Protein tyrosine phosphatase (PTP) inhibitors are potent activators of T lymphocytes, most likely by affecting the early steps of T-cell receptor (TCR) signaling. We have analyzed the effect of the PTP inhibitor bis-peroxovanadium (bpV) on expression of the human cyclooxygenase 2 (COX-2) gene, which is induced following TCR triggering. Here we show that COX-2 promoter activity is markedly up-regulated following exposure of Jurkat T cells to bpV(pic). Interestingly enough, treatment of Jurkat cells with cyclic-AMP elevating agents such as forskolin in combination with bpV resulted in a more important COX-2 transcriptional activation. Such activation is inhibited by the immunosuppressive drugs FK506 and cyclosporin A. The two nuclear factor of activated T cells (NFAT) binding sites located within the COX-2 promoter region are involved in bpV-mediated positive effect on COX-2 promoter. Electromobility shift assays showed that NFAT1 and activator protein-1 (AP-1) are both translocated to the nucleus following bpV treatment. The active participation of p56^lck, ZAP-70, p36^lat and calcium in the bpV-dependent signaling cascade leading to COX-2 transcriptional activation was demonstrated using deficient cell lines and specific inhibitors. Although several PTPs are most likely targeted by bpV, our data suggest that the bpV-mediated signaling cascade is initiated by inhibition of SHP-1, which leads to phosphorylation of p56^lck and ZAP-70, and, ultimately, to NFAT and AP-1 nuclear translocation. These results suggest that PTP inhibitors can activate COX-2 gene expression in a manner very similar to the stimulation induced by TCR triggering.