c-Cbl is not required for ERK1/2-dependent degradation of BimEL

Cell Signal. 2007 Dec;19(12):2605-11. doi: 10.1016/j.cellsig.2007.08.008. Epub 2007 Aug 23.

Abstract

Bim(EL) the most abundant Bim splice variant, is subject to ERK1/2-catalysed phosphorylation, which targets it for ubiquitination and proteasome-dependent destruction. In contrast, inactivation of ERK1/2, following withdrawal of survival factors, promotes stabilization of Bim(EL). It has been proposed that the RING finger protein Cbl binds to Bim(EL) and serves as its E3 ubiquitin ligase. However, this is controversial since most Cbl substrates are tyrosine phosphoproteins and yet Bim(EL) is targeted for destruction by ERK1/2-catalysed serine phosphorylation. Consequently, a role for Cbl could suggest a second pathway for Bim(EL) turnover, regulated by direct tyrosine phosphorylation, or could suggest that Bim(EL) is a coincidence detector, requiring phosphorylation by ERK1/2 and a tyrosine kinase. Here we show that degradation of Bim(EL) does not involve its tyrosine phosphorylation; indeed, Bim(EL) is not a tyrosine phosphoprotein. Furthermore, Bim(EL) fails to interact with Cbl and growth factor-stimulated, ERK1/2-dependent Bim(EL) turnover proceeds normally in Cbl-containing or Cbl-/- fibroblasts. These results indicate that Cbl is not required for ERK1/2-dependent Bim(EL) turnover in fibroblasts and epithelial cells and any role it has in other cell types is likely to be indirect.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Bcl-2-Like Protein 11
  • Cell Line
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Epithelial Cells / metabolism*
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mutation
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-cbl / deficiency
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Serine / metabolism
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Tyrosine / metabolism
  • Ubiquitin / metabolism*
  • Vanadates / pharmacology

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Enzyme Inhibitors
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Ubiquitin
  • pervanadate
  • Tamoxifen
  • afimoxifene
  • Vanadates
  • Tyrosine
  • Serine
  • Epidermal Growth Factor
  • Proto-Oncogene Proteins c-cbl
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Protein Tyrosine Phosphatases
  • Proteasome Endopeptidase Complex
  • Cbl protein, mouse