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The metastasis-promoting protein S100A4 stimulates metastatic progression through both intracellular and extracellular functions. Extracellular activities of S100A4 include stimulation of angiogenesis, regulation of cell death and increased cell motility and invasion, but the exact molecular mechanisms by which extracellular S100A4 exerts these effects are incompletely elucidated. The aim of the present study was to characterize S100A4-induced signal transduction mechanisms and to identify S100A4 target genes. We demonstrate that extracellular S100A4 activates the transcription factor NF-κB in a subset of human cancer cell lines through induction of phosphorylation and subsequent degradation of the NF-κB inhibitor IκBα. Concomitantly, S100A4 induced a sustained activation of the MAP kinase JNK, whereas no increased activity of the MAP kinases p38 or ERK was observed. Microarray analyses identified 136 genes as being significantly regulated by S100A4 treatment, and potentially interesting S100A4-induced gene products include IκBα, p53, ephrin-A1 and optineurin. Increased expression of ephrin-A1 and optineurin was validated using RT-PCR, Western blotting and functional assays. Furthermore, S100A4-stimulated transcription of these target genes was dependent on activation of the NF-κB pathway. In conclusion, these findings contribute to the understanding of the complex molecular mechanisms responsible for the diverse biological functions of extracellular S100A4, and provide further evidence of how S100A4 may stimulate metastatic progression. © 2008 Wiley-Liss, Inc.