p38α antagonizes p38γ activity through c-jun-dependent ubiquitin-proteasome pathways in regulating ras transformation and stress response

Xiaomei Qi, Nicole M. Pohl, Mathew Loesch, Songwang Hou, Rongshan Li, Jian Zhong Qin, Ana Cuenda, Guan Chen*

*Corresponding author for this work

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

p38 MAPK family consists of four isoform proteins (α, β, γ, and δ) that are activated by the same stimuli, but the information about how these proteins act together to yield a biological response is missing. Here we show a feed-forward mechanism by which p38α may regulate Ras transformation and stress response through depleting its family member p38γ protein via c-Jun-dependent ubiquitin-proteasome pathways. Analyses of MAPK kinase 6 (MKK6)-p38 fusion proteins showed that constitutively active p38α (MKK6-p38α) and p38γ (MKK6-p38γ) stimulates and inhibits c-Jun phosphorylation respectively, leading to a distinct AP-1 regulation. Depending on cell type and/or stimuli, p38α phosphorylation results in either Rastransformation inhibition or a cell-death escalation that invariably couples with a decrease in p38γ protein expression. p38γ, on the other hand, increases Ras-dependent growth or inhibits stress induced cell-death independent of phosphorylation. In cells expressing both proteins, p38α phosphorylation decreases p38γ protein expression, whereas its inhibition increases cellular p38γ concentrations, indicating an active role of p38α phosphorylation in negatively regulating p38γ protein expression. Mechanistic analyses show that p38α requires c-Jun activation to deplete p38γ proteins by ubiquitin-proteasome pathways. These results suggest that p38α may, upon phosphorylation, act as a gatekeeper of the p38 MAPK family to yield a coordinative biological response through disrupting its antagonistic p38γ family protein.

Original languageEnglish (US)
Pages (from-to)31398-31408
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number43
DOIs
StatePublished - Oct 26 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'p38α antagonizes p38γ activity through c-jun-dependent ubiquitin-proteasome pathways in regulating ras transformation and stress response'. Together they form a unique fingerprint.

Cite this