neurodegenerative diseases. The activity of Rho GTPases is controlled by two families of regulators, guanine nucleotide exchange factors (GEFs) as the activators and GTPase-activating proteins (GAPs) as the inhibitors. Through coordinated regulation by GEFs and GAPs, Rho GTPases act as converging signaling molecules that convey different upstream signals in the nervous system. So far, more than 70 members of either GEFs or GAPs of Rho GTPases have been identified in mammals, but only a small subset of them have well-known functions. Thus, characterization of important GEFs and GAPs in the nervous system is crucial for the understanding of spatiotemporal dynamics of Rho GTPase activity in different neuronal functions. In this review, we summarize the current understanding of GEFs and GAPs for Rac1, with emphasis on the molecular function and disease implication of these regulators in the nervous system.
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Herbrand, Ulrike, i Mohammad Reza Ahmadian. "p190-RhoGAP as an integral component of the Tiam1/Rac1-induced downregulation of Rho". Biological Chemistry 387, nr 3 (1.03.2006): 311–17. http://dx.doi.org/10.1515/bc.2006.041.
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Abstract The Rho family of small GTPases plays a central role in intracellular signal transduction, particularly in reorganization of the actin cytoskeleton. Rho activity induces cell contractility, whereas Rac promotes cellular protrusion, which counteracts Rho signaling. In this regard, the reciprocal balance between these GTPases determines cell morphology and migratory behavior. Here we demonstrate that Tiam1/Rac1 signaling is able to antagonize Rho activity directly at the GTPase level in COS-7 cells. p190-RhoGAP plays a central regulatory role in this signaling pathway. Interfering with its activation by Src-kinase-dependent tyrosine phosphorylation or its recruitment to the membrane through interaction with the SH2 domains of p120-RasGAP blocks the Tiam1-mediated rapid downregulation of Rho. This process is mediated by Rac1, but not by Rac2 or Rac3 isoforms. Our data provide evidence for a biochemical pathway of the reciprocal regulation of two related small GTPases, which are key elements in cell migration.
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Van Aelst, L., i C. D'Souza-Schorey. "Rho GTPases and signaling networks". Genes & Development 11, nr 18 (15.09.1997): 2295–322. http://dx.doi.org/10.1101/gad.11.18.2295.
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Saliani, Mahsa, Amin Mirzaiebadizi, Niloufar Mosaddeghzadeh i Mohammad Reza Ahmadian. "RHO GTPase-Related Long Noncoding RNAs in Human Cancers". Cancers 13, nr 21 (27.10.2021): 5386. http://dx.doi.org/10.3390/cancers13215386.
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RHO GTPases are critical signal transducers that regulate cell adhesion, polarity, and migration through multiple signaling pathways. While all these cellular processes are crucial for the maintenance of normal cell homeostasis, disturbances in RHO GTPase-associated signaling pathways contribute to different human diseases, including many malignancies. Several members of the RHO GTPase family are frequently upregulated in human tumors. Abnormal gene regulation confirms the pivotal role of lncRNAs as critical gene regulators, and thus, they could potentially act as oncogenes or tumor suppressors. lncRNAs most likely act as sponges for miRNAs, which are known to be dysregulated in various cancers. In this regard, the significant role of miRNAs targeting RHO GTPases supports the view that the aberrant expression of lncRNAs may reciprocally change the intensity of RHO GTPase-associated signaling pathways. In this review article, we summarize recent advances in lncRNA research, with a specific focus on their sponge effects on RHO GTPase-targeting miRNAs to crucially mediate gene expression in different cancer cell types and tissues. We will focus in particular on five members of the RHO GTPase family, including RHOA, RHOB, RHOC, RAC1, and CDC42, to illustrate the role of lncRNAs in cancer progression. A deeper understanding of the widespread dysregulation of lncRNAs is of fundamental importance for confirmation of their contribution to RHO GTPase-dependent carcinogenesis.
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Navarro-Lérida, Inmaculada, Miguel Sánchez-Álvarez i Miguel Ángel del Pozo. "Post-Translational Modification and Subcellular Compartmentalization: Emerging Concepts on the Regulation and Physiopathological Relevance of RhoGTPases". Cells 10, nr 8 (5.08.2021): 1990. http://dx.doi.org/10.3390/cells10081990.
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Cells and tissues are continuously exposed to both chemical and physical stimuli and dynamically adapt and respond to this variety of external cues to ensure cellular homeostasis, regulated development and tissue-specific differentiation. Alterations of these pathways promote disease progression—a prominent example being cancer. Rho GTPases are key regulators of the remodeling of cytoskeleton and cell membranes and their coordination and integration with different biological processes, including cell polarization and motility, as well as other signaling networks such as growth signaling and proliferation. Apart from the control of GTP–GDP cycling, Rho GTPase activity is spatially and temporally regulated by post-translation modifications (PTMs) and their assembly onto specific protein complexes, which determine their controlled activity at distinct cellular compartments. Although Rho GTPases were traditionally conceived as targeted from the cytosol to the plasma membrane to exert their activity, recent research demonstrates that active pools of different Rho GTPases also localize to endomembranes and the nucleus. In this review, we discuss how PTM-driven modulation of Rho GTPases provides a versatile mechanism for their compartmentalization and functional regulation. Understanding how the subcellular sorting of active small GTPase pools occurs and what its functional significance is could reveal novel therapeutic opportunities.
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Delaguillaumie, Alix, Cécile Lagaudrière-Gesbert, Michel R. Popoff i Hélène Conjeaud. "Rho GTPases link cytoskeletal rearrangements and activation processes induced via the tetraspanin CD82 in T lymphocytes". Journal of Cell Science 115, nr 2 (15.01.2002): 433–43. http://dx.doi.org/10.1242/jcs.115.2.433.
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Activation of T lymphocytes requires the engagement of the T-cell receptor and costimulation molecules through cell-to-cell contacts. The tetraspanin CD82 has previously been shown to act as a cytoskeleton-dependent costimulation molecule. We show here that CD82 engagement leads to the tyrosine phosphorylation and association of both the Rho GTPases guanosine exchange factor Vav1 and adapter protein SLP76, suggesting that Rho GTPases participate in CD82 signaling. Indeed, broad inactivation of all Rho GTPases, or a specific blockade of RhoA, Rac1 or Cdc42, inhibited the morphological changes linked to CD82 engagement but failed to modulate the inducible association of CD82 with the actin network. Rho GTPase inactivation, as well as actin depolymerization, reduced the ability of CD82 to phosphorylate Vav and SLP76 and to potentiate the phosphorylation of two early TcR signaling intermediates: the tyrosine kinases ZAP70 and membrane adapter LAT. Taken together, this suggests that an amplification loop, via early Vav and SLP76 phosphorylations and Rho-GTPases activation, is initiated by CD82 association with the cytoskeleton, which permits cytoskeletal rearrangements and costimulatory activity. Moreover, the involvement of CD82 in the formation of the immunological synapse is strongly suggested by its accumulation at the site of TcR engagement. This novel link between a tetraspanin and the Rho GTPase cascade could explain why tetraspanins, which are known to form heterocomplexes, are involved in cell activation, adhesion, growth and metastasis.
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Aslan, Joseph E., Sandra M. Baker, Cassandra P. Loren, Kristina M. Haley, Asako Itakura, Jiaqing Pang, Daniel L. Greenberg i in. "The PAK system links Rho GTPase signaling to thrombin-mediated platelet activation". American Journal of Physiology-Cell Physiology 305, nr 5 (1.09.2013): C519—C528. http://dx.doi.org/10.1152/ajpcell.00418.2012.
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Regulation of the platelet actin cytoskeleton by the Rho family of small GTPases is essential for the proper maintenance of hemostasis. However, little is known about how intracellular platelet activation from Rho GTPase family members, including Rac, Cdc42, and Rho, translate into changes in platelet actin structures. To better understand how Rho family GTPases coordinate platelet activation, we identified platelet proteins associated with Rac1, a Rho GTPase family member, and actin regulatory protein essential for platelet hemostatic function. Mass spectrometry analysis revealed that upon platelet activation with thrombin, Rac1 associates with a set of effectors of the p21-activated kinases (PAKs), including GIT1, βPIX, and guanine nucleotide exchange factor GEFH1. Platelet activation by thrombin triggered the PAK-dependent phosphorylation of GIT1, GEFH1, and other PAK effectors, including LIMK1 and Merlin. PAK was also required for the thrombin-mediated activation of the MEK/ERK pathway, Akt, calcium signaling, and phosphatidylserine (PS) exposure. Inhibition of PAK signaling prevented thrombin-induced platelet aggregation and blocked platelet focal adhesion and lamellipodia formation in response to thrombin. Together, these results demonstrate that the PAK signaling system is a key orchestrator of platelet actin dynamics, linking Rho GTPase activation downstream of thrombin stimulation to PAK effector function, MAP kinase activation, calcium signaling, and PS exposure in platelets.
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Dipankar, Pankaj, Puneet Kumar, Shiba Prasad Dash i Pranita P. Sarangi. "Functional and Therapeutic Relevance of Rho GTPases in Innate Immune Cell Migration and Function during Inflammation: An In Silico Perspective". Mediators of Inflammation 2021 (13.02.2021): 1–10. http://dx.doi.org/10.1155/2021/6655412.
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Systematic regulation of leukocyte migration to the site of infection is a vital step during immunological responses. Improper migration and localization of immune cells could be associated with disease pathology as seen in systemic inflammation. Rho GTPases act as molecular switches during inflammatory cell migration by cycling between Rho-GDP (inactive) to Rho-GTP (active) forms and play an essential role in the precise regulation of actin cytoskeletal dynamics as well as other immunological functions of leukocytes. Available reports suggest that the dysregulation of Rho GTPase signaling is associated with various inflammatory diseases ranging from mild to life-threatening conditions. Therefore, it is crucial to understand the step-by-step activation and inactivation of GTPases and the functioning of different Guanine Nucleotide Exchange Factors (GEFs) and GTPase-Activating Proteins (GAPs) that regulate the conversion of GDP to GTP and GTP to GDP exchange reactions, respectively. Here, we describe the molecular organization and activation of various domains of crucial elements associated with the activation of Rho GTPases using solved PDB structures. We will also present the latest evidence available on the relevance of Rho GTPases in the migration and function of innate immune cells during inflammation. This knowledge will help scientists design promising drug candidates against the Rho-GTPase-centric regulatory molecules regulating inflammatory cell migration.
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Jung, Haiyoung, Suk Ran Yoon, Jeewon Lim, Hee Jun Cho i Hee Gu Lee. "Dysregulation of Rho GTPases in Human Cancers". Cancers 12, nr 5 (7.05.2020): 1179. http://dx.doi.org/10.3390/cancers12051179.
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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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Mosaddeghzadeh, Niloufar, Kazem Nouri, Oliver H. F. Krumbach, Ehsan Amin, Radovan Dvorsky i Mohammad R. Ahmadian. "Selectivity Determinants of RHO GTPase Binding to IQGAPs". International Journal of Molecular Sciences 22, nr 22 (22.11.2021): 12596. http://dx.doi.org/10.3390/ijms222212596.
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IQ motif-containing GTPase-activating proteins (IQGAPs) modulate a wide range of cellular processes by acting as scaffolds and driving protein components into distinct signaling networks. Their functional states have been proposed to be controlled by members of the RHO family of GTPases, among other regulators. In this study, we show that IQGAP1 and IQGAP2 can associate with CDC42 and RAC1-like proteins but not with RIF, RHOD, or RHO-like proteins, including RHOA. This seems to be based on the distribution of charged surface residues, which varies significantly among RHO GTPases despite their high sequence homology. Although effector proteins bind first to the highly flexible switch regions of RHO GTPases, additional contacts outside are required for effector activation. Sequence alignment and structural, mutational, and competitive biochemical analyses revealed that RHO GTPases possess paralog-specific residues outside the two highly conserved switch regions that essentially determine the selectivity of RHO GTPase binding to IQGAPs. Amino acid substitution of these specific residues in RHOA to the corresponding residues in RAC1 resulted in RHOA association with IQGAP1. Thus, electrostatics most likely plays a decisive role in these interactions.
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Schlessinger, K., A. Hall i N. Tolwinski. "Wnt signaling pathways meet Rho GTPases". Genes & Development 23, nr 3 (1.02.2009): 265–77. http://dx.doi.org/10.1101/gad.1760809.
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Schmitz, Arndt A. P., Eve-Ellen Govek, Benjamin Böttner i Linda Van Aelst. "Rho GTPases: Signaling, Migration, and Invasion". Experimental Cell Research 261, nr 1 (listopad 2000): 1–12. http://dx.doi.org/10.1006/excr.2000.5049.
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Arrazola Sastre, Alazne, Miriam Luque Montoro, Patricia Gálvez-Martín, Hadriano M. Lacerda, Alejandro Lucia, Francisco Llavero i José Luis Zugaza. "Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases". International Journal of Molecular Sciences 21, nr 17 (31.08.2020): 6312. http://dx.doi.org/10.3390/ijms21176312.
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Small guanosine triphosphatases (GTPases) of the Ras superfamily are key regulators of many key cellular events such as proliferation, differentiation, cell cycle regulation, migration, or apoptosis. To control these biological responses, GTPases activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in some small GTPases also guanine nucleotide dissociation inhibitors (GDIs). Moreover, small GTPases transduce signals by their downstream effector molecules. Many studies demonstrate that small GTPases of the Ras family are involved in neurodegeneration processes. Here, in this review, we focus on the signaling pathways controlled by these small protein superfamilies that culminate in neurodegenerative pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Specifically, we concentrate on the two most studied families of the Ras superfamily: the Ras and Rho families. We summarize the latest findings of small GTPases of the Ras and Rho families in neurodegeneration in order to highlight these small proteins as potential therapeutic targets capable of slowing down different neurodegenerative diseases.
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Dahmene, Manel, Laura Quirion i Mélanie Laurin. "High Throughput strategies Aimed at Closing the GAP in Our Knowledge of Rho GTPase Signaling". Cells 9, nr 6 (9.06.2020): 1430. http://dx.doi.org/10.3390/cells9061430.
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Since their discovery, Rho GTPases have emerged as key regulators of cytoskeletal dynamics. In humans, there are 20 Rho GTPases and more than 150 regulators that belong to the RhoGEF, RhoGAP, and RhoGDI families. Throughout development, Rho GTPases choregraph a plethora of cellular processes essential for cellular migration, cell–cell junctions, and cell polarity assembly. Rho GTPases are also significant mediators of cancer cell invasion. Nevertheless, to date only a few molecules from these intricate signaling networks have been studied in depth, which has prevented appreciation for the full scope of Rho GTPases’ biological functions. Given the large complexity involved, system level studies are required to fully grasp the extent of their biological roles and regulation. Recently, several groups have tackled this challenge by using proteomic approaches to map the full repertoire of Rho GTPases and Rho regulators protein interactions. These studies have provided in-depth understanding of Rho regulators specificity and have contributed to expand Rho GTPases’ effector portfolio. Additionally, new roles for understudied family members were unraveled using high throughput screening strategies using cell culture models and mouse embryos. In this review, we highlight theses latest large-scale efforts, and we discuss the emerging opportunities that may lead to the next wave of discoveries.
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Simon, Cory M., Emily M. Vaughan, William M. Bement i Leah Edelstein-Keshet. "Pattern formation of Rho GTPases in single cell wound healing". Molecular Biology of the Cell 24, nr 3 (luty 2013): 421–32. http://dx.doi.org/10.1091/mbc.e12-08-0634.
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The Rho GTPases—Rho, Rac, and Cdc42—control an enormous variety of processes, many of which reflect activation of these GTPases in spatially confined and mutually exclusive zones. By using mathematical models and experimental results to establish model parameters, we analyze the formation and segregation of Rho and Cdc42 zones during Xenopus oocyte wound repair and the role played by Abr, a dual guanine nucleotide exchange factor–GTPase-activating protein, in this process. The Rho and Cdc42 zones are found to be best represented as manifestations of spatially modulated bistability, and local positive feedback between Abr and Rho can account for the maintenance and dynamic properties of the Rho zone. In contrast, the invocation of an Abr-independent positive feedback loop is required to account for Cdc42 spatial bistability. In addition, the model replicates the results of previous in vivo experiments in which Abr activity is manipulated. Further, simulating the model with two closely spaced wounds made nonintuitive predictions about the Rho and Cdc42 patterns; these predictions were confirmed by experiment. We conclude that the model is a useful tool for analysis of Rho GTPase signaling and that the Rho GTPases can be fruitfully considered as components of intracellular pattern formation systems.
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DerMardirossian, Céline, Gabriel Rocklin, Ji-Yeon Seo i Gary M. Bokoch. "Phosphorylation of RhoGDI by Src Regulates Rho GTPase Binding and Cytosol-Membrane Cycling". Molecular Biology of the Cell 17, nr 11 (listopad 2006): 4760–68. http://dx.doi.org/10.1091/mbc.e06-06-0533.
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Rho GTPases (Rac, Rho, and Cdc42) play important roles in regulating cell function through their ability to coordinate the actin cytoskeleton, modulate the formation of signaling reactive oxidant species, and control gene transcription. Activation of Rho GTPase signaling pathways requires the regulated release of Rho GTPases from RhoGDI complexes, followed by their reuptake after membrane cycling. We show here that Src kinase binds and phosphorylates RhoGDI both in vitro and in vivo at Tyr156. Analysis of Rho GTPase–RhoGDI complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that Src-mediated phosphorylation of Tyr156 causes a dramatic decrease in the ability of RhoGDI to form a complex with RhoA, Rac1, or Cdc42. Phosphomimetic mutation of Tyr156→Glu results in the constitutive association of RhoGDIY156E with the plasma membrane and/or associated cortical actin. Substantial cortical localization of tyrosine-phosphorylated RhoGDI is also observed in fibroblasts expressing active Src, where it is most evident in podosomes and regions of membrane ruffling. Expression of membrane-localized RhoGDIY156E mutant is associated with enhanced cell spreading and membrane ruffling. These results suggest that Src-mediated RhoGDI phosphorylation is a novel physiological mechanism for regulating Rho GTPase cytosol membrane–cycling and activity.
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Herrmann, Andrea, Britta A. M. Tillmann, Janine Schürmann, Michael Bölker i Paul Tudzynski. "Small-GTPase-Associated Signaling by the Guanine Nucleotide Exchange Factors CpDock180 and CpCdc24, the GTPase Effector CpSte20, and the Scaffold Protein CpBem1 in Claviceps purpurea". Eukaryotic Cell 13, nr 4 (31.01.2014): 470–82. http://dx.doi.org/10.1128/ec.00332-13.
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ABSTRACTMonomeric GTPases of the Rho subfamily are important mediators of polar growth and NADPH (Nox) signaling in a variety of organisms. These pathways influence the ability ofClaviceps purpureato infect host plants. GTPase regulators contribute to the nucleotide loading cycle that is essential for proper functionality of the GTPases. Scaffold proteins gather GTPase complexes to facilitate proper function. The guanine nucleotide exchange factors (GEFs) CpCdc24 and CpDock180 activate GTPase signaling by triggering nucleotide exchange of the GTPases. Here we show that CpCdc24 harbors nucleotide exchange activity for both Rac and Cdc42 homologues. The GEFs partly share the cellular distribution of the GTPases and interact with the putative upstream GTPase CpRas1. Interaction studies show the formation of higher-order protein complexes, mediated by the scaffold protein CpBem1. Besides the GTPases and GEFs, these complexes also contain the GTPase effectors CpSte20 and CpCla4, as well as the regulatory protein CpNoxR. Functional characterizations suggest a role of CpCdc24 mainly in polarity, whereas CpDock180 is involved in stress tolerance mechanisms. These findings indicate the dynamic formation of small GTPase complexes and improve the model for GTPase-associated signaling inC. purpurea.
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Li, Xiaoyu, Xia Bu, Binfeng Lu, Hava Avraham, Richard A. Flavell i Bing Lim. "The Hematopoiesis-Specific GTP-Binding Protein RhoH Is GTPase Deficient and Modulates Activities of Other Rho GTPases by an Inhibitory Function". Molecular and Cellular Biology 22, nr 4 (15.02.2002): 1158–71. http://dx.doi.org/10.1128/mcb.22.4.1158-1171.2002.
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ABSTRACT The Rho subfamily of small GTP-binding proteins mediates many fundamental cellular functions. The commonly studied members (Rho, Rac, and CDC42) regulate actin reorganization, affecting diverse cellular responses, including adhesion, cytokinesis, and motility. Another major function of the Rho GTPases is their role in regulating transcriptional factors and nuclear signaling. RhoH is encoded by a hematopoiesis-specific Rho-related gene recently identified in a fusion transcript with bcl6 in lymphoma cell lines. Significantly, translocations and a high frequency of RhoH mutation have been detected in primary lymphoma cells. We show here that RhoH functions differently from other Rho GTPases. RhoH exerts no significant effect on actin reorganization. However, RhoH is a potent inhibitor of the activation of NFκB and p38 by other Rho GTPases. This property, together with the differential expression of RhoH in the Th1 subset of T cells, suggests a role for RhoH in the functional differentiation of T cells. RhoH has different amino acids in two highly conserved residues critical for GTPase activity. Consequently, RhoH is GTPase deficient, remaining in a GTP-bound activated state without cycling. Reduction of RhoH levels in T cells augments the response to Rac activation. Furthermore, RhoH is dramatically down regulated after phorbol myristate acetate treatment and in Th1 cells after activation by anti-CD3. Hence, a mechanism for regulation of RhoH function is likely to exist at the transcriptional level. The inhibitory function of RhoH supports a model in which Rho GTPases with opposing functions may compete to modulate the final outcome of a particular GTPase-activated pathway.
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Platre, Matthieu Pierre, Vincent Bayle, Laia Armengot, Joseph Bareille, Maria del Mar Marquès-Bueno, Audrey Creff, Lilly Maneta-Peyret i in. "Developmental control of plant Rho GTPase nano-organization by the lipid phosphatidylserine". Science 364, nr 6435 (4.04.2019): 57–62. http://dx.doi.org/10.1126/science.aav9959.
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Rho guanosine triphosphatases (GTPases) are master regulators of cell signaling, but how they are regulated depending on the cellular context is unclear. We found that the phospholipid phosphatidylserine acts as a developmentally controlled lipid rheostat that tunes Rho GTPase signaling in Arabidopsis. Live superresolution single-molecule imaging revealed that the protein Rho of Plants 6 (ROP6) is stabilized by phosphatidylserine into plasma membrane nanodomains, which are required for auxin signaling. Our experiments also revealed that the plasma membrane phosphatidylserine content varies during plant root development and that the level of phosphatidylserine modulates the quantity of ROP6 nanoclusters induced by auxin and hence downstream signaling, including regulation of endocytosis and gravitropism. Our work shows that variations in phosphatidylserine levels are a physiological process that may be leveraged to regulate small GTPase signaling during development.
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Brakebusch, Cord. "Rho GTPase Signaling in Health and Disease: A Complex Signaling Network". Cells 10, nr 2 (16.02.2021): 401. http://dx.doi.org/10.3390/cells10020401.
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Lawson, Campbell D., i Anne J. Ridley. "Rho GTPase signaling complexes in cell migration and invasion". Journal of Cell Biology 217, nr 2 (12.12.2017): 447–57. http://dx.doi.org/10.1083/jcb.201612069.
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Cell migration is dependent on the dynamic formation and disassembly of actin filament–based structures, including lamellipodia, filopodia, invadopodia, and membrane blebs, as well as on cell–cell and cell–extracellular matrix adhesions. These processes all involve Rho family small guanosine triphosphatases (GTPases), which are regulated by the opposing actions of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPase activity needs to be precisely tuned at distinct cellular locations to enable cells to move in response to different environments and stimuli. In this review, we focus on the ability of RhoGEFs and RhoGAPs to form complexes with diverse binding partners, and describe how this influences their ability to control localized GTPase activity in the context of migration and invasion.
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Reyes, Steve B., Anjana S. Narayanan, Hye Shin Lee, Jeremy H. Tchaicha, Kenneth D. Aldape, Frederick F. Lang, Kimberly F. Tolias i Joseph H. McCarty. "αvβ8 integrin interacts with RhoGDI1 to regulate Rac1 and Cdc42 activation and drive glioblastoma cell invasion". Molecular Biology of the Cell 24, nr 4 (15.02.2013): 474–82. http://dx.doi.org/10.1091/mbc.e12-07-0521.
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The malignant brain cancer glioblastoma multiforme (GBM) displays invasive growth behaviors that are regulated by extracellular cues within the neural microenvironment. The adhesion and signaling pathways that drive GBM cell invasion remain largely uncharacterized. Here we use human GBM cell lines, primary patient samples, and preclinical mouse models to demonstrate that integrin αvβ8 is a major driver of GBM cell invasion. β8 integrin is overexpressed in many human GBM cells, with higher integrin expression correlating with increased invasion and diminished patient survival. Silencing β8 integrin in human GBM cells leads to impaired tumor cell invasion due to hyperactivation of the Rho GTPases Rac1 and Cdc42. β8 integrin coimmunoprecipitates with Rho-GDP dissociation inhibitor 1 (RhoGDI1), an intracellular signaling effector that sequesters Rho GTPases in their inactive GDP-bound states. Silencing RhoGDI1 expression or uncoupling αvβ8 integrin–RhoGDI1 protein interactions blocks GBM cell invasion due to Rho GTPase hyperactivation. These data reveal for the first time that αvβ8 integrin, via interactions with RhoGDI1, regulates activation of Rho proteins to promote GBM cell invasiveness. Hence targeting the αvβ8 integrin–RhoGDI1 signaling axis might be an effective strategy for blocking GBM cell invasion.
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Annan, Robert B., Cunle Wu, Daniel D. Waller, Malcolm Whiteway i David Y. Thomas. "Rho5p Is Involved in Mediating the Osmotic Stress Response in Saccharomyces cerevisiae, and Its Activity Is Regulated via Msi1p and Npr1p by Phosphorylation and Ubiquitination". Eukaryotic Cell 7, nr 9 (11.07.2008): 1441–49. http://dx.doi.org/10.1128/ec.00120-08.
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ABSTRACT Small GTPases of the Rho family act as molecular switches, and modulation of the GTP-bound state of Rho proteins is a well-characterized means of regulating their signaling activity in vivo. In contrast, the regulation of Rho-type GTPases by posttranslational modifications is poorly understood. Here, we present evidence of the control of the Saccharomyces cerevisiae Rho-type GTPase Rho5p by phosphorylation and ubiquitination. Rho5p binds to Ste50p, and the expression of the activated RHO5(Q91H) allele in an Δste50 strain is lethal under conditions of osmotic stress. An overexpression screen identified RGD2 and MSI1 as being high-copy suppressors of the osmotic sensitivity of this lethality. Rgd2p had been identified as being a possible Rho5p GTPase-activating protein based on an in vitro assay; this result supports its function as a regulator of Rho5p activity in vivo. MSI1 was previously identified as being a suppressor of hyperactive Ras/cyclic AMP signaling, where it antagonizes Npr1p kinase activity and promotes ubiquitination. Here, we show that Msi1p also acts via Npr1p to suppress activated Rho5p signaling. Rho5p is ubiquitinated, and its expression is lethal in a strain that is compromised for proteasome activity. These data identify Rho5p as being a target of Msi1p/Npr1p regulation and describe a regulatory circuit involving phosphorylation and ubiquitination.
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Zhang, Bo, Guohua Yang, Yu Chen, Yihong Zhao, Peng Gao, Bo Liu, Haiyang Wang i Zhi-Liang Zheng. "C-terminal domain (CTD) phosphatase links Rho GTPase signaling to Pol II CTD phosphorylation in Arabidopsis and yeast". Proceedings of the National Academy of Sciences 113, nr 50 (28.11.2016): E8197—E8206. http://dx.doi.org/10.1073/pnas.1605871113.
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Rho GTPases, including the Rho, Cdc42, Rac, and ROP subfamilies, act as pivotal signaling switches in various growth and developmental processes. Compared with the well-defined role of cytoskeletal organization in Rho signaling, much less is known regarding transcriptional regulation. In a mutant screen for phenotypic enhancers of transgenic Arabidopsis plants expressing a constitutively active form of ROP2 (designated CA1-1), we identified RNA polymerase II (Pol II) C-terminal domain (CTD) phosphatase-like 1 (CPL1) as a transcriptional regulator of ROP2 signaling. We show that ROP2 activation inhibits CPL1 activity by promoting its degradation, leading to an increase in CTD Ser5 and Ser2 phosphorylation. We also observed similar modulation of CTD phosphorylation by yeast Cdc42 GTPase and enhanced degradation of the yeast CTD phosphatase Fcp1 by activated ROP2 signaling. Taken together, our results suggest that modulation of the Pol II CTD code by Rho GTPase signaling represents an evolutionarily conserved mechanism in both unicellular and multicellular eukaryotes.
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Danley, D. E., T. H. Chuang i G. M. Bokoch. "Defective Rho GTPase regulation by IL-1 beta-converting enzyme-mediated cleavage of D4 GDP dissociation inhibitor." Journal of Immunology 157, nr 2 (15.07.1996): 500–503. http://dx.doi.org/10.4049/jimmunol.157.2.500.
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Abstract GTPases of the Rho family regulate many aspects of inflammatory cell activity, including motility, formation of toxic oxygen metabolites, and generation of proinflammatory cytokines. Defective regulation of such signaling pathways leads to a variety of acute and chronic inflammatory disorders, although the mechanisms by which this occurs have not been well defined. We describe in this work specific proteolytic cleavage of D4 GDI, a critical regulator of Rho GTPase activity in inflammatory leukocytes, by IL-1 beta-converting enzyme (ICE). Cleavage of D4 GDI by ICE occurs at Asp55, leading to the formation of the truncated D4 that is unable to effectively bind and regulate GTPases of the Rho family. Our data suggest that activation of ICE protease(s) at inflammatory sites leads to defective Rho GTPase regulation. Release of these critical regulatory proteins may contribute substantially to the inflammatory response at these sites, exacerbating and perpetuating the resulting tissue damage.
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Dautt-Castro, Mitzuko, Montserrat Rosendo-Vargas i Sergio Casas-Flores. "The Small GTPases in Fungal Signaling Conservation and Function". Cells 10, nr 5 (28.04.2021): 1039. http://dx.doi.org/10.3390/cells10051039.
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Monomeric GTPases, which belong to the Ras superfamily, are small proteins involved in many biological processes. They are fine-tuned regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Several families have been identified in organisms from different kingdoms. Overall, the most studied families are Ras, Rho, Rab, Ran, Arf, and Miro. Recently, a new family named Big Ras GTPases was reported. As a general rule, the proteins of all families have five characteristic motifs (G1–G5), and some specific features for each family have been described. Here, we present an exhaustive analysis of these small GTPase families in fungi, using 56 different genomes belonging to different phyla. For this purpose, we used distinct approaches such as phylogenetics and sequences analysis. The main functions described for monomeric GTPases in fungi include morphogenesis, secondary metabolism, vesicle trafficking, and virulence, which are discussed here. Their participation during fungus–plant interactions is reviewed as well.
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Zuo, Yan, Wonkyung Oh, Arzu Ulu i Jeffrey A. Frost. "Minireview: Mouse Models of Rho GTPase Function in Mammary Gland Development, Tumorigenesis, and Metastasis". Molecular Endocrinology 30, nr 3 (1.03.2016): 278–89. http://dx.doi.org/10.1210/me.2015-1294.
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Abstract Ras homolog (Rho) family small GTPases are critical regulators of actin cytoskeletal organization, cell motility, proliferation, and survival. Surprisingly, the large majority of the studies underlying our knowledge of Rho protein function have been carried out in cultured cells, and it is only recently that researchers have begun to assess Rho GTPase regulation and function in vivo. The purpose of this review is to evaluate our current knowledge of Rho GTPase function in mouse mammary gland development, tumorigenesis and metastasis. Although our knowledge is still incomplete, these studies are already uncovering important themes as to the physiological roles of Rho GTPase signaling in normal mammary gland development and function. Essential contributions of Rho proteins to breast cancer initiation, tumor progression, and metastatic dissemination have also been identified.
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Fusco, Ludovico, Riwal Lefort, Kevin Smith, Fethallah Benmansour, German Gonzalez, Caterina Barillari, Bernd Rinn, Francois Fleuret, Pascal Fua i Olivier Pertz. "Computer vision profiling of neurite outgrowth dynamics reveals spatiotemporal modularity of Rho GTPase signaling". Journal of Cell Biology 212, nr 1 (4.01.2016): 91–111. http://dx.doi.org/10.1083/jcb.201506018.
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Rho guanosine triphosphatases (GTPases) control the cytoskeletal dynamics that power neurite outgrowth. This process consists of dynamic neurite initiation, elongation, retraction, and branching cycles that are likely to be regulated by specific spatiotemporal signaling networks, which cannot be resolved with static, steady-state assays. We present NeuriteTracker, a computer-vision approach to automatically segment and track neuronal morphodynamics in time-lapse datasets. Feature extraction then quantifies dynamic neurite outgrowth phenotypes. We identify a set of stereotypic neurite outgrowth morphodynamic behaviors in a cultured neuronal cell system. Systematic RNA interference perturbation of a Rho GTPase interactome consisting of 219 proteins reveals a limited set of morphodynamic phenotypes. As proof of concept, we show that loss of function of two distinct RhoA-specific GTPase-activating proteins (GAPs) leads to opposite neurite outgrowth phenotypes. Imaging of RhoA activation dynamics indicates that both GAPs regulate different spatiotemporal Rho GTPase pools, with distinct functions. Our results provide a starting point to dissect spatiotemporal Rho GTPase signaling networks that regulate neurite outgrowth.
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Puetz, Sandra, Lubomir T. Lubomirov i Gabriele Pfitzer. "Regulation of Smooth Muscle Contraction by Small GTPases". Physiology 24, nr 6 (grudzień 2009): 342–56. http://dx.doi.org/10.1152/physiol.00023.2009.
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Next to changes in cytosolic [Ca2+], members of the Rho subfamily of small GTPases, in particular Rho and its effector Rho kinase, also known as ROK or ROCK, emerged as key regulators of smooth muscle function in health and disease. In this review, we will focus on the regulation of the contractile machinery by Rho/ROK signaling and its interaction with PKC and cyclic nucleotide signaling. We will briefly discuss the emerging evidence that remodeling of cortical actin is necessary for contraction.
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Essler, Markus, Stefan Linder, Barbara Schell, Katharina Hüfner, Agnès Wiedemann, Katharina Randhahn, James M. Staddon i Martin Aepfelbacher. "Cytotoxic Necrotizing Factor 1 of Escherichia coli Stimulates Rho/Rho-Kinase-Dependent Myosin Light-Chain Phosphorylation without Inactivating Myosin Light-Chain Phosphatase in Endothelial Cells". Infection and Immunity 71, nr 9 (wrzesień 2003): 5188–93. http://dx.doi.org/10.1128/iai.71.9.5188-5193.2003.
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ABSTRACT Cytotoxic necrotizing factor 1 (CNF-1) is an exotoxin of Escherichia coli that constitutively activates the GTPases Rho, Rac, and CDC42. Stimulation of Rho was shown to enhance myosin light-chain (MLC) phosphorylation via Rho kinase-mediated inhibition of MLC phosphatase in endothelial cells. Here we report that 3 h after CNF stimulation of endothelial cells, RhoA was activated and MLC phosphorylation was increased in a Rho/Rho-kinase-dependent manner, but no decrease in MLC phosphatase activity could be detected. Despite continuous RhoA activation, MLC phosphatase activity was doubled after 24 h of CNF stimulation, and this coincided with decreased MLC phosphorylation and cell spreading. Rac was also activated at 3 to 24 h but did not contribute to MLC phosphorylation, and its amount gradually decreased in the CNF-stimulated cells. CDC42Hs was not activated above control values by CNF. These results suggest that CNF can induce specific decoupling (Rho kinase from MLC phosphatase) and deactivation events in Rho GTPase signaling, potentially reflecting cellular protection mechanisms against permanently active Rho GTPases.
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Bokoch, Gary M., i Becky A. Diebold. "Current molecular models for NADPH oxidase regulation by Rac GTPase". Blood 100, nr 8 (15.10.2002): 2692–95. http://dx.doi.org/10.1182/blood-2002-04-1149.
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Reactive oxygen species (ROS) have been increasingly recognized as important components of cell signaling in addition to their well-established roles in host defense. The formation of ROS in phagocytic and nonphagocytic cells involves membrane-localized and Rac guanosine triphosphatase (GTPase)–regulated reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase(s). We discuss here the current molecular models for Rac GTPase action in the control of the phagocytic leukocyte NADPH oxidase. As a mechanistically detailed example of Rac GTPase signaling, the NADPH oxidase provides a potential paradigm for signaling by Rho family GTPases in general.
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Eroumé, K., A. Vasilevich, S. Vermeulen, J. de Boer i A. Carlier. "On the influence of cell shape on dynamic reaction-diffusion polarization patterns". PLOS ONE 16, nr 3 (18.03.2021): e0248293. http://dx.doi.org/10.1371/journal.pone.0248293.
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The distribution of signaling molecules following mechanical or chemical stimulation of a cell defines cell polarization, with regions of high active Cdc42 at the front and low active Cdc42 at the rear. As reaction-diffusion phenomena between signaling molecules, such as Rho GTPases, define the gradient dynamics, we hypothesize that the cell shape influences the maintenance of the “front-to-back” cell polarization patterns. We investigated the influence of cell shape on the Cdc42 patterns using an established computational polarization model. Our simulation results showed that not only cell shape but also Cdc42 and Rho-related (in)activation parameter values affected the distribution of active Cdc42. Despite an initial Cdc42 gradient, the in silico results showed that the maximal Cdc42 concentration shifts in the opposite direction, a phenomenon we propose to call “reverse polarization”. Additional in silico analyses indicated that “reverse polarization” only occurred in a particular parameter value space that resulted in a balance between inactivation and activation of Rho GTPases. Future work should focus on a mathematical description of the underpinnings of reverse polarization, in combination with experimental validation using, for example, dedicated FRET-probes to spatiotemporally track Rho GTPase patterns in migrating cells. In summary, the findings of this study enhance our understanding of the role of cell shape in intracellular signaling.
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Engelhardt, Stefan, Adriana Trutzenberg i Ralph Hückelhoven. "Regulation and Functions of ROP GTPases in Plant–Microbe Interactions". Cells 9, nr 9 (2.09.2020): 2016. http://dx.doi.org/10.3390/cells9092016.
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Rho proteins of plants (ROPs) form a specific clade of Rho GTPases, which are involved in either plant immunity or susceptibility to diseases. They are intensively studied in grass host plants, in which ROPs are signaling hubs downstream of both cell surface immune receptor kinases and intracellular nucleotide-binding leucine-rich repeat receptors, which activate major branches of plant immune signaling. Additionally, invasive fungal pathogens may co-opt the function of ROPs for manipulation of the cytoskeleton, cell invasion and host cell developmental reprogramming, which promote pathogenic colonization. Strikingly, mammalian bacterial pathogens also initiate both effector-triggered susceptibility for cell invasion and effector-triggered immunity via Rho GTPases. In this review, we summarize central concepts of Rho signaling in disease and immunity of plants and briefly compare them to important findings in the mammalian research field. We focus on Rho activation, downstream signaling and cellular reorganization under control of Rho proteins involved in disease progression and pathogen resistance.
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Clark, Edwin A., Warren G. King, Joan S. Brugge, Marc Symons i Richard O. Hynes. "Integrin-mediated Signals Regulated by Members of the Rho Family of GTPases". Journal of Cell Biology 142, nr 2 (27.07.1998): 573–86. http://dx.doi.org/10.1083/jcb.142.2.573.
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The organization of the actin cytoskeleton can be regulated by soluble factors that trigger signal transduction events involving the Rho family of GTPases. Since adhesive interactions are also capable of organizing the actin-based cytoskeleton, we examined the role of Cdc42-, Rac-, and Rho-dependent signaling pathways in regulating the cytoskeleton during integrin-mediated adhesion and cell spreading using dominant-inhibitory mutants of these GTPases. When Rat1 cells initially adhere to the extracellular matrix protein fibronectin, punctate focal complexes form at the cell periphery. Concomitant with focal complex formation, we observed some phosphorylation of the focal adhesion kinase (FAK) and Src, which occurred independently of Rho family GTPases. However, subsequent phosphorylation of FAK and paxillin occurs in a Rho-dependent manner. Moreover, we found Rho dependence of the assembly of large focal adhesions from which actin stress fibers radiate. Initial adhesion to fibronectin also stimulates membrane ruffling; we show that this ruffling is independent of Rho but is dependent on both Cdc42 and Rac. Furthermore, we observed that Cdc42 controls the integrin-dependent activation of extracellular signal–regulated kinase 2 and of Akt, a kinase whose activity has been demonstrated to be dependent on phosphatidylinositol (PI) 3-kinase. Since Rac-dependent membrane ruffling can be stimulated by PI 3-kinase, it appears that Cdc42, PI 3-kinase, and Rac lie on a distinct pathway that regulates adhesion-induced membrane ruffling. In contrast to the differential regulation of integrin-mediated signaling by Cdc42, Rac, and Rho, we observed that all three GTPases regulate cell spreading, an event that may indirectly control cellular architecture. Therefore, several separable signaling pathways regulated by different members of the Rho family of GTPases converge to control adhesion-dependent changes in the organization of the cytoskeleton, changes that regulate cell morphology and behavior.
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Boueid, Marie-José, Aya Mikdache, Emilie Lesport, Cindy Degerny i Marcel Tawk. "Rho GTPases Signaling in Zebrafish Development and Disease". Cells 9, nr 12 (8.12.2020): 2634. http://dx.doi.org/10.3390/cells9122634.
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Cells encounter countless external cues and the specificity of their responses is translated through a myriad of tightly regulated intracellular signals. For this, Rho GTPases play a central role and transduce signals that contribute to fundamental cell dynamic and survival events. Here, we review our knowledge on how zebrafish helped us understand the role of some of these proteins in a multitude of in vivo cellular behaviors. Zebrafish studies offer a unique opportunity to explore the role and more specifically the spatial and temporal dynamic of Rho GTPases activities within a complex environment at a level of details unachievable in any other vertebrate organism.
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Ueyama, Takehiko. "Rho-Family Small GTPases: From Highly Polarized Sensory Neurons to Cancer Cells". Cells 8, nr 2 (28.01.2019): 92. http://dx.doi.org/10.3390/cells8020092.
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The small GTPases of the Rho-family (Rho-family GTPases) have various physiological functions, including cytoskeletal regulation, cell polarity establishment, cell proliferation and motility, transcription, reactive oxygen species (ROS) production, and tumorigenesis. A relatively large number of downstream targets of Rho-family GTPases have been reported for in vitro studies. However, only a small number of signal pathways have been established at the in vivo level. Cumulative evidence for the functions of Rho-family GTPases has been reported for in vivo studies using genetically engineered mouse models. It was based on different cell- and tissue-specific conditional genes targeting mice. In this review, we introduce recent advances in in vivo studies, including human patient trials on Rho-family GTPases, focusing on highly polarized sensory organs, such as the cochlea, which is the primary hearing organ, host defenses involving reactive oxygen species (ROS) production, and tumorigenesis (especially associated with RAC, novel RAC1-GSPT1 signaling, RHOA, and RHOBTB2).
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Schwartz, Martin A., i Sanford J. Shattil. "Signaling networks linking integrins and Rho family GTPases". Trends in Biochemical Sciences 25, nr 8 (sierpień 2000): 388–91. http://dx.doi.org/10.1016/s0968-0004(00)01605-4.
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Hanna, Samer, i Mirvat El-Sibai. "Signaling networks of Rho GTPases in cell motility". Cellular Signalling 25, nr 10 (październik 2013): 1955–61. http://dx.doi.org/10.1016/j.cellsig.2013.04.009.
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El Baba, Nada, Mohammad Farran, Elie Abi Khalil, Leila Jaafar, Isabelle Fakhoury i Mirvat El-Sibai. "The Role of Rho GTPases in VEGF Signaling in Cancer Cells". Analytical Cellular Pathology 2020 (16.04.2020): 1–11. http://dx.doi.org/10.1155/2020/2097214.
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Vascular endothelial growth factors (VEGFs) consist of five molecules (VEGFA through D as well as placental growth factor) which are crucial for regulating key cellular and tissue functions. The role of VEGF and its intracellular signaling and downstream molecular pathways have been thoroughly studied. Activation of VEGF signal transduction can be initiated by the molecules’ binding to two classes of transmembrane receptors: (1) the VEGF tyrosine kinase receptors (VEGF receptors 1 through 3) and (2) the neuropilins (NRP1 and 2). The involvement of Rho GTPases in modulating VEGFA signaling in both cancer cells and endothelial cells has also been well established. Additionally, different isoforms of Rho GTPases, namely, RhoA, RhoC, and RhoG, have been shown to regulate VEGF expression as well as blood vessel formation. This review article will explore how Rho GTPases modulate VEGF signaling and the consequences of such interaction on cancer progression.