Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer

Abstract

The maintenance and preservation of distinct phases during the cell cycle is a highly complex and coordinated process. It is regulated by phosphorylation--through the activity of cyclin-dependent kinases (CDKs)--and protein degradation, which occurs through ubiquitin ligases such as SCF (SKP1-CUL1-F-box protein) complexes and APC/C (anaphase-promoting complex/cyclosome). Here, we explore the functionality and biology of the F-box proteins, SKP2 (S-phase kinase-associated protein 2) and beta-TrCP (beta-transducin repeat-containing protein), which are emerging as important players in cancer biogenesis owing to the deregulated proteolysis of their substrates.

Figure 1. The UPS controls the cell cycle

The cell division cycle is regulated primarily by the activity of cyclin-dependent kinases (CDKs) and protein degradation by the ubiquitin–proteasome system (UPS). Each CDK complex contains one of many activating subunits, termed cyclins, the levels of which oscillate during the cell cycle. CKIs (CDK inhibitors), such as p27 and p21, inhibit CDK activity and promote cell cycle arrest and/or delay. SCF complexes and the APC/C (anaphase-promoting complex/cyclosome) provide the specific, rapid and timely proteolysis of cell cycle regulators, which ultimately controls CDK1 and CDK2 to finely modulate their activities during cell cycle progression. The best characterized cell cycle ubiquitin ligases are SCF^SKP2, SCF^FBXW7 (not shown), SCF^β-TrCP, APC/C^CDH1 and APC/C^CDC20. SCF^SKP2 is a positive regulator of cell cycle progression (by promoting the degradation of p21 and p27), whereas SCF^β-TrCP is both a positive and negative regulator of the cell cycle (by targeting CDC25A (cell division cycle 25A), claspin, WEE1 and EMI1 (also known as F-box protein 5)). APC/C^CDH1 and APC/C^CDC20 always attenuate CDK1 activity (by directing the degradation of cyclins A and B), except in early mitosis, when APC/C^CDC20 targets p21 for degradation. Finally, SCF^FBXW7 attenuates CDK1 and CDK2 by inducing the degradation of cyclin E. SCF complexes and the APC/C control each other, with SKP2 being ubiquitylated by APC/C^CDH1 in G1 and SCF^β-TrCP targeting EMI1, which is an inhibitor of APC/C^CDH1, for proteolysis in early mitosis. Additionally, SCF complexes and the APC/C share common substrates that are targeted by their respective ubiquitin ligase(s) only at particular times during the cell cycle. For example, SCF^SKP2 targets p21 for degradation at G1–S, whereas APC/C^CDC20 targets p21 during prometaphase. This scenario is also true for the targeted degradation of CDC25A by APC/C^CDH1 in G1 phase, which is followed by SCF^β-TrCP-mediated degradation during S phase. Moreover, phosphorylation by CDKs modulates the activity of SCF complexes and the APC/C. CDK activity inhibits binding of CDH1 to the APC/C while promoting the activation of APC/C^CDC20, and phosphorylation of certain SCF substrates by CDKs allows recognition by the F-box protein subunit. β-TrCP, β-transducin repeat-containing protein; CDH1, also known as FZR1 (fizzy/cell division cycle 20 related 1); FBXW7, F-box protein with WD domain 7; SKP2, S-phase kinase-associated protein 2.