scholarly journals Post-Translational Modification and Subcellular Compartmentalization: Emerging Concepts on the Regulation and Physiopathological Relevance of RhoGTPases

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1990
Author(s):  
Inmaculada Navarro-Lérida ◽  
Miguel Sánchez-Álvarez ◽  
Miguel Ángel del Pozo
Keyword(s):  
Rho Gtpases ◽  
Rho Gtpase ◽  
Protein Complexes ◽  
Specific Protein ◽  
Cell Polarization ◽  
Small Gtpase ◽  
Post Translational Modification ◽  
Functional Regulation ◽  
Subcellular Compartmentalization ◽  
Cellular Compartments

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.

scholarly journals Ubiquitination of the scaffold protein IQGAP1 diminishes its interaction with and activation of the Rho GTPase CDC42

2020 ◽  
Vol 295 (15) ◽  
pp. 4822-4835 ◽  
Author(s):  
Laëtitia Gorisse ◽  
Zhigang Li ◽  
Craig D. Wagner ◽  
David K. Worthylake ◽  
Francesca Zappacosta ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Rho Gtpase ◽  
Scaffold Protein ◽  
Small Gtpase ◽  
Hek293 Cells ◽  
Post Translational Modification ◽  
Iq Motif ◽  
Lysine Residues ◽  
Self Association

IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a scaffold protein that interacts with numerous binding partners and thereby regulates fundamental biological processes. The functions of IQGAP1 are modulated by several mechanisms, including protein binding, self-association, subcellular localization, and phosphorylation. Proteome-wide screens have indicated that IQGAP1 is ubiquitinated, but the possible effects of this post-translational modification on its function are unknown. Here we characterized and evaluated the function of IQGAP1 ubiquitination. Using MS-based analysis in HEK293 cells, we identified six lysine residues (Lys-556, -1155, -1230, -1465, -1475, and -1528) as ubiquitination sites in IQGAP1. To elucidate the biological consequences of IQGAP1 ubiquitination, we converted each of these lysines to arginine and found that replacing two of these residues, Lys-1155 and Lys-1230, in the GAP-related domain of IQGAP1 (termed IQGAP1 GRD-2K) reduces its ubiquitination. Moreover, IQGAP1 GRD-2K bound a significantly greater proportion of the two Rho GTPases cell division cycle 42 (CDC42) and Rac family small GTPase 1 (RAC1) than did WT IQGAP1. Consistent with this observation, reconstitution of IQGAP1-null cells with IQGAP1 GRD-2K significantly increased the amount of active CDC42 and enhanced cell migration significantly more than WT IQGAP1. Our results reveal that ubiquitination of the CDC42 regulator IQGAP1 alters its ability to bind to and activate this GTPase, leading to physiological effects. Collectively, these findings expand our view of the role of ubiquitination in cell signaling and provide additional insight into CDC42 regulation.

scholarly journals Cdc42 Promotes Host Defenses against Fatal Infection

2013 ◽  
Vol 81 (8) ◽  
pp. 2714-2723 ◽  
Author(s):  
Keunwook Lee ◽  
Kelli L. Boyd ◽  
Diptiben V. Parekh ◽  
Thomas E. Kehl-Fie ◽  
H. Scott Baldwin ◽  
...  
Keyword(s):  
Rho Gtpase ◽  
Critical Role ◽  
Upper Airway ◽  
Specific Protein ◽  
Small Gtpase ◽  
Host Protection ◽  
Cell Functions ◽  
Airway Infections ◽  
Multiple Cell

ABSTRACTThe small Rho GTPase Cdc42 regulates key signaling pathways required for multiple cell functions, including maintenance of shape, polarity, proliferation, invasion, migration, differentiation, and morphogenesis. As the role of Cdc42-dependent signaling in fibroblastsin vivois unknown, we attempted to specifically delete it in these cells by crossing the Cdc42fl/flmouse with an fibroblast-specific protein 1 (FSP1)-Cre mouse, which is thought to mediate recombination exclusively in fibroblasts. Surprisingly, the FSP1-Cre;Cdc42fl/flmice died at 3 weeks of age due to overwhelming suppurative upper airway infections that were associated with neutrophilia and lymphopenia. Even though major aberrations in lymphoid tissue development were present in the mice, the principal cause of death was severe migration and killing abnormalities of the neutrophil population resulting in an inability to control infection. We also show that in addition to fibroblasts, FSP1-Cre deleted Cdc42 very efficiently in all leukocytes. Thus, by using this nonspecific Cre mouse, we inadvertently demonstrated the importance of Cdc42 in host protection from lethal infections and suggest a critical role for this small GTPase in innate immunity.

scholarly journals Title: In vivo phosphatidylserine variations steer Rho GTPase signaling in a cell-context dependent manner

2018 ◽  
Author(s):  
Matthieu Pierre Platre ◽  
Vincent Bayle ◽  
Laia Armengot ◽  
Joseph Bareille ◽  
Maria Mar Marques-Bueno ◽  
...  
Keyword(s):  
Single Molecule ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Plant Root ◽  
Super Resolution ◽  
Small Gtpase ◽  
Auxin Signaling ◽  
Dependent Manner ◽  
Downstream Signaling

AbstractRho GTPases are master regulators of cell signaling, but how they are regulated depending on the cellular context is unclear. Here, we show that the phospholipid phosphatidylserine acts as a developmentally-controlled lipid rheostat that tunes Rho GTPase signaling in Arabidopsis. Live super-resolution single molecule imaging revealed that RHO-OF-PLANT6 (ROP6) is stabilized by phosphatidylserine into plasma membrane (PM) nanodomains, which is required for auxin signaling. Furthermore, we uncovered that the PM 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 reveals that variations in phosphatidylserine levels are a physiological process that may be leveraged to regulate small GTPase signaling during development.One Sentence SummaryPhosphatidylserine acts as a developmentally-controlled lipid rheostat that regulates cellular auxin sensitivity and plant development.

Cell motility: can Rho GTPases and microtubules point the way?

2001 ◽  
Vol 114 (21) ◽  
pp. 3795-3803 ◽  
Author(s):  
Torsten Wittmann ◽  
Clare M. Waterman-Storer
Keyword(s):  
Actin Cytoskeleton ◽  
Cell Motility ◽  
Rho Gtpases ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
Cell Types ◽  
Small Gtpases ◽  
Cell Polarization ◽  
Microtubule Cytoskeleton ◽  
Filament Bundles

Migrating cells display a characteristic polarization of the actin cytoskeleton. Actin filaments polymerise in the protruding front of the cell whereas actin filament bundles contract in the cell body, which results in retraction of the cell’s rear. The dynamic organization of the actin cytoskeleton provides the force for cell motility and is regulated by small GTPases of the Rho family, in particular Rac1, RhoA and Cdc42. Although the microtubule cytoskeleton is also polarized in a migrating cell, and microtubules are essential for the directed migration of many cell types, their role in cell motility is not well understood at a molecular level. Here, we discuss the potential molecular mechanisms for interplay of microtubules, actin and Rho GTPase signalling in cell polarization and motility. Recent evidence suggests that microtubules locally modulate the activity of Rho GTPases and, conversely, Rho GTPases might be responsible for the initial polarization of the microtubule cytoskeleton. Thus, microtubules might be part of a positive feedback mechanism that maintains the stable polarization of a directionally migrating cell.

scholarly journals Turnover Regulation of the Rho GTPase Cdc42 by Heat Shock Protein Chaperones and the MAPK Pathway Scaffold Bem4

2021 ◽  
Author(s):  
Paul J Cullen ◽  
Beatriz Gonzalez
Keyword(s):  
Heat Shock ◽  
Cell Polarity ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Mapk Pathway ◽  
Cell Types ◽  
Cell Polarization ◽  
Extrinsic Cues ◽  
Dependent Cell ◽  
Map Kinase Pathway

All cells maintain an axis of polarity that directs the orientation of growth. Cell polarity can be reorganized during development and in response to extrinsic cues to produce new cell types. Rho GTPases are central regulators of cell polarity and signal-dependent cell differentiation. We show here that one of the best understood Rho GTPases, the highly conserved yeast Cdc42p, is turned over by members of the Heat Shock family of Proteins (HSPs). The Hsp40p chaperone, Ydj1p, was required for turnover of Cdc42p by the NEDD4 E3 ubiquitin ligase, Rsp5p, in the proteosome. Cdc42p turnover was regulated by HSPs at high temperatures, and in aging cells where the protein formed aggregates, implicating HSPs in Rho GTPase quality control. We also show that Cdc42pQ61L, which mimics the active (GTP-bound) conformation of the protein, was turned over at elevated levels by Ydj1p and Rsp5p. A turnover-defective version of Cdc42pQ61L led to multibudding phenotypes, implicating Cdc42 turnover in singularity in cell polarization. Cdc42p turnover also impacted MAP kinase pathway specificity. A pathway-specific scaffold, Bem4p, stabilized Cdc42p levels, which biased Cdc42p function in one MAPK pathway over another. Turnover regulation of Rho GTPases by HSPs and scaffolds provides new dimensions to the regulation of cell polarity and signal-dependent morphogenesis.

scholarly journals Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

2021 ◽  
Vol 15 ◽  
Author(s):  
William Guiler ◽  
Addison Koehler ◽  
Christi Boykin ◽  
Qun Lu
Keyword(s):  
Neurodegenerative Diseases ◽  
Therapeutic Intervention ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Therapeutic Potential ◽  
Disease Model ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Cellular Functions ◽  
Pharmacological Modulators

Classical Rho GTPases, including RhoA, Rac1, and Cdc42, are members of the Ras small GTPase superfamily and play essential roles in a variety of cellular functions. Rho GTPase signaling can be turned on and off by specific GEFs and GAPs, respectively. These features empower Rho GTPases and their upstream and downstream modulators as targets for scientific research and therapeutic intervention. Specifically, significant therapeutic potential exists for targeting Rho GTPases in neurodegenerative diseases due to their widespread cellular activity and alterations in neural tissues. This study will explore the roles of Rho GTPases in neurodegenerative diseases with focus on the applications of pharmacological modulators in recent discoveries. There have been exciting developments of small molecules, nonsteroidal anti-inflammatory drugs (NSAIDs), and natural products and toxins for each classical Rho GTPase category. A brief overview of each category followed by examples in their applications will be provided. The literature on their roles in various diseases [e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), and Multiple sclerosis (MS)] highlights the unique and broad implications targeting Rho GTPases for potential therapeutic intervention. Clearly, there is increasing knowledge of therapeutic promise from the discovery of pharmacological modulators of Rho GTPases for managing and treating these conditions. The progress is also accompanied by the recognition of complex Rho GTPase modulation where targeting its signaling can improve some aspects of pathogenesis while exacerbating others in the same disease model. Future directions should emphasize the importance of elucidating how different Rho GTPases work in concert and how they produce such widespread yet different cellular responses during neurodegenerative disease progression.

scholarly journals On the influence of cell shape on dynamic reaction-diffusion polarization patterns

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248293
Author(s):  
K. Eroumé ◽  
A. Vasilevich ◽  
S. Vermeulen ◽  
J. de Boer ◽  
A. Carlier
Keyword(s):  
Rho Gtpases ◽  
In Silico ◽  
Intracellular Signaling ◽  
Cell Shape ◽  
Rho Gtpase ◽  
Reaction Diffusion ◽  
Signaling Molecules ◽  
Cell Polarization ◽  
Polarization Model ◽  
Diffusion Phenomena

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.

scholarly journals Control of the cytokinetic apparatus by flux of the Rho GTPases

2008 ◽  
Vol 36 (3) ◽  
pp. 378-380 ◽  
Author(s):  
Ann L. Miller ◽  
George von Dassow ◽  
William M. Bement
Keyword(s):  
Rho Gtpases ◽  
Bound States ◽  
Rho Gtpase ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Filamentous Actin ◽  
Animal Cells ◽  
Apparatus Function ◽  
Tightly Coupled ◽  
Gtpase Cycle

Cytokinesis in animal cells is powered by the cytokinetic apparatus, a ring of filamentous actin and myosin-2 that underlies the plasma membrane and closes between the separating chromosomes. Formation of the cytokinetic apparatus is at least partially dependent on the small GTPase, Rho. Similar to other small GTPases, Rho cycles between the active (GTP-bound) and inactive (GDP-bound) states. Because of this switch-like behaviour, Rho and other members of the Rho GTPase family, such as Rac and Cdc42, have long been thought to work in a manner such that their activation and inactivation are not tightly coupled. That is, a given Rho-dependent event, such as cytokinesis, has been thought to be initiated by activation of Rho, and then, many minutes later, terminated by inactivation of Rho. Here we discuss evidence suggesting that in fact Rho undergoes rapid movement through the GTPase cycle throughout the entire process of cytokinesis, and that this cycling is necessary for proper cytokinetic apparatus function.

scholarly journals Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1037 ◽  
Author(s):  
Cho ◽  
Kim ◽  
Baek ◽  
Kim ◽  
Lee
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Regulatory Mechanisms ◽  
Malignant Phenotype ◽  
Cellular Processes ◽  
Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

scholarly journals EpCAM promotes endosomal modulation of the cortical RhoA zone for epithelial organization

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cécile Gaston ◽  
Simon De Beco ◽  
Bryant Doss ◽  
Meng Pan ◽  
Estelle Gauquelin ◽  
...  
Keyword(s):  
Cell Shape ◽  
Specific Protein ◽  
Cell Polarization ◽  
Stress Fiber ◽  
Fiber Formation ◽  
Endosomal Trafficking ◽  
Transient Zone ◽  
And Behavior ◽  
Fine Tune

AbstractAt the basis of cell shape and behavior, the organization of actomyosin and its ability to generate forces are widely studied. However, the precise regulation of this contractile network in space and time is unclear. Here, we study the role of the epithelial-specific protein EpCAM, a contractility modulator, in cell shape and motility. We show that EpCAM is required for stress fiber generation and front-rear polarity acquisition at the single cell level. In fact, EpCAM participates in the remodeling of a transient zone of active RhoA at the cortex of spreading epithelial cells. EpCAM and RhoA route together through the Rab35/EHD1 fast recycling pathway. This endosomal pathway spatially organizes GTP-RhoA to fine tune the activity of actomyosin resulting in polarized cell shape and development of intracellular stiffness and traction forces. Impairment of GTP-RhoA endosomal trafficking either by silencing EpCAM or by expressing Rab35/EHD1 mutants prevents proper myosin-II activity, stress fiber formation and ultimately cell polarization. Collectively, this work shows that the coupling between co-trafficking of EpCAM and RhoA, and actomyosin rearrangement is pivotal for cell spreading, and advances our understanding of how biochemical and mechanical properties promote cell plasticity.

Sign in / Sign up

Export Citation Format

Share Document