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J Mol Biol. 2015 Jan 30;427(2):371-386. doi: 10.1016/j.jmb.2014.11.011. Epub 2014 Nov 20.

The activity and stability of the intrinsically disordered Cip/Kip protein family are regulated by non-receptor tyrosine kinases.

Author information

1
Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38103, USA.
2
Centre de RMN à Trés Hauts Champs, Institut de Sciences Analytiques (CNRS/ENS Lyon/UCB Lyon 1), 69100 Villeurbanne, France.
3
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA.
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Contributed equally

Abstract

The Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors includes p21(Cip1), p27(Kip1) and p57(Kip2). Their kinase inhibitory activities are mediated by a homologous N-terminal kinase inhibitory domain. The Cdk inhibitory activity and stability of p27 have been shown to be regulated by a two-step phosphorylation mechanism involving a tyrosine residue within the kinase inhibitory domain and a threonine residue within the flexible C-terminus. We show that these residues are conserved in p21 and p57, suggesting that a similar phosphorylation cascade regulates these Cdk inhibitors. However, the presence of a cyclin binding motif within its C-terminus alters the regulatory interplay between p21 and Cdk2/cyclin A, as well as its responses to tyrosine phosphorylation and altered p21:Cdk2/cyclin A stoichiometry. We also show that the Cip/Kip proteins can be phosphorylated in vitro by representatives of many non-receptor tyrosine kinase (NRTK) sub-families, suggesting that NRTKs may generally regulate the activity and stability of these Cdk inhibitors. Our results further suggest that the Cip/Kip proteins integrate signals from various NRTK pathways and cell cycle regulation.

KEYWORDS:

cell cycle; cyclin-dependent kinase; intrinsically disordered protein; non-receptor tyrosine kinase; protein phosphorylation

PMID:
25463440
PMCID:
PMC4297576
DOI:
10.1016/j.jmb.2014.11.011
[Indexed for MEDLINE]
Free PMC Article

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