Targeting of Ran: variation on a common theme?

2001 ◽  
Vol 114 (18) ◽  
pp. 3233-3241 ◽  
Author(s):  
Markus Künzler ◽  
Ed Hurt
Keyword(s):  
Nuclear Envelope ◽  
Mitotic Spindle ◽  
Nucleocytoplasmic Transport ◽  
Common Theme ◽  
Spindle Formation ◽  
Ran Gtpase ◽  
Cellular Processes ◽  
Important Target ◽  
Transport Receptors ◽  
Nuclear Envelope Formation

The Ran GTPase plays a key role in nucleocytoplasmic transport. In its GTP-bound form, it directly interacts with members of the importin β family of nuclear transport receptors and modulates their association with cargo. Work in cell-free higher-eukaryote systems has demonstrated additional roles for Ran in spindle and nuclear envelope formation during mitosis. However, until recently, no Ran-target proteins in these cellular processes were known. Several groups have now identified importin β as one important target of Ran during mitotic spindle formation. This finding suggests that Ran uses the same effectors to regulate different cellular processes.

scholarly journals Subgroup II PAK-mediated phosphorylation regulates Ran activity during mitosis

2010 ◽  
Vol 190 (5) ◽  
pp. 807-822 ◽  
Author(s):  
Guillaume Bompard ◽  
Gabriel Rabeharivelo ◽  
Marie Frank ◽  
Julien Cau ◽  
Claude Delsert ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Mitotic Spindle ◽  
Nucleocytoplasmic Transport ◽  
Mitotic Progression ◽  
Subgroup Ii ◽  
Egg Extracts ◽  
Xenopus Egg ◽  
P21 Activated Kinase ◽  
Nuclear Envelope Formation ◽  
Xenopus Egg Extracts

Ran is an essential GTPase that controls nucleocytoplasmic transport, mitosis, and nuclear envelope formation. These functions are regulated by interaction of Ran with different partners, and by formation of a Ran-GTP gradient emanating from chromatin. Here, we identify a novel level of Ran regulation. We show that Ran is a substrate for p21-activated kinase 4 (PAK4) and that its phosphorylation on serine-135 increases during mitosis. The endogenous phosphorylated Ran and active PAK4 dynamically associate with different components of the microtubule spindle during mitotic progression. A GDP-bound Ran phosphomimetic mutant cannot undergo RCC1-mediated GDP/GTP exchange and cannot induce microtubule asters in mitotic Xenopus egg extracts. Conversely, phosphorylation of GTP-bound Ran facilitates aster nucleation. Finally, phosphorylation of Ran on serine-135 impedes its binding to RCC1 and RanGAP1. Our study suggests that PAK4-mediated phosphorylation of GDP- or GTP-bound Ran regulates the assembly of Ran-dependent complexes on the mitotic spindle.

scholarly journals Ran GTPase Cycle and Importins α and β Are Essential for Spindle Formation and Nuclear Envelope Assembly in LivingCaenorhabditis elegans Embryos

2002 ◽  
Vol 13 (12) ◽  
pp. 4355-4370 ◽  
Author(s):  
Peter Askjaer ◽  
Vincent Galy ◽  
Eva Hannak ◽  
Iain W. Mattaj
Keyword(s):  
Nuclear Envelope ◽  
Cell Function ◽  
Small Gtpase ◽  
Spindle Formation ◽  
Ran Gtpase ◽  
Early Embryos ◽  
Nuclear Envelope Assembly ◽  
Importin Α ◽  
Gtpase Cycle

The small GTPase Ran has been found to play pivotal roles in several aspects of cell function. We have investigated the role of the Ran GTPase cycle in spindle formation and nuclear envelope assembly in dividing Caenorhabditis elegans embryos in real time. We found that Ran and its cofactors RanBP2, RanGAP, and RCC1 are all essential for reformation of the nuclear envelope after cell division. Reducing the expression of any of these components of the Ran GTPase cycle by RNAi leads to strong extranuclear clustering of integral nuclear envelope proteins and nucleoporins. Ran, RanBP2, and RanGAP are also required for building a mitotic spindle, whereas astral microtubules are normal in the absence of these proteins. RCC1(RNAi) embryos have similar abnormalities in the initial phase of spindle formation but eventually recover to form a bipolar spindle. Irregular chromatin structures and chromatin bridges due to spindle failure were frequently observed in embryos where the Ran cycle was perturbed. In addition, connection between the centrosomes and the male pronucleus, and thus centrosome positioning, depends upon the Ran cycle components. Finally, we have demonstrated that both IMA-2 and IMB-1, the homologues of vertebrate importin α and β, are essential for both spindle assembly and nuclear formation in early embryos.

Time-resolved, in vivo studies of mitotic spindle formation and nuclear lamina breakdown in Drosophila early embryos

1996 ◽  
Vol 109 (3) ◽  
pp. 591-607 ◽  
Author(s):  
M.R. Paddy ◽  
H. Saumweber ◽  
D.A. Agard ◽  
J.W. Sedat
Keyword(s):  
Nuclear Envelope ◽  
Mitotic Spindle ◽  
Nuclear Periphery ◽  
Nuclear Lamina ◽  
In Vivo Studies ◽  
Time Interval ◽  
Microscopy Imaging ◽  
Spindle Formation ◽  
Time Resolved ◽  
Early Embryos

Time-resolved, two-component, three-dimensional fluorescence light microscopy imaging in living Drosophila early embryos is used to demonstrate that a large fraction of the nuclear envelope lamins remain localized to a rim in the nuclear periphery until well into metaphase. The process of lamin delocalization and dispersal, typical of ‘open’ forms of mitosis, does not begin until about the time the final, metaphase geometry of the mitotic spindle is attained. Lamin dispersal is completed about the time that the chromosomal movements of anaphase begin. This pattern of nuclear lamina breakdown appears to be intermediate between traditional designations of ‘open’ and ‘closed’ mitoses. These results thus clarify earlier observations of lamins in mitosis in fixed Drosophila early embryos, clearly showing that the observed lamin localization does not result from a structurally defined ‘spindle envelope’ that persists throughout mitosis. During this extended time interval of lamin localization in the nuclear periphery, the lamina undergoes an extensive series of structural rearrangements that are closely coupled to, and likely driven by, the movements of the centrosomes and microtubules that produce the mitotic spindle. Furthermore, throughout this time the nuclear envelope structure is permeable to large macromolecules, which are excluded in interphase. While the functional significance of these structural dynamics is not yet clear, it is consistent with a functional role for the lamina in mitotic spindle formation.

scholarly journals Ran-Binding Protein 3 Is a Cofactor for Crm1-Mediated Nuclear Protein Export

2001 ◽  
Vol 153 (7) ◽  
pp. 1391-1402 ◽  
Author(s):  
Mark E. Lindsay ◽  
James M. Holaska ◽  
Katie Welch ◽  
Bryce M. Paschal ◽  
Ian G. Macara
Keyword(s):  
Nuclear Protein ◽  
Binding Protein ◽  
Nucleocytoplasmic Transport ◽  
Nuclear Pore ◽  
Yeast Protein ◽  
Permeabilized Cell ◽  
Ran Gtpase ◽  
Transport Receptors ◽  
Human Orthologue ◽  
Dependent Mechanism

Crm1 is a member of the karyopherin family of nucleocytoplasmic transport receptors and mediates the export of proteins from the nucleus by forming a ternary complex with cargo and Ran:GTP. This complex translocates through the nuclear pores and dissociates in the cytosol. The yeast protein Yrb2p participates in this pathway and binds Crm1, but its mechanism of action has not been established. We show that the human orthologue of Yrb2p, Ran-binding protein 3 (RanBP3), acts as a cofactor for Crm1-mediated export in a permeabilized cell assay. RanBP3 binds directly to Crm1, and the complex posseses an enhanced affinity for both Ran:GTP and cargo. RanBP3 shuttles between the nucleus and the cytoplasm by a Crm1-dependent mechanism, and the Crm1–RanBP3-NES-Ran:GTP quarternary complex can associate with nucleoporins. We infer that this complex translocates through the nuclear pore to the cytoplasm where it is disassembled by RanBP1 and Ran GTPase–activating protein.

The Ran GTPase as a marker of chromosome position in spindle formation and nuclear envelope assembly

2002 ◽  
Vol 4 (7) ◽  
pp. E177-E184 ◽  
Author(s):  
Martin Hetzer ◽  
Oliver J. Gruss ◽  
Iain W. Mattaj
Keyword(s):  
Nuclear Envelope ◽  
Spindle Formation ◽  
Ran Gtpase ◽  
Chromosome Position ◽  
Nuclear Envelope Assembly

scholarly journals Conquering the Nuclear Envelope Barriers by EBV Lytic Replication

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 702
Author(s):  
Chung-Pei Lee ◽  
Mei-Ru Chen
Keyword(s):  
Nuclear Envelope ◽  
Nuclear Lamina ◽  
Nucleocytoplasmic Transport ◽  
Lytic Replication ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Lipid Bilayer Membranes ◽  
Barr Virus ◽  
Cellular Processes ◽  
Structural Architecture

The nuclear envelope (NE) of eukaryotic cells has a highly structural architecture, comprising double lipid-bilayer membranes, nuclear pore complexes, and an underlying nuclear lamina network. The NE structure is held in place through the membrane-bound LINC (linker of nucleoskeleton and cytoskeleton) complex, spanning the inner and outer nuclear membranes. The NE functions as a barrier between the nucleus and cytoplasm and as a transverse scaffold for various cellular processes. Epstein–Barr virus (EBV) is a human pathogen that infects most of the world’s population and is associated with several well-known malignancies. Within the nucleus, the replicated viral DNA is packaged into capsids, which subsequently egress from the nucleus into the cytoplasm for tegumentation and final envelopment. There is increasing evidence that viral lytic gene expression or replication contributes to the pathogenesis of EBV. Various EBV lytic proteins regulate and modulate the nuclear envelope structure in different ways, especially the viral BGLF4 kinase and the nuclear egress complex BFRF1/BFRF2. From the aspects of nuclear membrane structure, viral components, and fundamental nucleocytoplasmic transport controls, this review summarizes our findings and recently updated information on NE structure modification and NE-related cellular processes mediated by EBV.

The ran decathlon: multiple roles of Ran

2000 ◽  
Vol 113 (7) ◽  
pp. 1111-1118 ◽  
Author(s):  
S. Sazer ◽  
M. Dasso
Keyword(s):  
Cell Cycle Progression ◽  
Cell Function ◽  
Nucleocytoplasmic Transport ◽  
Multiple Roles ◽  
Ran Gtpase ◽  
Biochemical Basis ◽  
Cellular Processes ◽  
Import And Export ◽  
Regulation Of Cell Cycle ◽  
And Function

The Ran GTPase system affects many cellular processes, including the regulation of cell cycle progression, nuclear envelope structure and function, and nucleocytoplasmic transport. The biochemical basis for the involvement of Ran in nuclear import and export has been well documented, but the direct targets of Ran in other cellular processes have not yet been identified. There is, however, mounting evidence that Ran directly affects at least some of these other cellular processes by mechanisms independent of its role in transport. In this Commentary we discuss evidence linking Ran to different aspects of cell function, and how these multiple facets of Ran's activity may relate to each other.

scholarly journals Mechanisms of MTOC clustering and spindle positioning in the budding yeast Cryptococcus neoformans: a microtubule grow-and-catch model

2019 ◽  
Author(s):  
Saptarshi Chatterjee ◽  
Subhendu Som ◽  
Neha Varshney ◽  
Kaustuv Sanyal ◽  
Raja Paul
Keyword(s):  
Nuclear Envelope ◽  
Cryptococcus Neoformans ◽  
Mitotic Spindle ◽  
Computational Models ◽  
Budding Yeast ◽  
Cell Cortex ◽  
Critical Determinant ◽  
Spindle Formation ◽  
Spindle Positioning ◽  
Septin Ring

AbstractMitotic spindle formation in the pathogenic budding yeast, Cryptococcus neoformans, depends on multitudes of inter-dependent interactions involving kinetochores (KTs), microtubules (MTs), spindle pole bodies (SPBs), and molecular motors. Before the formation of the mitotic spindle, multiple visible microtubule organizing centers (MTOCs), coalesce into a single focus to serve as an SPB. We propose a ‘grow-and-catch’ model, in which cytoplasmic MTs (cMTs) nucleated by MTOCs grow and catch each other to promote MTOC clustering. Our quantitative modeling identifies multiple redundant mechanisms mediated by a combination of cMT-cell cortex interactions and inter-cMT coupling to facilitate MTOC clustering within the physiological time limit as determined by time-lapse live-cell microscopy. Besides, we screened various possible mechanisms by computational modeling and propose optimal conditions that favor proper spindle positioning - a critical determinant for timely chromosome segregation. These analyses also reveal that a combined effect of MT buckling, dynein pull, and cortical push maintain spatiotemporal spindle localization.Author summaryCells actively self-assemble a bipolar spindle to facilitate chromosomal segregation. Multiple MTOCs, on the outer nuclear envelope, cluster into a single SPB before spindle formation during semi-open mitosis of the budding yeast Cryptococcus neoformans. Eventually, the SPB duplicates and organizes the spindle to position it within the daughter bud near the septin ring during anaphase. In this work, we tested various computational models to match physiological phenomena in an attempt to find plausible mechanisms of MTOC clustering and spindle positioning in C. neoformans. Notably, we propose an MT ‘grow-and-catch’ model that relies on possible redundant mechanisms for timely MTOC clustering mediated by (a) minus end-directed motors that crosslink and slide anti-parallel cMTs from different MTOCs on the nuclear envelope and (b) a Bim1 mediated biased sliding of cMTs along the cell cortex toward the septin ring that pulls MTOCs in the presence of suppressed dynein activity. By combining an analytical model and stochastic MT dynamics simulations, we screened various MT-based forces to detect steady spindle positioning. By screening the outputs of various models, it is revealed that proper spindle positioning near the septin ring requires MT buckling from the cell cortex.

Ran GTPase in Nuclear Envelope Formation and Cancer Metastasis

2014 ◽  
pp. 323-351 ◽  
Author(s):  
Kyle B. Matchett ◽  
Suzanne McFarlane ◽  
Sophie E. Hamilton ◽  
Yousef S. A. Eltuhamy ◽  
Matthew A. Davidson ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Cancer Metastasis ◽  
Ran Gtpase ◽  
Nuclear Envelope Formation

EML4 and NUDC in mitotic spindle formation

Reactome ◽  
2020 ◽  
Author(s):  
Susanne Bechstedt ◽  
Andrew M. Fry ◽  
Kellie J Lucken ◽  
Laura O'Regan
Keyword(s):  
Mitotic Spindle ◽  
Spindle Formation
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