TGFβ‐mediated BIM expression and apoptosis are regulated through SMAD3‐dependent expression of the MAPK phosphatase MKP2

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Abstract
Transforming growth factor‐β (TGFβ) 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 TGFβ induces BIM through its rapid inhibition of ERK, thereby preventing the phosphorylation and degradation of BIM. TGFβ, 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 TGFβ, whereas its ablation in pro‐B cells, derived from MKP2‐deficient mice, protects cells from TGFβ‐mediated apoptosis, and blocks TGFβ‐induced ERK inhibition and BIM induction. Furthermore, in pro‐B cells derived from SMAD3‐deficient mice, induction of MKP2 by TGFβ, inhibition of ERK, induction of BIM and apoptosis do not occur. Our results indicate that MKP2 mediates TGFβ‐dependent apoptosis by linking SMAD3 to the modulation of ERK activity and mitochondrial‐mediated pro‐apoptotic events.

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