scholarly journals RSK2 drives cell motility by serine phosphorylation of LARG and activation of Rho GTPases

2017 ◽  
Vol 115 (2) ◽  
pp. E190-E199 ◽  
Author(s):  
Geng-Xian Shi ◽  
Won Seok Yang ◽  
Ling Jin ◽  
Michelle L. Matter ◽  
Joe W. Ramos
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Serine Phosphorylation ◽  
Migration And Invasion ◽  
Signaling Mechanism ◽  
Directed Cell Migration ◽  
Gtpase Activation ◽  
Rhoa Signaling

Directed migration is essential for cell motility in many processes, including development and cancer cell invasion. RSKs (p90 ribosomal S6 kinases) have emerged as central regulators of cell migration; however, the mechanisms mediating RSK-dependent motility remain incompletely understood. We have identified a unique signaling mechanism by which RSK2 promotes cell motility through leukemia-associated RhoGEF (LARG)-dependent Rho GTPase activation. RSK2 directly interacts with LARG and nucleotide-bound Rho isoforms, but not Rac1 or Cdc42. We further show that epidermal growth factor or FBS stimulation induces association of endogenous RSK2 with LARG and LARG with RhoA. In response to these stimuli, RSK2 phosphorylates LARG at Ser1288 and thereby activates RhoA. Phosphorylation of RSK2 at threonine 577 is essential for activation of LARG-RhoA. Moreover, RSK2-mediated motility signaling depends on RhoA and -B, but not RhoC. These results establish a unique RSK2-dependent LARG-RhoA signaling module as a central organizer of directed cell migration and invasion.

Engineering Tools for Studying Coordination Between Biochemical and Biomechanical Activities in Cell Migration

2011 ◽  
Author(s):  
Sungsoo Na
Keyword(s):  
Cell Migration ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Resonance Energy Transfer ◽  
Focal Adhesions ◽  
Resonance Energy ◽  
Leading Edge ◽  
Dynamic Feedback ◽  
Chemical Signaling ◽  
Directed Cell Migration

Cell migration is achieved by the dynamic feedback interactions between traction forces generated by the cell and exerted onto the underlying extracellular matrix (ECM), and intracellular mechano-chemical signaling pathways, e.g., Rho GTPase (RhoA, Rac1, and Cdc42) activities [1,2,3]. These components are differentially distributed within a cell, and thus the coordination between tractions and mechanotransduction (i.e, RhoA and Rac1 activities) must be implemented at a precise spatial and temporal order to achieve optimized, directed cell migration [4,5]. Recent studies have shown that focal adhesions at the leading edge exert strong tractions [6], and these traction sites are co-localized with focal adhesion sites [7]. Further, by using the fluorescence resonance energy transfer (FRET) technology coupled with genetically encoded biosensors, researchers reported that Rho GTPases, such as RhoA [8], Rac1 [9], and Cdc42 [10] are maximally activated at the leading edge, suggesting the leading edge of the cell as its common functional site for Rho GTPase activities. All these works, however, were done separately, and the relationship between tractions and mechanotransduction during cell migration has not been demonstrated directly because of the difficulty in simultaneously recording tractions and mechanotransduction in migrating cells, precluding direct comparison between these results. Furthermore, these studies have been conducted by monitoring cells on glass coverslips, the stiffness of which is ∼ 65 giga pascal (GPa), at least three to six order higher than the physiological range of ECM stiffness. Although it is increasingly accepted that ECM stiffness influences cell migration, it is not known exactly how physiologically relevant ECM stiffness (order of kPa range) affects the dynamics of RhoA and Rac1 activities. For a complete understanding of the mechanism of mechano-chemical signaling in the context of cell migration, the dynamics and interplay between biomechanical (e.g., tractions) and biochemical (e.g., Rho GTPase) activities should be visualized within the physiologically relevant range of ECM stiffness.

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 Chronic lymphocytic leukemia cells induce defective LFA-1–directed T-cell motility by altering Rho GTPase signaling that is reversible with lenalidomide

Blood ◽  
2013 ◽  
Vol 121 (14) ◽  
pp. 2704-2714 ◽  
Author(s):  
Alan G. Ramsay ◽  
Rachel Evans ◽  
Shahryar Kiaii ◽  
Lena Svensson ◽  
Nancy Hogg ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Motility ◽  
Rho Gtpase ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Key Points ◽  
Gtpase Activation ◽  
Activation Signaling

Key Points CLL cells induce defects in T-cell LFA-1–mediated migration by altering Rho GTPase activation signaling, downregulating RhoA and Rac1, and upregulating Cdc42. Lenalidomide repairs these T-cell defects by restoring normal Rho GTPase activation signaling.

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

Rho GTPase Activating Protein 9 (ARHGAP9) in Human Cancers

2021 ◽  
Vol 16 ◽  
Author(s):  
Wenping Song ◽  
Jinhua Chen ◽  
Shuolei Li ◽  
Ding Li ◽  
Yongna Zhang ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Cancer Progression ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
Clinical Success ◽  
Predictive Biomarker ◽  
Migration And Invasion ◽  
Targeted Drugs ◽  
Gtpase Activating Protein

Background: In recent years, targeted therapy combined with traditional chemoradiotherapy and surgery has brought new opportunities for cancer treatment. However, the complex characteristics of cancer, such as heterogeneity and diversity, limit the clinical success of targeted drugs. The discovery of new cancer targets and deepening the understanding of their functional mechanisms will bring additional promising application prospects for the research and development of personalized cancer-targeted drugs. Objective: This study aimed to summarize the role of the Rho GTPase activating protein 9 (ARHGAP9) gene in tumorigenesis and development to discover therapeutic targets for cancer in the future. Methods: For this review, we collected patents from the databases of Espacenet and WIPO and articles from PubMed that were related to the ARHGAP9 gene. Results: Genetic/epigenetic variations and abnormal expression of the ARHGAP9 gene are closely associated with a variety of diseases, including cancer. ARHGAP9 can inactivate Rho GTPases by hydrolyzing GTP into GDP and regulate cancer cellular events, including proliferation, differentiation, apoptosis, migration and invasion, by inhibiting JNK/ERK/p38 and PI3K/AKT signaling pathways. In addition to reviewing these mechanisms, we assessed various patents on ARHGAP9 to determine whether ARHGAP9 might be used as a predictive biomarker for diagnosis/prognosis evaluation and a druggable target for cancer treatment. Conclusion: In this review, the current knowledge of ARHGAP9 in cancer is summarized with an emphasis on its molecular function, regulatory mechanism and disease implications. Its characterization is crucial to understanding its important roles during different stages of cancer progression and therapy as a predictive biomarker and/or target.

scholarly journals Targeting and activation of Rac1 are mediated by the exchange factor β-Pix

2006 ◽  
Vol 172 (5) ◽  
pp. 759-769 ◽  
Author(s):  
Jean Paul ten Klooster ◽  
Zahara M. Jaffer ◽  
Jonathan Chernoff ◽  
Peter L. Hordijk
Keyword(s):  
Rho Gtpases ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
Focal Adhesions ◽  
Exchange Factor ◽  
Downstream Signaling ◽  
Intracellular Targeting ◽  
Dynamics And Control ◽  
P21 Activated Kinase ◽  
Gtpase Activation

Rho guanosine triphosphatases (GTPases) are critical regulators of cytoskeletal dynamics and control complex functions such as cell adhesion, spreading, migration, and cell division. It is generally accepted that localized GTPase activation is required for the proper initiation of downstream signaling events, although the molecular mechanisms that control targeting of Rho GTPases are unknown. In this study, we show that the Rho GTPase Rac1, via a proline stretch in its COOH terminus, binds directly to the SH3 domain of the Cdc42/Rac activator β-Pix (p21-activated kinase [Pak]–interacting exchange factor). The interaction with β-Pix is nucleotide independent and is necessary and sufficient for Rac1 recruitment to membrane ruffles and to focal adhesions. In addition, the Rac1–β-Pix interaction is required for Rac1 activation by β-Pix as well as for Rac1-mediated spreading. Finally, using cells deficient for the β-Pix–binding kinase Pak1, we show that Pak1 regulates the Rac1–β-Pix interaction and controls cell spreading and adhesion-induced Rac1 activation. These data provide a model for the intracellular targeting and localized activation of Rac1 through its exchange factor β-Pix.

Vaccinia Virus-Induced Cell Motility Requires F11L-Mediated Inhibition of RhoA Signaling

Science ◽  
2006 ◽  
Vol 311 (5759) ◽  
pp. 377-381 ◽  
Author(s):  
Ferran Valderrama ◽  
João V. Cordeiro ◽  
Sibylle Schleich ◽  
Friedrich Frischknecht ◽  
Michael Way
Keyword(s):  
Cell Migration ◽  
Rna Interference ◽  
Vaccinia Virus ◽  
Cell Motility ◽  
Binding Site ◽  
Critical Role ◽  
Cellular Processes ◽  
Downstream Effectors ◽  
Viral Morphogenesis ◽  
Rhoa Signaling

RhoA signaling plays a critical role in many cellular processes, including cell migration. Here we show that the vaccinia F11L protein interacts directly with RhoA, inhibiting its signaling by blocking the interaction with its downstream effectors Rho-associated kinase (ROCK) and mDia. RNA interference–mediated depletion of F11L during infection resulted in an absence of vaccinia-induced cell motility and inhibition of viral morphogenesis. Disruption of the RhoA binding site in F11L, which resembles that of ROCK, led to an identical phenotype. Thus, inhibition of RhoA signaling is required for both vaccinia morphogenesis and virus-induced cell motility.

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