Fbw7? and Fbw7? collaborate to shuttle cyclin E1 into the nucleolus for multiubiquitylation.

ABSTRACT: Cyclin E1, an activator of cyclin-dependent kinase 2 (Cdk2) that promotes replicative functions, is normally expressed periodically within the mammalian cell cycle, peaking at the G(1)-S-phase transition. This periodicity is achieved by E2F-dependent transcription in late G(1) and early S phases and by ubiquitin-mediated proteolysis. The ubiquitin ligase that targets phosphorylated cyclin E is SCF(Fbw7) (also known as SCF(Cdc4)), a member of the cullin ring ligase (CRL) family. Fbw7, a substrate adaptor subunit, is expressed as three splice-variant isoforms with different subcellular distributions: Fbw7? is nucleoplasmic but excluded from the nucleolus, Fbw7? is cytoplasmic, and Fbw7? is nucleolar. Degradation of cyclin E in vivo requires SCF complexes containing Fbw7? and Fbw7?, respectively. In vitro reconstitution showed that the role of SCF(Fbw7?) in cyclin E degradation, rather than ubiquitylation, is to serve as a cofactor of the prolyl cis-trans isomerase Pin1 in the isomerization of a noncanonical proline-proline bond in the cyclin E phosphodegron. This isomerization is required for subsequent binding and ubiquitylation by SCF(Fbw7?). Here we show that Pin1-mediated isomerization of the cyclin E phosphodegron and subsequent binding to Fbw7? drive nucleolar localization of cyclin E, where it is ubiquitylated by SCF(Fbw7?) prior to its degradation by the proteasome. It is possible that this constitutes a mechanism for rapid inactivation of phosphorylated cyclin E by nucleolar sequestration prior to its multiubiquitylation and degradation.

SUBMITTER: Bhaskaran N 

PROVIDER: S-EPMC3536299 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature