In or out? Regulating nuclear transport

https://doi.org/10.1016/S0955-0674(99)80032-5Get rights and content

Abstract

The compartmentalization of proteins within the nucleus or cytoplasm of a eukaryotic cell offers opportunity for regulation of cell cycle progression and signalling pathways. Nuclear localization of proteins is determined by their ability to interact with specific nuclear import and export factors. In the past year, substrate phosphorylation has emerged as a common mechanism for controlling this interaction.

Introduction

In the past two years, our understanding of macromolecular trafficking across the nuclear membrane has grown exponentially with an increased repertoire of identified transport receptors, including the importin/karyopherin-β superfamily. These receptors were primarily identified by sequence homology or by biochemical interaction with the small GTPase Ran [1], which is a general factor required for both nuclear import and export 2, 3, 4, 5, 6, 7, 8. Subsequently, a number of groups have focused considerable effort on pairing the importin-β family members with their cognate import or export substrates. In fact, progress on this front has been very rapid, and several excellent reviews have recently catalogued these findings 9•, 10•, 11•; however, assigning roles to a list of players represents only the first step in understanding the regulatory mechanisms of nuclear transport. Given the basic sequence of receptor-substrate recognition, nuclear envelope docking, translocation and release, there exist numerous opportunities for regulation in response to environmental stimuli, intracellular signaling, or cell cycle cues.

A differential affinity for receptor binding to modified and unmodified forms of a substrate could offer one level of control. Indeed, new findings in several different fields point to regulated phosphorylation as a mechanism for determining whether a protein is recognized by components of the transport machinery. This article will focus on the regulation of nuclear transport by substrate phosphorylation, with special attention to recent examples from yeast model systems.

Section snippets

Models of regulated nuclear transport

A scheme in which substrate modification regulates nuclear transport could have many permutations. We have grouped a number of these possibilities into three basic models, shown in Figure 1, and we will refer to these models in our discussion of specific examples from the recent literature.

The first model of nuclear transport regulation exhibits unidirectional control. In this case, a protein moves consititutively in one direction across the nuclear membrane, but its movement in the other

Elucidating the mechanism of cyclin B localization

In the early 1990s, cell-cycle researchers observed a difference in the cellular location of human mitotic cyclins A and B1. Whereas cyclin A localized to the nucleus from S phase until its degradation during metaphase, cyclin B1 initially localized to the cytoplasm during S and G2 phases, then translocated into the nucleus at the beginning of mitosis, before nuclear envelope breakdown [15]. Because both cyclins A and B associate with the cyclin-dependent kinase (CDK)1 it is possible that their

Regulated nuclear localization and control of gene expression

Regulated nuclear localization also provides a mechanism by which cells can rapidly respond to changing environmental conditions. Certain transcription factors or signaling molecules may be sequestered in the cytoplasm until the appropriate signal triggers their translocation into the nucleus where they can then interact with their cognate DNA binding sites or signaling partners. One well-studied example is the transcription factor NF-κB (nuclear factor κB). In uninduced cells, the NLS of NF-κB

Conclusions and future directions

Rapid advances in the field suggest that we have entered the golden age of nuclear transport as a control mechanism for a wide variety of cellular processes. It has long been appreciated that the separation of eukaryotic cells into nuclear and cytoplasmic compartments confers a versatile means of regulation but we have only recently begun to elucidate the molecular details of these regulatory possibilities.

From the small number of examples presented here, it is already clear that multiple

Acknowledgements

The authors would like to thank Jonathan Moore and Sally Kornbluth for communication of data prior to publication, Anne McBride for critical reading of the manuscript, and Tetsuya Taura for technical assistance.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Table 1

References (47)

  • D. Görlich et al.

    A novel class of RanGTP binding proteins

    J Cell Biol

    (1997)
  • F. Melchior et al.

    Inhibition of nuclear protein import by nonhydrolyzable analogues of GTP and identification of the small GTPase Ran/TC4 as an essential transport factor

    J Cell Biol

    (1993)
  • M.S. Moore et al.

    The GTP-binding protein Ran/TC4 is required for protein import into the nucleus

    Nature

    (1993)
  • G. Schlenstedt et al.

    The GTP-bound form of the yeast Ran/TC4 homologue blocks nuclear protein import and appearance of poly(A)+ RNA in the cytoplasm

    Proc Natl Acad Sci USA

    (1995)
  • D. Görlich et al.

    Identification of different roles for RanGDP and RanGTP in nuclear protein import

    EMBO J

    (1996)
  • I. Palacios et al.

    Ran/TC4 mutants identify a common requirement for snRNP and protein import into the nucleus

    J Cell Biol

    (1996)
  • S.A. Richards et al.

    Requirement of guanosine triphosphate-bound Ran for signal-mediated nuclear protein export

    Science

    (1997)
  • E. Izaurralde et al.

    The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus

    EMBO J

    (1997)
  • E. Izaurralde et al.

    Transport of macromolecules between the nucleus and the cytoplasm

    RNA

    (1998)
  • P. Ferrigno et al.

    Regulated nucleocytoplasmic exchange of HOG1 MAPK requires the importin-β homologues NMD5 and XPO1

    EMBO J

    (1998)
  • J. Pines et al.

    The differential localization of human cyclins A and B is due to a cytoplasmic retention signal in cyclin B

    EMBO J

    (1994)
  • F. Gaits et al.

    Phosphorylation and association with the transcription factor Atf1 regulate localization of Spc1/Sty1 stress-activated kinase in fission yeast

    Genes Dev

    (1998)
  • J. Pines et al.

    Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-dependent nuclear transport

    J Cell Biol

    (1991)
  • Cited by (115)

    • Parts plus pipes: Synthetic biology approaches to metabolic engineering

      2012, Metabolic Engineering
      Citation Excerpt :

      The pairing of microcompartment shells with novel biosynthetic pathways may expand the reach of bacterial metabolic engineering. In eukaryotes, methods have been developed for the targeting of heterologous proteins to many membrane-bound organelles (Hood and Silver, 1999; Léon et al., 2006; Soll and Schleiff, 2004; Truscott et al., 2003). Efforts to synthesize methyl halides in S. cerevisiae have demonstrated the utility of localizing exogenous enzymes in appropriate subcellular environments.

    • Chapter 5 Nuclear Trafficking of Regulator of G Protein Signaling Proteins and Their Roles in the Nucleus

      2009, Progress in Molecular Biology and Translational Science
      Citation Excerpt :

      In yeast, phosphorylation of the transcription factor Pho4 at ser‐152, which resides within its NLS, prevents interaction between NLS and import receptor, while phosphorylation at other two residues, ser‐114 and ser‐128, promotes interaction of Pho4 with export receptors and nuclear export.87,88 Phosphorylation of another yeast protein, HOG1, is also essential for its stress‐induced nuclear translocation by affecting interaction between HOG1 and import and export receptors.89 In mammalian cells, phosphorylation of two serine residues within the N‐terminal NES of p53 prevents its nuclear export.90

    • MAP Kinase in Yeast

      2009, Handbook of Cell Signaling, Second Edition
    View all citing articles on Scopus
    View full text