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J. Cell Biol.,
Volume 144, Number 2, January 25, 1999 213-224
Department of Pharmacology and Cancer Biology, and * Howard Hughes Medical Institute, Duke University Medical Center,
Durham, North Carolina 27710
Reversible phosphorylation of nuclear proteins is required for both DNA replication and entry
into mitosis. Consequently, most cyclin-dependent kinase (Cdk)/cyclin complexes are localized to the nucleus when active. Although our understanding of nuclear transport processes has been greatly enhanced by
the recent identification of nuclear targeting sequences
and soluble nuclear import factors with which they interact, the mechanisms used to target Cdk/cyclin complexes to the nucleus remain obscure; this is in part because these proteins lack obvious nuclear localization
sequences. To elucidate the molecular mechanisms
responsible for Cdk/cyclin transport, we examined
nuclear import of fluorescent Cdk2/cyclin E and
Cdc2/cyclin B1 complexes in digitonin-permeabilized
mammalian cells and also examined potential physical
interactions between these Cdks, cyclins, and soluble
import factors. We found that the nuclear import machinery recognizes these Cdk/cyclin complexes through
direct interactions with the cyclin component. Surprisingly, cyclins E and B1 are imported into nuclei via distinct mechanisms. Cyclin E behaves like a classical basic nuclear localization sequence-containing protein,
binding to the 
adaptor subunit of the importin-/
heterodimer. In contrast, cyclin B1 is imported via a direct interaction with a site in the NH2 terminus of importin- that is distinct from that used to bind importin-.
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