Keywords XPO1, CRM1, nucleocytoplasmic transport, Selinexor Introduction In , a kDa protein called CRM1, known to function as a chromosome region maintenance factor in yeast, was identified as the first receptor for the nuclear export of proteins, and it was consequently renamed exportin 1 XPO1 [ 1 - 4 ].
Over the last two decades, many aspects of XPO1 physiopathology have been elucidated. Thus, XPO1 has been shown to mediate the nuclear export of not only hundreds of cellular and viral proteins, but also of different types of RNA molecules [ 5 , 6 ]. In addition, export-independent functions of XPO1 in mitosis have also been identified [ 8 ]. The normal function of XPO1 appears to be often disrupted in malignant cells.
Thus, overexpression of the XPO1 mRNA or protein has been frequently reported in a variety of tumor types and recurrent XPO1 gene mutations have been detected in certain hematological malignancies, suggesting that XPO1 may represent a therapeutic target in cancer [ 9 , 10 ]. Importantly, the results of multiple cellular, biochemical and structural analyses have led to a detailed mechanistic understanding of XPO1 function [ 11 - 13 ] , paving the way for the development of clinically useful inhibitors of XPO1.
Several compounds targeting XPO1 have been extensively tested in preclinical studies, and one of them, Selinexor, is now undergoing clinical trials, with promising results in patients with different types of cancer. In eukaryotic cells, the nuclear envelope establishes a physical separation between the two major cellular compartments: the nucleus and the cytoplasm.
Cellular homeostasis requires continuous communication between these compartments through the bidirectional trafficking of molecules. This trafficking may occur by diffusion in the case of small molecules, or by budding of nuclear envelope-derived vesicles for a minority of specific proteins [ 14 ].
However, the vast majority of proteins can only enter and exit the nucleus through proteinaceous channels embedded in the nuclear envelope termed nuclear pore complexes NPCs [ 15 , 16 ].
For most proteins, nucleocytoplasmic transport is an active, energy-dependent process that requires a specialized transport machinery with three crucial components: 1 the NPCs; 2 a family of soluble transport receptors karyopherins that recognize and bind specific transport signals in the cargo proteins; 3 a gradient of the small GTPase Ran bound to either GTP or GDP across the nuclear envelope, which confers directionality to the transport [Figure 1A] [ 17 - 19 ].
Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. NPCs, recently reviewed by Knockenhauer and Schwartz [ 15 ] and Pemberton and Paschal [ 17 ] , are very large complexes over MDa in size formed by the assembly of several copies of each of approximately 30 different proteins called nucleoporins NUPs.
NPCs present a characteristic eight-fold rotational symmetry and are composed by three stacked rings inserted into the nuclear envelope, with a series of filaments emanating to the cytoplasmic side of the NPC and a basket-like structure protruding to the nucleoplasmic side [Figure 1B]. NUPs in the inner channel of the pore contain intrinsically disordered domains rich in phenyalanine-glycine FG repeats.
These so-called FG-nucleoporins constitute a barrier that efficiently prevents proteins above a certain size from freely diffusing across the NPC. This threshold size for exclusion has long been believed to be relatively sharp kDa , but a recent study suggests that the NPC lacks such a firm size threshold [ 20 ]. The selective barrier of the NPC can be overcome by large proteins and even by very large nucleoprotein complexes, such as ribosomal subunits through binding to karyopherins [ 21 ].
The human genome codes for approximately 20 different karyopherins [ 22 ]. While some of these receptors can mediate bidirectional transport of cargos in and out of the nucleus, most of them function exclusively as either import receptors importins or export receptors exportins , such as XPO1. Karyopherins can recognize and bind specific peptide sequences in the cargo protein, which function as transport signals, and can be broadly classified as nuclear localization signals NLSs, recognized by importins or nuclear export signals NESs, recognized by exportins [Figure 1C].
XPO1, the first nuclear export receptor to be identified, is also the best-characterized exportin. Of note, some proteins possess both an NLS and an NES and can undergo cyclic shuttling between the nucleus and the cytoplasm [ 24 ]. Other karyopherins, which are less well characterized, seem to have a more limited repertoire of cargos, and the transport signals that may mediate their binding remain, in most cases, yet to be identified. This complex is disassembled upon GTP hydrolysis in the cytoplasmic side of the NPC, leading to release of the export cargo in the cytoplasm.
In fact, it has been shown that, by artificially raising the concentration of RanGTP in the cytoplasm, the direction of the transport can be inverted [ 25 ]. Beyond the basic transport machinery described above, multiple additional mechanisms may contribute to regulate the nucleocytoplasmic distribution of a given protein in a dynamic and finely-tuned manner. XPO1 has a wide repertoire of cargos, including not only cellular proteins, but also viral proteins expressed in infected cells reviewed by Ding et al.
This experimental approach cannot be used to demonstrate XPO1-mediated export of proteins that are constitutively located to the nucleus.
An alternative approach in this case could be ectopic overexpression of the receptor, which promotes export of NES-containing nuclear cargos to the cytoplasm [ 32 ]. In over 15 years of research, hundreds of individual proteins were studied using these approaches and around bona-fide XPO1-exported cargos were identified [ 33 ].
The search for novel cargos is still on-going, and continues to provide further insight into the physiological relevance of XPO1. For example, it has been recently found that the NES-containing protein POST and the ubiquitin-binding protein UBIN form a complex that mediates XPO1-dependent nuclear export of polyubiquitinated proteins [ 35 ] , a process that seems to be exacerbated in cancer cells treated with the proteasome inhibitor bortezomib [ 36 ].
These findings reveal a novel role for XPO1 in nuclear protein homeostasis that might also have important implications for cancer therapy. From a mechanistic point of view, XPO1-mediated nuclear export consists essentially in the binding of an NES-containing protein in the nucleus and its release in the cytoplasm.
As schematically illustrated in Figure 2A , XPO1 is a ring-shaped protein with a concave inner surface and a convex outer surface. Figure 2. Structural features of XPO1 related to its nuclear export function, its role in cancer and its potential as a therapeutic target. A: Schematic representation of XPO1 protein illustrating its general ring-shaped conformation, and showing the three structural motifs that are crucial for its function as a nuclear export receptor: the NES-binding groove, the H9 loop and the C-terminal extension; B: detailed views of the NES-binding groove on the molecular surface of XPO1.
The right panel shows residues E and C highlighted in blue. E is a mutational hotspot in several hematological malignancies. These compounds attach covalently to C and physically occupy the groove, blocking NES binding. As illustrated in Figure 1C , "leucine-rich" NESs conform to a loose consensus sequence with a characteristic spacing of hydrophobic residues [ 40 , 41 ]. Hundreds of different amino acid sequences have been experimentally validated as bona-fide NESs that bind the receptor with different affinity, and may be exported with different efficiency [ 33 , 42 , 43 ].
This high variability can be explained by the recent finding that NESs with different backbone conformations can bind the receptor, and that not all export signals occupy the XPO1 NES-binding groove to the same extent [ 44 ].
Two non-hydrophobic amino acids C and E located in or near the NES-binding groove [Figure 2B] are of particular interest regarding the targeting of XPO1 and its potential role in cancer. On one hand, the amino acid E is recurrently mutated in certain hematological malignancies see below , suggesting that mutation of this particular residue can be a driver event in some types of cancer. On the other hand, C is the crucial target for the effect of LMB and more clinically relevant XPO1 inhibitors, which covalently bind to this residue and block NES binding by physically occupying the groove.
In fact, experimental mutation of C renders cells resistant to these inhibitors [ 45 ]. Nuclear export of RNA is a tightly regulated process that involves the coordinated function of many different factors, including a large array of RNA-binding adaptor proteins as well as dedicated export receptors [ 6 ]. XPO1 plays a pervasive role in this process, mediating the nuclear export of several different classes of RNA.
XPO1 plays a prominent role in the export of 40S and 60S ribosomal subunits, containing rRNA, to the cytoplasm, which is a necessary step for their final maturation. The NES-containing protein Nmd3 functions as the adaptor for 60S subunit export, while the adaptor involved in the export of the 40S subunit remains to be identified [ 47 ]. Interestingly, several mRNAs exported by XPO1 code for proteins that are involved in tumorigenesis-related processes, such as invasion and metastasis [ 46 ].
Besides mediating the export of proteins and RNA to the cytoplasm, XPO1 also plays a role in processes that do not directly involve nuclear export, such as intranuclear trafficking of small nucleolar RNAs snoRNAs from Cajal bodies to the nucleolus [ 58 ]. A particularly relevant aspect of cell physiology where XPO1 carries out export-independent functions is mitosis [ 8 ].
This role of XPO1 has been reviewed by Forbes et al. In eukaryotic cells undergoing open mitosis, the breakdown of the nuclear envelope at the onset of prometaphase dramatically disrupts the nucleocytoplasmic compartmentalization. With no physical separation between nucleus and cytoplasm, the nuclear transport machinery, including certain transport receptors, NUPs and the Ran GTPase, is "repurposed" to carry out transport-independent mitotic functions, such as regulating the assembly of the mitotic spindle [ 59 ].
In this context, XPO1 has been shown to function as a "mitotic effector" of Ran, mediating RanGTP-dependent targeting of key mitotic proteins to specific spindle structures, such as the centrosomes or the kinetochore. Thus, the NES-containing protein pericentrin, a crucial scaffold for microtubule nucleation at the spindle poles, is recruited to the centrosomes by XPO1 in a RanGTP-containing trimeric complex that resembles the nuclear export complexes described above [ 60 ].
On the other hand, the stable microtubule-kinetochore interactions necessary for proper chromosome segregation appear to require XPO1-mediated recruitment of a protein complex containing RanGTP, RanGAP1 and the nucleoporin RanBP2 to the kinetochores [ 8 ]. The mitotic functions of XPO1, like its nuclear export activity, seem to be the subject of careful regulation through mechanisms that include phosphorylation [ 61 ] and competition with importins [ 62 ].
In summary, although its primary role may be in protein nuclear export, XPO1 is a multifaceted protein with roles in other processes. This functional complexity should be taken into account when interpreting the results of XPO1 inhibition studies. Normal cell function relies on the correct subcellular distribution of thousands of proteins. The presence of a critical protein in the wrong cellular compartment may have severe pathological consequences.
For example, aberrant cytoplasmic localization of a physiologically nuclear tumor suppressor protein may render this protein inactive, and thus contribute to tumorigenesis. In fact, mislocalization of cancer-related proteins, including the products of prominent oncogenes and tumor suppressor genes, has been often demonstrated in human tumors [ 63 , 64 - 66 ].
Nucleocytoplasmic localization of proteins can be disrupted by different mechanisms in cancer cells. On one hand, the trafficking of a specific protein can be altered by mutations that either interfere with the activity of its transport signals NLSs or NESs or that create a novel signal in the mutant protein.
For example, aberrant localization of tumor suppressors BRCA2 [ 67 ] and PALB2 [ 68 ] to the cytoplasm can result from mutations that unmask normally hidden NESs, whereas cytoplasmic mislocalization of certain NPM1 mutants is the result of a frameshift mutation that creates a novel strong NES, not present in the wild-type protein [ 69 ].
On the other hand, a general defect in the nucleocytoplasmic localization of proteins and RNA may arise in tumor cells, if elements of the transport machinery themselves are genetically altered or aberrantly expressed [ 70 ]. Examples of genetic alterations targeting the nuclear transport machinery include chromosome rearrangements involving nucleoporin genes e. The abnormal fusion proteins resulting from these translocations have been reported to disrupt XPO1-mediated export [ 72 , 73 ].
In the case of XPO1, both aberrant expression and genetic alterations have been detected in different types of cancer, as detailed below. The abnormal XPO1 function that may result from these alterations would, in turn, hinder the normal nucleocytoplasmic localization of hundreds of XPO1 cargo proteins. In the context of the present review, those XPO1 cargos with a known role in the development of human tumors are of particular interest.
The set of cancer-related proteins exported by XPO1 which could be referred to as the "XPO1 cancer exportome" includes prominent tumor suppressors, such as p53 [ 75 ] and BRCA1 [ 76 ] , as well as protooncogenes, such as c-abl [ 77 ].
A more extensive account of cancer-related proteins that undergo XPO1-mediated nuclear export can be found in previous reviews [ 10 , 65 , 66 , 78 , 79 ]. Figure 3. The "XPO1 cancer exportome". The Venn diagram shows the overlap between the list of potential XPO1 cargos identified in HeLa cells [ 34 ] and the group of "cancer related genes" defined in the Human Protein Atlas v.
The diagram was created using the jvenn web tool [ ]. As summarized in Table 1 , XPO1 is frequently overexpressed in tumor samples with respect to the corresponding normal tissue samples [ 80 - 99 ].
In fact, XPO1 overexpression was observed in all solid tumor types and hematologic malignances examined, with the exception of liver cancer [ 91 ].
In several of these studies, the potential prognostic significance of XPO1 expression has been evaluated. Higher XPO1 expression was associated with poorer patient prognosis in patients with ovarian tumors [ 90 ] , pancreatic tumors [ 94 ] , esophageal tumors [ 92 ] , gliomas [ 84 , 85 ] , thymic epithelial tumors [ 89 ] , and breast tumors [ 96 ].
In contrast, high XPO1 expression was related to better prognosis in osteosarcoma patients [ 98 ]. Finally, contradictory findings on the prognostic value of XPO1 expression in gastric cancer have been reported [ 87 , 88 ].
The molecular mechanisms responsible for XPO1 overexpression in cancer cells are still poorly characterized. In addition, XPO1 transcription has been reported to be regulated by cMyc and p53 [ , ] , two proteins that are frequently altered in cancer. Conceivably, disruption of this regulation may contribute to aberrant XPO1 expression in some tumors, although further studies are required to test this possibility.
Recurrent XPO1 mutations in hematological malignancies. Isolated instances of mutant XPO1 have been reported in esophageal [ ] and thyroid cancer [ ] , but XPO1 genetic alterations seem to be a very rare event in solid tumors.
It is still unclear why XPO1 E mutations are particularly common in certain types of cancer, and why they may have different prognostic significance in different types of hematological malignancies.
In fact, the molecular mechanisms that may be responsible for the pathogenic effect of XPO1 mutations remain to be established. Consistent with the location of the mutational "hotspot" proximal to the NES-binding site [Figure 2B] , it has been reported that the EK mutation subtly increases the affinity of the receptor for some NESs with a negatively charged carboxy-terminal end [ 32 ].
Conceivably, this could lead to altered export of one or more cargos, whose mislocalization might in turn contribute to tumorigenesis. Given its frequent alteration in human tumors, and its crucial cellular roles described above, XPO1 has long been regarded as a potentially relevant target in cancer therapy. Even before XPO1 was identified as its cellular target, LMB also called elactocin had been found to possess antitumor activity, and it had been tested in a clinical trial [ ].
LMB was found to have severe toxicities when administered to patients, precluding its development as a clinically useful drug [ ]. Nevertheless, the availability of this potent and specific inhibitor made it possible to carry out proof-of-concept experiments testing the effect of XPO1 inhibition in different tumor settings. These and other encouraging findings in different tumor types reviewed by Turner and Sullivan [ 7 ] suggested that XPO1 inhibition might represent a valid strategy for cancer treatment, fostering the search for other XPO1 inhibitors.
Over the next years, several natural and synthetic inhibitors of XPO1 were reported reviewed by Tan et al. However, unlike LMB, some of these novel inhibitors, such as CBS or S, bind to XPO1 in a reversible manner, which was associated to less severe toxicity in preclinical in vivo models [ 84 , ].
Studies with these compounds further validated XPO1 inhibition as a relevant strategy for cancer treatment. For example, blocking nuclear export of topoisomerase II with the XPO1 inhibitor Ratjadone C was found to sensitize multiple myeloma MM cells to doxorubicin and etoposide [ ].
While most XPO1 inhibitors have only been tested in vitro or in mouse xenograft, there is a series of compounds, termed selective inhibitors of nuclear export SINEs that are undergoing development as potential anticancer drugs, and some of these compounds are already being evaluated in clinical trials [ ]. SINEs were developed in using structure-assisted relationship methodology combined with a novel computational approach termed consensus-induced fit docking [ , ] , a strategy that relied crucially on the recently solved structures of NES-bound XPO1.
As summarized in Tables 3 and 4 , SINE compounds have been extensively tested in preclinical models of many different hematological malignancies [ 80 , 82 , 83 , , , - ] and solid tumors [ 89 , 95 , 97 , - ].
In these models, SINEs have demonstrated potent in vitro and in vivo activity against cancer cells including growth inhibition, induction of apoptosis, and cell cycle arrest , with only minor toxic effects on normal cells. Importantly, several SINEs most prominently Selinexor have been shown to increase the sensitivity of cancer cells to currently used drugs, such as doxorubicin or the proteasome inhibitors bortezomib and carfilzomib, and also to synergize with other targeted therapeutic agents, such as ibrutinib an inhibitor of Bruton tyrosine kinase or linsitinib an inhibitor of insulin-like growth factor receptor A more extensive and detailed discussion of the preclinical results obtained with SINEs in specific tumor settings can be found in recent reviews [ 9 , 10 , 79 , , ].
Summary of preclinical studies with "first-generation" SINEs in hematological malignancies. In general terms, the anticancer effect of XPO1 inhibition is thought to rely on the relocation of mislocalized XPO1 cargos with tumor-suppressive and growth-regulatory functions e.
In our opinion, this may be an overly simplistic view. Given the large number of potential XPO1 cargos with a role in cancer, the export-independent roles of XPO1, and the complex nature of the tumorigenesis process, the specific molecular and cellular mechanisms underlying the anticancer effect of SINEs may differ in different tumor settings.
Intriguingly, there is emerging evidence that, in addition to cancer, other conditions, such as demyelinating diseases [ ] or viral infections [ ] might be amenable to treatment with SINEs. Selinexor, an orally available drug, is the only compound of the series that has advanced into clinical development for human cancer.
The ClinicalTrials. Interim data from some clinical studies with Selinexor have been reported as meeting proceedings some of these data are reviewed by Mahipal and Malafa [ ]. Here, we will limit our discussion to the results of phase I and II trials that have undergone full peer-reviewed publication as PubMed-indexed articles summarized in Table 5. Structural basis for leucine-rich nuclear export signal recognition by CRM1.
Nature , — EMBO J 19 , — Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66 , — EMBO J 17 , — J Cell Biol , — Mol Biol Cell 29 , — Structural determinants of nuclear export signal orientation in binding to exportin CRM1.
Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals. Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol 15 , — Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group guidelines. Blood , — P-body purification reveals the condensation of repressed mRNA regulons.
Mol Cell 68 , — Recurrent mutations of the exportin 1 gene XPO1 and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma. Am J Hematol 91 , — Nuclear export signal consensus sequences defined using a localization-based yeast selection system. Traffic 9 , — Bioinformatics 36 , — Structural prerequisites for CRM1-dependent nuclear export signaling peptides: accessibility, adapting conformation, and the stability at the binding site.
Sci Rep 9 , Regulation of a nuclear export signal by an adjacent inhibitory sequence: the effector domain of the influenza virus NS1 protein.
HKL the integration of data reduction and structure solution — from diffraction images to an initial model in minutes. Acta Crystallogr D Biol Crystallogr 62 , — Structural and functional characterization of CRM1-Nup interactions reveals multiple FG-binding sites involved in nuclear export. Cell Rep 13 , — Genes Dev 34 , — On the acquisition and analysis of microscale thermophoresis data.
Anal Biochem , 79— Altered nuclear export signal recognition as a driver of oncogenesis. Cancer Discov 9 , — Skip Nav Destination Content Menu. Close Abstract. Article Navigation.
Lymphoid Neoplasia October 6, This Site. Google Scholar. Naoya Saito , Naoya Saito. Takuji Sato , Takuji Sato. Atsushi Suzuki , Atsushi Suzuki. Yoko Hasegawa , Yoko Hasegawa. Jonathan M. Friedman , Jonathan M. Donald W. Kufe , Donald W. Daniel D. VonHoff , Daniel D.
Tadahiko Iwami , Tadahiko Iwami. Takumi Kawabe Takumi Kawabe. Blood 14 : — Article history Submitted:. Cite Icon Cite. Figure 1. View large Download PPT. Table 1 Antiproliferative effect of CBS on 60 human cancer cell lines in vitro. IC 50 , nM. View Large. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. The online version of this article contains a data supplement.
The authors thank Dr W. Dunphy for scientific discussion. Search ADS. Nucleo-cytoplasmic transport of proteins as a target for therapeutic drugs. Imatinib and leptomycin B are effective in overcoming imatinib-resistance due to Bcr-Abl amplification and clonal evolution but not due to Bcr-Abl kinase domain mutation.
Nuclear retention of IkBa protects it from signal-induced degradation and inhibits nuclear factor kB transcriptional activation. Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes. A new fork for clinical application: targeting forkhead transcription factors in cancer.
Supplementary file 3. CRM1 binder analysis of HeLa proteins. Supplementary file 4. CRM1 binder analysis of yeast proteins. Supplementary file 5. Supplementary file 6. Preparation of nuclear and cytoplasmic extracts from mammalian cells.
Current Protocols in Pharmacology. The Journal of Cell Biology. Crm1 is a mitotic effector of ran-GTP in somatic cells. Nature Cell Biology. Participation of xenopus elr-type proteins in vegetal mRNA localization during oogenesis. The Journal of Biological Chemistry. The role of exportin-t in selective nuclear export of mature tRNAs. The creatine-creatine phosphate energy shuttle. Annual Review of Biochemistry. Nuclei from rat liver: isolation method that combines purity with high yield.
Exp5 exports eEF1A via tRNA from nuclei and synergizes with other transport pathways to confine translation to the cytoplasm.
Protein migration into nuclei. The centrosome in cells and organisms. Arx1 functions as an unorthodox nuclear export receptor for the 60S preribosomal subunit. Molecular Cell. Exportinmediated nuclear export of eukaryotic elongation factor 1A and tRNA. Nucleic Acids Research. Current Biology. Structures of the tRNA export factor in the nuclear and cytosolic states. MaxQuant enables high peptide identification rates, individualized p.
Nature Biotechnology. Andromeda: a peptide search engine integrated into the MaxQuant environment. Journal of Proteome Research. Intracellular migration of nuclear proteins in xenopus oocytes. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei.
Structural basis for leucine-rich nuclear export signal recognition by CRM1. Oogenesis inXenopus laevis daudin. Journal of Morphology. The nuclear annuli as pathways for nucleocytoplasmic exchanges.
Journal of Cell Science. The HIV-1 rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. A non-canonical mechanism for Crm1-export cargo complex assembly.
CRM1 is an export receptor for leucine-rich nuclear export signals. A new set of highly efficient, tag-cleaving proteases for purifying recombinant proteins. Journal of Chromatography. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nuclear export of 60s ribosomal subunits depends on Xpo1p and requires a nuclear export sequence-containing factor, Nmd3p, that associates with the large subunit protein Rpl10p.
Molecular and Cellular Biology. Proteome survey reveals modularity of the yeast cell machinery. Ran-dependent nuclear export mediators: a structural perspective. MPF localization is controlled by nuclear export. Catastrophic nuclear envelope collapse in cancer cell micronuclei. A census of human soluble protein complexes. The mitochondrial cloud of xenopus oocytes: the source of germinal granule material.
Developmental Biology. Accelerated gene evolution and subfunctionalization in the pseudotetraploid frog xenopus laevis. BMC Biology. Nmd3p is a Crm1p-dependent adapter protein for nuclear export of the large ribosomal subunit.
The KEGG resource for deciphering the genome. Identification of cargo proteins specific for the nucleocytoplasmic transport carrier transportin by combination of an in vitro transport system and stable isotope labeling by amino acids in cell culture sILAC -based quantitative proteomics.
Three ways to make a vesicle. Nature Reviews. Molecular Cell Biology. Systematic identification of cell cycle-dependent yeast nucleocytoplasmic shuttling proteins by prediction of composite motifs. Structural insights into how Yrb2p accelerates the assembly of the Xpo1p nuclear export complex. Cell Reports. Yeast ran-binding protein 1 yrb1 shuttles between the nucleus and cytoplasm and is exported from the nucleus via a CRM1 xPO1 -dependent pathway.
MTOR signaling at a glance. Hyperphosphorylation of nucleoplasmin facilitates xenopus sperm decondensation at fertilization. Exportin 4: a mediator of a novel nuclear export pathway in higher eukaryotes. Oocyte isolation and enucleation. Methods in Molecular Biology. Proofreading and aminoacylation of tRNAs before export from the nucleus.
Peroxisome assembly: matrix and membrane protein biogenesis. An unusual membrane system in the oocyte of the ascidian botryllus schlosseri.
Tissue and Cell. Characterisation of the passive permeability barrier of nuclear pore complexes. Structural basis for cooperativity of CRM1 export complex formation. Septins: the fourth component of the cytoskeleton. Nuclear export of the small ribosomal subunit requires the ran-GTPase cycle and certain nucleoporins.
Leptomycin b targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression. Maturation of eukaryotic ribosomes: acquisition of functionality. Trends in Biochemical Sciences. CRM1-mediated recycling of snurportin 1to the cytoplasm.
P bodies and the control of mRNA translation and degradation. Facilitated nucleocytoplasmic shuttling of the ran binding protein RanBP1. Organizing principles of mammalian nonsense-mediated mRNA decay. Annual Review of Genetics.
Autophagic processes in yeast: mechanism, machinery and regulation. The permeability barrier of nuclear pore complexes appears to operate via hydrophobic exclusion. Nuclear export and cytoplasmic processing of precursors to the 40S ribosomal subunits in mammalian cells. CORUM: the comprehensive resource of mammalian protein complexes PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis.
Journal of Molecular Biology. The nuclear f-actin interactome of xenopus oocytes reveals an actin-bundling kinesin that is essential for meiotic cytokinesis. Use of peptide libraries to map the substrate specificity of a peptide-modifying enzyme: a 13 residue consensus peptide specifies biotinylation in escherichia coli.
Nup98 FG domains from diverse species spontaneously phase-separate into particles with nuclear pore-like permselectivity. A constitutive nucleolar protein identified as a member of the nucleoplasmin family. Global quantification of mammalian gene expression control. Ltv1 is required for efficient nuclear export of the ribosomal small subunit in saccharomyces cerevisiae. In-gel digestion for mass spectrometric characterization of proteins and proteomes.
Nature Protocols. Nature Methods. Exportin 1 crm1p is an essential nuclear export factor. BioGRID: a general repository for interaction datasets. Nuclear export inhibition through covalent conjugation and hydrolysis of leptomycin b by CRM1.
Identification of CRM1-dependent nuclear export cargos using quantitative mass spectrometry. UniProt Consortium UniProt: a hub for protein information. Biogenesis and nuclear export of ribosomal subunits in higher eukaryotes depend on the CRM1 export pathway. Eukaryotic ribosome biogenesis at a glance. ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Heat-stable inhibitors of cAMP-dependent protein kinase carry a nuclear export signal.
Deep proteomics of the xenopus laevis egg using an mRNA-derived reference database. Current Biology : CB. Sequence and structural analyses of nuclear export signals in the NESdb database. Molecular Biology of the Cell.
Crm1p mediates regulated nuclear export of a yeast APlike transcription factor. Control of cyclin B1 localization through regulated binding of the nuclear export factor CRM1.
Control of cytoplasmic actin gel—sol transformation by gelsolin, a calcium-dependent regulatory protein. Copyright and License information Disclaimer. Copyright notice. Essential revisions: A concern amongst the reviewers was the fact that the purifications were apparently only performed once and no biological replicates are presented in the study.
0コメント