BMP2-induced Apoptosis Is Mediated by Activation of the TAK1-p38 Kinase Pathway That Is Negatively Regulated by Smad6

Abstract

Bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor-beta (TGF-␤) superfamily, regulates a variety of cell fates and functions. At present, the molecular mechanism by which BMP2 induces apoptosis has not been fully elucidated. Here we propose a BMP2 signaling pathway that mediates apoptosis in mouse hybridoma MH60 cells whose growth is interleukin-6 (IL-6)-dependent. BMP2 dose-dependently induces apoptosis in MH60 cells even in the presence of IL-6. BMP2 has no inhibitory effect on the IL-6-induced tyrosine phosphorylation of STAT3, and the bcl-2 gene expression which is known to be regulated by STAT3, suggesting that BMP2-induced apoptosis is not attributed to alteration of the IL-6-mediated bcl-2 pathway. We demonstrate that BMP2 induces activation of TGF-␤-activated kinase (TAK1) and subsequent phosphorylation of p38 stress-activated protein kinase. In addition, forced expression of kinase-negative TAK1 in MH60 cells blocks BMP2-induced apoptosis. These results indicate that BMP2-induced apoptosis is mediated through the TAK1-p38 pathway in MH60 cells. We also show that MH60-derived transfectants expressing Smad6 are resistant to the apoptotic signal of BMP2. Interestingly, this ectopic expression of Smad6 blocks BMP2-induced TAK1 activation and p38 phosphorylation. Moreover, Smad6 can directly bind to TAK1. These findings suggest that Smad6 is likely to function as a negative regulator of the TAK1 pathway in the BMP2 signaling, in addition to the previously reported Smad pathway.

BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways

“…XIAP has been implicated in connecting the type I receptors of BMPs and TGF-␤s with the mitogen-activated protein kinase (MAPK) p38 pathway (17)(18)(19)(20). Contrary to previous findings in which BMP signaling up-regulates p38 MAP kinase (17,20,21), our findings reveal that BMP4 inhibits MAP kinase pathways in ES cells.…”

BMP-4 induces a Smad-dependent apoptotic cell death of mouse embryonic stem cell-derived neural precursors

“…This apoptotic cell death involves the characteristic mitochondrial damages leading to the cleavage of caspase-3 and targets early neural Sox-1 positive precursor cells. We further demonstrate that this mechanism does not involve the p38 MAP kinase pathway usually associated with BMP proapoptotic effects, 18 but proceeds rather through the activation of both the Smad pathway and Msx1/2 gene expression. Altogether, our results indicate that part of the inhibition of neuralization by BMP-4, in mammals, involves the apoptotic cell death of neural precursor cells, resulting in enrichment of epithelial/epidermal lineages.…”

“…21 Some of the apoptotic effects of BMPs have been shown to involve the activation of p38. 18,22,23 In our cell system, we were unable to detect the activation of the p38 pathway after BMP-4 treatment. No phosphorylation of p38 nor its substrates could be detected (not shown).…”

Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation

“…This observation is consistent with the essential role of IKK-1 in NF-kB activation by TGFb1, although we cannot exclude that TAK1 might be activating IKK-2 as well. Previously, TAK1 has been shown to induce MKK4, MKK3, and MKK6 activities in response to TGF-b1 and BMP-2 (Moriguchi et al, 1996;Shirakabe et al, 1997;Kimura et al, 2000), thereby promoting apoptosis through JNK and p38 activation (Kimura et al, 2000;Yamamura et al, 2000). Thus, it appears that TGF-b family members are able to activate through common mediators both proapoptotic (JNK/AP-1) and antiapoptotic (IKK/NF-kB) pathways, and consequently the balance between these two signaling cascades determines the fate of a cell.…”