A CDK-independent function of mammalian Cks1: Targeting of SCFSkp2 to the CDK inhibitor p27(Kip1)

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