The cell cycle regulatory protein Cks1 is required for the SCFSkp2-mediated ubiquitinylation of p27
D. Ganoth, G. Bornstein, T. K. Ko, B. Larsen, M. Tyers, M. Pagano and A. Hershko
Nature Cell Biol 2001; 3: 321-324
The cyclin-dependent kinase (Cdk) inhibitor p27 is degraded in late G1 by the ubiquitin pathway allowing Cdk activity to drive cells into S-phase. Ubiquitinylation of p27 requires its phosphorylation on Thr-187 and the subsequent recognition by Skp2 (S-phase kinase associated protein 2), a member of the F-box family of proteins that associates with Skp1, Cul-1 and ROC1/Rbx1 to form an SCF ubiquitin ligase complex. Yet, in vitro ligation of p27 to ubiquitin could not be reconstituted by known purified components of the SCFSkp2 complex. Here we show that the missing factor is Cks1 (cyclin-dependent kinase subunit 1). Cks1 belongs to the highly conserved Suc1/Cks family of proteins that bind to some cyclin-dependent kinases and phosphorylated proteins and are essential for cell cycle progression. Human Cks1, but not other members of this protein family, reconstitutes p27-ubiquitin ligation in a completely purified system, binds to Skp2 and greatly increases the binding of Thr-187-phosphorylated p27 to Skp2. Our findings represent the first evidence that an SCF complex requires an accessory protein for activity as well as for its binding to the phosphorylated substrate.
Featured in: Nature Cell Biol. 2001; 4: E95-E97 and Current Biology 2001; 11: 431-434.