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- Title
Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-κB.
- Authors
Boukerche, H.; Aissaoui, H.; Prévost, C.; Hirbec, H.; Das, S. K.; Su, Z.-Z.; Sarkar, D.; Fisher, P. B.
- Abstract
The scaffolding postsynaptic density-95/disks large/zonula occludens-1 (PDZ) domain-containing protein melanoma differentiation associated gene-9 (MDA-9)/syntenin is a tandem PDZ protein overexpressed in human melanoma, and breast and gastric cancer cells. MDA-9/syntenin affects cancer cell motility and invasion through distinct biochemical and signaling pathways, including focal adhesion kinase and p38 mitogen-activated protein kinase (MAPK), resulting in activation of the nuclear factor (NF)-κB pathway. MDA-9/syntenin also promotes melanoma metastasis by activating c-Src, but how c-Src regulates NF-κB activation is unclear. Using a human melanoma model, we document that MDA-9/syntenin–c-Src interactions are positive regulators of NF-κB activation. Inhibition of c-Src by PP2 treatment, by blocking c-Src or mda-9/syntenin expression with small interfering RNA, or in c-Src (−/−) knockout cell lines, reduces NF-κB activation following overexpression of mda-9/syntenin or c-Src. Deletion or point mutations of the PDZ binding motif preventing MDA-9/syntenin association with c-Src reveals that both PDZ domains, with PDZ2 being the dominant module, are required for activating downstream signaling pathways, including p38 MAPK and NF-κB. We also document that MDA-9/syntenin–c-Src complexes functionally cooperate with NF-κB to promote anchorage-independent growth, motility and invasion of melanoma cells. These findings underscore PDZ domains of MDA-9/syntenin as promising potential therapeutic targets for intervening in a decisive component of cancer progression, namely, metastatic tumor spread.
- Subjects
NF-kappa B; TIGHT junctions; MELANOMA; GASTRIC mucosa; CELL motility; FOCAL adhesion kinase; MITOGEN-activated protein kinases; METASTASIS; CANCER
- Publication
Oncogene, 2010, Vol 29, Issue 21, p3054
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2010.65