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31
Actin can reorganize into podosomes in aortic endothelial cells, a process controlled by Cdc42
, 2003
"... Members of the Rho GTPase family play a central role in the orchestration of cytoskeletal rearrangements, which are of prime importance in endothelial cell physiology. To explore their role in this specialized cell type, we used the bacterial toxin cytotoxic necrotizing factor 1 (CNF1) as a Rho GTPa ..."
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Members of the Rho GTPase family play a central role in the orchestration of cytoskeletal rearrangements, which are of prime importance in endothelial cell physiology. To explore their role in this specialized cell type, we used the bacterial toxin cytotoxic necrotizing factor 1 (CNF1) as a Rho GTPase activator. Punctate filamentous actin structures appeared along the ventral plasma membrane of endothelial cells and were identified as the core of podosomes by the distinctive vinculin ring around the F-actin. Rho, Rac, and Cdc42 were all identified as targets of CNF1, but only a constitutively active mutant of Cdc42 could substitute for CNF1 in podosome induction. Accordingly, organization of F-actin in these structures was highly dependent on the main Cdc42 cytoskeletal effector N-Wiskott-Aldrich syndrome protein. Other components of the actin machinery such as Arp2/3 and for the first time WIP also colocalized at these sites. Like CNF1 treatment, sustained Cdc42 activity induced a time-dependent F-actin–vinculin reorganization, prevented cytokinesis, and downregulated Rho activity. Finally, podosomes were also detected on endothelial cells explanted from patients undergoing cardiac surgery. These data provide the first description of podosomes in endothelial cells. The identification of such specialized structures opens up a new field of investigation in terms of endothelium pathophysiology. Actin cytoskeleton rearrangements are the basis of many
2001. Rac mediates cytoskeletal rearrangements and increased cell motility induced by urokinase-type plasminogen activator receptor binding to vitronectin
- J. Cell
"... Abstract. The urokinase-type plasminogen activator receptor (uPAR) is involved in the regulation of cell motility in a variety of cell types. We show here that expression of human uPAR in growing murine fibroblasts leads to a dramatic reorganization of the actin cytoskeleton. uPAR expression induces ..."
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Cited by 24 (1 self)
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Abstract. The urokinase-type plasminogen activator receptor (uPAR) is involved in the regulation of cell motility in a variety of cell types. We show here that expression of human uPAR in growing murine fibroblasts leads to a dramatic reorganization of the actin cytoskeleton. uPAR expression induces multiple rapidly advancing protrusions that resemble the leading edge of migrating cells. The cytoskeletal changes are independent of uPA and activation of the RGD-binding activity of integrins but require uPAR binding to vitronectin (VN). The actin reorganization is blocked by coexpression of dominant negative versions of either Rac (N17Rac) or p130Cas, but not by inhibitors of Cdc42 or Rho, and is accompanied by a Rac-dependent increase in cell motility. In addition, a fourfold increase in the
Cell membrane alignment along adhesive surfaces: contribution of active and passive cell processes
- Biophys. J
, 2003
"... ABSTRACT Cell adhesion requires nanometer scale membrane alignment to allow contact between adhesion receptors. Little quantitative information is presently available on this important biological process. Here we present an interference reflection microscopic study of the initial interaction between ..."
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Cited by 13 (0 self)
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ABSTRACT Cell adhesion requires nanometer scale membrane alignment to allow contact between adhesion receptors. Little quantitative information is presently available on this important biological process. Here we present an interference reflection microscopic study of the initial interaction betweenmonocytic THP-1 cells and adhesive surfaces, with concomitant determination of cell deformability, using micropipette aspiration, and adhesiveness, using a laminar flow assay. We report that 1), during the first few minutes after contact, cells form irregular-shaped interaction zones reaching;100 mm2 with a margin extension velocity of 0.01–0.02 mm/s. This happens before the overall cell deformations usually defined as spreading. 2), These interference reflection microscopic-detected zones represent bona fide adhesion inasmuch as cells are not released by hydrodynamic forces. 3), Alignment is markedly decreased but not abolished by microfilament blockade with cytochalasin or even cell fixation with paraformaldehyde. 4), In contrast, exposing cells to hypotonic medium increased the rate of contact extension. 5), Contacts formed in presence of cytochalasin, after paraformaldehyde fixation or in hypotonic medium, were much more regular-shaped than controls and their extension matched cell deformability. 6), None of the aforementioned treatments altered adhesiveness to the surface. It is concluded that adhesive forces and passive membrane deformations are sufficient to generate initial cell alignment to adhesive surfaces, and this process is accelerated by spontaneous cytoskeletally-driven membrane motion.
Comment Rho GTPases: Integrating Integrin Signaling
"... The composition of the extracellular matrix (ECM) surrounding cells is key to their behavior: it modulates their ability to proliferate, differentiate, and migrate (Giancotti and Ruoslahti, 1999). ECM components can signal directly to cells through transmembrane receptors such as integrins, and can ..."
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The composition of the extracellular matrix (ECM) surrounding cells is key to their behavior: it modulates their ability to proliferate, differentiate, and migrate (Giancotti and Ruoslahti, 1999). ECM components can signal directly to cells through transmembrane receptors such as integrins, and can also present soluble cytokines and growth factors to cells. The morphology of cells varies greatly depending on the composition of the extracellular matrix to which they are exposed, but the molecular basis for these differences has not been clarified. Now, two papers in this issue of The Journal of Cell Biology (Adams and Schwartz, 2000; Wenk et al., 2000) show that these variations in cell morphology reflect differential activation of specific Rho GTPases. Cell morphology and migration are known to be regulated
Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo
"... ABSTRACT Reperfusion of ischemic tissue results in the generation of reactive oxygen species that contribute to tissue injury. The sources of reactive oxygen species in reperfused tissue are not fully characterized. We hypothesized that the small GT-Pase Rac1 mediates the oxidative burst in reperfus ..."
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ABSTRACT Reperfusion of ischemic tissue results in the generation of reactive oxygen species that contribute to tissue injury. The sources of reactive oxygen species in reperfused tissue are not fully characterized. We hypothesized that the small GT-Pase Rac1 mediates the oxidative burst in reperfused tissue and thereby contributes to reperfusion injury. In an in vivo model of mouse hepatic ischemia/reperfusion injury, recombinant adenoviral expression of a dominant negative Rac1 (Rac1N17) completely suppressed the ischemia/reperfusion-induced production of reactive oxygen species and lipid peroxides, activation of nuclear factor-kappa B, and resulted in a significant reduction of acute liver necrosis. Expression of Rac1N17 also suppressed ischemia/reperfusion-induced acute apoptosis. The protection offered by Rac1N17 was also evident in knockout mice deficient for the gp91phox component of the phagocyte NADPH oxidase. This work demonstrates the crucial role of a Rac1-regulated oxidase in mediating the production of injurious reactive oxygen species, which contribute to acute necrotic and apoptotic cell death induced by ischemia/reperfusion in vivo. Targeted inhibition of this oxidase, which is distinct from the phagocyte NADPH oxidase, should provide a new avenue for in vivo therapy aimed at protecting organs at risk from ischemia/reperfusion injury.—Ozaki, M., Deshpande,
Upregulation of the Rac1/JNK signaling pathway in primary human schwannoma cells. Human Molecular Genetics
, 2003
"... Schwann cells lacking the tumor-suppressor-protein merlin tend in man to build benign tumors (schwannoma). We observed that characteristic features of these cells which are relevant to tumorigenicity resemble those described in cells with high Rac activity. Moreover this small GTPase also phosphoryl ..."
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Schwann cells lacking the tumor-suppressor-protein merlin tend in man to build benign tumors (schwannoma). We observed that characteristic features of these cells which are relevant to tumorigenicity resemble those described in cells with high Rac activity. Moreover this small GTPase also phosphorylates merlin via PAK activation. We hypothesized that merlin deficiency might cause an activation of Rac and its dependent signaling pathways, in particular the pro-tumorigenic JNK pathway. We show an enhanced activation of Rac1 in primary human schwannoma cells, find both Rac and its effector PAK at the membrane where they colocalize, and describe increased levels of phosphorylated JNK in the nucleus of these cells. Further we describe regulation at post-transcriptional level with upregulated protein, but not mRNA levels for Rac1, and JNK1/2. We conclude that merlin regulates Rac activation, and suggest that this is important for human schwannoma cell dedifferentiation.
2003. Role of Rho-family GTPase Cdc42 in polarized expression of lymphocyte appendages
"... Abstract: Lymphocytes polarize for motility by developing a broad anterior, where lamellipodia arise, and a simple stalk-like posterior appendage, the uropod. Through time-lapse analysis of normal and leukemic human T cells, it was found that this polarized form is maintained by a mechanism that exc ..."
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Abstract: Lymphocytes polarize for motility by developing a broad anterior, where lamellipodia arise, and a simple stalk-like posterior appendage, the uropod. Through time-lapse analysis of normal and leukemic human T cells, it was found that this polarized form is maintained by a mechanism that excludes lamellipodia from the uropod. Lamellipo-dia regularly traveled rearward to encroach upon the uropod but disassembled abruptly at the uro-pod border. This exclusion of lamellipodia from the uropod required the Rho-family guanosine triphosphatase Cdc42. Reduction of Cdc42 activ-ity by expression of dominant-negative Cdc42 re-sulted in “two headed ” cells in which lamellipodia persisted at the distal end of the uropod. Random and chemotactic motility were impaired. Increased Cdc42 activity, induced by expression of activated, mutant Cdc42, was accompanied by a general loss of lamellipodia. The results suggest that one role of Cdc42 in lymphocyte motility is to preserve polar-ity by concentrating lamellipodial disassembly sig-nals in the uropod. J. Leukoc. Biol. 73: 830–840;
Signaling networks regulating �1 integrin-mediated adhesion of T lymphocytes to extracellular matrix
"... Abstract: T-cell recognition of foreign antigen and migration to specific anatomic sites in vivo involves transient adhesive contacts between �1 integrins expressed on T cells and cell surface proteins or extracellular-matrix components. Engagement of the CD3-T-cell receptor (CD3-TCR) complex initia ..."
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Abstract: T-cell recognition of foreign antigen and migration to specific anatomic sites in vivo involves transient adhesive contacts between �1 integrins expressed on T cells and cell surface proteins or extracellular-matrix components. Engagement of the CD3-T-cell receptor (CD3-TCR) complex initiates a complex signaling cascade involving coordinated regulation and recruitment of tyrosine and lipid kinases to specific regions or microdomains in the plasma membrane. Although considerable attention has been focused on the signaling events by which the CD3-TCR complex regulates transcriptional events in the nucleus, CD3-TCR signaling also rapidly enhances integrin-mediated adhesion without increasing surface expression of integrins. Recent studies suggest that CD3-TCR signaling to �1 integrins involves coordinated recruitment and activation of the Tec family tyrosine kinase Itk by src family tyrosine kinases and phosphatidylinositol 3-kinase. These signaling events that regulate integrin-mediated T-cell adhesion share both common and distinct features with the signaling pathways regulating interleukin-2 gene
Studies on the Transmembrane Signaling of β1 Integrins BY
"... Armulik, A. 2000. Studies on the transmembrane signaling of β1 integrins. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 963. 92 pp. Uppsala. ISBN 91-544-4832-1. Integrins are heterodimeric cell surface receptors, composed of an α and a ..."
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Armulik, A. 2000. Studies on the transmembrane signaling of β1 integrins. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 963. 92 pp. Uppsala. ISBN 91-544-4832-1. Integrins are heterodimeric cell surface receptors, composed of an α and a β subunit, mainly for binding extracellular matrix proteins. Integrin subunit β1 can combine with at least 12 α subunits and thus form the biggest subfamily within the integrin family. In this thesis, functional properties of the splice variant β1B, and the effects of several mutations in the cytoplasmic tail of integrin subunit β1A were studied. In addition, the border between the transmembrane and cytoplasmic domains of several integrin subunits was determined. The β1B splice variant has been reported to have a dominant negative effect on functions of β1A integrins. In this study, it was studied if the expression of β1B had similar negative effects on the αvβ3 integrin functions since the β3 subunit is structurally similar to β1A. The β1B subunit was expressed in an integrin β1-deficient cell line and it was found that the presence of β1B does not interfere with adhesion or signaling of endogenous αvβ3.
Chemokine stromal cell-derived factor-1a modulates VLA-4 integrin-mediated
"... multiple myeloma cell adhesion to CS-1/fibronectin and VCAM-1 ..."
