scholarly journals The Intrinsic GDP/GTP Exchange Activities of Cdc42 and Rac1 Are Critical Determinants for Their Specific Effects on Mobilization of the Actin Filament System

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 759 ◽  
Author(s):  
Pontus Aspenström
Keyword(s):  
Actin Filament ◽  
Rho Gtpases ◽  
Focal Adhesions ◽  
Small Gtpases ◽  
Migration And Invasion ◽  
Actin Nucleation ◽  
Filament System ◽  
Prevailing Paradigm ◽  
Specific Effects ◽  
Cytoskeletal Dynamics

The Rho GTPases comprise a subfamily of the Ras superfamily of small GTPases. Their importance in regulation of cell morphology and cell migration is well characterized. According to the prevailing paradigm, Cdc42 regulates the formation of filopodia, Rac1 regulates the formation of lamellipodia, and RhoA triggers the assembly of focal adhesions. However, this scheme is clearly an oversimplification, as the Rho subfamily encompasses 20 members with diverse effects on a number of vital cellular processes, including cytoskeletal dynamics and cell proliferation, migration, and invasion. This article highlights the importance of the catalytic activities of the classical Rho GTPases Cdc42 and Rac1, in terms of their specific effects on the dynamic reorganization of the actin filament system. GTPase-deficient mutants of Cdc42 and Rac1 trigger the formation of broad lamellipodia and stress fibers, and fast-cycling mutations trigger filopodia formation and stress fiber dissolution. The filopodia response requires the involvement of the formin family of actin nucleation promotors. In contrast, the formation of broad lamellipodia induced by GTPase-deficient Cdc42 and Rac1 is mediated through Arp2/3-dependent actin nucleation.

scholarly journals RhoD regulates cytoskeletal dynamics via the actin nucleation–promoting factor WASp homologue associated with actin Golgi membranes and microtubules

2012 ◽  
Vol 23 (24) ◽  
pp. 4807-4819 ◽  
Author(s):  
Annica K. B. Gad ◽  
Vishal Nehru ◽  
Aino Ruusala ◽  
Pontus Aspenström
Keyword(s):  
Cell Migration ◽  
Actin Filament ◽  
Rho Gtpases ◽  
Actin Dynamics ◽  
Filamin A ◽  
Actin Nucleation ◽  
Cellular Processes ◽  
Golgi Membranes ◽  
Cytoskeletal Dynamics ◽  
Nucleation Promoting Factor

The Rho GTPases have mainly been studied in association with their roles in the regulation of actin filament organization. These studies have shown that the Rho GTPases are essential for basic cellular processes, such as cell migration, contraction, and division. In this paper, we report that RhoD has a role in the organization of actin dynamics that is distinct from the roles of the better-studied Rho members Cdc42, RhoA, and Rac1. We found that RhoD binds the actin nucleation–promoting factor WASp homologue associated with actin Golgi membranes and microtubules (WHAMM), as well as the related filamin A–binding protein FILIP1. Of these two RhoD-binding proteins, WHAMM was found to bind to the Arp2/3 complex, while FILIP1 bound filamin A. WHAMM was found to act downstream of RhoD in regulating cytoskeletal dynamics. In addition, cells treated with small interfering RNAs for RhoD and WHAMM showed increased cell attachment and decreased cell migration. These major effects on cytoskeletal dynamics indicate that RhoD and its effectors control vital cytoskeleton-driven cellular processes. In agreement with this notion, our data suggest that RhoD coordinates Arp2/3-dependent and FLNa-dependent mechanisms to control the actin filament system, cell adhesion, and cell migration.

scholarly journals Activated Rho GTPases in Cancer—The Beginning of a New Paradigm

2018 ◽  
Vol 19 (12) ◽  
pp. 3949 ◽  
Author(s):  
Pontus Aspenström
Keyword(s):  
Cancer Progression ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Small Gtpases ◽  
Cell Morphogenesis ◽  
New Paradigm ◽  
Direct Involvement ◽  
Cell Locomotion ◽  
Human Cancers ◽  
Cytoskeletal Dynamics

Involvement of Rho GTPases in cancer has been a matter of debate since the identification of the first members of this branch of the Ras superfamily of small GTPases. The Rho GTPases were ascribed important roles in the cell, although these were restricted to regulation of cytoskeletal dynamics, cell morphogenesis, and cell locomotion, with initially no clear indications of direct involvement in cancer progression. This paradigm has been challenged by numerous observations that Rho-regulated pathways are often dysregulated in cancers. More recently, identification of point mutants in the Rho GTPases Rac1, RhoA, and Cdc42 in human tumors has finally given rise to a new paradigm, and we can now state with confidence that Rho GTPases serve as oncogenes in several human cancers. This article provides an exposé of current knowledge of the roles of activated Rho GTPases in cancers.

scholarly journals Regulation of Rho GTPases in the Vasculature by Cullin3-Based E3 Ligase Complexes

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabienne Podieh ◽  
Peter L. Hordijk
Keyword(s):  
Rho Gtpases ◽  
Vascular Function ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
E3 Ligase ◽  
Small Gtpases ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Ubiquitin E3 Ligase ◽  
Cytoskeletal Dynamics

Cullin3-based ubiquitin E3 ligases induce ubiquitination of substrates leading to their proteasomal or lysosomal degradation. BTB proteins serve as adaptors by binding to Cullin3 and recruiting substrate proteins, which enables specific recognition of a broad spectrum of targets. Hence, Cullin3 and its adaptors are involved in myriad cellular processes and organ functions. Cullin3-based ubiquitin E3 ligase complexes target small GTPases of the Rho subfamily, which are key regulators of cytoskeletal dynamics and cell adhesion. In this mini review, we discuss recent insights in Cullin3-mediated regulation of Rho GTPases and their impact on cellular function and disease. Intriguingly, upstream regulators of Rho GTPases are targeted by Cullin3 complexes as well. Thus, Rho GTPase signaling is regulated by Cullin3 on multiple levels. In addition, we address current knowledge of Cullin3 in regulating vascular function, focusing on its prominent role in endothelial barrier function, angiogenesis and the regulation of blood pressure.

External mechanical strain regulates membrane targeting of Rho GTPases by controlling microtubule assembly

2003 ◽  
Vol 284 (3) ◽  
pp. C627-C639 ◽  
Author(s):  
Andrew J. Putnam ◽  
James J. Cunningham ◽  
Brendan B. L. Pillemer ◽  
David J. Mooney
Keyword(s):  
Rho Gtpases ◽  
Tensile Strain ◽  
Compressive Strain ◽  
Mechanical Strain ◽  
Focal Adhesions ◽  
Small Gtpases ◽  
Microtubule Assembly ◽  
A Cell ◽  
Applied Forces ◽  
Triton X

Transmission of externally applied mechanical forces to the interior of a cell requires coordination of biochemical signaling pathways with changes in cytoskeletal assembly and organization. In this study, we addressed one potential mechanism for this signal integration by applying uniform single external mechanical strains to aortic smooth muscle cells (SMCs) via their adhesion substrate. A tensile strain applied to the substrate for 15 min significantly increased microtubule (MT) assembly by 32 ± 7%, with no apparent effect on the cells' focal adhesions as revealed by immunofluorescence and quantitative analysis of Triton X-100-insoluble vinculin levels. A compressive strain decreased MT mass by 24 ± 9% but did not influence the level of vinculin in focal adhesions. To understand the decoupling of these two cell responses to mechanical strain, we examined a redistribution of the small GTPases RhoA and Rac. Tensile strain was found to decrease the amount of membrane-associated RhoA and Rac by 70 ± 9% and 45 ± 11%, respectively, compared with static controls. In contrast, compressive strain increased membrane-associated RhoA and Rac levels by 74 ± 17% and 36 ± 13%, respectively. Disruption of the MT network by prolonged treatments with low doses of either nocodazole or paclitaxel before the application of strain abolished the redistribution of RhoA and Rac in response to the applied forces. Combined, these results indicate that the effects of externally applied mechanical strain on the distribution and activation of the Rho family GTPases require changes in the state of MT polymerization.

scholarly journals Rho GTPases Control Polarity, Protrusion, and Adhesion during Cell Movement

1999 ◽  
Vol 144 (6) ◽  
pp. 1235-1244 ◽  
Author(s):  
Catherine D. Nobes ◽  
Alan Hall
Keyword(s):  
Rho Gtpases ◽  
Actin Filaments ◽  
Cell Movement ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Small Gtpases ◽  
Animal Cells ◽  
Forward Movement ◽  
Direction Of Movement

Cell movement is essential during embryogenesis to establish tissue patterns and to drive morphogenetic pathways and in the adult for tissue repair and to direct cells to sites of infection. Animal cells move by crawling and the driving force is derived primarily from the coordinated assembly and disassembly of actin filaments. The small GTPases, Rho, Rac, and Cdc42, regulate the organization of actin filaments and we have analyzed their contributions to the movement of primary embryo fibroblasts in an in vitro wound healing assay. Rac is essential for the protrusion of lamellipodia and for forward movement. Cdc42 is required to maintain cell polarity, which includes the localization of lamellipodial activity to the leading edge and the reorientation of the Golgi apparatus in the direction of movement. Rho is required to maintain cell adhesion during movement, but stress fibers and focal adhesions are not required. Finally, Ras regulates focal adhesion and stress fiber turnover and this is essential for cell movement. We conclude that the signal transduction pathways controlled by the four small GTPases, Rho, Rac, Cdc42, and Ras, cooperate to promote cell movement.

scholarly journals GGA2 and RAB13 promote activity-dependent β1-integrin recycling

2018 ◽  
Author(s):  
Pranshu Sahgal ◽  
Jonna Alanko ◽  
Jaroslav Icha ◽  
Ilkka Paatero ◽  
Hellyeh Hamidi ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cell ◽  
Focal Adhesions ◽  
Small Gtpases ◽  
Migration And Invasion ◽  
Β1 Integrin ◽  
Dynamic Regulation ◽  
Mediate Cell ◽  
Cell Matrix Interactions ◽  
Activity Dependent

Abstractβ1-integrins mediate cell-matrix interactions and their trafficking is important in the dynamic regulation of cell adhesion, migration and malignant processes like cancer cell invasion. Here we employ an RNAi screen to characterize regulators of integrin traffic and identify the association of Golgi-localized gamma ear-containing Arf-binding protein 2 (GGA2) with β1-integrin and its role in recycling of the active but not inactive β1-integrin receptors. Silencing of GGA2 limits active β1-integrin levels in focal adhesions and decreases cancer cell migration and invasion congruent with its ability to regulate the dynamics of active integrins. Using the proximity-dependent biotin identification (BioID) method, we identify two RAB family small GTPases, RAB13 and RAB10, associating with GGA2 and β1-integrin. Functionally, RAB13 silencing triggers the intracellular accumulation of active β1-integrin, reduces integrin activity, in focal adhesions, and cell migration, similarly to GGA2 depletion, indicating that both facilitate active β1-integrin recycling the plasma membrane. Thus, GGA2 and RAB13 are important specificity determinants for integrin activity-dependent traffic.

scholarly journals Rho GTPases have diverse effects on the organization of the actin filament system

2004 ◽  
Vol 377 (2) ◽  
pp. 327-337 ◽  
Author(s):  
Pontus ASPENSTRÖM ◽  
Åsa FRANSSON ◽  
Jan SARAS
Keyword(s):  
Endothelial Cells ◽  
Actin Filament ◽  
Focal Adhesion ◽  
Rho Gtpases ◽  
Actin Filaments ◽  
Rho Gtpase ◽  
Major Influence ◽  
Aortic Endothelial Cells ◽  
Filament System ◽  
Porcine Aortic Endothelial Cells

The Rho GTPases are related to the Ras proto-oncogenes and consist of 22 family members. These proteins have important roles in regulating the organization of the actin filament system, and thereby the morphogenesis of vertebrate cells as well as their ability to migrate. In an effort to compare the effects of all members of the Rho GTPase family, active Rho GTPases were transfected into porcine aortic endothelial cells and the effects on the actin filament system were monitored. Cdc42, TCL (TC10-like), Rac1–Rac3 and RhoG induced the formation of lamellipodia, whereas Cdc42, Rac1 and Rac2 also induced the formation of thick bundles of actin filaments. In contrast, transfection with TC10 or Chp resulted in the formation of focal adhesion-like structures, whereas Wrch-1 induced long and thin filopodia. Transfection with RhoA, RhoB or RhoC induced the assembly of stress fibres, whereas Rnd1–Rnd3 resulted in the loss of stress fibres, but this effect was associated with the formation of actin- and ezrin-containing dorsal microvilli. Cells expressing RhoD and Rif had extremely long and flexible filopodia. None of the RhoBTB or Miro GTPases had any major influence on the organization of the actin filament system; instead, RhoBTB1 and RhoBTB2 were present in vesicular structures, and Miro-1 and Miro-2 were present in mitochondria. Collectively, the data obtained in this study to some extent confirm earlier observations, but also allow the identification of previously undetected roles of the different members of the Rho GTPases.

scholarly journals Bacterial Guanine Nucleotide Exchange Factors SopE-Like and WxxxE Effectors

2010 ◽  
Vol 78 (4) ◽  
pp. 1417-1425 ◽  
Author(s):  
Richard Bulgin ◽  
Benoit Raymond ◽  
James A. Garnett ◽  
Gad Frankel ◽  
Valerie F. Crepin ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Rho Gtpases ◽  
Shigella Flexneri ◽  
Small Gtpases ◽  
Effector Proteins ◽  
Actin Dynamics ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
T3ss Effector

ABSTRACT Subversion of Rho family small GTPases, which control actin dynamics, is a common infection strategy used by bacterial pathogens. In particular, Salmonella enterica serovar Typhimurium, Shigella flexneri, enteropathogenic Escherichia coli (EPEC), and enterohemorrhagic Escherichia coli (EHEC) translocate type III secretion system (T3SS) effector proteins to modulate the Rho GTPases RhoA, Cdc42, and Rac1, which trigger formation of stress fibers, filopodia, and lamellipodia/ruffles, respectively. The Salmonella effector SopE is a guanine nucleotide exchange factor (GEF) that activates Rac1 and Cdc42, which induce “the trigger mechanism of cell entry.” Based on a conserved Trp-xxx-Glu motif, the T3SS effector proteins IpgB1 and IpgB2 of Shigella, SifA and SifB of Salmonella, and Map of EPEC and EHEC were grouped together into a WxxxE family; recent studies identified the T3SS EPEC and EHEC effectors EspM and EspT as new family members. Recent structural and functional studies have shown that representatives of the WxxxE effectors share with SopE a 3-D fold and GEF activity. In this minireview, we summarize contemporary findings related to the SopE and WxxxE GEFs in the context of their role in subverting general host cell signaling pathways and infection.

Sign in / Sign up

Export Citation Format

Share Document