The movement of many transcription factors, kinases and replication factors
between the nucleus and cytoplasm is important in regulating their activit
y(1). In some cases, phosphorylation of a protein regulates its entry into
the nucleus(2); in others, it causes the protein to be exported to the cyto
plasm(3-6). The mechanism by which phosphorylation promotes protein export
from the nucleus is poorly understood. Here we investigate how the export o
f the yeast transcription factor Pho4 is regulated in response to changes i
n phosphate availability. We show that phosphorylation of Pho4 by a nuclear
complex of a cyclin with a cyclin-dependent kinase, Pho80-Pho85, triggers
its export from the nucleus. We also find that the shuttling receptor used
by Pho4 for nuclear export is the importin-beta-family member Msn5 (refs 7,
8), which is required for nuclear export of Pho4 in vivo and binds only to
phosphorylated Pho4 in the presence of the GTP-bound form of yeast Ran in
vitro. Our results reveal a simple mechanism by which phosphorylation can c
ontrol the nuclear export of a protein.