The TGFß-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1.

ABSTRACT

The signalling pathways downstream of the transforming growth factor beta (TGFß) family of cytokines play critical roles in all aspects of cellular homeostasis. The phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in TGFß-induced epithelial-to-mesenchymal transition and apoptosis. The precise molecular mechanisms by which TGFß cytokines induce the phosphorylation and activation of p38 MAPK are unclear. In this study, I demonstrate that TGFß-activated kinase 1 (TAK1/MAP3K7) does not play a role in the TGFß-induced phosphorylation and activation of p38 MAPK in MEFs and HaCaT keratinocytes. Instead, RNAi-mediated depletion of MAP3K4 and MAP3K10 results in the inhibition of the TGFß-induced p38 MAPK phosphorylation. Furthermore, the depletion of MAP3K10 from cells homozygously knocked-in with a catalytically inactive mutant of MAP3K4 completely abolishes the TGFß-induced phosphorylation of p38 MAPK, implying that among MAP3Ks, MAP3K4 and MAP3K10 are sufficient for mediating the TGFß-induced activation of p38 MAPK.