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Mol. Cell. Biol. doi:10.1128/MCB.02171-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Differential modification of p27Kip1 controls its cyclin D-cdk4 inhibitory activity

Program in Molecular and Cellular Biology of the School of Graduate Studies, Departments of Pediatrics and Anatomy and Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203 USA

^* To whom correspondence should be addressed. Email: stacy.blain{at}downstate.edu.

	Abstract

Whether p27 is a cyclin D-cdk4/6 inhibitor or not is controversial, and how it might switch between these two modes is unknown. Arguing for a two state mechanism, we show that p27 bound to cyclin D-cdk4 can be both inhibitory and non-inhibitory, due to its differential growth state dependent tyrosine phosphorylation. We found that p27 from proliferating cells was non-inhibitory, while p27 from arrested cells was inhibitory, and the transition from bound-non-inhibited to bound-inhibited was not due to an increase in p27 concentration. Rather, two tyrosine residues (Y88,Y89) in the p27 cdk interaction domain were phosphorylated preferentially in proliferating cells, converting it to a non-inhibitor. Concordantly, mutation of these sites rendered p27 resistant to phosphorylation and locked it into the bound-inhibitor mode in vivo and in vitro. Y88 was directly phosphorylated in vitro by the tyrosine kinase Abl, converting p27 to a cdk4 bound-non-inhibitor. These data show that the growth state dependent tyrosine phosphorylation of p27 modulates its inhibitory activity in vivo.