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J. Biol. Chem., Vol. 275, Issue 33, 25146-25154, August 18, 2000
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From the Department of Molecular and Cellular Biology, Medical
Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi,
Higashi-ku, Fukuoka, Fukuoka 812-8582 and CREST, Japan Science and
Technology Corporation, Kawaguchi 332-0012, Japan
The association of the p27Kip1 protein
with cyclin and cyclin-dependent kinase complexes inhibits
their kinase activities and contributes to the control of cell
proliferation. The p27Kip1 protein has now been shown to be
phosphorylated in vivo, and this phosphorylation reduces
the electrophoretic mobility of the protein. Substitution of
Ser10 with Ala (S10A) markedly reduced the extent of
p27Kip1 phosphorylation and prevented the shift in
electrophoretic mobility. Phosphopeptide mapping and phosphoamino acid
analysis revealed that phosphorylation at Ser10 accounted
for ~70% of the total phosphorylation of p27Kip1, and the
extent of phosphorylation at this site was ~25- and 75-fold greater
than that at Ser178 and Thr187, respectively.
The phosphorylation of p27Kip1 was markedly reduced when the
positions of Ser10 and Pro11 were reversed,
suggesting that a proline-directed kinase is responsible for the
phosphorylation of Ser10. The extent of Ser10
phosphorylation was markedly increased in cells in the
G0-G1 phase of the cell cycle compared with
that apparent for cells in S or M phase. The p27Kip1 protein
phosphorylated at Ser10 was significantly more stable than
the unphosphorylated form. Furthermore, a mutant p27Kip1 in
which Ser10 was replaced with glutamic acid in order to
mimic the effect of Ser10 phosphorylation exhibited a
marked increase in stability both in vivo and in
vitro compared with the wild-type or S10A mutant proteins. These
results suggest that Ser10 is the major site of
phosphorylation of p27Kip1 and that phosphorylation at this
site, like that at Thr187, contributes to regulation of
p27Kip1 stability.
To whom correspondence should be addressed: Dept. of Molecular and
Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. Tel.: 81-92-642-6815; Fax: 81-92-642-6819; E-mail:
nakayak1@bioreg.kyushu-u.ac.jp.
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