Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-kappaB

Oncogene. 2010 May 27;29(21):3054-66. doi: 10.1038/onc.2010.65. Epub 2010 Mar 15.


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)-kappaB pathway. MDA-9/syntenin also promotes melanoma metastasis by activating c-Src, but how c-Src regulates NF-kappaB activation is unclear. Using a human melanoma model, we document that MDA-9/syntenin-c-Src interactions are positive regulators of NF-kappaB 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-kappaB 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-kappaB. We also document that MDA-9/syntenin-c-Src complexes functionally cooperate with NF-kappaB 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Knockout Techniques
  • Gene Silencing
  • Genes, src / genetics
  • Humans
  • Melanoma / genetics
  • Melanoma / prevention & control
  • NF-kappa B / metabolism*
  • PDZ Domains / genetics
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Point Mutation
  • RNA, Small Interfering / genetics
  • Sequence Deletion
  • Syntenins / genetics
  • Syntenins / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation / genetics


  • NF-kappa B
  • Phosphoproteins
  • RNA, Small Interfering
  • SDCBP protein, human
  • SKAP1 protein, human
  • Syntenins