scholarly journals The GTPase RhoA increases utrophin expression and stability, as well as its localization at the plasma membrane

2005 ◽  
Vol 391 (2) ◽  
pp. 261-268 ◽  
Author(s):  
Armelle Bonet-Kerrache ◽  
Mathieu Fortier ◽  
Franck Comunale ◽  
Cécile Gauthier-Rouvière
Keyword(s):  
Plasma Membrane ◽  
Transcriptional Activation ◽  
Myogenic Differentiation ◽  
Active Form ◽  
Small Gtpases ◽  
Skeletal Muscle Differentiation ◽  
Signalling Molecules ◽  
Cellular Processes ◽  
Rhoa Activation ◽  
Rho Family

The Rho family of small GTPases are signalling molecules involved in cytoskeleton remodelling and gene transcription. Their activities are important for many cellular processes, including myogenesis. In particular, RhoA positively regulates skeletal-muscle differentiation. We report in the present study that the active form of RhoA increases the expression of utrophin, the autosomal homologue of dystrophin in the mouse C2C12 and rat L8 myoblastic cell lines. Even though this RhoA-dependent utrophin increase is higher in proliferating myoblasts, it is maintained during myogenic differentiation. This occurs via two mechanisms: (i) transcriptional activation of the utrophin promoter A and (ii) post-translational stabilization of utrophin. In addition, RhoA increases plasma-membrane localization of utrophin. Thus RhoA activation up-regulates utrophin levels and enhances its localization at the plasma membrane.

scholarly journals The RhoGAP activity of CYK-4/MgcRacGAP functions non-canonically by promoting RhoA activation during cytokinesis

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Donglei Zhang ◽  
Michael Glotzer
Keyword(s):  
Active Form ◽  
Underlying Mechanism ◽  
Contractile Ring ◽  
Gtp Hydrolysis ◽  
Activating Mutations ◽  
Catalytic Domains ◽  
Rhoa Activation ◽  
Ring Assembly ◽  
Rho Family ◽  
Spatiotemporal Control

Cytokinesis requires activation of the GTPase RhoA. ECT-2, the exchange factor responsible for RhoA activation, is regulated to ensure spatiotemporal control of contractile ring assembly. Centralspindlin, composed of the Rho family GTPase-activating protein (RhoGAP) MgcRacGAP/CYK-4 and the kinesin MKLP1/ZEN-4, is known to activate ECT-2, but the underlying mechanism is not understood. We report that ECT-2-mediated RhoA activation depends on the ability of CYK-4 to localize to the plasma membrane, bind RhoA, and promote GTP hydrolysis by RhoA. Defects resulting from loss of CYK-4 RhoGAP activity can be rescued by activating mutations in ECT-2 or depletion of RGA-3/4, which functions as a conventional RhoGAP for RhoA. Consistent with CYK-4 RhoGAP activity contributing to GEF activation, the catalytic domains of CYK-4 and ECT-2 directly interact. Thus, counterintuitively, CYK-4 RhoGAP activity promotes RhoA activation. We propose that the most active form of the cytokinetic RhoGEF involves complex formation between ECT-2, centralspindlin and RhoA.

The Golgi architecture and cell sensing

2018 ◽  
Vol 46 (5) ◽  
pp. 1063-1072 ◽  
Author(s):  
Christian Makhoul ◽  
Prajakta Gosavi ◽  
Paul A. Gleeson
Keyword(s):  
Membrane Trafficking ◽  
Small Gtpases ◽  
Signalling Pathways ◽  
Diverse Range ◽  
Signalling Molecules ◽  
Cellular Processes ◽  
A Cell ◽  
Ribbon Structure ◽  
Golgi Ribbon ◽  
The Relationship

An array of signalling molecules are located at the Golgi apparatus, including phosphoinositides, small GTPases, kinases, and phosphatases, which are linked to multiple signalling pathways. Initially considered to be associated predominantly with membrane trafficking, signalling pathways at the Golgi are now recognised to regulate a diverse range of higher-order functions. Many of these signalling pathways are influenced by the architecture of the Golgi. In vertebrate cells, the Golgi consists of individual stacks fused together into a compact ribbon structure and the function of this ribbon structure has been enigmatic. Notably, recent advances have identified a role for the Golgi ribbon in regulation of cellular processes. Fragmentation of the Golgi ribbon results in modulation of many signalling pathways. Various diseases and disorders, including cancer and neurodegeneration, are associated with the loss of the Golgi ribbon and the appearance of a dispersed fragmented Golgi. Here, we review the emerging theme of the Golgi as a cell sensor and highlight the relationship between the morphological status of the Golgi in vertebrate cells and the modulation of signalling networks.

scholarly journals Distinct Effects of Rac1 on Differentiation of Primary Avian Myoblasts

1999 ◽  
Vol 10 (10) ◽  
pp. 3137-3150 ◽  
Author(s):  
Rita Gallo ◽  
Marco Serafini ◽  
Loriana Castellani ◽  
Germana Falcone ◽  
Stefano Alemà
Keyword(s):  
Myogenic Differentiation ◽  
Terminal Differentiation ◽  
Dominant Negative ◽  
Skeletal Muscle Differentiation ◽  
Rho Family Gtpases ◽  
Specific Proteins ◽  
Rho Family ◽  
Selective Disassembly ◽  
Jnk Activation ◽  
Constitutively Active

Rho family GTPases have been implicated in the regulation of the actin cytoskeleton in response to extracellular cues and in the transduction of signals from the membrane to the nucleus. Their role in development and cell differentiation, however, is little understood. Here we show that the transient expression of constitutively active Rac1 and Cdc42 in unestablished avian myoblasts is sufficient to cause inhibition of myogenin expression and block of the transition to the myocyte compartment, whereas activated RhoA affects myogenic differentiation only marginally. Activation of c-Jun N-terminal kinase (JNK) appears not to be essential for block of differentiation because, although Rac1 and Cdc42 GTPases modestly activate JNK in quail myoblasts, a Rac1 mutant defective for JNK activation can still inhibit myogenic differentiation. Stable expression of active Rac1, attained by infection with a recombinant retrovirus, is permissive for terminal differentiation, but the resulting myotubes accumulate severely reduced levels of muscle-specific proteins. This inhibition is the consequence of posttranscriptional events and suggests the presence of a novel level of regulation of myogenesis. We also show that myotubes expressing constitutively active Rac1 fail to assemble ordered sarcomeres. Conversely, a dominant-negative Rac1 variant accelerates sarcomere maturation and inhibits v-Src–induced selective disassembly of I-Z-I complexes. Collectively, our findings provide a role for Rac1 during skeletal muscle differentiation and strongly suggest that Rac1 is required downstream of v-Src in the signaling pathways responsible for the dismantling of tissue-specific supramolecular structures.

scholarly journals Socius Is a Novel Rnd GTPase-Interacting Protein Involved in Disassembly of Actin Stress Fibers

2002 ◽  
Vol 22 (9) ◽  
pp. 2952-2964 ◽  
Author(s):  
Hironori Katoh ◽  
Amane Harada ◽  
Kazutoshi Mori ◽  
Manabu Negishi
Keyword(s):  
Actin Cytoskeleton ◽  
Cell Body ◽  
Inhibitory Effect ◽  
Small Gtpases ◽  
Fiber Formation ◽  
Stress Fibers ◽  
Cell Periphery ◽  
Cellular Processes ◽  
Rho Family ◽  
Actin Stress Fibers

ABSTRACT Rho family small GTPases are key regulators of the actin cytoskeleton in various cell types. The Rnd proteins, Rnd1, Rnd2, and Rnd3/RhoE, have been recently identified as new members of the Rho family of GTPases, and expression of Rnd1 or Rnd3 in fibroblasts causes the disassembly of actin stress fibers and the retraction of the cell body to produce extensively branching cellular processes. Here we have performed a yeast two-hybrid screening by using Rnd1 as bait and identified a novel protein that specifically binds to Rnd GTPases. We named this protein Socius. Socius directly binds to Rnd GTPases through its COOH-terminal region. When transfected into COS-7 cells, Socius is translocated to the cell periphery in response to Rnd1 and Rnd3 and colocalized with the GTPases. While expression of wild-type Socius in Swiss 3T3 fibroblasts has little effect on the actin cytoskeleton, the expression of a membrane-targeted form of Socius, containing a COOH-terminal farnesylation motif (Socius-CAAX), induces a dramatic loss of stress fibers. The inhibitory effect of Socius-CAAX on stress fiber formation is enhanced by truncation of its NH2 terminus. On the other hand, the expression of Socius-CAAX or its NH2 terminus-truncated form suppresses the Rnd-induced retraction of the cell body and the production of extensively branching cellular processes, although the disassembly of stress fibers is observed. We propose that Socius participates in the Rnd GTPase-induced signal transduction pathways, leading to reorganization of the actin cytoskeleton.

scholarly journals The Small GTPases Rho and Rac Are Required for the Establishment of Cadherin-dependent Cell–Cell Contacts

1997 ◽  
Vol 137 (6) ◽  
pp. 1421-1431 ◽  
Author(s):  
Vania M.M. Braga ◽  
Laura M. Machesky ◽  
Alan Hall ◽  
Neil A. Hotchin
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Active Form ◽  
Intercellular Junctions ◽  
Small Gtpases ◽  
Cell Contacts ◽  
Calcium Dependent ◽  
Dependent Cell ◽  
Rho Family ◽  
Cell Cell

Cadherins are calcium-dependent cell–cell adhesion molecules that require the interaction of the cytoplasmic tail with the actin cytoskeleton for adhesive activity. Because of the functional relationship between cadherin receptors and actin filament organization, we investigated whether members of the Rho family of small GTPases are necessary for cadherin adhesion. In fibroblasts, the Rho family members Rho and Rac regulate actin polymerization to produce stress fibers and lamellipodia, respectively. In epithelial cells, we demonstrate that Rho and Rac are required for the establishment of cadherin-mediated cell–cell adhesion and the actin reorganization necessary to stabilize the receptors at sites of intercellular junctions. Blocking endogenous Rho or Rac selectively removed cadherin complexes from junctions induced for up to 3 h, while desmosomes were not perturbed. In addition, withdrawal of cadherins from intercellular junctions temporally precedes the removal of CD44 and integrins, other microfilament-associated receptors. Our data showed that the concerted action of Rho and Rac modulate the establishment of cadherin adhesion: a constitutively active form of Rac was not sufficient to stabilize cadherindependent cell–cell contacts when endogenous Rho was inhibited. Upon induction of calcium-dependent intercellular adhesion, there was a rapid accumulation of actin at sites of cell–cell contacts, which was prevented by blocking cadherin function, Rho or Rac activity. However, if cadherin complexes are clustered by specific antibodies attached to beads, actin recruitment to the receptors was perturbed by inhibiting Rac but not Rho. Our results provide new insights into the role of the small GTPases in the cadherin-dependent cell– cell contact formation and the remodelling of actin filaments in epithelial cells.

scholarly journals S-Palmitoylation-Dependent Regulation of Cardiomyocyte Rac1 Signaling Activity and Cardiac Hypertrophy

2021 ◽  
Author(s):  
Matthew J Brody ◽  
Tanya A. Baldwin ◽  
Arasakumar Subramani ◽  
Onur Kanisicak ◽  
Ronald J Vagnozzi ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Transgenic Mice ◽  
Cardiac Disease ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Transferase Activity ◽  
Related Enzyme ◽  
Rho Family ◽  
Novel Therapeutic Strategies

S-palmitoylation is a reversible lipid modification that regulates trafficking, localization, activity, and/or stability of protein substrates by serving as a fatty acid anchor to cell membranes. However, S-palmitoylation-dependent control of signal transduction in cardiomyocytes and its effects on cardiac physiology are not well understood. We performed an in vivo gain-of-function screen of zinc finger Asp-His-His-Cys (zDHHC) family S-acyl transferases that catalyze S-palmitoylation and identified the Golgi-localized enzyme zDHHC3 as a critical regulator of cardiac maladaptation. The closely-related enzyme, zDHHC7, also induced severe cardiomyopathy but this effect was not observed with overexpression of plasma membrane enzyme zDHHC5, endoplasmic reticulum enzyme zDHHC6, or Golgi enzyme zDHHC13. To identify effectors that may underlie zDHHC3-induced cardiomyopathy we performed quantitative site-specific S-acyl proteomics in zDHHC3-overexpressing cells that revealed the small GTPase Rac1 as a novel substrate. We generated cardiomyocyte-specific transgenic mice overexpressing zDHHC3, which develop severe cardiac disease. Cardiomyopathy and congestive heart failure in zDHHC3 transgenic mice are preceded by enhanced S-palmitoylation of Rac1 and induction of additional Rho family small GTPases including RhoA, Cdc42, and the Rho family-specific chaperone RhoGDI. In contrast, transgenic mice overexpressing an enzymatically-dead mutant of zDHHC3 do not exhibit this profound induction of RhoGTPase signaling or develop cardiac disease. Rac1 S-palmitoylation, plasma membrane localization, activity, and downstream hypertrophic signaling were substantially increased in zDHHC3 overexpressing hearts. Taken together, these data suggest inhibition of zDHHC3/7 S-acyl transferase activity at the cardiomyocyte Golgi or disruption of Rac1 S-palmitoylation as novel therapeutic strategies to treat cardiac disease or other diseases associated with enhanced RhoGTPase signaling.

scholarly journals The GTP-binding Protein RhoA Mediates Na,K-ATPase Exocytosis in Alveolar Epithelial Cells

2003 ◽  
Vol 14 (9) ◽  
pp. 3888-3897 ◽  
Author(s):  
Emilia Lecuona ◽  
Karen Ridge ◽  
Liuska Pesce ◽  
Daniel Batlle ◽  
Jacob I. Sznajder
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cells ◽  
Adrenergic Receptor ◽  
Specific Inhibitor ◽  
Small Gtpases ◽  
Dominant Negative ◽  
Alveolar Epithelial Cells ◽  
Dependent Manner ◽  
Alveolar Epithelial ◽  
Rhoa Activation

The purpose of this study was to define the role of the Rho family of small GTPases in the β-adrenergic regulation of the Na,K-ATPase in alveolar epithelial cells (AEC). The β-adrenergic receptor agonist isoproterenol (ISO) increased the Na,K-ATPase protein abundance at the plasma membrane and activated RhoA in a time-dependent manner. AEC pretreated with mevastatin, a specific inhibitor of prenylation, or transfected with the dominant negative RhoAN19, prevented ISO-mediated Na,K-ATPase exocytosis to the plasma membrane. The ISO-mediated activation of RhoA in AEC occurred via β2-adrenergic receptors and involved Gs-PKA as demonstrated by incubation with the protein kinase A (PKA)-specific inhibitors H89 and PKI (peptide specific inhibitor), and Gi, as incubation with pertussis toxin or cells transfected with a minigene vector for Gi inhibited the ISO-mediated RhoA activation. However, cells transfected with minigene vectors for G12 and G13 did not prevent RhoA activation by ISO. Finally, the ISO-mediated Na,K-ATPase exocytosis was regulated by the Rho-associated kinase (ROCK), as preincubation with the specific inhibitor Y-27632 or transfection with dominant negative ROCK, prevented the increase in Na,K-ATPase at the plasma membrane. Accordingly, ISO regulates Na,K-ATPase exocytosis in AEC via the activation of β2-adrenergic receptor, Gs, PKA, Gi, RhoA, and ROCK.

scholarly journals Coordination between Rac1 and Rab Proteins: Functional Implications in Health and Disease

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 396 ◽  
Author(s):  
Margiotta ◽  
Bucci
Keyword(s):  
Reactive Oxygen Species ◽  
Small Gtpases ◽  
Actin Dynamics ◽  
Rab Proteins ◽  
Oxygen Species ◽  
Cellular Processes ◽  
Functional Implications ◽  
Health And Disease ◽  
Rho Family ◽  
Regulation Of Actin Cytoskeleton

The small GTPases of the Rho family regulate many aspects of actin dynamics, but are functionally connected to many other cellular processes. Rac1, a member of this family, besides its known function in the regulation of actin cytoskeleton, plays a key role in the production of reactive oxygen species, in gene transcription, in DNA repair, and also has been proven to have specific roles in neurons. This review focuses on the cooperation between Rac1 and Rab proteins, analyzing how the coordination between these GTPases impact on cells and how alterations of their functions lead to disease.

vitreal cells and specialized phagocytes in the chick embryo retina: A TEM and SEM study

1990 ◽  
Vol 48 (3) ◽  
pp. 330-331
Author(s):  
M.A. Cuadros ◽  
M.J. Martinez-Guerrero ◽  
A. Rios
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Acid Phosphatase ◽  
Chick Embryo ◽  
Basement Membrane ◽  
Sem Images ◽  
Intimate Contact ◽  
Cellular Processes ◽  
Sem Study ◽  
Free Cells

In the chick embryo retina (days 3-4 of incubation), coinciding with an increase in cell death, specialized phagocytes characterized by intense acid phosphatase activity have been described. In these preparations, all free cells in the vitreal humor (vitreal cells) were strongly labeled. Conventional TEM and SEM techniques were used to characterize them and attempt to determine their relationship with retinal phagocytes.Two types of vitreal cells were distinguished. The first are located at some distance from the basement membrane of the neuroepithelium, and are rounded, with numerous vacuoles and thin cytoplasmic prolongations. Images of exo- and or endocytosis were frequent; the cells showed a well-developed Golgi apparatus (Fig. 1) In SEM images, the cells was covered with short cellular processes (Fig. 3). Cells lying parallel to or alongside the basement membrane are elongated. The plasma membrane is frequently in intimate contact with the basement membrane. These cells have generally a large cytoplasmic expansion (Fig. 5).

Caveolin-1, galectin-3 and lipid raft domains in cancer cell signalling

2015 ◽  
Vol 57 ◽  
pp. 189-201 ◽  
Author(s):  
Jay Shankar ◽  
Cecile Boscher ◽  
Ivan R. Nabi
Keyword(s):  
Plasma Membrane ◽  
Lipid Rafts ◽  
Cancer Cell ◽  
Cellular Response ◽  
Spatial Organization ◽  
Essential Feature ◽  
Cell Signalling ◽  
Coated Pits ◽  
Signalling Molecules ◽  
Raft Domains

Spatial organization of the plasma membrane is an essential feature of the cellular response to external stimuli. Receptor organization at the cell surface mediates transmission of extracellular stimuli to intracellular signalling molecules and effectors that impact various cellular processes including cell differentiation, metabolism, growth, migration and apoptosis. Membrane domains include morphologically distinct plasma membrane invaginations such as clathrin-coated pits and caveolae, but also less well-defined domains such as lipid rafts and the galectin lattice. In the present chapter, we will discuss interaction between caveolae, lipid rafts and the galectin lattice in the control of cancer cell signalling.

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