p38γ MAPK Cooperates with c-Jun in trans-Activating Matrix Metalloproteinase 9

Mitogen-activated protein kinases (MAPKs) regulate gene expression through transcription factors. However, the precise mechanisms in this critical signal event are largely unknown. Here, we show that the transcription factor c-Jun is activated by p38 gamma MAPK, and the activated c-Jun then recruits p38 gamma as a cofactor into the matrix metalloproteinase 9 (MMP9) promoter to induce its trans-activation and cell invasion. This signaling event was initiated by hyperexpressed p38 gamma that led to increased c-Jun synthesis, MMP9 transcription, and MMP9-dependent invasion through p38 gamma interacting with c-Jun. p38 gamma requires phosphorylation and its C terminus to bind c-Jun, whereas both c-Jun and p38 gamma are required for the trans-activation of MMP9. The active p38 gamma/c-Jun/MMP9 pathway also exists in human colon cancer, and there is a coupling of increased p38 gamma and MMP9 expression in the primary tissues. These results reveal a new paradigm in which a MAPK acts both as an activator and a cofactor of a transcription factor to regulate gene expression leading to an invasive response.