In or out? Regulating nuclear transport
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
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