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PubMed2004

ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression.

The ets domain transcriptional repressor ERF is an effector of the receptor tyrosine kinase/Ras/Erk pathway, which, it has been suggested, is regulated by subcellular localization as a result of Erk-dependent phosphorylation and is capable of suppressing cell proliferation and ras-induced tumorigenicity. Here, we analyze the effect of ERF phosphorylation on nuclear import and export, the timing of its phosphorylation and dephosphorylation in relation to its subcellular location, Erk activity, and the requirements for ERF-induced cell cycle arrest. Our findings indicate that ERF continuously shuttles between the nucleus and the cytoplasm and that both phosphorylation and dephosphorylation of ERF occur within the nucleus. While nuclear import is not affected by phosphorylation, ERF nuclear export and cytoplasmic release require multisite phosphorylation and dephosphorylation. ERF export is CRM1 dependent, although ERF does not have a detectable nuclear export signal. ERF phosphorylation and export correlate with the levels of nuclear Erk activity. The cell cycle arrest induced by nonphosphorylated ERF requires the wild-type retinoblastoma protein and can be suppressed by overexpression of cyclin. These data suggest that ERF may be a very sensitive and constant sensor of Erk activity that can affect cell cycle progression through G(1), providing another link between the Ras/Erk pathway and cellular proliferation.

Animals↗
PubMed2001

Mapping the functional domains of HAP95, a protein that binds RNA helicase A and activates the constitutive transport element of type D retroviruses.

The complex retroviruses such as human immunodeficiency virus, type 1, employ a virally encoded protein, Rev, to mediate the nuclear export of unspliced and partially spliced mRNA. In contrast, the simian type D retroviruses act through a cis-acting constitutive transport element (CTE) that presumably interacts directly with cellular export proteins. We first reported that RNA helicase A (RHA) is a shuttle protein that binds to functional CTE in vitro and in vivo. Recently, we isolated a novel protein, HAP95, that specifically binds to the nuclear transport domain of RHA and up-regulates CTE-mediated gene expression. Here, using truncation and deletion mutations, we mapped the domains of HAP95 that are important for RHA binding, transactivation of CTE, and nuclear cytoplasmic shuttling. We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA.

Active Transport, Cell Nucleus↗
PubMed2001

Nuclear export of mammalian PERIOD proteins.

The timing of mammalian circadian rhythm is determined by interlocking negative and positive transcriptional feedback loops that govern the cyclic expression of both clock regulators and output genes. In mammals, nuclear localization of the circadian regulators PER1-3 is controlled by multiple mechanisms, including multimerization with PER and CRY proteins. In addition, nuclear entry of mammalian PER1 (mPER1) can be regulated by a phosphorylation-dependent masking of its nuclear localization signal. Here we present evidence suggesting that nuclear localization of PER proteins is a dynamic process determined by both nuclear import and previously unrecognized nuclear export pathways. Examination of the subcellular localization of a series of truncated mPER1 proteins demonstrated that cytoplasmic localization is mediated by an 11-amino acid region with homology to leucine-rich nuclear export signals (NESs). Similar sequences were identified in mPER2 and mPER3 as well as in several insect PER proteins. The putative NESs from mPER1 and mPER2 were able to direct cytoplasmic accumulation when fused to a heterologous protein. Mutations in conserved NES residues and the nuclear export inhibitor leptomycin B each blocked the function of the NES. Full-length mPER1 was also exported from microinjected Xenopus laevis oocyte nuclei in an NES-dependent manner. The presence of a functional NES in mPER1 and mPER2 as well as related sequences in a variety of other PER proteins suggests that nuclear export may be a conserved and important feature of circadian regulators.

Amino Acid Sequence↗
PubMed2006

Mouse Disabled1 (DAB1) is a nucleocytoplasmic shuttling protein.

Disabled1 (DAB1) is an intracellular mediator of the Reelin-signaling pathway and essential for correct neuronal positioning during brain development. So far, DAB1 has been considered a cytoplasmic protein. Here, we show that DAB1 is subject to nucleocytoplasmic shuttling. In its steady state, DAB1 is mainly located in the cytoplasm. However, treatment with leptomycine B, a specific inhibitor of the CRM1 (chromosomal region maintenance 1)-RanGTP-dependent nuclear export, resulted in nuclear accumulation of DAB1. By using deletion or substitutional mutants of DAB1 fused with enhanced green fluorescent protein, we have mapped a bipartite nuclear localization signal and two CRM1-dependent nuclear export signals. These targeting signals were functional in both Neuro2a cells and primary cerebral cortical neurons. Using purified recombinant proteins, we have shown that CRM1 binds to DAB1 directly in a RanGTP-dependent manner. We also show that tyrosine phosphorylation of DAB1, which is indispensable for the layer formation of the brain, by Fyn tyrosine kinase or Reelin stimulation did not affect the subcellular localization of DAB1 in vitro. These results suggest that DAB1 is a nucleocytoplasmic shuttling protein and raise the possibility that DAB1 plays a role in the nucleus as well as in the cytoplasm.

Amino Acid Sequence↗
PubMed2003

Nucleocytoplasmic shuttling of p53 is essential for MDM2-mediated cytoplasmic degradation but not ubiquitination.

As a shuttling protein, p53 is constantly transported through the nuclear pore complex. p53 nucleocytoplasmic transport is carried out by a bipartite nuclear localization signal (NLS) located at its C-terminal domain and two nuclear export signals (NES) located in its N- and C-terminal regions, respectively. The role of nucleocytoplasmic shuttling in p53 ubiquitination and degradation has been a subject of debate. Here we show that the two basic amino acid groups in the p53 bipartite NLS function collaboratively to import p53. Mutations disrupting individual amino acids in the NLS, although causing accumulation of p53 in the cytoplasm to various degrees, reduce but do not eliminate the NLS activity, and these mutants remain sensitive to MDM2 degradation. However, disrupting both parts of the bipartite NLS completely blocks p53 from entering the nucleus and causes p53 to become resistant to MDM2-mediated degradation. Similarly, mutations disrupting four conserved hydrophobic amino acids in the p53 C-terminal NES block p53 export and prohibit it from MDM2 degradation. We also show that colocalization of a nonshuttling p53 with MDM2 either in the nucleus or in the cytoplasm is sufficient for MDM2-induced p53 polyubiquitination but not degradation. Our data provide new insight into the mechanism and regulation of p53 nucleocytoplasmic shuttling and degradation.

Active Transport, Cell Nucleus↗
PubMed1999

Receptor-mediated substrate translocation through the nuclear pore complex without nucleotide triphosphate hydrolysis.

BACKGROUND: The transport of macromolecules between the nucleus and cytoplasm is an energy-dependent process. Substrates are translocated across the nuclear envelope through nuclear pore complexes (NPCs). Translocation requires nucleocytoplasmic transport receptors of the importin beta family, which interact both with the NPC and, either directly or via an adaptor, with the transport substrate. Although certain receptors have recently been shown to cross the NPC in an energy-independent manner, translocation of substrate-receptor complexes through the NPC has generally been regarded as an energy-requiring step. RESULTS: We describe an in vitro system that is based on permeabilised cells and supports nuclear export mediated by leucine-rich nuclear export signals. In this system, export is dependent on exogenous CRM1/Exportin1 - a nuclear export receptor - the GTPase Ran and nucleotide triphosphates (NTPs), and is further stimulated by Ran-binding protein 1 (RanBP1) and nuclear transport factor 2 (NTF2). Unexpectedly, non-hydrolysable NTP analogues completely satisfy the NTP requirements for a single-round of CRM1-mediated translocation of protein substrates across the NPC. Similarly, single transportin-mediated nuclear protein import events are shown not to require hydrolysable NTPs and to occur in the absence of the Ran GTPase. CONCLUSIONS: Our data show that, contrary to expectation and prior conclusions, the translocation of substrate-receptor complexes across the NPC in either direction occurs in the absence of NTP hydrolysis and is thus energy independent. The energy needed to drive substrate transport against a concentration gradient is supplied at the step of receptor recycling in the cytoplasm.

Adenosine Diphosphate↗
PubMed2004

Nuclear-cytoplasmic shuttling of the oncogenic mouse UNP/USP4 deubiquitylating enzyme.

The oncogenic deubiquitylating enzyme (DUB) Unp/Usp4, which binds to the retinoblastoma family of tumor suppressor proteins, was originally described as a nuclear protein. However, more recent studies have shown it to be cytoplasmic. In addition, analysis of its subcellular localization has been complicated by the existence of the paralog Usp15. In this study, we resolved this controversy by investigating the localization of exogenously expressed Usp4 (using red fluorescent protein-Usp4) and of endogenous Usp4 (using highly specific antibodies that can distinguish Usp4 from Usp15). We found that by inhibiting nuclear export with leptomycin B, both exogenous and endogenous Usp4 accumulate in the nucleus. Further, using a Rev-green fluorescent protein-based export assay, we confirmed the existence of a nuclear export signal ((133)VEVYLLELKL(142)) in Usp4. In addition, a functional nuclear import signal ((766)QPQKKKK(772)) was also identified, which was specifically recognized by importin alpha/beta. Finally, we show that the equilibrium of Usp4 subcellular localization varies between different cell types. Usp4 is thus the first DUB reported to have nucleocytoplasmic shuttling properties. The implications of this shuttling for its function as a DUB are discussed.

Animals↗
PubMed2002

Plk1 promotes nuclear translocation of human Cdc25C during prophase.

The nuclear accumulation of active M-phase promoting factor (MPF) during prophase is thought to be essential for coordinating M-phase events in vertebrate cells. The protein phosphatase Cdc25C, an activator of MPF, enters the nucleus to keep MPF active in the nucleus during prophase. However, the molecular mechanisms that control nuclear translocation of Cdc25C during prophase are unknown. We show that phosphorylation of a serine residue (Ser198) in a nuclear export signal sequence of human Cdc25C occurs during prophase and promotes nuclear localization of Cdc25C. We also show that Polo-like kinase 1 (Plk1) is responsible for this phosphorylation and that constitutively active Plk1 promotes nuclear localization of Cdc25C. Remarkably, a mutant Cdc25C in which Ser198 is replaced by alanine remains in the cytoplasm when wild-type Cdc25C accumulates in the nucleus during prophase. These results suggest that Plk1 phosphorylates Cdc25C on Ser198 and regulates nuclear translocation of Cdc25C during prophase.

Cell Cycle Proteins↗
PubMed1997

Purification and nucleic-acid-binding properties of a Saccharomyces cerevisiae protein involved in the control of ploidy.

Scp160p (Saccharomyces cerevisiae protein involved in the control of ploidy), a polypeptide with a molecular mass of around 160 kDa, is associated with the nuclear envelope and the endoplasmic reticulum. The most noteworthy phenotype of SCP160 deletion mutants is a decrease in viability and an increased number of chromosomes in the surviving cells [Wintersberger, U., Kühne, C. & Karwan, A. (1995) Yeast 11, 929-944]. Scp160p contains 14 KH domains, conserved motifs that have lately been identified in a variety of RNA-binding proteins. In this report, we demonstrate that the Scp160p sequence shows nearly perfect colinearity with the putative gene product of C08H9.2 from the nematode Caenorhabditis elegans as well as with the vigilins, vertebrate RNA-binding proteins with a cellular location similar to that of Scp160p. Moreover, we found that Scp160p contains a potential nuclear-export signal (NES) near its N-terminus and a potential nuclear-localization signal (NLS) between KH domains 3 and 4. To determine whether the protein is able to bind to RNA, we purified Scp160p from yeast cell extract by DNA-cellulose and anti-Scp160p affinity chromatography. In northwestern blotting experiments, the electrophoretically homogeneous protein bound to ribohomopolymers and ribosomal RNA as well as to single-stranded and double-stranded DNA. Subcellular fractionation studies revealed that the major part of Scp160p is membrane associated via ionic interactions and can be released from the membrane fraction under conditions that lead to a dissociation of ribosomes. Together, our findings suggest that Scp160p is the yeast homologue of the vigilins, and point to a role for Scp160p in nuclear RNA export or in RNA transport within the cytoplasm.

Amino Acid Sequence↗
PubMed2001

Intracellular trafficking determinants in APOBEC-1, the catalytic subunit for cytidine to uridine editing of apolipoprotein B mRNA.

The posttranscriptional deamination editing of apolipoprotein B (apoB) mRNA catalyzed by APOBEC-1 (apoB mRNA editing catalytic subunit 1) is a nuclear process. The signals in APOBEC-1 responsible for its dual cytoplasmic/nuclear distribution have been evaluated. Residues 97-172 in the middle of APOBEC-1 together with its N-terminal 56 residues affect nuclear localization. Mutagenesis studies however revealed no discrete nuclear localization signal in APOBEC-1. Fifteen amino acids (Leu 173-Leu 187) within the previously identified C-terminal domain of APOBEC-1 were sufficient as a determinant for cytoplasmic distribution in that context. These residues failed to demonstrate nuclear export function in a reporter assay. Further, the distribution of APOBEC-1 in the cytoplasm did not respond to leptomycin B, suggesting that APOBEC-1 did not have nuclear export activity. The data suggested that there are at least three regions in APOBEC-1 that participate in its distribution in both the nucleus and the cytoplasm of editing competent cells; however, none of these meet the functional criteria of nuclear localization or nuclear export signals. The findings are discussed in terms of their implications in the regulation of nuclear editing activity and the possibility that interactions with chaperones may play a role in the cellular distribution of APOBEC-1.

APOBEC-1 Deaminase↗
PubMed2003

Distribution, levels, and activation of MEK1 in Alzheimer's disease.

Extracellular-signal-regulated kinase (ERK) has been implicated in the pathogenesis of Alzheimer's disease (AD), but the upstream cascade leading to ERK activation has not been elucidated. In this study, we focused on one of the physiological activators of ERK, mitogen-activated protein kinase (MAPK)/ERK kinase 1 (MEK1). Although there was no significant difference in the level and distribution of total MEK1 between AD and age-matched control cases, increased levels of activated phospho-MEK1 were specifically localized to neuronal intracytoplasmic granular structures in severe AD (Braak stage V-VI). The considerable overlap between MEK1 and its downstream effector, phospho-ERK, suggests both a functional and mechanistic link. Nuclear localization of phospho-MEK1 was a prominent feature in both mild AD cases (Braak stage III-IV) and control cases with limited pathology (Braak stage I-II). Since MEK1 is normally cytoplasmic due to the active export from nucleus because of the presence of nuclear export signal in its amino-terminus, we suspect that the apparent nuclear accumulation of phospho-MEK1 in AD patients at early stages suggests that abnormal nuclear trafficking may contribute to the pathogenesis of AD. By immunoblot analyses, phospho-MEK1 was significantly increased in AD over control cases. Together, these findings lend further credence to the notion that the ERK pathway is dysregulated in AD and also indicate an active role for this pathway in disease pathogenesis.

Active Transport, Cell Nucleus↗
PubMed1999

The open reading frame 57 gene product of herpesvirus saimiri shuttles between the nucleus and cytoplasm and is involved in viral RNA nuclear export.

The herpesvirus saimiri open reading frame (ORF) 57 is homologous to genes identified in all classes of herpesviruses. It has previously been shown to regulate gene expression through a posttranscriptional mechanism. We demonstrate in this report that the expression of the ORF 57 protein leads to the cytoplasmic accumulation of glycoprotein B and capsid mRNAs. We also demonstrate that ORF 57 has the ability to specifically bind viral RNA transcripts. Utilizing an interspecies heterokaryon assay, we show that ORF 57 has the ability to shuttle between the nucleus and the cytoplasm. Furthermore, we show that ORF 57 contains a relatively leucine-rich sequence which shares some homology with nuclear export signals (NES) found in a number of proteins with the ability to shuttle between the nucleus and the cytoplasm. Moreover, we demonstrate that the ORF 57 NES enables the nuclear export of a heterologous protein and that mutation of the conserved leucine residues contained within the ORF 57 NES signal abrogates the ability of the ORF 57 protein to shuttle between the nucleus and cytoplasm. These results suggest that ORF 57 is involved in mediating the nuclear export of viral transcripts.

Animals↗
PubMed2002

The Rho exchange factor Net1 is regulated by nuclear sequestration.

Net1 is a guanine nucleotide exchange factor specific for the small GTPase Rho. Oncogenic activation of Net1 occurs by truncation of the N-terminal part of the protein, which functions as a negative regulatory domain. Here, we have investigated the mechanism of Net1 regulation via its N terminus. We find that Net1 localizes to the nucleus, whereas oncogenic Net1 is found in the cytoplasm. Nuclear import of Net1 is mediated by two nuclear localization signals present in the N terminus of the protein, and forced cytoplasmic localization of Net1 is sufficient to activate Rho. In addition, the pleckstrin homology (PH) domain of Net1 acts as a nuclear export signal. Because an amino acid substitution in the PH domain that inhibits guanine nucleotide exchange factor activity does not inhibit nuclear export, we conclude that this PH domain has at least two functions. Together, our results suggest that Net1 can shuttle in and out of the nucleus, and that activation of Rho by Net1 is controlled by changes in its subcellular localization.

3T3 Cells↗
PubMed2002

Differential nucleocytoplasmic trafficking between the related endocytic proteins Eps15 and Eps15R.

Eps15 and Eps15R are constitutive components of clathrin-coated pits that are required for clathrin-dependent endocytosis. The most striking difference between these two related proteins is that Eps15R is also found in the nucleus, whereas Eps15 is excluded from this compartment at steady state. To better understand the individual functions of these two proteins, the mechanisms responsible for their different localization were investigated. Interestingly, some mutants of Eps15 were found in the nucleus. This nuclear localization was correlated with the loss of the last approximately 100 amino acids of Eps15, suggesting the presence of a nuclear export signal (NES) within this region. As expected, the last 25 amino acids contain a leucine-rich sequence matching with classical NESs, show a leptomycin B-sensitive nuclear export activity, and bind to the exportin CRM1 in a leucine residue-dependent manner. In contrast, no NES could be found in Eps15R, a result in keeping with its constitutive nuclear localization that appears to be regulated by alternative splicing. Altogether, these results are the first characterization of nucleocytoplasmic shuttling signals for endocytic proteins. They also provide an explanation for the different nuclear localization of Eps15 and Eps15R and further evidence for a possible nuclear function for Eps15 protein family members.

3T3 Cells↗
PubMed1999

Control of NF-kappa B transcriptional activation by signal induced proteolysis of I kappa B alpha.

In unstimulated cells the transcription factor NF-kappa B is held in the cytoplasm in an inactive state by I kappa B inhibitor proteins. Ultimately activation of NF-kappa B is achieved by ubiquitination and proteasome-mediated degradation of I kappa B alpha and we have therefore investigated factors which control this proteolysis. Signal-induced degradation of I kappa B alpha exposes the nuclear localization signal of NF-kappa B, thus allowing it to translocate into the nucleus and activate transcription from responsive genes. An autoregulatory loop is established when NF-kappa B induces expression of the I kappa B alpha gene and newly synthesized I kappa B alpha accumulates in the nucleus where it negatively regulates NF-kappa B-dependent transcription. As part of this post-induction repression, the nuclear export signal on I kappa B alpha mediates transport of NF-kappa B-I kappa B alpha complexes from the nucleus to the cytoplasm. As nuclear export of I kappa B alpha is blocked by leptomycin B this drug was used to examine the effect of cellular location on susceptibility of I kappa B alpha to signal-induced degradation. In the presence of leptomycin B, I kappa B alpha is accumulated in the nucleus and in this compartment is resistant to signal-induced degradation. Thus signal-induced degradation of I kappa B alpha is mainly, if not exclusively a cytoplasmic process. An efficient nuclear export of I kappa B alpha is therefore essential for maintaining a low level of I kappa B alpha in the nucleus and allowing NF-kappa B to be transcriptionally active upon cell stimulation. We have detected a modified form of I kappa B alpha, conjugated to the small ubiquitin-like protein SUMO-1, which is resistant to signal-induced degradation. SUMO-1 modified I kappa B alpha remains associated with NF-kappa B and thus overexpression of SUMO-1 inhibits the signal-induced activation of NF-kappa B-dependent transcription. Reconstitution of the conjugation reaction with highly purified proteins demonstrated that in the presence of a novel E1 SUMO-1 activating enzyme, Ubch9 directly conjugated SUMO-1 to I kappa B alpha on residues K21 and K22, which are also used for ubiquitin modification. Thus, while ubiquitination targets proteins for rapid degradation, SUMO-1 modification acts antagonistically to generate proteins resistant to degradation.

Animals↗
PubMed1997

Nuclear-cytoplasmic shuttling of the focal contact protein, zyxin: a potential mechanism for communication between sites of cell adhesion and the nucleus.

Integrin-dependent cell adhesion to specific extracellular matrix molecules has been demonstrated to trigger dramatic changes in gene expression that can affect cell fate. However, little is understood about the molecular mechanism by which events at sites of cell- substratum adhesion are communicated to the cell interior to regulate the transcriptional apparatus. By analogy to classical mechanisms of cell surface receptor function, it seems likely that some components of the integrin-activated signal transduction machinery will be colocalized with cell adhesion molecules. Zyxin is a low abundance phosphoprotein that accumulates with integrins at sites of cell-substratum attachment. Here we show that zyxin exhibits a functional nuclear export signal that is required to keep zyxin concentrated in the cytoplasm and is sufficient to direct nuclear proteins to the cytosol. Furthermore, we demonstrate that native zyxin shuttles between the nucleus and sites of cell adhesion in fibroblasts and is thus an excellent candidate for relaying information between these two compartments.

Amino Acid Sequence↗
PubMed2005

Oxidant-specific folding of Yap1p regulates both transcriptional activation and nuclear localization.

The yeast transcriptional regulator Yap1p is a key determinant in oxidative stress resistance. This protein is found in the cytoplasm under non-stressed conditions but rapidly accumulates in the nucleus following oxidant exposure. There it activates transcription of genes encoding antioxidants that return the redox balance of the cell to an acceptable range. Yap1p localization to the nucleus requires the oxidant-specific formation of disulfide bonds in the N-terminal cysteine-rich domain (N-CRD) and/or the C-terminal cysteine-rich domain (C-CRD). H(2)O(2) exposure triggers the formation of two interdomain disulfide bonds between the N-and C-CRDs. This dually disulfide-bonded structure has been argued to mask the nuclear export signal in the C-CRD that would otherwise prevent Yap1p nuclear accumulation. The C-CRD is required for wild-type H(2)O(2) tolerance but dispensable for resistance to diamide. The Saccharomyces cerevisiae TRX2 gene, encoding a thioredoxin protein, cannot be induced by H(2)O(2) in the presence of various mutant forms of Yap1p lacking the normally functioning C-CRD. In this work, we demonstrate that the proper folding of Yap1p in the presence of H(2)O(2) is required for recruitment of the mediator component Rox3p to the TRX2 promoter in addition to the nuclear accumulation of Yap1p during stress by this oxidant. These data demonstrate that the dually disulfide-bonded Yap1p N- and C-CRDs form a bifunctional protein domain controlling both nuclear localization and transcriptional activation.

Binding Sites↗
PubMed2002

Nuclear entry and CRM1-dependent nuclear export of the Rous sarcoma virus Gag polyprotein.

The retroviral Gag polyprotein directs budding from the plasma membrane of infected cells. Until now, it was believed that Gag proteins of type C retroviruses, including the prototypic oncoretrovirus Rous sarcoma virus, were synthesized on cytosolic ribosomes and targeted directly to the plasma membrane. Here we reveal a previously unknown step in the subcellular trafficking of the Gag protein, that of transient nuclear localization. We have identified a targeting signal within the N-terminal matrix domain that facilitates active nuclear import of the Gag polyprotein. We also found that Gag is transported out of the nucleus through the CRM1 nuclear export pathway, based on observations that treatment of virus-expressing cells with leptomycin B resulted in the redistribution of Gag proteins from the cytoplasm to the nucleus. Internal deletion of the C-terminal portion of the Gag p10 region resulted in the nuclear sequestration of Gag and markedly diminished budding, suggesting that the nuclear export signal might reside within p10. Finally, we observed that a previously described matrix mutant, Myr1E, was insensitive to the effects of leptomycin B, apparently bypassing the nuclear compartment during virus assembly. Myr1E has a defect in genomic RNA packaging, implying that nuclear localization of Gag might be involved in viral RNA interactions. Taken together, these findings provide evidence that nuclear entry and egress of the Gag polyprotein are intrinsic components of the Rous sarcoma virus assembly pathway.

Active Transport, Cell Nucleus↗