Physiological Reviews, Vol 76, 651-685, Copyright © 1996 by American Physiological Society
Regulation of protein transport to the nucleus: central role of phosphorylation
D. A. Jans and S. Hubner
Nuclear Signalling Laboratory, Division for Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Nuclear protein transport is integral to eukaryotic cell processes such as
differentiation, transformation, and the control of gene expression.
Although the targeting role of nuclear localization signals (NLSs) has been
known for some time, more recent results indicate that NLS-dependent
nuclear protein import is precisely regulated. Phosphorylation appears to
be the main mechanism controlling the nuclear transport of a number of
proteins, including transcription factors such as NFkappaB, c-rel, dorsal,
and SWI5 from yeast. Cytoplasmic retention factors, intra- and
intermolecular NLS masking, and NLS masking by phosphorylation are some of
the mechanisms by which phosphorylation specifically regulates nuclear
transport. Even nuclear localization of the archetypal NLS-containing
simian virus 40 large tumor antigen (T-ag) is regulated, namely by the "CcN
motif," which comprises the T-ag NLS ("N") determining ultimate subcellular
destination, a casein kinase II site ("C") 13 amino acids NH2-terminal to
the NLS modulating the rate of nuclear import, and a cyclin-dependent
kinase site ("c") adjacent to the NLS regulating the maximal level of
nuclear accumulation. The CcN motif appears to be a special form of
phosphorylation-regulated NLS (prNLS), where phosphorylation at site(s)
close to the NLS specifically regulates NLS function. The regulation of
nuclear transport through phosphorylation and prNLSs appears to be common
in eukaryotic cells from yeast and plants to higher mammals.
