p38gamma 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 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.
Departments of Pharmacology and Toxicology, Milwaukee Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Mathew
M
Loesch
Departments of Pharmacology and Toxicology, Milwaukee Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Hui-Ying
HY
Zhi
Departments of Pharmacology and Toxicology, Milwaukee Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Song-Wang
SW
Hou
Departments of Pharmacology and Toxicology, Milwaukee Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Xiao-Mei
XM
Qi
Departments of Pathology, Milwaukee Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Rong-Shan
RS
Li
Departments of Pathology, Milwaukee Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Zainab
Z
Basir
Section of Experimental Virology, Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital of Tübingen, Tübingen D-72076, Germany.
Thomas
T
Iftner
Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain.
Ana
A
Cuenda
Departments of Pharmacology and Toxicology, Milwaukee Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Research Services, the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee Medical College of Wisconsin, Milwaukee, Wisconsin 53226. Electronic address: gchen@mcw.edu.
Guan
G
Chen
D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017931:DNA Primers; D016755:Proto-Oncogene Proteins c-jun; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9