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C‐terminal phosphorylation controls the stability and function of p27kip1
Author(s) -
Kossatz Uta,
Vervoorts Jörg,
Nickeleit Irina,
Sundberg Holly A,
Arthur J Simon C,
Manns Michael P,
Malek Nisar P
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601388
Subject(s) - cyclin dependent kinase , phosphorylation , microbiology and biotechnology , phosphorylation cascade , cell cycle , cyclin , kinase , cyclin dependent kinase 2 , cyclin a , biology , ubiquitin , protein phosphorylation , chemistry , protein kinase a , biochemistry , cell , gene
Entry of cells into the cell division cycle requires the coordinated activation of cyclin‐dependent kinases (cdks) and the deactivation of cyclin kinase inhibitors. Degradation of p27kip1 is known to be a central component of this process as it allows controlled activation of cdk2‐associated kinase activity. Turnover of p27 at the G1/S transition is regulated through phosphorylation at T187 and subsequent SCF skp2 ‐dependent ubiquitylation. However, detailed analysis of this process revealed the existence of additional pathways that regulate the abundance of the protein in early G1 and as cells exit quiescence. Here, we report on a molecular mechanism that regulates p27 stability by phosphorylation at T198. Phosphorylation of p27 at T198 prevents ubiquitin‐dependent degradation of free p27. T198 phosphorylation also controls progression through the G1 phase of the cell cycle by regulating the association of p27 with cyclin–cdk complexes. Our results unveil the molecular composition of a pathway, which regulates the abundance and activity of p27kip1 during early G1. They also explain how the T187‐ and the T198‐dependent turnover systems synergize to allow cell cycle progression in G1.