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

Open Biol. 2013 Jun 12;3(6):130067. doi: 10.1098/rsob.130067.

Abstract

The signalling pathways downstream of the transforming growth factor beta (TGFβ) 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 TGFβ-induced epithelial-to-mesenchymal transition and apoptosis. The precise molecular mechanisms by which TGFβ cytokines induce the phosphorylation and activation of p38 MAPK are unclear. In this study, I demonstrate that TGFβ-activated kinase 1 (TAK1/MAP3K7) does not play a role in the TGFβ-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 TGFβ-induced p38 MAPK phosphorylation. Furthermore, the depletion of MAP3K10 from cells homozygously knocked-in with a catalytically inactive mutant of MAP3K4 completely abolishes the TGFβ-induced phosphorylation of p38 MAPK, implying that among MAP3Ks, MAP3K4 and MAP3K10 are sufficient for mediating the TGFβ-induced activation of p38 MAPK.

Keywords: MAP3K10; MAP3K4; MLK2; SMAD; TAK1; transforming growth factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gene Knock-In Techniques
  • Humans
  • MAP Kinase Kinase Kinase 4 / antagonists & inhibitors
  • MAP Kinase Kinase Kinase 4 / genetics
  • MAP Kinase Kinase Kinase 4 / metabolism*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Phosphorylation / drug effects
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • RNA, Small Interfering
  • Transforming Growth Factor beta
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 4
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • MAP3K10 protein, human
  • MAP3K4 protein, human