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  • Original Article
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Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-κB

Oncogene volume 29, pages 3054–3066 (2010)Cite this article

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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.

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Acknowledgements

This work was supported by the National Institutes of Health, National Cancer Institute Grants R01 CA035675 and CA097318, the Samuel Waxman Cancer Research Foundation (SWCRF), the National Foundation for Cancer Research (NFCR) (PBF); the Goldhirsh Foundation and the Dana Foundation (DS); and the Ligue nationale contre le Cancer and Association pour la Recherche sur le Cancer grant 1019 (HB). DS is the Harrison Endowed Scholar in Cancer Research and PBF holds the Thelma Newmeyer Corman Chair in Cancer Research at the VCU Massey Cancer Center. PBF is a SWCRF Investigator.

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  1. H Boukerche and H Aissaoui: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA

    H Boukerche, S K Das, Z-Z Su, D Sarkar & P B Fisher

  2. EA4174, Université Claude Bernard, Lyon 1 INSERM, Lyon, France

    H Boukerche, H Aissaoui & C Prévost

  3. INSERM U583, Montpellier, France

    H Hirbec

  4. VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

    D Sarkar & P B Fisher

  5. VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA

    D Sarkar & P B Fisher

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  1. H Boukerche
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Correspondence to H Boukerche or P B Fisher.

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Boukerche, H., Aissaoui, H., Prévost, C. et al. Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-κB. Oncogene 29, 3054–3066 (2010). https://doi.org/10.1038/onc.2010.65

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