Src kinase activation is mandatory for mda-9/syntenin-mediated activation of nuclear factor-κb

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. Access through your institution Buy

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_Invest Ophthalmol Vis Sci_ 45: 2314–2323. Article  Google Scholar  Download references 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. AUTHOR INFORMATION Author notes * H Boukerche and H Aissaoui: These

authors contributed equally to this work. AUTHORS AND AFFILIATIONS * 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 * EA4174, Université Claude Bernard, Lyon 1 INSERM, Lyon, France H Boukerche, H Aissaoui & C Prévost * INSERM U583, Montpellier, France H Hirbec * VCU

Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA D Sarkar & P B Fisher * VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA

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conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 20 November 2009 *

Revised: 21 January 2010 * Accepted: 29 January 2010 * Published: 15 March 2010 * Issue Date: 27 May 2010 * DOI: https://doi.org/10.1038/onc.2010.65 SHARE THIS ARTICLE Anyone you share the

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Nature SharedIt content-sharing initiative KEYWORDS * mda-9/syntenin * src * NF-κB