scholarly journals Big roles for small GTPases in the control of directed cell movement

2006 ◽  
Vol 401 (2) ◽  
pp. 377-390 ◽  
Author(s):  
Pascale G. Charest ◽  
Richard A. Firtel
Keyword(s):  
Molecular Mechanisms ◽  
Cell Movement ◽  
Small Gtpases ◽  
Cell Polarization ◽  
Small Gtpase ◽  
Cellular Growth ◽  
Cellular Motility ◽  
Gradient Sensing ◽  
Directed Cell Migration ◽  
Shed Light

Small GTPases are involved in the control of diverse cellular behaviours, including cellular growth, differentiation and motility. In addition, recent studies have revealed new roles for small GTPases in the regulation of eukaryotic chemotaxis. Efficient chemotaxis results from co-ordinated chemoattractant gradient sensing, cell polarization and cellular motility, and accumulating data suggest that small GTPase signalling plays a central role in each of these processes as well as in signal relay. The present review summarizes these recent findings, which shed light on the molecular mechanisms by which small GTPases control directed cell migration.

Osmotic stress activates Rac and Cdc42 in neutrophils: role in hypertonicity-induced actin polymerization

2002 ◽  
Vol 282 (2) ◽  
pp. C271-C279 ◽  
Author(s):  
Alison Lewis ◽  
Caterina Di Ciano ◽  
Ori D. Rotstein ◽  
András Kapus
Keyword(s):  
Actin Polymerization ◽  
Cell Movement ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Phosphatidylinositol 3 Kinase ◽  
Cytoskeleton Remodeling ◽  
Clostridium Difficile Toxin ◽  
Clostridium Difficile Toxin B ◽  
Gtpase Activation ◽  
Fold Activation

Hypertonicity inhibits a variety of neutrophil functions through poorly defined mechanisms. Our earlier studies suggest that osmotically induced actin polymerization and cytoskeleton remodeling is a key component in the hypertonic block of exocytosis and cell movement. To gain insight into the signaling mechanisms underlying the hyperosmotic F-actin response, we investigated whether hypertonicity stimulates Rac and Cdc42 and, if so, whether their activation contributes to the hypertonic rise in F-actin. Using a recently developed pull-down assay that specifically captures the active forms of these small GTPases, we found that hypertonicity caused an ∼2.5- and ∼7.2-fold activation of Rac and Cdc42, respectively. This response was rapid and sustained. Small GTPase activation was not mediated by the osmotic stimulation of Src kinases, heterotrimeric G proteins, or phosphatidylinositol 3-kinase. Interestingly, an increase in intracellular ionic strength was sufficient to activate Rac even in the absence of cell shrinkage. Inhibition of Rac and Cdc42 by Clostridium difficile toxin B substantially reduced but did not abolish the hypertonicity-induced F-actin response. Thus hypertonicity is a potent activator of Rac and Cdc42, and this effect seems to play an important but not exclusive role in the hyperosmolarity-triggered cytoskeleton remodeling.

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.

Clinical, Cellular, and Molecular Aspects of Cancer Invasion

2003 ◽  
Vol 83 (2) ◽  
pp. 337-376 ◽  
Author(s):  
Marc Mareel ◽  
Ancy Leroy
Keyword(s):  
Cancer Cells ◽  
Cross Talk ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Platelet Activating Factor ◽  
Tumor Development ◽  
Genetic Alterations ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Host Cells

Invasion causes cancer malignancy. We review recent data about cellular and molecular mechanisms of invasion, focusing on cross-talk between the invaders and the host. Cancer disturbs these cellular activities that maintain multicellular organisms, namely, growth, differentiation, apoptosis, and tissue integrity. Multiple alterations in the genome of cancer cells underlie tumor development. These genetic alterations occur in varying orders; many of them concomitantly influence invasion as well as the other cancer-related cellular activities. Examples discussed are genes encoding elements of the cadherin/catenin complex, the nonreceptor tyrosine kinase Src, the receptor tyrosine kinases c-Met and FGFR, the small GTPase Ras, and the dual phosphatase PTEN. In microorganisms, invasion genes belong to the class of virulence genes. There are numerous clinical and experimental observations showing that invasion results from the cross-talk between cancer cells and host cells, comprising myofibroblasts, endothelial cells, and leukocytes, all of which are themselves invasive. In bone metastases, host osteoclasts serve as targets for therapy. The molecular analysis of invasion-associated cellular activities, namely, homotypic and heterotypic cell-cell adhesion, cell-matrix interactions and ectopic survival, migration, and proteolysis, reveal branching signal transduction pathways with extensive networks between individual pathways. Cellular responses to invasion-stimulatory molecules such as scatter factor, chemokines, leptin, trefoil factors, and bile acids or inhibitory factors such as platelet activating factor and thrombin depend on activation of trimeric G proteins, phosphoinositide 3-kinase, and the Rac and Rho family of small GTPases. The role of proteolysis in invasion is not limited to breakdown of extracellular matrix but also causes cleavage of proinvasive fragments from cell surface glycoproteins.

scholarly journals Cdc42 Is Not Essential for Filopodium Formation, Directed Migration, Cell Polarization, and Mitosis in Fibroblastoid Cells

2005 ◽  
Vol 16 (10) ◽  
pp. 4473-4484 ◽  
Author(s):  
Aleksandra Czuchra ◽  
Xunwei Wu ◽  
Hannelore Meyer ◽  
Jolanda van Hengel ◽  
Timm Schroeder ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Cell Shape ◽  
Cell Polarization ◽  
Small Gtpase ◽  
Dominant Negative ◽  
Directed Migration ◽  
Membrane Blebbing ◽  
Directed Cell Migration ◽  
Rho Family ◽  
Filopodium Formation

Cdc42 is a small GTPase involved in the regulation of the cytoskeleton and cell polarity. To test whether Cdc42 has an essential role in the formation of filopodia or directed cell migration, we generated Cdc42-deficient fibroblastoid cells by conditional gene inactivation. We report here that loss of Cdc42 did not affect filopodium or lamellipodium formation and had no significant influence on the speed of directed migration nor on mitosis. Cdc42-deficient cells displayed a more elongated cell shape and had a reduced area. Furthermore, directionality during migration and reorientation of the Golgi apparatus into the direction of migration was decreased. However, expression of dominant negative Cdc42 in Cdc42-null cells resulted in strongly reduced directed migration, severely reduced single cell directionality, and complete loss of Golgi polarization and of directionality of protrusion formation toward the wound, as well as membrane blebbing. Thus, our data show that besides Cdc42 additional GTPases of the Rho-family, which share GEFs with Cdc42, are involved in the establishment and maintenance of cell polarity during directed migration.

scholarly journals Rab17, a novel small GTPase, is specific for epithelial cells and is induced during cell polarization.

1993 ◽  
Vol 121 (3) ◽  
pp. 553-564 ◽  
Author(s):  
A Lütcke ◽  
S Jansson ◽  
R G Parton ◽  
P Chavrier ◽  
A Valencia ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Small Gtpases ◽  
Cell Polarization ◽  
Small Gtpase ◽  
Rab Proteins ◽  
Transport Pathways ◽  
Basolateral Plasma Membrane ◽  
Developing Kidney ◽  
Kidney Liver

The rab subfamily of small GTPases has been demonstrated to play an important role in the regulation of membrane traffic in eukaryotic cells. Compared with nonpolarized cells, epithelial cells have distinct apical and basolateral transport pathways which need to be separately regulated. This raises the question whether epithelial cells require specific rab proteins. However, all rab proteins identified so far were found to be equally expressed in polarized and nonpolarized cells. Here we report the identification of rab17, the first epithelial cell-specific small GTPase. Northern blot analysis on various mouse organs, revealed that the rab17 mRNA is present in kidney, liver, and intestine but not in organs lacking epithelial cells nor in fibroblasts. To determine whether rab17 is specific for epithelial cells we studied its expression in the developing kidney. We found that rab17 is absent from the mesenchymal precursors but is induced upon their differentiation into epithelial cells. In situ hybridization studies on the embryonic kidney and intestine revealed that rab17 is restricted to epithelial cells. By immunofluorescence and immunoelectron microscopy on kidney sections, rab17 was localized to the basolateral plasma membrane and to apical tubules. Rab proteins associated with two distinct compartments have been found to regulate transport between them. Therefore, our data suggest that rab17 might be involved in transcellular transport.

The polarization of the motile cell

1999 ◽  
Vol 112 (12) ◽  
pp. 1803-1811 ◽  
Author(s):  
I.R. Nabi
Keyword(s):  
Targeted Delivery ◽  
Molecular Mechanisms ◽  
Cell Movement ◽  
Leading Edge ◽  
Small Gtpases ◽  
Motile Cell ◽  
Vesicular Traffic ◽  
Substrate Adhesion ◽  
Molecular Machinery ◽  
Plasma Membrane Domain

Polarization of the motile cell is associated with the formation of a distinct plasma membrane domain, the pseudopod, whose stabilization determines the directionality of cell movement. The rapid movement of cells over a substrate requires that an essential aspect of cell motility must be the supply of the necessary molecular machinery to the site of pseudopodial extension. Renewal of this pseudopodial domain requires the directed delivery to the site of pseudopodial protrusion of proteins which regulate actin cytoskeleton dynamics, cell-substrate adhesion, and localized degradation of the extracellular matrix. Polarized targeting mechanisms include the targeted delivery of beta-actin mRNA to the leading edge and microtubule-based vesicular traffic. The latter may include Golgi-derived vesicles of the biosynthetic pathway as well as clathrin-dependent and clathrin-independent endocytosis and recycling. Coordination of protrusive activities and supply mechanisms is critical for efficient cellular displacement and may implicate small GTPases of the Rho family. While the specific molecular mechanisms underlying pseudopodial protrusion of the motile cell are well-characterized, discussion of these diverse mechanisms in the context of cellular polarization has been limited.

Crucial polarity regulators in axon specification

2012 ◽  
Vol 53 ◽  
pp. 55-68 ◽  
Author(s):  
Giovanna Lalli
Keyword(s):  
Nervous System ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Membrane Traffic ◽  
Small Gtpases ◽  
Cell Polarization ◽  
Microtubule Cytoskeleton ◽  
Morphological Asymmetry ◽  
Neuronal Polarization

Cell polarization is critical for the correct functioning of many cell types, creating functional and morphological asymmetry in response to intrinsic and extrinsic cues. Neurons are a classical example of polarized cells, as they usually extend one long axon and short branched dendrites. The formation of such distinct cellular compartments (also known as neuronal polarization) ensures the proper development and physiology of the nervous system and is controlled by a complex set of signalling pathways able to integrate multiple polarity cues. Because polarization is at the basis of neuronal development, investigating the mechanisms responsible for this process is fundamental not only to understand how the nervous system develops, but also to devise therapeutic strategies for neuroregeneration. The last two decades have seen remarkable progress in understanding the molecular mechanisms responsible for mammalian neuronal polarization, primarily using cultures of rodent hippocampal neurons. More recent efforts have started to explore the role of such mechanisms in vivo. It has become clear that neuronal polarization relies on signalling networks and feedback mechanisms co-ordinating the actin and microtubule cytoskeleton and membrane traffic. The present chapter will highlight the role of key molecules involved in neuronal polarization, such as regulators of the actin/microtubule cytoskeleton and membrane traffic, polarity complexes and small GTPases.

scholarly journals Nanodomain-mediated lateral sorting drives polarization of the small GTPase ROP2 in the plasma membrane of root hair cells

2021 ◽  
Author(s):  
Vanessa Aphaia Fiona Fuchs ◽  
Philipp Denninger ◽  
Milan Župunski ◽  
Yvon Jaillais ◽  
Ulrike Engel ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Single Molecule ◽  
Root Hair ◽  
Root Hairs ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Cellular Growth ◽  
Epifluorescence Microscopy ◽  
Anionic Phospholipids ◽  
Downstream Effectors

Formation of root hairs involves the targeted recruitment of the cellular growth machinery to the root hair initiation domain (RHID), a specialized site at the plasma membrane (PM) of trichoblast cells. Early determinants in RHID establishment are small GTPases of the Rho-of-plants (ROP) protein family, which are required for polarization of downstream effectors, membrane modification and targeted secretion during tip growth. It remains, however, not fully understood how ROP GTPases themselves are polarized. To investigate the mechanism underlying ROP2 recruitment, we employed Variable Angle Epifluorescence Microscopy (VAEM) and exploited mCitrine fluorophore blinking for single molecule localization, particle tracking and super-resolved imaging of the trichoblast plasma membrane. We observed the association of mCit-ROP2 within distinct membrane nanodomains, whose polar occurrence at the RHID was dependent on the presence of the RopGEF GEF3, and found a gradual, localized decrease of mCit-ROP2 protein mobility that preceded polarization. We provide evidence for a step-wise model of ROP2 polarization that involves (i) an initial non-polar recruitment to the plasma membrane via interactions with anionic phospholipids, (ii) ROP2 assembly into membrane nanodomains independent of nucleotide-binding state and, sub-sequently, (iii) lateral sorting into the RHID, driven by GEF3-mediated localized reduction of ROP2 mobility.

Zoledronate Exerts Direct Antiproliferative and Apoptotic Effects on Human Myeloma Cells In Vitro and In Vivo.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3387-3387
Author(s):  
Andreas Guenther ◽  
Sharon Gordon ◽  
Frank Bakker ◽  
Renate Burger ◽  
Markus Tiemann ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Specific Effect ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Control Group ◽  
Dependent Manner ◽  
Myeloma Cells ◽  
Osteolytic Bone Disease

Abstract Zoledronate (ZOL) is the most potent nitrogen-containing bisphosphonate and is effective at preventing osteolytic bone disease in patients with multiple myeloma (MM) and solid tumors. ZOL inhibits the enzyme farnesylpyrophosphate synthase and thus blocks the prenylation of small GTPases. In vitro studies have demonstrated that ZOL can also directly affect the growth and viability of myeloma cells, however, the molecular mechanisms underlying this activity have not been fully elucidated. The goal of our study was to investigate direct antimyeloma effects of ZOL in vitro and in vivo. In five myeloma cell lines (RPMI8226, L363, U266, JK-6L, and the IL-6 dependent INA-6), growth was inhibited and apoptosis induced by ZOL in a dose-dependent manner (IC50’s between 30 μM and 285 μM). Similar results were obtained in the presence of bone marrow stromal cells, IL-6 (20 ng/mL), IGF-1 (200 ng/mL), or a combination of both cytokines. The potential antitumor effect of ZOL on myeloma cells in vivo was studied in the INA-6 SCID model, in which mice are injected intraperitoneally with INA-6 cells and subsequently develop plasmacytomas. Mice treated with ZOL had reduced tumor burden and a significant survival benefit compared to the control group (p=0.002). Histological examination of plasmacytomas explanted 72 hours after a single injection of 8 μg ZOL revealed extensive apoptotic/necrotic areas while no such areas were found in tumors of untreated animals. Induction of apoptosis was confirmed by Western blot analysis of tumor lysates, which revealed increased levels of cleaved poly (ADP-ribose) polymerase (PARP) in tumors of ZOL treated vs. untreated animals. This correlated with an accumulation of the unprenylated form of the small GTPase Rap1A, which was virtually absent in tumors of untreated mice. Our findings demonstrate a direct and specific effect of ZOL in plasmacytomas in vitro and in vivo and point to a therapeutic potential in MM beyond the prevention of osteolytic lesions.

scholarly journals Effects of cell tension on the small GTPase Rac

2002 ◽  
Vol 158 (1) ◽  
pp. 153-164 ◽  
Author(s):  
Akira Katsumi ◽  
Julie Milanini ◽  
William B. Kiosses ◽  
Miguel A. del Pozo ◽  
Roland Kaunas ◽  
...  
Keyword(s):  
Critical Role ◽  
Cell Movement ◽  
Cell Polarization ◽  
Mechanical Stresses ◽  
Small Gtpase ◽  
The Body ◽  
Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Biochemical Signals ◽  
Constitutively Active

Cells in the body are subjected to mechanical stresses such as tension, compression, and shear stress. These mechanical stresses play important roles in both physiological and pathological processes; however, mechanisms transducing mechanical stresses into biochemical signals remain elusive. Here, we demonstrated that equibiaxial stretch inhibited lamellipodia formation through deactivation of Rac. Nearly maximal effects on Rac activity were obtained with 10% strain. GAP-resistant, constitutively active V12Rac reversed this inhibition, supporting a critical role for Rac inhibition in the response to stretch. In contrast, activation of endogenous Rac with a constitutively active nucleotide exchange factor did not, suggesting that regulation of GAP activity most likely mediates the inhibition. Uniaxial stretch suppressed lamellipodia along the sides lengthened by stretch and increased it at the adjacent ends. A fluorescence assay for localized Rac showed comparable changes in activity along the sides versus the ends after uniaxial stretch. Blocking polarization of Rac activity by expressing V12Rac prevented subsequent alignment of actin stress fibers. Treatment with Y-27632 or ML-7 that inhibits myosin phosphorylation and contractility increased lamellipodia through Rac activation and decreased cell polarization. We hypothesize that regulation of Rac activity by tension may be important for motility, polarization, and directionality of cell movement.

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