Transportin acts to regulate mitotic assembly events by target binding rather than Ran sequestration

Bernis, Cyril; Swift-Taylor, Beth; Nord, Matthew; Carmona, Sarah; Chook, Yuh Min; Forbes, Douglass J.

doi:10.1091/mbc.e13-08-0506

Cited by 24 publications

(43 citation statements)

References 152 publications

(244 reference statements)

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“…TRN‐1 also reduced the assembly of NPCs, first by inhibiting the initial recruitment of the nucleoporin ELYS/MEL‐28 to AT‐rich regions of the chromatin and second by inhibiting the incorporation of FG‐nucleoporins into nascent nuclear pore complexes. Finally, TRN‐1 negatively regulated the assembly of the mitotic spindle [75]; in particular, it bound ELYS/MEL‐28 and the Nup107–160 complex and prevented their recruitment to the kinetochores [39]. All these effects were reverted by adding excess Ran‐GTP [75], as described previously for those mediated by Importin‐β [80–83], but also by adding the M9M inhibitor peptide [39].…”

Section: Potential Roles Of Tranportin‐1 and ‐2 Beyond Protein Nucleamentioning

confidence: 60%

“…Beside their important role in nuclear import, Transportin‐1 appear to be involved in several other cellular processes. These functions include the assembly of the mitotic spindle [39,75], ciliogenesis [86,87], and the formation of cytoplasmic RNA granules [99]. In conclusion, the research on this importinis livelier than ever and probably still reserves us exciting new discoveries.…”

Section: Discussionmentioning

confidence: 99%

“…Because M9M is essentially a combination of two PY‐NLSs and because PY‐NLSs seem to be recognized exclusively by TRN‐1 and TRN‐2, M9M is not expected to target unrelated β‐karyopherins. Consistently, it has been demonstrated that M9M expression does not disturb Importin‐β‐dependent pathways [24,26,39]. On the other hand, the specificity of M9M towards Transportin‐1, ‐2A and ‐2B has not been thoroughly characterized.…”

Section: M9m a Potent Inhibitor Of Transportin‐1 And Probably Of Tramentioning

confidence: 96%

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Transportin‐1 and Transportin‐2: Protein nuclear import and beyond

2014

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Edited by Ulrike KutayKeywords: Transportin Importins Karyopherins Nuclear import Nucleo-cytoplasmic transport NLS Kap104p Transportin-1 Transportin-2 Karyopherin-b2 hnRNP A1 FUS a b s t r a c t Nearly 20 years after its identification as a new b-karyopherin mediating the nuclear import of the RNA-binding protein hnRNP A1, Transportin-1 is still commonly overlooked in comparison with its best known cousin, Importin-b. Transportin-1 is nonetheless a considerable player in nucleo-cytoplasmic transport. Over the past few years, significant progress has been made in the characterization of the nuclear localization signals (NLSs) that Transportin-1 recognizes, thereby providing the molecular basis of its diversified repertoire of cargoes. The recent discovery that mutations in the Transportin-dependent NLS of FUS cause mislocalization of this protein and result in amyotrophic lateral sclerosis illustrates the importance of Transportin-dependent import for human health. Besides, new functions of Transportin-1 are emerging in processes other than nuclear import. Here, we summarize what is known about Transportin-1 and the related b-karyopherin Transportin-2. Ó 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Basis of protein nucleo-cytoplasmic transportActive nucleo-cytoplasmic transport of proteins is mostly carried out by b-karyopherins, a family of factors functionally divided into importins and exportins. Importins bind to the nuclear localization signal (NLS) of their cargoes in the cytoplasm, either directly or through an adaptor. The importin/cargo complexes cross the nuclear pore complex (NPC) through the interactions of the importin with nucleoporins. In the nucleus, importins are bound by Ran-GTP, which releases the cargo. Importins are then recycled to the cytoplasm in association with Ran-GTP. On the cytoplasmic face of the NPC, Ran hydrolyzes its bound GTP into GDP and dissociates, freeing the importin for a new import cycle (see for example [1] for review). Exportins work in a similar way but in reverse. In the nucleus, exportins cooperatively bind Ran-GTP and a cargo featuring a fitting nuclear export signal (NES). Once the trimeric complexes reach the cytoplasm, they are dissociated and free exportins return to the nucleus to complete the cycle (see for example [2] for review). Thus, while Ran-GTP binding causes importins to release their cargoes, it is required for exportins to bind theirs. Neither importins nor exportins have significant binding affinity for the GDP-bound form of Ran. Therefore, the directionality of the transfers is maintained by mechanisms that ensure that nuclear Ran is bound to GTP and cytoplasmic Ran to GDP. The nuclear part of this task is carried out by the chromatin-associated guanine exchange factor RCC1, which promotes the exchange of GDP for GTP on nuclear Ran. Three factors located on the cytosolic face of the NPC (RanBP1, RanBP2, and RanGAP) collaborate to ensure the hydrolysis of Ran-bound GTP by Ran as soon as it goes ou...

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Section: Potential Roles Of Tranportin‐1 and ‐2 Beyond Protein Nucleamentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: M9m a Potent Inhibitor Of Transportin‐1 And Probably Of Tramentioning

confidence: 96%

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Transportin‐1 and Transportin‐2: Protein nuclear import and beyond

2014

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“…M9M peptide was designed to have a significantly greater affinity for Karyopherin-β2 than natural PY-NLSs present in hnRNPA1 and several closely related RNA-binding proteins (Bernis et al, 2014; Cansizoglu et al, 2007). As a result, M9M prevents Karyopherin-β2 from binding a select subset of PY-NLS-containing endogenous clients and results in their accumulation in the cytoplasm (Cansizoglu et al, 2007; Dormann et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization

Molliex

Temirov

Lee

et al. 2015

Cell

2,240

104

2,780

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SUMMARY Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, frontotemporal dementia and multisystem proteinopathy - diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here we demonstrate that the RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties, and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.

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“…Transportin 1 (TNPO1) has documented effects on the mitotic apparatus and on post‐mitotic reorganization of the interphase nucleus, a critical process that is evidently crucial for resuming transcription and replication via the cell cycle . Disruption of this process by altered TNPO1 function will also affect the genetic identity of the newly formed daughter cells after mitosis.…”

Section: Dysregulation Of Nuclear Transport In Cancermentioning

confidence: 99%

Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential

et al. 2016

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The Karyopherin superfamily is a major class of soluble transport receptors consisting of both import and export proteins. The trafficking of proteins involved in transcription, cell signalling and cell cycle regulation among other functions across the nuclear membrane is essential for normal cellular functioning. However, in cancer cells, the altered expression or localization of nuclear transporters as well as the disruption of endogenous nuclear transport inhibitors are some ways in which the Karyopherin proteins are dysregulated. The value of nuclear transporters in the diagnosis, prognosis and treatment of cancer is currently being elucidated with recent studies highlighting their potential as biomarkers and therapeutic targets. V C 2016 IUBMB Life, 68(4): [268][269][270][271][272][273][274][275][276][277][278][279][280] 2016

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Transportin acts to regulate mitotic assembly events by target binding rather than Ran sequestration

Cited by 24 publications

References 152 publications

Transportin‐1 and Transportin‐2: Protein nuclear import and beyond

Transportin‐1 and Transportin‐2: Protein nuclear import and beyond

Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization

Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential

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