Exp Mol Med.  2005 Jun;37(3):230-239.

Tetraspanin CD9 induces MMP-2 expression by activating p38 MAPK, JNK and c-Jun pathways in human melanoma cells

• Hong IK
• Kim YM
• Jeoung DI
• Kim KC
• Lee H

Abstract

Expression of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), which correlates with tumor invasion and metastasis, has been known to be regulated by several intracellular signaling pathways. Since the CD9 membrane protein has been implicated in signal transduction and malignant progression of cancer cells, we examined the functional involvement of CD9 in the regulation of MMP-2 and MMP-9 expression by using stable CD9 transfectant clones of MelJuso human melanoma cells. The CD9 cDNA-transfected cells with elevated CD9 expression displayed increased MMP-2 and decreased MMP-9 expression when compared with the mock transfectant cells. Among several signal pathway inhibitors tested, SB203580 and SP600125, which inhibit p38 MAPK and JNK respectively, completely blocked the CD9-stimulated MMP-2 expression. Phosphorylation levels of p38 MAPK and c-Jun in MelJuso cells were also significantly increased by CD9 transfection. In addition, the down-regulation of p38 MAPK and JNK by siRNA transfection resulted in a decrease in MMP-2 expression by MelJuso cells. Promoter analysis and gel shift assay showed that the CD9-induced MMP-2 expression is mediated by a functional AP-1 site through interactions with AP-1 transcription factors including c-Jun. These results suggest that CD9 induces MMP-2 expression by activating c- Jun through p38 MAPK and JNK signaling pathways in human melanoma cells.

Keyword

AP-1; CD9; c-Jun; JNK; melanoma; MMP- 2; p38 MAPK; tetraspanin

MeSH Terms

Antigens, CD/*metabolism
Electrophoretic Mobility Shift Assay
Enzyme Activation
Gelatinase A/genetics/*metabolism
Gelatinase B/metabolism
Humans
JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/genetics/*metabolism
Melanoma/*metabolism/pathology
Membrane Glycoproteins/*metabolism
Promoter Regions (Genetics)
Proto-Oncogene Proteins c-jun/*metabolism
RNA, Small Interfering/pharmacology
Research Support, Non-U.S. Gov't
*Signal Transduction
Skin Neoplasms/metabolism/pathology
Transcription Factor AP-1/metabolism
Transfection
p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/genetics/*metabolism