Sam68 plays a role in TNF-dependent signaling, including NF-kB signaling and extrinsic activation of apoptosis. In some embodiments, inhibitors of Sam68 are administered to inhibit TNF-dependent signaling, for example to inhibit NF-kB signaling or apoptosis in a patient in need. In some embodiments, functional Sam68 is administered to increase TNF-dependent signaling, for example to induce apoptosis in a patient in need. In some embodiments, methods are provided determining whether the TNF-dependent or TNF-independent branch of a signaling pathway is active in a cell or cells, or for drug screening applications.