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

Mol Cell. 2006 Jul 7;23(1):37-48. doi: 10.1016/j.molcel.2006.05.020.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Cycle Proteins / classification*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology*
  • Cell Line
  • Cyclin E / metabolism*
  • F-Box Proteins / classification*
  • F-Box Proteins / genetics
  • F-Box Proteins / physiology*
  • F-Box-WD Repeat-Containing Protein 7
  • Gene Silencing / physiology
  • Humans
  • Isoenzymes / classification*
  • Isoenzymes / physiology
  • Models, Biological
  • Mutation
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / physiology
  • SKP Cullin F-Box Protein Ligases / physiology*
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / classification*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / physiology*


  • Cell Cycle Proteins
  • Cyclin E
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Isoenzymes
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Ubiquitin
  • SKP Cullin F-Box Protein Ligases
  • Ubiquitin-Protein Ligases
  • PIN1 protein, human
  • Peptidylprolyl Isomerase