A CDK-independent function of mammalian Cks1:: Targeting of SCFSkp2 to the CDK inhibitor p27Kip1

The Cks/Suc1 proteins associate with CDK/cyclin complexes, but their precise function(s) is not well defined. Here we demonstrate that Cks1 directs the ubiquitin-mediated proteolysis of the CDK-bound substrate p27(Kip1) by the protein ubiquitin ligase (E3) SCFSkp2. Cks1 associates with the F box protein Skp2 and is essential for recognition of the p27(Kip1) substrate for ubiquitination in vivo and in vitro. Using purified recombinant proteins, we reconstituted p27(Kip1) Ubiquitination activity and show that it is dependent on Cks1. CKS1(-/-) mice are abnormally small, and cells derived from them proliferate poorly, particularly under limiting mitogen conditions, possibly due to elevated levels of p27(Kip1).