TGF beta-mediated BIM expression and apoptosis are regulated through SMAD3-dependent expression of the MAPK phosphatase MKP2.
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.
Ramesh
Sneha
S
Department of Cancer Biology, NB4, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Qi
Xiao-Jun
XJ
Wildey
Gary M
GM
Robinson
Janet
J
Molkentin
Jeffery
J
Letterio
John
J
Howe
Philip H
PH
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000072224:Bcl-2-Like Protein 11; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D051900:Smad3 Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases; C522186:Dusp4 protein, mouse; D017027:Protein Tyrosine Phosphatases