TGF beta-mediated BIM expression and apoptosis are regulated through SMAD3-dependent expression of the MAPK phosphatase MKP2

EMBO Rep. 2008 Oct;9(10):990-7. doi: 10.1038/embor.2008.158. Epub 2008 Aug 15.

Abstract

Transforming growth factor-beta (TGFbeta) induces the expression of the pro-apoptotic protein BIM, and mediates apoptosis in hepatocytes and B lymphocytes. BIM is regulated through a post-translational mechanism involving ERK-dependent phosphorylation and ubiquitin-mediated proteasomal degradation. Here, we show that TGFbeta induces BIM through its rapid inhibition of ERK, thereby preventing the phosphorylation and degradation of BIM. TGFbeta, through a SMAD3-dependent mechanism, transcriptionally induces the mitogen-activated protein kinase (MAPK) phosphatase MKP2, encoded by an immediate early gene, to attenuate ERK and promote the accumulation of BIM protein. Overexpression of MKP2 in hepatocytes modulates ERK-mediated phosphorylation of BIM and apoptosis in the absence of TGFbeta, whereas its ablation in pro-B cells, derived from MKP2-deficient mice, protects cells from TGFbeta-mediated apoptosis, and blocks TGFbeta-induced ERK inhibition and BIM induction. Furthermore, in pro-B cells derived from SMAD3-deficient mice, induction of MKP2 by TGFbeta, inhibition of ERK, induction of BIM and apoptosis do not occur. Our results indicate that MKP2 mediates TGFbeta-dependent apoptosis by linking SMAD3 to the modulation of ERK activity and mitochondrial-mediated pro-apoptotic events.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics*
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Bcl-2-Like Protein 11
  • COS Cells
  • Cell Line
  • Cells, Cultured
  • Chlorocebus aethiops
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Knockout
  • Protein Tyrosine Phosphatases / biosynthesis
  • Protein Tyrosine Phosphatases / deficiency
  • Protein Tyrosine Phosphatases / genetics*
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics*
  • Smad3 Protein / deficiency
  • Smad3 Protein / genetics
  • Smad3 Protein / physiology*
  • Transforming Growth Factor beta / physiology*

Substances

  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • Extracellular Signal-Regulated MAP Kinases
  • MKP2 protein, mouse
  • Protein Tyrosine Phosphatases