Rac GTPase

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Konstantin G Birukov - One of the best experts on this subject based on the ideXlab platform.

  • Rac GTPase is a hub for protein kinase a and epac signaling in endothelial barrier protection by camp
    Microvascular Research, 2010
    Co-Authors: Anna A. Birukova, Nurgul Moldobaeva, Dylan Burdette, Panfeng Fu, Junjie Xing, Konstantin G Birukov
    Abstract:

    AbstRact Elevation in intRacellular cAMP level has been associated with increased endothelial barrier integrity and linked to the activation of protein kinase A (PKA). Recent studies have shown a novel mechanism of cAMP-mediated endothelial barrier regulation via cAMP-dependent nucleotide exchange factor Epac1 and Rap1 GTPase. This study examined a contribution of PKA-dependent and PKA-independent pathways in the human pulmonary endothelial (EC) barrier protection by cAMP. Synthetic cAMP analog, 8-bromoadenosine-3′,5′-cyclic monophosphate (Br-cAMP), induced dose-dependent increase in EC transendothelial electrical resistance which was associated with activation of PKA, Epac/Rap1, and Tiam/Vav/Rac cascades and significantly attenuated thrombin-induced EC barrier disruption. Both specific Epac/Rap1 activator 8CPT-2Me-cAMP (8CPT) and specific PKA activator N 6 -benzoyl-adenosine-3′,5′-cyclic monophosphate (6Bnz) enhanced EC barrier, suppressed thrombin-induced EC permeability, and independently activated small GTPase Rac. SiRNA-induced Rac knockdown suppressed barrier protective effects of both PKA and Epac signaling in pulmonary EC. Intravenous administration of either 6Bnz, or 8CPT, significantly reduced lung vascular leak in the murine model of lung injury induced by high tidal volume mechanical ventilation (HTV, 30 ml/kg, 4 h), whereas combined treatment with 6Bnz and 8CPT showed no further additive effects. This study dissected for the first time PKA and Epac pathways of lung EC barrier protection caused by cAMP elevation and identified Rac GTPase as a hub for PKA and Epac signaling leading to enhancement of lung vascular barrier.

  • hgf attenuates thrombin induced endothelial permeability by tiam1 mediated activation of the Rac pathway and by tiam1 Rac dependent inhibition of the rho pathway
    The FASEB Journal, 2007
    Co-Authors: Anna A. Birukova, Elena Alekseeva, A S Mikaelyan, Konstantin G Birukov
    Abstract:

    Reorganization of the endothelial cell (EC) cytoskeleton and cell adhesive complexes provides a structural basis for increased vascular permeability implicated in the pathogenesis of many diseases, including asthma, sepsis, and acute respiratory distress syndrome (ARDS). We have recently described the barrier-protective effects of hepatocyte growth factor (HGF) on the human pulmonary EC. In the present study, we explored the involvement of Rac-GTPase and Rac-specific nucleotide exchange factor Tiam1 in the mechanisms of EC barrier protection by HGF. HGF protected EC monolayers from thrombin-induced hyperpermeability, disruption of intercellular junctions, and formation of stress fibers and paRacellular gaps by inhibiting thrombin-induced activation of Rho GTPase, Rho association with nucleotide exchange factor p115-RhoGEF, and myosin light chain phosphorylation, which was opposed by stimulation of Rac-dependent signaling. The pharmacological Rac inhibitor or silencing RNA (siRNA) based depletion of either...

  • s1p induces fa remodeling in human pulmonary endothelial cells role of Rac git1 fak and paxillin
    Journal of Applied Physiology, 2003
    Co-Authors: Yasushi Shikata, Konstantin G Birukov, Joe G N Garcia
    Abstract:

    Sphingosine 1-phosphate (S1P) enhances human pulmonary endothelial monolayer integrity via Rac GTPase-dependent formation of a cortical actin ring (Garcia et al.J Clin Invest 108: 689–701, 2001). T...

  • s1p induces fa remodeling in human pulmonary endothelial cells role of Rac git1 fak and paxillin
    Journal of Applied Physiology, 2003
    Co-Authors: Yasushi Shikata, Konstantin G Birukov, Joe G N Garcia
    Abstract:

    Sphingosine 1-phosphate (S1P) enhances human pulmonary endothelial monolayer integrity via Rac GTPase-dependent formation of a cortical actin ring (Garcia et al. J Clin Invest 108: 689-701, 2001). The mechanisms underlying this response are not well understood but may involve rapid redistribution of focal adhesions (FA) as attachment sites for actin filaments. We evaluate the effects of S1P on the redistribution of paxillin, FA kinase (FAK), and the G protein-coupled receptor kinase-inteRacting proteins (GITs). S1P induced Rac GTPase activation and cortical actin ring formation at physiological concentrations (0.5 microM), whereas 5 microM S1P caused prominent stress fiber formation and activation of Rho and Rac GTPases. S1P (0.5 microM) stimulated the tyrosine phosphorylation of FAK Y(576), and paxillin was linked to FA disruption and redistribution to the cell periphery. Furthermore, S1P induced a transient association of GIT1 with paxillin and redistribution of the GIT2-paxillin complex to the cell cortical area without affecting GIT2-paxillin association. These results suggest a role of FA rearrangement in S1P-mediated barrier enhancement via Rac- and GIT-mediated processes.

Joe G N Garcia - One of the best experts on this subject based on the ideXlab platform.

  • s1p induces fa remodeling in human pulmonary endothelial cells role of Rac git1 fak and paxillin
    Journal of Applied Physiology, 2003
    Co-Authors: Yasushi Shikata, Konstantin G Birukov, Joe G N Garcia
    Abstract:

    Sphingosine 1-phosphate (S1P) enhances human pulmonary endothelial monolayer integrity via Rac GTPase-dependent formation of a cortical actin ring (Garcia et al.J Clin Invest 108: 689–701, 2001). T...

  • s1p induces fa remodeling in human pulmonary endothelial cells role of Rac git1 fak and paxillin
    Journal of Applied Physiology, 2003
    Co-Authors: Yasushi Shikata, Konstantin G Birukov, Joe G N Garcia
    Abstract:

    Sphingosine 1-phosphate (S1P) enhances human pulmonary endothelial monolayer integrity via Rac GTPase-dependent formation of a cortical actin ring (Garcia et al. J Clin Invest 108: 689-701, 2001). The mechanisms underlying this response are not well understood but may involve rapid redistribution of focal adhesions (FA) as attachment sites for actin filaments. We evaluate the effects of S1P on the redistribution of paxillin, FA kinase (FAK), and the G protein-coupled receptor kinase-inteRacting proteins (GITs). S1P induced Rac GTPase activation and cortical actin ring formation at physiological concentrations (0.5 microM), whereas 5 microM S1P caused prominent stress fiber formation and activation of Rho and Rac GTPases. S1P (0.5 microM) stimulated the tyrosine phosphorylation of FAK Y(576), and paxillin was linked to FA disruption and redistribution to the cell periphery. Furthermore, S1P induced a transient association of GIT1 with paxillin and redistribution of the GIT2-paxillin complex to the cell cortical area without affecting GIT2-paxillin association. These results suggest a role of FA rearrangement in S1P-mediated barrier enhancement via Rac- and GIT-mediated processes.

Erik A. Lundquist - One of the best experts on this subject based on the ideXlab platform.

  • Rack 1 acts with Rac GTPase signaling and unc 115 ablim in caenorhabditis elegans axon pathfinding and cell migration
    PLOS Genetics, 2010
    Co-Authors: Rafael Senos Demarco, Erik A. Lundquist
    Abstract:

    Migrating cells and growth cones extend lamellipodial and filopodial protrusions that are required for outgrowth and guidance. The mechanisms of cytoskeletal regulation that underlie cell and growth cone migration are of much interest to developmental biologists. Previous studies have shown that the Arp2/3 complex and UNC-115/abLIM act redundantly to mediate growth cone lamellipodia and filopodia formation and axon pathfinding. While much is known about the regulation of Arp2/3, less is known about regulators of UNC-115/abLIM. Here we show that the Caenorhabditis elegans counterpart of the Receptor for Activated C Kinase (RacK-1) inteRacts physically with the actin-binding protein UNC-115/abLIM and that RacK-1 is required for axon pathfinding. Genetic inteRactions indicate that RacK-1 acts cell-autonomously in the UNC-115/abLIM pathway in axon pathfinding and lamellipodia and filopodia formation, downstream of the CED-10/Rac GTPase and in parallel to MIG-2/RhoG. Furthermore, we show that RacK-1 is involved in migration of the gonadal distal tip cells and that the signaling pathways involved in this process might be distinct from those involved in axon pathfinding. In sum, these studies pinpoint RacK-1 as a component of a novel signaling pathway involving Rac GTPases and UNC-115/abLIM and suggest that RacK-1 might be involved in the regulation of the actin cytoskeleton and lamellipodia and filopodia formation in migrating cells and growth cones.

  • the netrin receptor unc 40 dcc stimulates axon attRaction and outgrowth through enabled and in parallel Rac and unc 115 ablim
    Neuron, 2003
    Co-Authors: Erik A. Lundquist, Zemer Gitai, Cornelia I Bargmann
    Abstract:

    Netrins promote axon outgrowth and turning through DCC/UNC-40 receptors. To chaRacterize Netrin signaling, we generated a gain-of-function UNC-40 molecule, MYR::UNC-40. MYR::UNC-40 causes axon guidance defects, excess axon branching, and excessive axon and cell body outgrowth. These defects are suppressed by loss-of-function mutations in ced-10 (a Rac GTPase), unc-34 (an Enabled homolog), and unc-115 (a putative actin binding protein). ced-10, unc-34, and unc-115 also function in endogenous unc-40 signaling. Our results indicate that Enabled functions in axonal attRaction as well as axon repulsion. UNC-40 has two conserved cytoplasmic motifs that mediate distinct downstream pathways: CED-10, UNC-115, and the UNC-40 P2 motif act in one pathway, and UNC-34 and the UNC-40 P1 motif act in the other. Thus, UNC-40 might act as a scaffold to deliver several independent signals to the actin cytoskeleton.

Jesús Vázquez - One of the best experts on this subject based on the ideXlab platform.

  • the intRacellular inteRactome of tetraspanin enriched microdomains reveals their function as sorting machineries toward exosomes
    Journal of Biological Chemistry, 2013
    Co-Authors: Jesús Vázquez, Daniel Perezhernandez, Cristina Gutierrezvazquez, Inmaculada Jorge, Soraya Lopezmartin, Angeles Ursa, Francisco Sanchezmadrid
    Abstract:

    ExtRacellular vesicles are emerging as a potent mechanism of intercellular communication because they can systemically exchange genetic and protein material between cells. Tetraspanin molecules are commonly used as protein markers of extRacellular vesicles, although their role in the unexplored mechanisms of cargo selection into exosomes has not been addressed. For that purpose, we have chaRacterized the intRacellular tetraspanin-enriched microdomain (TEM) inteRactome by high throughput mass spectrometry, in both human lymphoblasts and their derived exosomes, revealing a clear pattern of inteRaction networks. Proteins inteRacting with TEM receptors cytoplasmic regions presented a considerable degree of overlap, although some highly specific CD81 tetraspanin ligands, such as Rac GTPase, were detected. Quantitative proteomics showed that TEM ligands account for a great proportion of the exosome proteome and that a selective repertoire of CD81-associated molecules, including Rac, is not correctly routed to exosomes in cells from CD81-deficient animals. Our data provide evidence that insertion into TEM may be necessary for protein inclusion into the exosome structure.

  • the intRacellular inteRactome of tetraspanin enriched microdomains reveals their function as sorting machineries toward exosomes
    Journal of Biological Chemistry, 2013
    Co-Authors: Jesús Vázquez, Daniel Perezhernandez, Cristina Gutierrezvazquez, Inmaculada Jorge, Soraya Lopezmartin, Angeles Ursa, Francisco Sanchezmadrid, Maria Yanezmo
    Abstract:

    AbstRact ExtRacellular vesicles are emerging as a potent mechanism of intercellular communication because they can systemically exchange genetic and protein material between cells. Tetraspanin molecules are commonly used as protein markers of extRacellular vesicles, although their role in the unexplored mechanisms of cargo selection into exosomes has not been addressed. For that purpose, we have chaRacterized the intRacellular tetraspanin-enriched microdomain (TEM) inteRactome by high throughput mass spectrometry, in both human lymphoblasts and their derived exosomes, revealing a clear pattern of inteRaction networks. Proteins inteRacting with TEM receptors cytoplasmic regions presented a considerable degree of overlap, although some highly specific CD81 tetraspanin ligands, such as Rac GTPase, were detected. Quantitative proteomics showed that TEM ligands account for a great proportion of the exosome proteome and that a selective repertoire of CD81-associated molecules, including Rac, is not correctly routed to exosomes in cells from CD81-deficient animals. Our data provide evidence that insertion into TEM may be necessary for protein inclusion into the exosome structure.

  • CD81 regulates cell migration through its association with Rac GTPase.
    Molecular biology of the cell, 2012
    Co-Authors: Emilio Tejera, Vera Rocha-perugini, Soraya López-martín, Daniel Pérez-hernández, Alexia I. Bachir, Alan Rick Horwitz, Jesús Vázquez, Francisco Sánchez-madrid, María Yáñez-mó
    Abstract:

    CD81 is a member of the tetraspanin family that has been described to have a key role in cell migration of tumor and immune cells. To unravel the mechanisms of CD81-regulated cell migration, we performed proteomic analyses that revealed an inteRaction of the tetraspanin C-terminal domain with the small GTPase Rac. Direct inteRaction was confirmed biochemically. Moreover, microscopy cross-correlation analysis demonstrated the in situ integration of both molecules into the same molecular complex. Pull-down experiments revealed that CD81-Rac inteRaction was direct and independent of Rac activation status. Knockdown of CD81 resulted in enhanced protrusion rate, altered focal adhesion formation, and decreased cell migration, correlating with increased active Rac. Reexpression of wild-type CD81, but not its truncated form lacking the C-terminal cytoplasmic domain, rescued these effects. The phenotype of CD81 knockdown cells was mimicked by treatment with a soluble peptide with the C-terminal sequence of the tetraspanin. Our data show that the inteRaction of Rac with the C-terminal cytoplasmic domain of CD81 is a novel regulatory mechanism of the GTPase activity turnover. Furthermore, they provide a novel mechanism for tetraspanin-dependent regulation of cell motility and open new avenues for tetraspanin-targeted reagents by the use of cell-permeable peptides.

Yasushi Shikata - One of the best experts on this subject based on the ideXlab platform.

  • s1p induces fa remodeling in human pulmonary endothelial cells role of Rac git1 fak and paxillin
    Journal of Applied Physiology, 2003
    Co-Authors: Yasushi Shikata, Konstantin G Birukov, Joe G N Garcia
    Abstract:

    Sphingosine 1-phosphate (S1P) enhances human pulmonary endothelial monolayer integrity via Rac GTPase-dependent formation of a cortical actin ring (Garcia et al.J Clin Invest 108: 689–701, 2001). T...

  • s1p induces fa remodeling in human pulmonary endothelial cells role of Rac git1 fak and paxillin
    Journal of Applied Physiology, 2003
    Co-Authors: Yasushi Shikata, Konstantin G Birukov, Joe G N Garcia
    Abstract:

    Sphingosine 1-phosphate (S1P) enhances human pulmonary endothelial monolayer integrity via Rac GTPase-dependent formation of a cortical actin ring (Garcia et al. J Clin Invest 108: 689-701, 2001). The mechanisms underlying this response are not well understood but may involve rapid redistribution of focal adhesions (FA) as attachment sites for actin filaments. We evaluate the effects of S1P on the redistribution of paxillin, FA kinase (FAK), and the G protein-coupled receptor kinase-inteRacting proteins (GITs). S1P induced Rac GTPase activation and cortical actin ring formation at physiological concentrations (0.5 microM), whereas 5 microM S1P caused prominent stress fiber formation and activation of Rho and Rac GTPases. S1P (0.5 microM) stimulated the tyrosine phosphorylation of FAK Y(576), and paxillin was linked to FA disruption and redistribution to the cell periphery. Furthermore, S1P induced a transient association of GIT1 with paxillin and redistribution of the GIT2-paxillin complex to the cell cortical area without affecting GIT2-paxillin association. These results suggest a role of FA rearrangement in S1P-mediated barrier enhancement via Rac- and GIT-mediated processes.