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J Biol Chem. 2010 May 14;285(20):15149-58. doi: 10.1074/jbc.M110.105429. Epub 2010 Mar 15.

p38gamma MAPK cooperates with c-Jun in trans-activating matrix metalloproteinase 9.

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Department of Pharmacology and Toxicology, The Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.


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 p38gamma MAPK, and the activated c-Jun then recruits p38gamma 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 p38gamma that led to increased c-Jun synthesis, MMP9 transcription, and MMP9-dependent invasion through p38gamma interacting with c-Jun. p38gamma requires phosphorylation and its C terminus to bind c-Jun, whereas both c-Jun and p38gamma are required for the trans-activation of MMP9. The active p38gamma/c-Jun/MMP9 pathway also exists in human colon cancer, and there is a coupling of increased p38gamma 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.

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