Ubiquitylation of the amino terminus of Myc by SCF(β-TrCP) antagonizes SCF(Fbw7)-mediated turnover

Nat Cell Biol. 2010 Oct;12(10):973-81. doi: 10.1038/ncb2104. Epub 2010 Sep 19.

Abstract

The SCFFbw7 ubiquitin ligase mediates growth-factor-regulated turnover of the Myc oncoprotein. Here we show that SCFβ-TrCP binds to Myc by means of a characteristic phosphodegron and ubiquitylates Myc; this results in enhanced Myc stability. SCFFbw7 and SCFβ-TrCP can exert these differential effects through polyubiquitylation of the amino terminus of Myc. Whereas SCFFbw7 with the Cdc34 ubiquitin-conjugating enzyme specifically requires lysine 48 (K48) of ubiquitin, SCFβ-TrCP uses the UbcH5 ubiquitin-conjugating enzyme to form heterotypic polyubiquitin chains on Myc. Ubiquitylation of Myc by SCFβ-TrCP is required for Myc-dependent acceleration of cell cycle progression after release from an arrest in S phase. Therefore, alternative ubiquitylation events at the N terminus can lead to the ubiquitylation-dependent stabilization of Myc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Anaphase-Promoting Complex-Cyclosome
  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cells, Cultured
  • Consensus Sequence
  • F-Box Proteins / metabolism*
  • F-Box-WD Repeat-Containing Protein 7
  • G2 Phase
  • HeLa Cells
  • Humans
  • Mice
  • Models, Biological
  • NIH 3T3 Cells
  • Polyubiquitin / metabolism
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-myc / chemistry*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • S Phase
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitin-Protein Ligase Complexes / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*
  • beta-Transducin Repeat-Containing Proteins / metabolism*

Substances

  • BTRC protein, human
  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • beta-Transducin Repeat-Containing Proteins
  • Polyubiquitin
  • CDC34 protein, human
  • UBE2D1 protein, human
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1