Ubiquitylation of cyclin E requires the sequential function of SCF complexes containing distinct hCdc4 isoforms.

Journal Article

Cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2), is targeted for proteasomal degradation by phosphorylation-dependent multiubiquitylation via the ubiquitin ligase SCF(hCdc4). SCF ubiquitin ligases are composed of a core of conserved subunits and one variable subunit (an F box protein) involved in substrate recognition. We show here that multiubiquitylation of cyclin E requires the sequential function of two distinct splice variant isoforms of the F box protein hCdc4 known as alpha and gamma. SCF(hCdc4alpha) binds a complex containing cyclin E, Cdk2, and the prolyl cis/trans isomerase Pin1 and promotes the activity of Pin1 without directly ubiquitylating cyclin E. However, due to the action of this SCF(hCdc4alpha)-Pin1 complex, cyclin E becomes an efficient ubiquitylation substrate of SCF(hCdc4gamma). Furthermore, in the context of Cdc4alpha and cyclin E, mutational data suggest that Pin1 isomerizes a noncanonical proline-proline bond, with the possibility that Cdc4alpha may serve as a cofactor for altering the specificity of Pin1.

Full Text

Duke Authors

Cited Authors

  • van Drogen, F; Sangfelt, O; Malyukova, A; Matskova, L; Yeh, E; Means, AR; Reed, SI

Published Date

  • July 7, 2006

Published In

Volume / Issue

  • 23 / 1

Start / End Page

  • 37 - 48

PubMed ID

  • 16818231

International Standard Serial Number (ISSN)

  • 1097-2765

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2006.05.020

Language

  • eng

Conference Location

  • United States