Ubiquitylation and proteasomal degradation of the p21(Cip1), p27(Kip1) and p57(Kip2) CDK inhibitors

Abstract

The expression levels of the p21(Cip1) family CDK inhibitors (CKIs), p21(Cip1), p27(Kip1) and p57(Kip2), play a pivotal role in the precise regulation of cyclin-dependent kinase (CDK) activity, which is instrumental to proper cell cycle progression. The stabilities of p21(Cip1), p27(Kip1) and p57(Kip2) are all tightly and differentially regulated by ubiquitylation and proteasome-mediated degradation during various stages of the cell cycle, either in steady state or in response to extracellular stimuli, which often elicit site-specific phosphorylation of CKIs triggering their degradation.

Figure 1

Phosphorylated p21^Cip1 is degraded by distinct E3 ligases. (A) E3 ligases involved in p21^Cip1 degradation. p21^Cip1 is ubiquitylated and degraded in late G₁ and S phases by SCF^Skp2 and CRL4^Cdt2, and in G₂ phase by APC/C^Cdc20 in the nucleus. A portion p21^Cip1 is phosphorylated and translocated into the cytosol where it is ubiquitylated and degraded by proteasomes. (B) Schematic structure of p21^Cip1 showing the regulatory phosphorylation sites and the cognate protein kinases. CDI: CDK inhibitor domain.

Figure 2

Phosphorylated 27^Kip1 is degraded by distinct E3 ligases. (A) E3 ligases involved in p27^Kip1 degradation. p27^Kip1 is ubiquitylated and degraded in late G₁, S and G₂ phases by SCF^Skp2 in the nucleus. p27^Kip1 phosphorylated at S10 is ubiquitylated by the KPC complex when exported to the cytoplasm. (B) Schematic structure of p27^Kip1 showing the regulatory phosphorylation sites and the cognate protein kinases. CDI, CDK inhibitor domain.

Figure 3

Phosphorylated p57^Kip2 is degraded by distinct E3 ligases. (A) E3 ligases involved in p57^Kip2 degradation. p57^KIP2 phosphorylated at T329 is ubiquitylated and degraded in late G₁ and S phases by SCF^FBL12 and SCF^Skp2. (B) Schematic structure of p57^Kip2 showing the single regulatory phosphorylation site. CDI, CDK inhibitor domain.