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J Biol Chem, Vol. 274, Issue 11, 7391-7398, March 12, 1999
From the Department of Biochemistry and Molecular Biology, John
Curtin School of Medical Research, Canberra, A.C.T.2601, Australia, and
Parathyroid hormone-related protein (PTHrP),
expressed in a range of tumors, has endocrine, autocrine/paracrine, and
intracrine actions, some of which relate to its ability to localize in
the nucleus. Here we show for the first time that extracellularly added
human PTHrP (amino acids 1-108) can be taken up specifically by
receptor-expressing UMR106.01 osteogenic sarcoma cells and accumulate
to quite high levels in the nucleus and nucleolus within 40 min.
Quantitation of recognition by the nuclear localization sequence
(NLS)-binding importin subunits indicated that in contrast to proteins
containing conventional NLSs, PTHrP is recognized exclusively by
importin
Importin
Recognizes Parathyroid Hormone-related Protein
with High Affinity and Mediates Its Nuclear Import in the Absence
of Importin 
,,, and St. Vincent's Medical Research Institute, Fitzroy,
Victoria 3065, Australia
and not by importin 
. The sequence of PTHrP responsible
for binding was mapped to amino acids 66-94, which includes an SV40
large tumor-antigen NLS-like sequence, although sequence determinants
amino-terminal to this region were also necessary for high affinity
binding (apparent dissociation constant of ~2 nM
for importin ). Nuclear import of PTHrP was assessed in
vitro using purified components, demonstrating that importin ,
together with the GTP-binding protein Ran, was able to mediate
efficient nuclear accumulation in the absence of importin , whereas
the addition of nuclear transport factor NTF2 reduced transport. The
polypeptide ligand PTHrP thus appears to be accumulated in the
nucleus/nucleolus through a novel, NLS-dependent nuclear import pathway independent of importin and perhaps also of NTF2.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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