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Article Dans Une Revue Journal of Molecular Biology Année : 2015

The activity and stability of the intrinsically disordered cip/kip protein family are regulated by non-receptor tyrosine kinases

Résumé

The Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors includes p21(Cip1) p27(Kip1) and d57(Kip2). Their kinase inhibitory activities are mediated by a homologous N-terminal kinaseinhibitory 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

Dates et versions

hal-01230103 , version 1 (17-11-2015)

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Citer

Yongqi Huang, Mi-Kyung Yoon, Steve Otieno, Moreno Lelli, Richard W Kriwacki. The activity and stability of the intrinsically disordered cip/kip protein family are regulated by non-receptor tyrosine kinases. Journal of Molecular Biology, 2015, 427 (2), pp.371-386. ⟨10.1016/j.jmb.2014.11.011⟩. ⟨hal-01230103⟩
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