Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-κB
Open Access
- 15 March 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 29 (21), 3054-3066
- https://doi.org/10.1038/onc.2010.65
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.Keywords
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