Rho-GTPase Regulation by GEFs, GAPs and GDIs in Cell Migration

2010 ◽  
Author(s):  
Xavier Diego ◽  
Eugenio On˜ate ◽  
Wing Kam Liu
Keyword(s):  
Cell Migration ◽  
Experimental Evidence ◽  
Crucial Role ◽  
General Class ◽  
Rho Gtpase ◽  
Mathematical Basis ◽  
Temporal Coordination ◽  
The Family ◽  
Turing Instabilities

The family of small RhoGTPases plays a crucial role in the spatial and temporal coordination cell migration. GEFs, GAPs and GDIs are the enzymes that regulate their activity, although the mechanism is poorly understood. Regulation models proposed to date have focused on GEFs as the main modulators of RhoGTPase activity, leaving a passive role to GAPs and GDIs. In this work we show that this assumption leads to models with properties that may be inconsistent with observations, more precisely, appearance of Turing instabilities and reduced sensitivity to secondary stimuli. The mathematical basis of this behavior is established, and a general class of interaction schemes that bypass it by including GAP and GDI regulation, which is supported by experimental evidence, is proposed.

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 Long non-coding RNA ARHGAP5-AS1 inhibits migration of breast cancer cell via stabilizing SMAD7 protein

2021 ◽  
Author(s):  
Chen-Long Wang ◽  
Jing-Chi Li ◽  
Ci-Xiang Zhou ◽  
Cheng-Ning Ma ◽  
Di-Fei Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Rho Gtpase ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Breast Cancer Cell Lines ◽  
Smad7 Protein

Abstract Purpose Tumor metastasis is the main cause of death from breast cancer patients and cell migration plays a critical role in cancer metastasis. Recent studies have shown long non-coding RNAs (lncRNAs) play an essential role in the initiation and progression of cancer. In the present study, the role of an LncRNA, Rho GTPase Activating Protein 5- Antisense 1 (ARHGAP5-AS1) in breast cancer was investigated. Methods RNA sequencing was performed to find out dysregulated LncRNAs in MDA-MB-231-LM2 cells. Transwell migration assays and F-actin staining were utilized to estimate cell migration ability. RNA pulldown assays and RNA immunoprecipitation were used to prove the interaction between ARHGAP5-AS1 and SMAD7. Western blot and immunofluorescence imaging were used to examine the protein levels. Dual luciferase reporter assays were performed to evaluate the activation of TGF-β signaling. Results We analyzed the RNA-seq data of MDA-MB-231 and its highly metastatic derivative MDA-MB-231-LM2 cell lines (referred to as LM2) and identified a novel lncRNA (NR_027263) named as ARHGAP5-AS1, which expression was significantly downregulated in LM2 cells. Further functional investigation showed ARHGAP5-AS1 could inhibit cell migration via suppression of stress fibers in breast cancer cell lines. Afterwards, SMAD7 was further identified to interact with ARHGAP5-AS1 by its PY motif and thus its ubiquitination and degradation was blocked due to reduced interaction with E3 ligase SMURF1 and SMURF2. Moreover, ARHGAP5-AS1 could inhibit TGF-β signaling pathway due to its inhibitory role on SMAD7. Conclusion ARHGAP5-AS1 inhibits breast cancer cell migration via stabilization of SMAD7 protein and could serve as a novel biomarker and a potential target for breast cancer in the future.

The atypical Rho GTPase RhoD is a regulator of actin cytoskeleton dynamics and directed cell migration

2017 ◽  
Vol 352 (2) ◽  
pp. 255-264 ◽  
Author(s):  
Magdalena Blom ◽  
Katarina Reis ◽  
Johan Heldin ◽  
Johan Kreuger ◽  
Pontus Aspenström
Keyword(s):  
Cell Migration ◽  
Actin Cytoskeleton ◽  
Rho Gtpase ◽  
Directed Cell Migration ◽  
Cytoskeleton Dynamics

scholarly journals Sigma Oscillations Protect or Reinstate Motor Memory Depending on their Temporal Coordination with Slow Waves

2021 ◽  
Author(s):  
Judith Nicolas ◽  
Brad R King ◽  
David Levesque ◽  
Latifa Lazzouni ◽  
Emily BJ Coffey ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Memory Consolidation ◽  
Crucial Role ◽  
Motor Performance ◽  
Irrelevant Information ◽  
Slow Waves ◽  
Motor Memory ◽  
Temporal Coordination ◽  
Phase Amplitude ◽  
Related Phase

Targeted memory reactivation (TMR) during post-learning sleep is known to enhance motor memory consolidation but the underlying neurophysiological processes remain unclear. Here, we confirm the beneficial effect of auditory TMR on motor performance. At the neural level, TMR enhanced slow waves (SW) characteristics. Additionally, greater TMR-related phase-amplitude coupling between slow (0.3-2 Hz) and sigma (12-16 Hz) oscillations after the SW peak was related to higher TMR effect on performance. Importantly, sounds that were not associated to learning strengthened SW-sigma coupling at the SW trough and the increase in sigma power nested in the trough of the potential evoked by these unassociated sounds was related to the TMR benefit. Altogether, our data suggest that, depending on their precise temporal coordination during post learning sleep, slow and sigma oscillations play a crucial role in either memory reinstatement or protection against irrelevant information; two processes that critically contribute to motor memory consolidation.

scholarly journals ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration

2008 ◽  
Vol 181 (2) ◽  
pp. 351-365 ◽  
Author(s):  
Junji Yamauchi ◽  
Yuki Miyamoto ◽  
Jonah R. Chan ◽  
Akito Tanoue
Keyword(s):  
Cell Migration ◽  
Schwann Cell ◽  
Rho Gtpase ◽  
Morphological Changes ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Schwann Cell Migration ◽  
Subsequent Activation

The cellular events that precede myelination in the peripheral nervous system require rapid and dynamic morphological changes in the Schwann cell. These events are thought to be mainly controlled by axonal signals. But how signals on the axons are coordinately organized and transduced to promote proliferation, migration, radial sorting, and myelination is unknown. We describe that the axonal signal neuregulin-1 (NRG1) controls Schwann cell migration via activation of the atypical Dock180-related guanine nucleotide exchange factor (GEF) Dock7 and subsequent activation of the Rho guanine triphosphatases (GTPases) Rac1 and Cdc42 and the downstream c-Jun N-terminal kinase. We show that the NRG1 receptor ErbB2 directly binds and activates Dock7 by phosphorylating Tyr-1118. Dock7 knockdown, or expression of Dock7 harboring the Tyr-1118–to–Phe mutation in Schwann cells, attenuates the effects of NRG1. Thus, Dock7 functions as an intracellular substrate for ErbB2 to promote Schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of Rho GTPase-GEFs of the Dock180 family.

Seduction and Surprise

2017 ◽  
pp. 188-205
Author(s):  
Dina Mendonça
Keyword(s):  
Lived Experience ◽  
Crucial Role ◽  
The Family ◽  
Situated Approach ◽  
The Way

The chapter explores the meaning of seduction from a situated approach to emotions by tracing the way surprise uncovers emotional traits that enable commitment. The adoption of a Situated Approach reveals how emotions are intrinsically tied to the situations from which they arise and the crucial role of surprise. The emotion of surprise is central for the value of experience because it amplifies other emotions as well as other traits, and details of the lived situations fixing the meaning of the lived experience. The examination of how various emotions belong to the family of surprise further explains the established differences between persuasion, manipulation and seduction. Ultimately the chapter shows that seduction asks for the recognition of various layers of emotional reality, and how they are made visible by the way in which seduction establishes commitments.

scholarly journals Role of Berry Anthocyanins and Phenolic Acids on Cell Migration and Angiogenesis: An Updated Overview

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1075 ◽  
Author(s):  
Panagiotis Tsakiroglou ◽  
Natalie E. VandenAkker ◽  
Cristian Del Bo’ ◽  
Patrizia Riso ◽  
Dorothy Klimis-Zacas
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Phenolic Acids ◽  
Rho Gtpase ◽  
Small Gtpases ◽  
Endothelial Cell Migration ◽  
Berry Extracts

Cell migration is a critical process that is highly involved with normal and pathological conditions such as angiogenesis and wound healing. Important members of the RHO GTPase family are capable of controlling cytoskeleton conformation and altering motility characteristics of cells. There is a well-known relationship between small GTPases and the PI3K/AKT pathway. Endothelial cell migration can lead to angiogenesis, which is highly linked to wound healing processes. Phenolics, flavonoids, and anthocyanins are major groups of phytochemicals and are abundant in many natural products. Their antioxidant, antimicrobial, anti-inflammatory, antidiabetic, angiogenenic, neuroprotective, hepatoprotective, and cardioprotective properties have been extensively documented. This comprehensive review focuses on the in vitro and in vivo role of berry extracts and single anthocyanin and phenolic acid compounds on cell migration and angiogenesis. We aim to summarize the most recent published studies focusing on the experimental model, type of berry extract, source, dose/concentration and overall effect(s) of berry extracts, anthocyanins, and phenolic acids on the above processes.

Defective LFA-1 Mediated T Cell Motility In Chronic Lymphocytic Leukemia Is Mediated by Defects In the Rho GTPase Signaling Pathway

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 914-914
Author(s):  
Alan G. Ramsay ◽  
Rachel Evans ◽  
Lena Svensson ◽  
Shahryar Kiaii ◽  
Nancy Hogg ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
Cell Adhesion ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Motility ◽  
Healthy Donor ◽  
Rho Gtpase ◽  
Lymphocytic Leukemia ◽  
Donor T Cells

Abstract Abstract 914 T lymphocytes have an essential role in adaptive immunity and rely on tightly regulated signaling through integrin lymphocyte function-associated antigen (LFA)-1 to migrate into lymph nodes and interact with antigen-presenting cells. Malignant cells modify their immune microenvironment to prevent effective host anti-tumor responses, promote tumor progression, and suppress the therapeutic benefit of immunotherapy treatments. Here we assessed LFA-1-mediated cell migration of highly purified T cells from treatment naïve chronic lymphocytic leukemia (CLL) patients compared to age-matched healthy donor T cells using CXCL12 stimulation and immobilized ICAM-1, the principal integrin ligand. Video microscopy with motility tracking analysis identified that both CD4 and CD8 T cells from CLL patients (n=14) exhibited significantly reduced migration rates (P < .01) compared to healthy donor T cells (5.5 ± 0.3 (SEM) μm/min and 4.4 ± 0.2 μm/min compared to 8.2 ± 0.3 μm/min and 7.5 ± 0.3 μm/min respectively). We further identified that direct CLL cell contact, and not soluble factors alone, induced similar T cell motility dysfunction in previously healthy CD3 T cells. Primary co-culture of healthy donor T cells with CLL cells caused a significant decrease in the speed of migration on ICAM-1 compared to coculture with control healthy B cells (6.2 ± 0.3 μm/min versus 9.5 ± 0.6 μm/min) (n=9) (P < .05). Next we sought to repair this T cell defect in CLL using a clinically relevant agent. We identify that treatment of CLL patient T cells (n=9) with lenalidomide restores rapid LFA-1 mediated migration on ICAM-1. Ex vivo treatment of CLL T cells with lenalidomide (1μM for 24 hours) significantly increased the speed of T cell migration compared to untreated patient T cells (7 ± 0.4 μm/min versus 2.5 ± 0.7 μm/min) (P < .05) and the rescued T cell migratory function of lenalidomide exposed patient T cells was comparable to healthy donor T cells treated with or without drug. Interference reflection microscopy (IRM) examining the contact zone between migrating T cells and ICAM-1 identified a significant CLL patient T cell adhesion defect (P < .05) with reduced spreading area and strength of adhesive contacts (pixel density) compared to healthy donor T cells. IRM was further utilized with pharmacological inhibitors to demonstrate that exposure to lenalidomide rescued CLL T cell adhesion by acting on the Rho family GTPases that are dysregulated in cancer patient T cells. Lenalidomide significantly increased (P < .05) levels of active RhoA in CLL patient T cells compared to untreated cells. In addition, untreated CLL patient T cells adhering to ICAM-1 exhibited significantly reduced expression levels of phosphorylated myosin light chain (MLC) compared to healthy donor T cells (P < .05) and this defect was repaired following lenalidomide treatment. MLC is normally phosphorylated by MLC kinase at the T cell leading edge and by the RhoA target, ROCK at the trailing edge, and is an important downstream signaling molecule during LFA-1-mediated T cell motility. Further expression analysis identified that lenalidomide significantly increased (P < .01) ICAM-1-engaged high-affinity LFA-1 in CLL patient T cells to levels comparable to healthy donor T cells. Overall, our results show that T cells in CLL patients have dysfunctional tumor-induced cytoskeletal signaling via the Rho GTPase signaling pathway, and this is reversed by lenalidomide, rescuing dynamic LFA-1 mediated outside-in signalling and migration. Lenalidomide's immunomodulatory activity was highly cancer T cell specific: rescuing defective LFA-1 migration and signaling in CLL T cells, but with no detectable effects on healthy donor T cells. These findings provide important mechanistic insight into the action of lenalidomide, and highlight the potential clinical utility of immunomodulatory drugs to rescue normal immune function in cancer. Disclosures: Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.

Familial Essential Thrombocythemia Associated With One-Base Deletion in the 5′-Untranslated Region of theThrombopoietin Gene

Blood ◽  
1998 ◽  
Vol 92 (4) ◽  
pp. 1091-1096 ◽  
Author(s):  
Takeshi Kondo ◽  
Mihiro Okabe ◽  
Masayoshi Sanada ◽  
Mitsutoshi Kurosawa ◽  
Sachiko Suzuki ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Crucial Role ◽  
Untranslated Region ◽  
Autosomal Dominant ◽  
Family Members ◽  
In Vitro Experiments ◽  
Platelet Production ◽  
The Family ◽  
American Society

Familial essential thrombocythemia (ET) is inherited in an autosomal-dominant manner. This finding implies that familial ET may arise as a consequence of a mutation(s) that activates platelet production. In 1994, the thrombopoietin (TPO) gene was isolated and cloned. The TPO-TPO receptor, encoded for by thec-mpl gene, are essential regulators of thrombopoiesis. Alterations of TPO or c-Mpl thus may constitute a pathogenic event leading to familial ET. In a case of familial ET presented in our institute, serum TPO levels were significantly elevated in affected members of the family as compared with nonaffected members. Moreover, we identified a one-base deletion in the 5′-untranslated region of theTPO gene in affected but not in nonaffected family members. In vitro experiments showed that the identified mutation increased TPO production. Based on our findings, we propose that this region of theTPO gene may play a crucial role in regulating TPO expression. Our results strongly suggest that the identified mutation leads to familial ET. © 1998 by The American Society of Hematology.

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