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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Saccharomyces cerevisiae Dnm1 protein is structurally related to dynamin, a GTPase required for membrane scission during endocytosis. Here we show that Dnm1p is essential for the maintenance of mitochondrial morphology. Disruption of the DNM1 gene causes the wild-type network of tubular mitochondrial membranes to collapse to one side of the cell but does not affect the morphology or distribution of other cytoplasmic organelles. Dnm1 proteins containing point mutations in the predicted GTP-binding domain or completely lacking the GTP-binding domain fail to rescue mitochondrial morphology defects in a dnm1 mutant and induce dominant mitochondrial morphology defects in wild-type cells. Indirect immunofluorescence reveals that Dnm1p is distributed in punctate structures at the cell cortex that colocalize with the mitochondrial compartment. These Dnm1p-containing structures remain associated with the spherical mitochondria found in an mdm10 mutant strain. In addition, a portion of Dnm1p cofractionates with mitochondrial membranes during differential sedimentation and sucrose gradient fractionation of wild-type cells. Our results demonstrate that Dnm1p is required for the cortical distribution of the mitochondrial network in yeast, a novel function for a dynamin-related protein.
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PMID:The dynamin-related GTPase, Dnm1p, controls mitochondrial morphology in yeast. 978 46

The Ran binding protein RanBP1 is localized to the cytosol of interphase cells. A leucine-rich nuclear export signal (NES) near the C terminus of RanBP1 is essential to maintain this distribution. We now show that RanBP1 accumulates in nuclei of cells treated with the export inhibitor, leptomycin B, and collapse of the nucleocytoplasmic Ran:GTP gradient leads to equilibration of RanBP1 across the nuclear envelope. Low temperature prevents nuclear accumulation of RanBP1, suggesting that import does not occur via simple diffusion. Glutathione S-transferase (GST)-RanBP1(1-161), which lacks the NES, accumulates in the nucleus after cytoplasmic microinjection. In permeabilized cells, nuclear accumulation of GST-RanBP1(1-161) requires nuclear Ran:GTP but is not inhibited by a dominant interfering G19V mutant of Ran. Nuclear accumulation is enhanced by addition of exogenous karyopherins/importins or RCC1, both of which also enhance nuclear Ran accumulation. Import correlates with Ran concentration. Remarkably, an E37K mutant of RanBP1 does not import into the nuclei under any conditions tested despite the fact that it can form a ternary complex with Ran and importin beta. These data indicate that RanBP1 translocates through the pores by an active, nonclassical mechanism and requires Ran:GTP for nuclear accumulation. Shuttling of RanBP1 may function to clear nuclear pores of Ran:GTP, to prevent premature release of import cargo from transport receptors.
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PMID:Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1. 1077 40

Activation of the EphB2 receptor tyrosine kinase by clustered ephrin-B1 induces growth cone collapse and neurite retraction in differentiated NG108 neuronal cells. We have investigated the cytoplasmic signaling events associated with EphB2-induced cytoskeletal reorganization in these neuronal cells. We find that unlike other receptor tyrosine kinases, EphB2 induces a pronounced downregulation of GTP-bound Ras and consequently of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. A similar inhibition of the Ras-MAPK pathway was observed on stimulation of endogenous EphB2 in COS-1 cells. Inactivation of Ras, induced by ephrin B1 stimulation of NG108 neuronal cells, requires EphB2 tyrosine kinase activity and is blocked by a truncated form of p120-Ras GTPase-activating protein (p120-RasGAP), suggesting that EphB2 signals through the SH2 domain protein p120-RasGAP to inhibit the Ras-MAPK pathway. Suppression of Ras activity appears functionally important, since expression of a constitutively active variant of Ras impaired the ability of EphB2 to induce neurite retraction. In addition, EphB2 attenuated the elevation in ERK activation induced by attachment of NG108 cells to fibronectin, indicating that the EphB2 receptor can modulate integrin signaling to the Ras GTPase. These results suggest that a primary function of EphB2, a member of the most populous family of receptor tyrosine kinases, is to inactivate the Ras-MAPK pathway in a fashion that contributes to cytoskeletal reorganization and adhesion responses in neuronal growth cones.
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PMID:Downregulation of the Ras-mitogen-activated protein kinase pathway by the EphB2 receptor tyrosine kinase is required for ephrin-induced neurite retraction. 1158 23

We have collected a set of 347 proteins that are found in eukaryotic cells but have no significant homology to proteins in Archaea and Bacteria. We call these proteins eukaryotic signature proteins (ESPs). The dominant hypothesis for the formation of the eukaryotic cell is that it is a fusion of an archaeon with a bacterium. If this hypothesis is accepted then the three cellular domains, Eukarya, Archaea, and Bacteria, would collapse into two cellular domains. We have used the existence of this set of ESPs to test this hypothesis. The evidence of the ESPs implicates a third cell (chronocyte) in the formation of the eukaryotic cell. The chronocyte had a cytoskeleton that enabled it to engulf prokaryotic cells and a complex internal membrane system where lipids and proteins were synthesized. It also had a complex internal signaling system involving calcium ions, calmodulin, inositol phosphates, ubiquitin, cyclin, and GTP-binding proteins. The nucleus was formed when a number of archaea and bacteria were engulfed by a chronocyte. This formation of the nucleus would restore the three cellular domains as the Chronocyte was not a cell that belonged to the Archaea or to the Bacteria.
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PMID:The origin of the eukaryotic cell: a genomic investigation. 1180

Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of diseases with excess bone resorption. Recent studies have shown that bisphosphonates can be divided into two groups with distinct molecular mechanisms of action depending on the nature of the R(2) side chain. Alendronate, like other nitrogen-containing bisphosphonates, inhibits bone resorption and causes apoptosis of osteoclasts and other cells in vitro by preventing post-translational modification of GTP-binding proteins with isoprenoid lipids. Clodronate, a bisphosphonate that lacks a nitrogen, does not inhibit protein isoprenylation but can be metabolized intracellularly to a beta-gamma-methylene (AppCp-type) analog of ATP, which is cytotoxic to macrophages in vitro. The detailed molecular basis for the cytotoxic effects of adenosine-5'-[beta,gamma-dichloromethylene]triphosphate (AppCCl(2)p) has not been determined yet. We addressed this question by studying the effects of alendronate, clodronate, and the clodronate metabolite AppCCl(2)p on isolated mitochondria, mitochondrial fractions, and mitochondrial membrane potential in isolated human osteoclasts. We found that AppCCl(2)p inhibits mitochondrial oxygen consumption by a mechanism that involves competitive inhibition of the ADP/ATP translocase. Alendronate or the native form of clodronate did not have any immediate effect on mitochondria. However, longer treatment with liposome-encapsulated clodronate caused collapse of the mitochondrial membrane potential, although prominent apoptosis was a late event. Hence, inhibition of the ADP/ATP translocase by the metabolite AppCCl(2)p is a likely route by which clodronate causes osteoclast apoptosis and inhibits bone resorption.
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PMID:Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. 1196 Nov 44

Pea stem mitochondria, resuspended in a KCl medium (de-energized mitochondria), underwent a swelling, as a consequence of K+ entry, that was inhibited by ATP. This inhibition was partially restored by GTP and diazoxide (K+ATP channel openers). In addition, glyburide and 5-hydroxydecanate (K+ATP channel blockers) induced an inhibition of the GTP-stimulated swelling. Mitochondrial swelling was inhibited by H2O2, but stimulated by NO. The same type of responses was also obtained in succinate-energized mitochondria. When the succinate-dependent transmembrane electrical potential (deltapsi) had reached a steady state, the addition of KCl induced a dissipation that was inhibited by H2O2 and stimulated by NO. The latter stimulation was prevented by carboxy-PTIO, a NO scavenger. Phenylarsine oxide (a thiol oxidant) and NEM (a thiol blocker) stimulated the KCl-induced dissipation of deltapsi, while DTE prevented this effect in both cases. In addition, DTE transiently inhibited the NO-induced dissipation of deltapsi, but then it caused a more rapid collapse. These results, therefore, show that the plant mitochondrial K+ATP channel resembles that present in mammalian mitochondria and that it appears to be modulated by dithiol-disulfide interconversion, NO and H2O2. The aperture of this channel was linked to the partial rupture of the outer membrane. The latter effect led to a release of cytochrome c, thus suggesting that this release may be involved in the manifestation of programmed cell death.
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PMID:Modulation of a plant mitochondrial K+ATP channel and its involvement in cytochrome c release. 1217 Oct 67

SEMA3F, isolated from a 3p21.3 deletion, has antitumor activity in transfected cells, and protein expression correlates with tumor stage and histology. In primary tumors, SEMA3F and VEGF surface staining is inversely correlated. Coupled with SEMA3F at the leading edge of motile cells, we previously suggested that both proteins competitively regulate cell motility and adhesion. We have investigated this using the breast cancer cell line, MCF7. SEMA3F inhibited cell attachment and spreading as evidenced by loss of lamellipodia extensions, membrane ruffling, and cell-cell contacts, with cells eventually rounding-up and detaching. In contrast, VEGF had opposite effects. Although SEMA3F binds NRP2 with 10-fold greater affinity than NRP1, the effects in MCF7 were mediated by NRP1. This was determined by receptor expression and blocking of anti-NRP1 antibodies. Similar effects, but through NRP2, were observed in the C100 breast cancer cell line. Although we were unable to demonstrate changes in total GTP-bound Rac1 or RhoA, we did observe changes in the localization of Rac1-GFP using time lapse microscopy. Following SEMA3F, Rac1 moved to the base of lamellipodia and - with their collapse - to the membrane. These results support the concept that SEMA3F and VEGF have antagonistic actions affecting motility in primary tumor cell.
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PMID:Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading. 1265 73

Plexins are cell surface receptors for semaphorin molecules, and their interaction governs cell adhesion and migration in a variety of tissues. We report that the Semaphorin 4D (Sema4D) receptor Plexin-B1 directly stimulates the intrinsic guanosine triphosphatase (GTPase) activity of R-Ras, a member of the Ras superfamily of small GTP-binding proteins that has been implicated in promoting cell adhesion and neurite outgrowth. This activity required the interaction of Plexin-B1 with Rnd1, a small GTP-binding protein of the Rho family. Down-regulation of R-Ras activity by the Plexin-B1-Rnd1 complex was essential for the Sema4D-induced growth cone collapse in hippocampal neurons. Thus, Plexin-B1 mediates Sema4D-induced repulsive axon guidance signaling by acting as a GTPase activating protein for R-Ras.
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PMID:The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. 1529 73

The organization and sorting of proteins within the Golgi stack to establish and maintain its cis to trans polarization remains an enigma. The function of Golgi compartments involves coat assemblages that facilitate vesicle traffic, Rab-tether-SNAP receptor (SNARE) machineries that dictate membrane identity, as well as matrix components that maintain structure. We have investigated how the Golgi complex achieves compartmentalization in response to a key component of the coat complex I (COPI) coat assembly pathway, the ARF1 GTPase, in relationship to GTPases-regulating endoplasmic reticulum (ER) exit (Sar1) and targeting fusion (Rab1). Following collapse of the Golgi into the ER in response to inhibition of activation of ARF1 by Brefeldin A, we found that Sar1- and Rab1-dependent Golgi reformation took place at multiple peripheral and perinuclear ER exit sites. These rapidly converged into immature Golgi that appeared as onion-like structures composed of multiple concentrically arrayed cisternae of mixed enzyme composition. During clustering to the perinuclear region, Golgi enzymes were sorted to achieve the degree of polarization within the stack found in mature Golgi. Surprisingly, we found that sorting of Golgi enzymes into their subcompartments was insensitive to the dominant negative GTP-restricted ARF1 mutant, a potent inhibitor of COPI coat disassembly and vesicular traffic. We suggest that a COPI-independent, Rab-dependent mechanism is involved in the rapid reorganization of resident enzymes within the Golgi stack following synchronized release from the ER, suggesting an important role for Rab hubs in directing Golgi polarization.
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PMID:The role of ARF1 and rab GTPases in polarization of the Golgi stack. 1610 83

Plexins are transmembrane receptors for semaphorins, guiding cell migration and axon extension. Plexin activation leads to the disassembly of integrin-based focal adhesive structures and to actin cytoskeleton remodelling and inhibition of cell migration; however, the underlying molecular mechanisms are unclear. We consistently observe a transient decrease of cellular RhoA-GTP levels upon plexin activation in adherent cells. One of the main effectors of RhoA downregulation is p190, a ubiquitously expressed GTPase activating protein (GAP). We show that, in p190-deficient fibroblasts, the typical functional activities mediated by plexins (such as cell collapse and inhibition of integrin-based adhesion) are blocked or greatly impaired. Notably, the functional response can be rescued in these cells by re-expressing exogenous p190, but not a mutant form specifically lacking RhoGAP activity. We furthermore demonstrate that semaphorin function is blocked in epithelial cells, primary endothelial cells and neuroblasts upon treatment with small interfering RNAs that knockdown p190 expression. Finally, we show that p190 transiently associates with plexins, and its RhoGAP activity is increased in response to semaphorin stimulation. We conclude that p190-RhoGAP is crucially involved in semaphorin signalling to the actin cytoskeleton, via interaction with plexins.
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PMID:p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling. 1618 38


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